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N Engl J Med 1987; 314:1429-35Background Prior to the publication of this study, digoxin and diuretics were the mainstay of chronic heart failure management. No therapy had yet been shown to reduce mortality or improve heart failure outcomes in patients with severe disease. The results of the V-HEFT trial had been published in the prior year, which demonstrated that the vasodilator combination of hydralazine and isosorbide reduced death in patients with chronic, stable heart failure. CONSENSUS was the first study to test whether vasodilator therapy in general, and angiotensin converting enzyme inhibitors in particular could modify heart failure disease trajectory for those with severe disease when used as part of chronic disease management. The CONSENSUS trial was designed to test the hypothesis that Enalapril compared to placebo reduced mortality in patients with severe (NYHA IV) congestive heart failure.Patients Men and women with severe (NYHA IV) congestive heart failure and cardiomegaly based on heart size >600 ml/m2 in men or >550 ml/m2 in women were recruited from 35 centers in Finland, Norway and Sweden. Measurement of LV function was not required. Patients were excluded if they had 1) acute pulmonary edema, 2) hemodynamically important aortic or mitral valve stenosis, 3) MI within the previous 2 months, 4) unstable angina, 5) planned cardiac surgery, 6) right heart failure due to pulmonary disease, or 7) serum creatinine >3.4 mg/dL.It is not specified whether patients could be recruited from the inpatient or outpatient setting or both but prior to randomization, a 14-day period was allowed to stabilize patients on digoxin and diuretics. If during this period, their condition improved to NYHA class III or less they were not randomized.Baseline characteristics The majority of participants were male (70%) and their average age was 70. The average heart rate and blood pressure were 80 bpm and 120/75 mmHg and the average serum creatinine was about 1.5 mg/dL. Coronary artery disease was present in over 70% of participants and nearly 50% had suffered a previous heart attack. Hypertension and diabetes were present in over 20% and atrial fibrillation in 50%. The use of medications at baseline was evenly distributed between groups with nearly all patients being on digoxin and furosemide. About 50% of participants were also taking spironolactone as well as other vasodilator drugs. About 50% of patients had heart failure for more than 4 years.Procedures Treatment with enalapril or an identical placebo was initially started in the hospital with a dose of 5 mg twice a day. After 1 week it was increased to 10 mg twice a day if the patient did not have symptoms of hypotension or other side effects. According to the clinical response, a further increase in dosage could occur up to a maximum dose of 20 mg twice a day.Patients were evaluated after 1, 2, 3, 6, and 16 weeks, 6, 9, and 12 months and at the end of the study. In patients with worsening symptoms, additional vasodilator therapy with isosorbide dinitrate, hydralazine, or prazosin, in that sequence was recommended.Early in the trial the occurrence of symptomatic hypotension led to revision of the protocol after 67 patients had been randomized. No patient's treatment was unblinded but in patients with 1) serum sodium
Watch here for a video interview with JACC Associate Editor Michelle Kittleson, MD, FACC, and author Mathew S. Muarer, MD, FACC, as they discuss Dr. Maurer's study published in JACC and presented at ACC.25. This exploratory analysis of HELIOS-B assessed the efficacy of vutrisiran versus placebo in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) by subgroups of baseline heart failure severity (primarily by NYHA class and NT-proBNP levels). Vutrisiran showed evidence of benefit vs placebo on mortality, cardiovascular events, functional capacity, quality of life, and cardiac biomarkers across the range of baseline disease severities in patients enrolled in HELIOS-B, with greatest benefit observed in patients with earlier, less severe disease.
The EVOLVED trial investigated whether early aortic valve intervention could improve outcomes in asymptomatic patients with severe aortic stenosis and myocardial fibrosis. The randomized, multicenter study of 224 patients found no significant difference in all-cause mortality or unplanned aortic stenosis-related hospitalizations between early intervention and guideline-directed conservative management. However, early intervention was associated with lower rates of NYHA class II-IV symptoms and fewer unplanned hospitalizations. The trial highlights the potential symptomatic benefits of early intervention but underscores the need for further research to assess long-term outcomes.
The Tri.Fr Randomized Clinical Trial evaluated the efficacy of Transcatheter Edge-to-Edge Repair (T-TEER) + Optimized Medical Therapy (OMT) versus OMT alone in 300 patients with severe, symptomatic tricuspid regurgitation (TR) across 24 centers in France and Belgium. At 1-year follow-up, 74.1% of patients in the T-TEER group improved, compared to 40.6% in the OMT-alone group (P < .001). T-TEER significantly reduced TR severity, improved NYHA class, patient global assessment (PGA), and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, and had a high procedural success rate (97.3%) with a low 30-day major adverse event rate (0.7%). The findings support T-TEER as an effective intervention for symptomatic severe TR, warranting long-term follow-up to assess mortality and hospitalization impact.
The following question refers to Sections 7.4 and 7.5 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.The question is asked by the Director of the CardioNerds Internship Dr. Akiva Rosenzveig, answered first by Vanderbilt AHFT cardiology fellow Dr. Jenna Skowronski, and then by expert faculty Dr. Randall Starling.Dr. Starling is Professor of Medicine and an advanced heart failure and transplant cardiologist at the Cleveland Clinic where he was formerly the Section Head of Heart Failure, Vice Chairman of Cardiovascular Medicine, and member of the Cleveland Clinic Board of Governors. Dr. Starling is also Past President of the Heart Failure Society of America in 2018-2019. Dr. Staring was among the earliest CardioNerds faculty guests and has since been a valuable source of mentorship and inspiration. Dr. Starling's sponsorship and support was instrumental in the origins of the CardioNerds Clinical Trials Program.The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. American Heart Association's Scientific Sessions 2024As heard in this episode, the American Heart Association's Scientific Sessions 2024 is coming up November 16-18 in Chicago, Illinois at McCormick Place Convention Center. Come a day early for Pre-Sessions Symposia, Early Career content, QCOR programming and the International Symposium on November 15. It's a special year you won't want to miss for the premier event for advancements in cardiovascular science and medicine as AHA celebrates its 100th birthday. Registration is now open, secure your spot here!When registering, use code NERDS and if you're among the first 20 to sign up, you'll receive a free 1-year AHA Professional Membership! Question #38 Mrs. M is a 65-year-old woman with non-ischemic dilated cardiomyopathy (LVEF 40%) and moderate to severe mitral regurgitation (MR) presenting for outpatient follow-up. Despite improvement overall, she continues to experience dyspnea on exertion with two flights of stairs and occasional PND. She reports adherence with her medication regimen of sacubitril-valsartan 97-103mg twice daily, metoprolol succinate 200mg daily, spironolactone 25mg daily, empagliflozin 10mg daily, and furosemide 80mg daily. A transthoracic echocardiogram today shows an LVEF of 35%, an LVESD of 60 mm, severe MR with a regurgitant fraction of 60%, and an estimated right ventricular systolic pressure of 40 mmHg. Her EKG shows normal sinus rhythm at 65 bpm and a QRS complex width of 100 ms. What is the most appropriate recommendation for management of her heart failure?AContinue maximally tolerated GDMT; no other changesBRefer for cardiac resynchronization therapy (CRT)CRefer for transcatheter mitral valve intervention Answer #38 ExplanationChoice C is correct. The 2020 ACC/AHA Guidelines for the management of patients with valvular heart disease outline specific recommendations.In patients with chronic severe secondary MR related to LV systolic dysfunction (LVEF
The following question refers to Section 7.4 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.The question is asked by the Director of the CardioNerds Internship Dr. Akiva Rosenzveig, answered first by Vanderbilt AHFT cardiology fellow Dr. Jenna Skowronski, and then by expert faculty Dr. Clyde Yancy.Dr. Yancy is Professor of Medicine and Medical Social Sciences, Chief of Cardiology, and Vice Dean for Diversity and Inclusion at Northwestern University, and a member of the ACC/AHA Joint Committee on Clinical Practice Guidelines.The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. American Heart Association's Scientific Sessions 2024As heard in this episode, the American Heart Association's Scientific Sessions 2024 is coming up November 16-18 in Chicago, Illinois at McCormick Place Convention Center. Come a day early for Pre-Sessions Symposia, Early Career content, QCOR programming and the International Symposium on November 15. It's a special year you won't want to miss for the premier event for advancements in cardiovascular science and medicine as AHA celebrates its 100th birthday. Registration is now open, secure your spot here!When registering, use code NERDS and if you're among the first 20 to sign up, you'll receive a free 1-year AHA Professional Membership! Question #37 Mr. S is an 80-year-old man with a history of hypertension, type II diabetes mellitus, and hypothyroidism who had an anterior myocardial infarction (MI) treated with a drug-eluting stent to the left anterior descending artery (LAD) 45 days ago. His course was complicated by a new LVEF reduction to 30%, and left bundle branch block (LBBB) with QRS duration of 152 ms in normal sinus rhythm. He reports he is feeling well and is able to enjoy gardening without symptoms, though he experiences dyspnea while walking to his bedroom on the second floor of his house. Repeat TTE shows persistent LVEF of 30% despite initiation of goal-directed medical therapy (GDMT). What is the best next step in his management?AMonitor for LVEF improvement for a total of 60 days prior to further interventionBImplantation of a dual-chamber ICDCImplantation of a CRT-DDContinue current management as device implantation is contraindicated given his advanced age Answer #37 Explanation Choice C is correct. Implantation of a CRT-D is the best next step. In patients with nonischemic DCM or ischemic heart disease at least 40 days post-MI with LVEF ≤35% and NYHA class II or III symptoms on chronic GDMT, who have reasonable expectation of meaningful survival for >1 year,ICD therapy is recommended for primary prevention of SCD to reduce total mortality (Class 1, LOE A). A transvenous ICD provides high economic value in this setting, particularly when a patient's risk of death from ventricular arrhythmia is deemed high and the risk of nonarrhythmic death is deemed low. In addition, for patients who have LVEF ≤35%, sinus rhythm, left bundle branch block (LBBB) with a QRS duration ≥150 ms, and NYHA class II, III, orambulatory IV symptoms on GDMT, cardiac resynchronization therapy (CRT) is indicated to reduce total mortality, reduce hospitalizations, and improve symptoms and QOL. Cardiac resynchronization provides high economic value in this setting. Mr.
Welcome to a mini podcast series where we take a deep dive on an herb. We hope to better aquaint you with the day's herb while we cover everything from the mystic to the science, the habitat to constiuents. Amy takes you on a journey to know our first Materia Medica Monday plant, Hawthorn. Hawthorn is known as heart food! Today we explore:-Actions-How to prepare it-Where to find it-The science behind why it's so usefulIf you enjoyed this podcast please leave a review or follow us on instagram @herbgirlsathensShow Notes:The Herb Girls Hawthorn Materia Medica (free)Materia Medica Resources:The Modern Herbal Dispensary - Thomas EasleyWinston & Kuhn's Herbal Therapy & Supplements - Merrily A. Khun & David Winston (Amy's favorite resource mentioned in the podcast)The Herbal Academy: Herbarium (online subscription ~$6.50 a month)Materia Medica Monthly: Sajah Popham - also subscription but very indepthAmerican Botanical CouncilStudies:Gildor A. (1998). Crataegus oxycantha and heart failure. Circulation. 98(19):2098.Loew D. (1994). Pharmacological and clinical results with Crataegus special extracts in cardiac insufficiency. ESCOP Phytotelegram. 6:20-26Tassell MC, Kingston R, Gilroy D, Lehane M, Furey A. Hawthorn (Crataegus spp.) in the treatment of cardiovascular disease. Pharmacogn Rev. 2010 Jan;4(7):32-41.Zapfe jun G. Clinical efficacy of crataegus extract WS 1442 in congestive heart failure NYHA class II. Phytomedicine. 2001 Jul;8(4):262-6.
Audio Commentary by Dr. Valentin Fuster, Emeritus Editor in Chief
Lancet 1993;342:821-28.Background The Survival After Ventricular Enlargement (SAVE) trial demonstrated that administration of the angiotensin converting enzyme inhibitor (ACEi) captopril, following MI complicated by LV dysfunction (EF ≤40%) but without clinical heart failure significantly improved morbidity and mortality over 3.5 years of follow-up. Yet many post-MI patients at the time had clinical heart failure and this represented a vulnerable population of patients with significantly increased morbidity and mortality compared to those without clinical heart failure. The Acute Infarction Ramipril Efficacy (AIRE) trial sought to test the hypothesis that administration of Ramipril to patients with AMI complicated by acute congestive heart failure would reduce morbidity and mortality vs a placebo. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients Eligible patients were 18 years of age or older with a definite AMI occurring 2 to 9 days prior to randomization with clinical evidence of congestive heart failure at any time after the index MI. While clinical evidence of heart failure was mandatory for study entry, it could be transient and not necessarily present at the time of randomization. Patients were excluded with NYHA IV heart failure (these patients would receive ACEi therapy regardless), heart failure of primary valvular or congenital etiology, or patients with any recognized contraindications to ACEi therapy were excluded.Baseline characteristics The average age of patients was 65 years and 74% were men. Approximately one quarter of patients had had a prior MI, 12% had diabetes, 30% had hypertension and smoking status was not listed. The ejection fraction of study participants was not systematically assessed as part of the study protocol. 62% had a Q wave MI and the predominant location was anterior. The mean time to randomization was 5 days. Approximately 60% of patients received thrombolysis. The average blood pressure and heart rate were not provided. At the time of randomization 22% of patients were receiving a beta blocker and 12% digoxin.Many more patients (52,019) were reviewed than ultimately enrolled (1,986). The main reasons for exclusion were no definitive MI (21,302) and no definite heart failure (16,989). The authors estimate that among eligible patients with a definitive MI and heart failure that approximately half were enrolled. Information on those enrolled versus not enrolled was not provided.Procedures Patients were initiated on Ramipril 2.5 mg twice daily or matching placebo for 2 days after which the dose was increased to 5 mg twice daily. If patients could not tolerate the 5 mg twice daily dose they were discharged on 2.5 mg twice daily. For patients who could not tolerate the 2.5 mg dose they were given 1.25 mg twice daily for 2 days with attempts to up-titrate to 2.5 mg and 5 mg at discharge. For patients that could not tolerate at least 2.5 mg twice daily at discharge they were NOT discharged on the 1.25 mg dose. These patients were withdrawn from study treatment but followed up at the prespecified visit intervals and were included in the intention-to-treat analysis.Outpatient visits were scheduled at 1 month and 3 months following discharge from the index hospitalization and every 3 months thereafter until study close. Monitoring of renal function and electrolytes was done at the discretion of study investigators based on their normal practice. During follow up patients could be started on any medication with exception of an ACEi.Endpoints The primary study endpoint was all-cause mortality. The secondary endpoint was time to first event including (death, progression to NYHA class 4 heart failure, reinfarction or stroke).The investigators estimated they would need a sample size of 2,000 patients to detect a 25% relative reduction in the risk of death with 80% power and 2-sided alpha of 5%. This was based on an estimated death rate of 20% at 15 months in the placebo group and 15% in the Ramipril group.Results 2,006 patients were recruited from 144 centers in 14 countries. However, 20 patients from 1 center were excluded from the final analysis due to inconsistencies in the data. According to investigators the exclusion of these patients did not meaningfully change the final results. The final analysis included 1,986 patients; 1004 in the Ramipril group and 982 in the placebo group.90% of study participants were discharged from the hospital on study drug. In the Ramipril group, 77% were on the 5 mg dose, 14% were on the 2.5 mg dose and 9% were on no therapy. In the placebo group, 86% were on the 5 mg dose, 7% on the 2.5 mg dose and 7% on no therapy.Patients were followed for an average of 15 months and only 1 was lost to follow-up. Compared to placebo, Ramipril significantly reduced all cause death by 27% (17% vs 23%; p = 0.002). Ramipril also significantly reduced the secondary composite endpoint of time to first validated event (including death, progression to severe heart failure, reinfarction or stroke) by 19% (28% vs 34%; p = 0.008). Differences in this composite endpoint were mainly driven by death and progression to severe heart failure.Examination of subgroups showed no evidence of treatment effect heterogeneity but again, similar to the SAVE trial, the size of the trial limits subgroup testing.Premature withdrawals from study drug, not including death, occurred in 352 patients in the Ramipril group compared to 318 in the placebo group. Intolerance to the drug was cited as a factor in 126 of the Ramipril withdrawals and 68 of the placebo withdrawals whereas progression to severe heart failure was cited in 58 Ramipril withdrawals and 92 placebo. Syncope was more common in Ramipril treated patients compared to placebo (2.4% vs 1.7%) and so was hypotension (4.2% vs 2.3%) but not renal failure (1.5% vs 1.2%).Conclusions In patients with AMI complicated by clinical congestive heart failure, Ramipril significantly reduced death over 1.3 years of follow-up with a number needed to treat of approximately 17 patients. Ramipril also significantly reduced a composite of events, which were mainly driven by death and progression to severe heart failure. Unlike the SAVE trial, which did not estimate a particular sample size for hypothesis testing, AIRE was specifically designed to test whether Ramipril would reduce death by 25% over 15 months and indeed, it did! Thus, results from AIRE not only support but add legitimacy to findings from SAVE.One perceived limitation of AIRE, particularly when viewed through a contemporary lens, is its lack of ejection fraction estimation. There should be no doubt that these were sick patients in whom, significant LV dysfunction would have been present in most. We base this claim on the observation that the death rate in AIRE at 1.3 years in the placebo group was nearly equal to SAVE at 3.5 years (23% vs 25%). This highlights that development of clinical heart failure (regardless of LV function) confers a worse prognosis than LV dysfunction without heart failure.In our opinion, the external validity of AIRE is high for a trial performed 30 years ago. The average start date for treatment was 5 days post MI complicated by clinical heart failure. This is longer than we would anticipate in contemporary practice by 2 or 3 days but not unreasonable, especially for post-MI patients with tenuous hemodynamics requiring intravenous diuretic therapy. Furthermore, the dose titration parameters and follow up schedule in AIRE can be approximated in clinical practice. Also, no obvious treatment effect heterogeneity was noted across important subgroups (e.g., age > vs < 65 years) but these analyses are limited due to the overall sample size. Finally, no strict limits were placed on blood pressure and heart rate at study entry.Thank you for reading Cardiology Trial's Substack. This post is public so feel free to share it. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe
Bitcoin Spot ETF-től hangos a kriptovaluta közösség, de pontosan ez a piac az, ahol sosem az történik, amire mindenki számít. Mi lesz a csavar?Milyen témákat fogunk érinteni a mai podcast során?Spot ETF lázban a kripto közösség, mennyire valós az elfogadás esélye?Ezért lehet 2024 jó év a Bitcoin és kripto piac számáraMás lesz a következő Bitcoin bika piac, mint a múltbanVáltoztathat eddigi szigorú politikáján a FED (it is not likely we will hike further.”)Szakértői tanácsok a következő bika piacraHogyan teljesíthetnek az altcoinok jövőben?Bincancen listázták a Sats BRC20 coint. Tovább hasít az OrdinalsA Coinbase is már az USA-n kívül terjeszkedneTénylegesen megvalósul El Salvadorban a Bitcoin államkötvényHa tetszik a műsorunk akkor kérjük értékelj minket iTunes-on vagy kövesd adásunkat Spotify-on! Ha pedig szeretnél támogatni minket, akkor oszd meg az itt kapott tudást a barátaiddal is ! :)Kövessetek minket Facebookon, Instagramon és Twitteren is! Ha pedig szeretnétek képben lenni a napi kriptovaluta és Bitcoin elemzésekkel, hírekkel látogassatok el a honlapunkra: https://cryptofalka.huSupport the show
Guest: Nancy M. Albert, PhD, CCNS, CHFN, CCRN, NE-BC, FAHA, FCCM, FHFSA, FAAN There are 4 stages of heart failure, ranging from being at risk for heart failure to having an advanced condition. So what key insights should we know about the ACC/AHA stages of heart failure and the NYHA heart failure functional classifications? Discover more with Dr. Nancy Albert, associate chief nursing officer for the Office of Nursing Research and Innovation.
Guest: Nancy M. Albert, PhD, CCNS, CHFN, CCRN, NE-BC, FAHA, FCCM, FHFSA, FAAN There are 4 stages of heart failure, ranging from being at risk for heart failure to having an advanced condition. So what key insights should we know about the ACC/AHA stages of heart failure and the NYHA heart failure functional classifications? Discover more with Dr. Nancy Albert, associate chief nursing officer for the Office of Nursing Research and Innovation. Sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. and Lilly USA, LLC. SC-US-75207 3/23
Host: Charles Turck, PharmD, BCPS, BCCCP Guest: Amy Sehnert, MD With the FDA's approval of CAMZYOS® (mavacamten), the first and only cardiac myosin inhibitor for symptomatic New York Heart Association (NYHA) class II-III adult patients, healthcare professionals and patients now have another treatment option that targets HCM at the source. Learn more about the clinical trial data that supported the FDA approval, and how healthcare professionals can prescribe CAMZYOS from Dr. Amy Sehnert, Vice President and Head of Cardiomyopathy and Heart Failure Clinical Development at Bristol Myers Squibb.
Host: Charles Turck, PharmD, BCPS, BCCCP Guest: Amy Sehnert, MD With the FDA's approval of CAMZYOS® (mavacamten), the first and only cardiac myosin inhibitor for symptomatic New York Heart Association (NYHA) class II-III adult patients, healthcare professionals and patients now have another treatment option that targets HCM at the source. Learn more about the clinical trial data that supported the FDA approval, and how healthcare professionals can prescribe CAMZYOS from Dr. Amy Sehnert, Vice President and Head of Cardiomyopathy and Heart Failure Clinical Development at Bristol Myers Squibb.
The following question refers to Section 7.3 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. The question is asked by Palisades Medical Center medicine resident & CardioNerds Academy Fellow Dr. Maryam Barkhordarian, answered first by Hopkins Bayview medicine resident & CardioNerds Academy Faculty Dr. Ty Sweeny, and then by expert faculty Dr. Gregg Fonarow. Dr. Fonarow is the Professor of Medicine and Interim Chief of UCLA's Division of Cardiology, Director of the Ahmanson-UCLA Cardiomyopathy Center, and Co-director of UCLA's Preventative Cardiology Program. The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #28 Mr. Gene D'aMeTi, a 53-year-old African American man with ischemic cardiomyopathy and heart failure with reduced ejection fraction (LVEF 30-35%), is recently admitted with acutely decompensated heart failure and acute kidney injury on chronic kidney disease stage III. His outpatient regiment includes sacubitril-valsartan 97-103mg BID, carvedilol 25mg BID, and hydralazine 50mg TID. Sacubitril-valsartan was held because of worsening renal function. Despite symptomatic improvement with diuresis, his renal function continues to decline. He is otherwise well perfused & with preservation of other end organ function. Throughout this hospitalization, he has steadily become more hypertensive with blood pressures persisting in the 170s/90s mmHg. What would be an appropriate adjustment to his medication regimen at this time? A Resume Losartan only B Start Amlodipine C Increase current Hydralazine dose D Start Isosorbide dinitrate therapy E Both C & D Answer #28 ExplanationThe correct answer is E – both increasing the current hydralazine dose (C) and starting isosorbide dinitrate therapy (D). Although ACEI/ARB therapy (choice A) has shown a mortality and morbidity benefit in HFrEF, caution should be used in patients with renal insufficiency. In this patient with ongoing decline in renal function, RAAS-inhibiting therapies (ACEi, ARB, ARNI, MRA) should be avoided. In this case, as his RAAS-I has been stopped, it would be reasonable to increase current therapies to target doses (or nearest dose tolerated), as these demonstrated both safety and efficacy in trials (Class 1, LOE A). Considering that his high dose ARNI was stopped, it is unlikely that either hydralazine or isosorbide dinitrate alone, even at maximal doses, would be sufficient to control his blood pressure (Options C and D, respectively). Interestingly, in the original study by Massie et. Al (1977), the decision was made to combine these therapies as the result was thought to be superior to either medication alone. ISDN would provide preload reduction, while Hydralazine would decrease afterload. Consequently, we do not have data looking at the individual benefit of either medication in isolation. In self-identified African Americans with NYHA class III or IV HFrEF already on optimal GDMT, the addition of hydralazine & isosorbide dinitrate is recommended to improve symptoms and reduce mortality and morbidity (Class 1, LOE A). In this case, as the patient has evidence of progressive renal disfunction, we are limited in using traditional RAAS-I, such as ACEI, ARB, or ARNI.
The following question refers to Sections 11.3 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. The question is asked by Western Michigan University medical student and CardioNerds Intern Shivani Reddy, answered first by Johns Hopkins Osler internal medicine resident and CardioNerds Academy Fellow Dr. Justin Brilliant, and then by expert faculty Dr. Harriette Van Spall. Dr. Van Spall is Associate Professor of Medicine, cardiologist, and Director of E-Health at McMaster University. Dr Van Spall is a Canadian Institutes of Health Research-funded clinical trialist and researcher with a focus on heart failure, health services, and health disparities. The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #16 Ms. Augustin is a 33 y/o G1P1 woman from Haiti who seeks counseling regarding family planning as she and her husband dream of a second child. Her 1st pregnancy 12 months ago was complicated by pre-eclampsia and peripartum cardiomyopathy (LVEF 35%). Thankfully she delivered a healthy baby via C-section. She has no other past medical history and is currently on losartan 25 mg daily and metoprolol succinate 200 mg daily. She has been asymptomatic. Which of the following statements is recommended to medically optimize Ms. Augustin prior to her 2nd pregnancy? A No medical optimization or preconception planning is needed as her 1st pregnancy resulted in a healthy infant. B Discontinue losartan and metoprolol with no other needed pregnancy planning C Change her medication regimen, consider repeat TTE, and provide patient-centered counseling regarding risk of a future pregnancy D Continue losartan and metoprolol and advise against repeat pregnancy Answer #16 Explanation The correct answer is C – change her medication regimen, consider repeat TTE, and provide patient-centered counseling regarding risk of a future pregnancy. Heart failure may complicate pregnancy either secondary to an existing pre-pregnancy cardiomyopathy or as a result of peripartum cardiomyopathy. In women with history of heart failure or cardiomyopathy, including previous peripartum cardiomyopathy, patient-centered counseling regarding contraception and the risks of cardiovascular deterioration during pregnancy should be provided (Class I, LOE C-LD) Peripartum cardiomyopathy (PPCM) is defined as systolic dysfunction, typically LVEF < 45%, often with LV dilation, occurring in late pregnancy or early postpartum with no other identifiable etiology. PPCM occurs worldwide, with the highest incidences in Haiti, Nigeria, and South Africa. Other clinical risk factors include maternal age > 30 years, African ancestry, multiparity, multigestation, preeclampsia/eclampsia, anemia, diabetes, obesity, and prolonged tocolysis. The pathogenesis of peripartum cardiomyopathy is complex and it is likely a multifactorial process. The combination of hemodynamic changes of pregnancy, inflammation of the myocardium, hormonal changes, genetic factors, and an autoimmune response have all been proposed as possible mechanisms and these may certainly be interrelated. While pregnancy is generally well-tolerated in women with cardiomyopathy and NYHA class I status pre-pregnancy, clinical deterioration can occur and so counseling a...
This week, please join author Milind Desai and Associate Editor Mark Link as they discuss the article "Dose-Blinded Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Outcomes Through 32 Weeks." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Oh, Greg. Today's feature paper is just so, so important. It's the long-term follow up or the longer term follow up of the VALOR-HCM trial. And this, if I can remind you, examined the effect of mavacampten on the need for septal reduction therapy in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy. So we're going to hear the results through 32 weeks, but not until we discuss the other papers in today's issue. And I'd like to go first. I'd like to tell you about a paper that really provides the foundation for deciphering chamber selective gene transcription. So in this study from Dr. William Pu of Boston Children's Hospital and colleagues, authors mapped the chromatin features of atrial and ventricular cardiomyocytes and nominated candidate chamber selective enhancers based on differential features. The candidate enhancers were tested in vivo using adeno associated virus delivered massively parallel reporter assay leading to identification of 229 chamber selective enhancers. They then characterized chromatin features of these chamber selective enhancers and used dense mutagenesis to identify their essential features. Altogether the study suggested that estrogen-related receptor promoted ventricular chamber selective enhancer activity. They validated this prediction by showing that estrogen-related receptor inactivation led to loss of ventricular cardiomyocyte identity. So in aggregate, the studies yielded a rich resource of chamber selective chromatin features and chamber selective enhancers, and began to unravel the molecular basis for chamber selective transcriptional programs. Dr. Greg Hundley: Wow. So Carolyn, estrogen-related receptor promotion and then inactivation and finding really very interested preclinical results. So tell us now what are the clinical implications of this very nice study. Dr. Carolyn Lam: Wow. I mean, there are just so many implications. It can facilitate functional interpretation of genetic associations between variants and cardiac disease. Of course, it opens the doors to potential gene therapies and regenerative medicine and finally, identification of transcription regulators of the chamber identity really yield important mechanistic insights into the pathogenesis of important diseases like atrial fibrillation and cardiomyopathy. Dr. Greg Hundley: Wow, Carolyn, beautifully summarized. Well, my next paper pertains to COVID vaccines. So Carolyn, as we have seen SARS-CoV-2 targeted mRNA vaccines are a life-saving medical advancement developed to combat, of course, the COVID-19 pandemic. But in rare cases, some individuals can develop myocarditis following these mRNA vaccinations. Cases of adolescents and young adults developing post vaccine myocarditis have been reported globally, although the underlying immuno profiles of these individuals, they really haven't been described in detail. So these authors led by Dr. Lael Yonker from Massachusetts General Hospital, performed extensive system serology SARS-CoV-2 specific T-cell analysis and cytokine and SARS-CoV-2 antigen profiling on blood samples collected from adolescents and young adults either developed myocarditis or were asymptomatic following SARS-CoV-2 targeted mRNA vaccination. Dr. Carolyn Lam: Wow. Wow. Important question. Everyone's interested in the results. So what did they find? Dr. Greg Hundley: Right, Carolyn. So 16 cases with post vaccine myocarditis and 45 asymptomatic vaccinated controls were enrolled with extensive antibodies profiling, including assessment for autoantibodies or antibodies against the human relevant virome. And Carolyn, they found that T-cell responses were essentially indistinguishable from controls despite a modest increase in cytokine production. Notably, markedly elevated levels of full length spike protein unbound by antibodies were detected in the plasma of individuals with post vaccine myocarditis, a finding that was absent. It was absent in the asymptomatic vaccinated controls. So Carolyn, in conclusion, immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine-induced immune responses did not differ between individuals that developed myocarditis versus individuals that did not. However, free spike antigen was detected in the blood of adolescents and young adults who developed post mRNA vaccine myocarditis. Now while this finding does not alter the risk benefit ratio favoring vaccination against COVID-19 to prevent severe clinical outcomes, it may provide some insight into the potential underlying etiology associated with post mRNA vaccine-induced myocarditis. Carolyn, this is accompanied by a wonderful editorial by Dr. Biykem Bozkurt indicating that these results raise a question as to why the circulating spike protein levels remain elevated despite adequate levels and functionality of the anti-spike antibodies. Well, Carolyn, we do have some other articles in the issue and from the mailbag we have a research letter from Professor Cho entitled PERM1 Protects the Heart From Pressure Overload Induced Dysfunction by Promoting Oxidative Metabolism. Also, there's a new drugs and devices piece from Professor Kabatano entitled Pharmacology and Clinical Development of Factor XI inhibitors. And then Tracy Hansen has a wonderful cardiology news summary regarding articles entitled The Study Reveals Rapid Intestinal Adaptations after Switching to High Fat Diet From Cell Research. Another article entitled New Insights into Immunotherapy Related Myocarditis from Nature. And finally, an article entitled Scientist Identified Genetic Variants Linked to Longevity published in the Journal of Science. Dr. Carolyn Lam: Wow. Interesting. There's also an exchange of letters between Drs. Monzo and Shah regarding the article, “Metabolomic Profiling of Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction.” That is a Perspective piece by Dr. Davenport on contrast induced acute kidney injury and cardiovascular imaging, danger or distraction? Wow. What a beautiful issue. Thank you so much, Greg. Let's go to our feature discussion, shall we? Dr. Greg Hundley: Absolutely. Welcome, listeners, to this feature discussion on March 14th. And we have with us today Dr. Milind Desai from Cleveland Clinic in Cleveland, Ohio, and our own associate editor, Dr. Mark Link from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentlemen, Milind, we'll begin with you and bringing to us this study of mavacampten. Can you describe for us some of the background information that went into the preparation of this study, and what was the hypothesis that you wanted to address? Dr. Milind Desai: Thank you to the editorial staff, Dr. Hundley and the editorial staff at Circulation. So yes, mavacampten, as we know, is a novel first in class cardiac myocin inhibitor that was developed in the context of managing patients with hypertrophic obstructive cardiomyopathy. So the preliminary early stage studies have shown that it helped significantly in reducing outflow tract gradients as well as improved symptoms. But we wanted to take the conversation a bit further. In highly symptomatic patients, the current standard of care treatment is septal reduction therapy, which requires an experienced center and an experienced set of providers. So what we wanted to see was in such patients that are referred for septal reduction therapy, what does mavacampten do versus placebo? So does it reduce the need for septal reduction therapy? We divided the study into three parts. The first part was the placebo controlled 16 week study. The second part was we wanted to see what happens when the placebo arm crossed over to mavacampten and the mavacampten arm continued long-term. And that was the genesis of the study that we are discussing today. Dr. Greg Hundley: Very nice. So we've got a planned study, patients with hypertrophic cardiomyopathy, they ordinarily, because of guideline related therapeutic recommendations would undergo septal reduction therapy, but before that you're going to randomize patients to mavacampten versus a placebo. So we've sort of described a little bit the study design, and let's clarify specifically perhaps the study population and how many patients did you enroll? Dr. Milind Desai: Yes. In the original study, we enrolled 112 patients, 56 to mavacampten and 56 to placebo. After week 16, four patients, two of which underwent SRT and two withdrew consent. So essentially for the 32 week analysis, we had 108 patients, 56 in the mavacampten group and 52 in the placebo group that crossed over to mavacampten. So 108 patients. Dr. Greg Hundley: Very nice. So Milind, what were your study results? Dr. Milind Desai: Yes. What we found was at week 16, we have previously demonstrated that the group that got randomized mavacampten had a significant reduction in outflow tract radius, both resting and Valsalva, as well as biomarkers. And at week 16, what we found was 82% patients from the original group did not meet criteria for septal reduction therapy. So a hundred percent to begin with, 82%, that was at week 16. What we wanted to see, is the effect continued longer lasting and what happens to the placebo group that crossed over? So essentially what we found was at week 32, 89% of the total population no longer met criteria for septal reduction therapy. In addition to that, the mavacampten group continued to have reduced outflow tract gradients, continued improvement in Kansas City Score as well as biomarkers. But more importantly, the similar findings were demonstrated in the placebo arm that cross over to the mavacampten where, again, a significant proportion continued to show improvement in outflow tract gradient, Kansas City Score, as well as biomarker. The important point here in this study was at week 32, 95% patients chose to remain on medical therapy as opposed to going for SRT. Remember, a hundred percent patients were referred at the outset to undergo SRT. Dr. Greg Hundley: And Milind, did you notice any differences in your study results based on the age of the patients or based on their sex? Dr. Milind Desai: No, actually, we did not. This had a beneficial effect across gender, age, all the other variables. In fact, this is one of the strengths of the study because almost 50% patients that were randomized were women. So this was well represented across different genders. Dr. Greg Hundley: And then you mentioned a marked reduction in the gradient across the left ventricular outflow tract. What about the patient's symptomatology? Did you notice differences there? Dr. Milind Desai: There were significant improvement in patient symptomatology. More than 70% patients had a improvement in one NYHA class, 30% or thereabouts had a significant improvement in two NYHA class compared to placebo. So yes, there was a significant improvement in their functional capacity. Dr. Greg Hundley: And then last question, hypertrophic cardiomyopathy. Were most of these patients, was this concentric? Was this asymmetric septal hypertrophy? What was the breakdown, if you will, of the morphology of the left ventricles? Dr. Milind Desai: The vast majority of the patients had asymmetric septal hypertrophy, the characteristic with dynamic outflow tract gradient. There were some patients, but the vast majority of them were asymmetric septal hypertrophy. Dr. Greg Hundley: Very nice. Well, listeners, we're going to turn to our associate editor, Dr. Mark Link. Mark, this really sounds striking, randomized clinical trial, patients needing septal reduction therapy. They're randomized. The group randomized to mavacampten has marked reductions in left ventricular outflow tract gradient, symptomatology, and so much so that they no longer met the criteria for septal reduction therapy. I know you have a lot of papers come across your desk. Can you help us put what seemingly are exciting results into the context of other studies pertaining to mavacampten as well as treatment for patients with symptomatic hypertrophic cardiomyopathy? Dr. Mark Link: Yeah. There are very few randomized studies in patients with hypertrophic cardiomyopathy, probably only two that I know of. And mavacampten is a very exciting new drug that's a novel drug, a novel mechanism and has the potential to really improve life for our patients with hypertrophic cardiomyopathy. So this is a longer term study of mavacampten that's ever been published. So yeah, it was very exciting for us to look at this data to see how the patients did and we were very, very pleased to publish this paper. Dr. Greg Hundley: Very nice. So maybe, Milind, turn this back to you. What do you think are some of the next studies that'll be performed really in this arena of research? Dr. Milind Desai: Yes. Obviously, as Mark pointed out, this was one of the longest term studies, but we need to do a lot longer. So long term extension studies are ongoing. We should be evaluating one year outcomes in this specific population as well as longer, number one. Number two, I think in the grand scheme of things, this is a brand new class. So overall it is obviously now FDA approved and post-marketing survey and analysis should help us see a signal in terms of outcomes, mortality, et cetera. In your sister journal Circulation Imaging, we have simultaneously also published that mavacampten is causing a significant improvement in the structural changes like diastolic dysfunction, like LV mass, LA volume index. So we need to see how that plays out. Another important piece is about 30% patients have non-obstructive hypertrophic cardiomyopathy and there's no real treatment for this group and there's no outflow tract obstruction to cure in this. So we have just recently launched and started to randomize ODYSSEY HCM trial, which is checking the role of mavacampten versus placebo in non-obstructive HCM group. And I am fortunate. So it's a multi-centered trial that is being led out of Cleveland Clinic. So more data in that exciting field. But overall, this entire field of hypertrophic cardiomyopathies is exploding with multiple randomized controlled trials. There's another drug that is being tested in phase three trials, cardiac myocin inhibition. So that story also remains to see how that plays out. So a lot of stuff that is happening in this space. And then now there's gene therapy emerging. Dr. Greg Hundley: Right. And Milind, since you have quite extensive experience here, for our listeners, what side effect profiles have you observed in some of these patients? And if someone is considering working with placing a patient on this therapy, what are some of the considerations that they should be thinking about? Dr. Milind Desai: So that's a very important question. So the drug, as you are aware, was approved by the FDA under the REMS or Risk Evaluation Mitigation Strategy program. So the fundamental thing is both the patient and the physician have to sign up for the REMS program. The biggest issue that FDA wants us to be careful about is this is a cardiac myosin inhibitor. So it means we have to be very careful about over inhibition of the cardiac myosin and a drop in ejection fraction and its downstream ramifications including heart failure. The other aspect is drug-drug interaction because of its pathway of metabolism. So these are the two key things we have to be on the careful about. Now you asked my clinical experience. So we have been prescribing this for almost six, seven months, and we have dozens of patients on this using the REMS strategy, careful echocardiographic monitoring and clinical decision making. So far, we have been very successfully able to navigate these patients without any major adverse events. And the vast majority of the patients, true to form as we have shown in the clinical trial, are doing very, very well in terms of their symptoms, their need for SRT, as well as their markers, including outflow tract gradient. Dr. Greg Hundley: Very nice. And Mark, turning to you from the perspective of an electrophysiologist, what potential future studies do you see forming in this space? Dr. Mark Link: Yeah, very similar to Milind. And I think the long term efficacy and safety really has to be looked at. There's a signal for potential harm in that the EF can drop, and Milind mentioned that too, that we have to learn how to deal with that. The way to prescribe it now, you have to be in a special program. You have to be trained, you have to agree to get echoes every three months, I believe it is, essentially for the rest of their life. So we need to see what happens long term with these drugs and we need to know how to dose them and how to do it safely. Dr. Greg Hundley: Very nice. So for our listeners, really a class of drugs that is emerging and at this time only under really strictly supervise protocols. Well, from the perspective of our listeners, we want to thank Dr. Milind Desai and our own associate editor, Dr. Mark Link, for bringing us this informative new early randomized trial study results indicating that in severely symptomatic patients with obstructive hypertrophic cardiomyopathy, 32 weeks of mavacampten treatment showed sustained reduction in the proportion proceeding to septal reduction therapy. Well, on behalf of Petter, Carolyn and myself, we want to wish you a great week and we will catch you next week on The Run. This program is copyright of the American Heart Association, 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
The following question refers to Section 7.3.1 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. The question is asked by Palisades Medical Center medicine resident & CardioNerds Intern Dr. Maryam Barkhordarian, answered first by MedStar Washington Hospital Center cardiology hospitalist & CardioNerds Academy Graduate Dr. Luis Calderon, and then by expert faculty Dr. Robert Mentz. Dr. Mentz is associate professor of medicine and section chief for Heart Failure at Duke University, a clinical researcher at the Duke Clinical Research Institute, and editor-in-chief of the Journal of Cardiac Failure. Dr. Mentz is a mentor for the CardioNerds Clinical Trials Network as lead principal investigator for PARAGLIDE-HF and is a series mentor for this very 2022 heart failure Decipher the Guidelines Series. For these reasons and many more, he was awarded the Master CardioNerd Award during ACC22. Welcome Dr. Mentz! The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #7 Ms. Valarie Sartan is a 55-year-old woman with a history of HFrEF (EF 35%) and well controlled, non-insulin dependent diabetes mellitus who presents to heart failure clinic for routine follow up. She is currently being treated with metoprolol succinate 200mg daily, lisinopril 10mg daily, empagliflozin 10mg daily, and spironolactone 50mg daily. She notes stable dyspnea with moderate exertion, making it difficult to do her yardwork. On exam she is well appearing, and blood pressure is 115/70 mmHg with normal jugular venous pulsations and trace bilateral lower extremity edema. On labs, her potassium is 4.0 mmol/L and creatinine is 0.7 mg/dL with an eGFR > 60 mL/min/1.73m2. Which of the following options would be the most appropriate next step in heart failure therapy? A Increase lisinopril to 40mg daily B Increase spironolactone to 100mg daily C Add sacubitril-valsartan to her regimen D Discontinue lisinopril and start sacubitril-valsartan in 36 hours E No change Answer #7 Explanation The correct answer is D – transitioning from an ACEi to an ARNi is the most appropriate next step in management. The renin-angiotensin aldosterone system (RAAS) is upregulated in patients with chronic heart failure with reduced ejection fraction (HFrEF). Blockade of the RAAS system with ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), or angiotensin receptor neprilysin inhibitors (ARNi) have proven mortality benefit in these patients. The PARADIGM-HF trial compared sacubitril-valsartan (an ARNi) with enalapril in symptomatic patients with HFrEF. Patients receiving ARNi incurred a 20% relative risk reduction in the composite primary endpoint of cardiovascular death or heart failure hospitalization. Based on these results, the 2022 heart failure guidelines recommend replacing an ACEi or ARB for an ARNi in patients with chronic symptomatic HFrEF with NYHA class II or III symptoms to further reduce morbidity and mortality (Option D). This is a class I recommendation with level of evidence of B-R and is also of high economic value. Making no changes at this time would be inappropriate (Option E). While it would be reasonable to increase the dose of lisinopril to 40mg (Option A), this should be pursued only if ARNi therapy is not tolerated. Mineralocorticoid receptor antagonists (MRAs) have a class I (LOE A...
CardioNerds Dr. Josh Saef, Dan Ambinder, join Dr. Jim Kimber and interview experts Dr. Adrienne Kovacs, and Dr. Lauren Lastinger and discuss behavioral health needs and psychosocial wellbeing in the congenital heart disease population. In this episode, our experts tackle issues surrounding mental and behavioral health including anxiety/depression, ADHD, neurodevelopmental disabilities, psychosocial challenges, stressors unique to patients with ACHD and their families, and how the healthcare system can better optimize mental health care for the CHD patient population. Audio editing by CardioNerds Academy Intern, Pace Wetstein. The CardioNerds Adult Congenital Heart Disease (ACHD) series provides a comprehensive curriculum to dive deep into the labyrinthine world of congenital heart disease with the aim of empowering every CardioNerd to help improve the lives of people living with congenital heart disease. This series is multi-institutional collaborative project made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Josh Saef, Dr. Agnes Koczo, and Dr. Dan Clark. The CardioNerds Adult Congenital Heart Disease Series is developed in collaboration with the Adult Congenital Heart Association, The CHiP Network, and Heart University. See more Disclosures: None Pearls • Notes • References • Guest Profiles • Production Team CardioNerds Adult Congenital Heart Disease PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls - Congenital Heart Disease and Psychosocial Wellbeing Among patients with congenital heart disease, symptoms of anxiety are more common than symptoms of depression. “Heart-focused anxiety” relates to symptoms attributable to a heart condition including fear of appointments, surgery, or health-uncertainty. It is important to differentiate this from generalized anxiety.Predictors of depression and anxiety include patient-reported physical health status. Defect severity (mild, moderate, great complexity) and physician-diagnosed NYHA class were NOT associated with rates of depression/anxiety [2].Despite CHD, patient self-reported Quality of Life (QoL) is relatively high. Predictors of decreased QoL include older age, lack of employment, never having married, and worse self-reported NYHA functional classImportant treatment strategies include: education for patients and caregivers, early identification and referral to mental health providers, incorporation of providers into CHD teams, and encouraging physical activity and peer-interaction. Show notes - Congenital Heart Disease and Psychosocial Wellbeing Notes (developed by Dr. Jim Kimber) Mental Health Terminology: Adults with CHD face the same mental health challenges as people who don't have a heart condition. Symptoms of depression and anxiety are the most common: Approximately 1/4 - 1/3 of CHD patients will struggle with clinically significant depression or anxiety at any one point. Up to ½ will meet lifetime diagnostic criteria for these conditions Mood and anxiety disorders differ in that they have separate diagnostic criteria. Importantly, research often uses self-reported symptoms, rather than patients who have formally met diagnostic criteria. Historically, the focus has been on depression. However, elevated symptoms of anxiety are much more common than elevated symptoms of depression. It is important to make the distinction between “Generalized Anxiety,” and “Heart-Focused Anxiety.”Heart-Focused Anxiety: symptoms of anxiety directly related to having a heart condition, such as fear of appointments / worry about a decline in health status, getting an ICD, preparing for surgery, transplants, or having a shortened life expectancy, etc. This may also include a significant component of he...
The following question refers to Section 6.2 of the 2021 ESC CV Prevention Guidelines. The question is asked by Dr. Christian Faaborg-Andersen, answered first by Houston Methodist medicine resident Dr. Najah Khan, and then by expert faculty Dr. Jaideep Patel. Dr. Patel recently graduated from Virginia Commonwealth University cardiology fellowship and is now a preventive cardiologist at the Johns Hopkins Hospital. The CardioNerds Decipher The Guidelines Series for the 2021 ESC CV Prevention Guidelines represents a collaboration with the ACC Prevention of CVD Section, the National Lipid Association, and Preventive Cardiovascular Nurses Association. Question #18 A 60-year-old Black woman with a history of hypertension and heart failure with reduced ejection fraction (EF 40%) presents to clinic for follow-up. She is currently doing well with NYHA class II symptoms. She is taking carvedilol 25 mg BID, sacubitril/valsartan 97/103 mg BID, and spironolactone 25 mg daily, all of which have been well tolerated. In clinic, her BP is 125/80 mmHg, and her HR is 55 bpm. Routine labs are within normal limits including Cr of 1.0, K of 4.0, and HbA1c of 6.0. What is the most appropriate next step in her management? A. No change in management B. Reduce beta blocker C. Add an SGLT2 inhibitor (dapagliflozin or empagliflozin) D. Add vericiguat E. Add hydralazine/isosorbide dinitrate Answer #18 The correct answer is C – Add an SGLT2 inhibitor (dapagliflozin or empagliflozin) For patients with symptomatic HFrEF, neurohormonal antagonists (ACEi, ARB, ARNI; BB; MRA) improve survival and reduce the risk of HF hospitalization. This patient is already on these agents. The addition of an SGLT2 inhibitor on top of neurohormonal blockade reduces the risk of CV death and worsening HF in patients with symptomatic HFrEF and is the next best step for this patient (Class I, LOE A). Vericiguat may be considered in patients with symptomatic HFrEF with HF worsening despite already being on maximally tolerated neurohormonal blockade (Class IIb, LOE B), but first-line therapies should be started first. Hydralazine/Isosorbide dinitrate should be considered in self-identified Black patients or people who have EF ≤ 35% or
The following question refers to Section 6.2 of the 2021 ESC CV Prevention Guidelines. The question is asked by Dr. Christian Faaborg-Andersen, answered first by Houston Methodist medicine resident Dr. Najah Khan, and then by expert faculty Dr. Jaideep Patel. Dr. Patel recently graduated from Virginia Commonwealth University cardiology fellowship and is now a preventive cardiologist at the Johns Hopkins Hospital. The CardioNerds Decipher The Guidelines Series for the 2021 ESC CV Prevention Guidelines represents a collaboration with the ACC Prevention of CVD Section, the National Lipid Association, and Preventive Cardiovascular Nurses Association. Question #18 A 60-year-old Black woman with a history of hypertension and heart failure with reduced ejection fraction (EF 40%) presents to clinic for follow-up. She is currently doing well with NYHA class II symptoms. She is taking carvedilol 25 mg BID, sacubitril/valsartan 97/103 mg BID, and spironolactone 25 mg daily, all of which have been well tolerated. In clinic, her BP is 125/80 mmHg, and her HR is 55 bpm. Routine labs are within normal limits including Cr of 1.0, K of 4.0, and HbA1c of 6.0. What is the most appropriate next step in her management? A. No change in management B. Reduce beta blocker C. Add an SGLT2 inhibitor (dapagliflozin or empagliflozin) D. Add vericiguat E. Add hydralazine/isosorbide dinitrate Answer #18 The correct answer is C – Add an SGLT2 inhibitor (dapagliflozin or empagliflozin) For patients with symptomatic HFrEF, neurohormonal antagonists (ACEi, ARB, ARNI; BB; MRA) improve survival and reduce the risk of HF hospitalization. This patient is already on these agents. The addition of an SGLT2 inhibitor on top of neurohormonal blockade reduces the risk of CV death and worsening HF in patients with symptomatic HFrEF and is the next best step for this patient (Class I, LOE A). Vericiguat may be considered in patients with symptomatic HFrEF with HF worsening despite already being on maximally tolerated neurohormonal blockade (Class IIb, LOE B), but first-line therapies should be started first. Hydralazine/Isosorbide dinitrate should be considered in self-identified Black patients or people who have EF ≤ 35% or
A first-in-class allosteric and reversible inhibitor selective for cardiac myosin approved based on the results of the EXPLORER-HCM trial, mavacamten was approved for the treatment of adults with symptomatic NYHA class 2-3 obstructive hypertrophic cardiomyopathy after their phase 3 data indicated use was with improved exercise capacity, LVOT obstruction, NYHA functional class, and health status patients with oHCM. In the latest edition of Don't Miss a Beat, hosts Stephen Greene, MD, and Muthiah Vaduganathan, MD, MPH, are joined by special guest Anjali Owens, MD, of Penn Medicine. An assistant professor of medicine in the Division of Cardiology and medical director of the Center for Inherited Cardiac Disease at the Perelman School of Medicine, Owens is a leading researcher in oHCM with real-world clinical experience treating the disease. During the episode, Owens takes our hosts on a deep dive into the disease state from her perspective.
Guest host Dr. Neeraj Agarwal, of the University of Utah Huntsman Cancer Institute and the ASCO Daily News editor-in-chief, discusses key therapeutic advances in mRCC and mUC, as well as new research that proposes periodic scans to monitor patients with mCSPC for disease progression, with Dr. Jeanny-Aragon-Ching of the Inova Schar Cancer Institute. Transcript: Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program, a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. My guest today is Dr. Jeanny Aragon-Ching, who is a medical oncologist and the Clinical Program Director of Genitourinary Cancers at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing key posters in genitourinary (GU) oncology that will be featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcast. Jeanny, it is great to have you on the podcast today. Dr. Jeanny Aragon-Ching: Thanks, Neeraj. It's a pleasure for me to be here as well. Dr. Neeraj Agarwal: Jeanny, let's begin with Abstract 4510. This is a trial that represents a growing interest among researchers worldwide in the microbiome and how it is impacted by antibiotics and how it modulates immune checkpoint inhibitor response. Can you tell us about this study? Dr. Jeanny Aragon-Ching: Thanks, Neeraj, I would be happy to. So, the title of the abstract is, “Characterization of the Microbial Resistome in a Prospective Trial of CBM 588 in Metastatic Renal Cell Carcinoma Offers Mechanism for Interplay Between Antibiotic Use and Immune Checkpoint Inhibitor Activity.” So, this is an interesting abstract that originated likely from the observation that getting antibiotics while on checkpoint inhibitors typically results in worse outcomes, perhaps because antibiotics can clear the normal gut flora and thereby increase these pathogenic antibiotic-resistant bacteria. Now, on the other hand, there were some retrospective studies using a live microbial product called CBM 588, which seems to improve outcomes in patients on checkpoint inhibitors and getting antibiotics. So, the idea, therefore, is that shifting the genes encoding antimicrobial resistance could result in a better checkpoint inhibitor response. So, this Abstract 4510 is a small study conducted by Dr. Nazli Dizman and Dr. Sumanta (Monty) Kumar Pal, and colleagues, and enrolled 29 metastatic clear cell RCC patients with intermediate or poorest disease. And they were stratified into receiving either nivolumab or ipilimumab compared to nivo/IPI with CBM 588. Now stool samples were collected at baseline in week 12. And they did this whole metagenome sequencing to analyze a stool microbiome composition, and they also looked at the antibiotic resistance genes for the most common classes of antibiotics. The results showed an astounding improvement in objective responses. So, 58%, for instance, in nivo/IPI and the CBM 588 arm compared to only 20% in the nivo/IPI arm. And it seems like also the antibiotics resistance genes were also decreased in those getting the CBM 588 alongside nivo/IPI. Therefore, responses were improved by shifting the gut microbiome alone. So, these findings were published actually recently by these authors in Nature Medicine. So, in case anyone wants to take a deep dive, it would be a good interesting read for this dataset. Dr. Neeraj Agarwal: Very interesting, indeed. Jeanny, what is the main message here for our colleagues? Dr. Jeanny Aragon-Ching: I think, Neeraj, the key takeaway message is that this is a very provocative proof of concept trial that suggests shifting the gut microbiome has the potential to improve responses to checkpoint inhibitors and outcomes. So, this is a very up-and-coming trial and is seen also across the board in other cancers. Dr. Neeraj Agarwal: Thanks, Jeanny. Moving on to urothelial cancer, there is a poster that I think is a must-see for our colleagues. This is Abstract 4577 titled, “Defining Platinum Ineligible Patients with Metastatic Urothelial Carcinoma.” Dr. Jeanny Aragon-Ching: So, Neeraj, what can you tell us about this abstract? Dr. Neeraj Agarwal: So, over the past few years, there has been a tremendous evolution in the treatment landscape for patients with metastatic urothelial carcinoma. For over 40 years the standard of care for these patients has been cisplatin-based chemotherapy. However, approximately 50% of patients are cisplatin-ineligible, due to underlying comorbidities, and are offered carboplatin as an alternative. So, although the checkpoint inhibitors pembrolizumab and atezolizumab were approved as first-line therapy for these patients in 2017, the U.S. Food and Drug Administration (FDA) has now restricted the use of first-line pembrolizumab to platinum ineligible patients with metastatic urothelial carcinoma. The challenge we face as oncologists since the FDA restriction is the absence of a formal definition of platinum ineligibility and the inclusion of this definition in the guidelines. So, in Abstract 4577, Drs. Shilpa Gupta and Jonathan Rosenberg, along with the team present an updated consensus definition for platinum ineligibility based on an online survey of 60 genitourinary oncologists in the United States. Based on the results from this survey, any patient with metastatic urothelial carcinoma, meeting 1 of the following 5 clinical and or laboratory parameters should be considered platinum ineligible, and these are 1 of the following: an ECOG performance status of 3 or more, creatinine clearance of fewer than 30 mils per minute, or peripheral neuropathy of grade 2 or more, or heart failure class of 3 or more—so, this is NYHA heart failure class of 3 or more—and lastly, the combination of performance status of 2 or more, plus a creatinine clearance of less than 30 mils per minute. Dr. Jeanny Aragon-Ching: Well, this is a timely update, Neeraj. So, what do you think is a key takeaway from this abstract? Dr. Neeraj Agarwal: These criteria based on simple and easily available clinical and or laboratory parameters will now allow us to readily define platinum ineligibility in our patients with metastatic urothelial carcinoma, which is a need in busy clinics, both in academic and community settings. So, I think once published and obviously once endorsed by guidelines, we really would like to be able to use this criterion to quickly define platinum ineligibility in our clinics. Dr. Jeanny Aragon-Ching: Agree. Yeah. Dr. Neeraj Agarwal: So, Jeanny, let me switch the gears. PSMA testing is a hot topic this year. And there is an abstract that could potentially have an impact on future guidelines, and how we will practice further down the road. So, I'm referring to the Abstract 5088 titled, “Predictive Value of Extra Prostatic Disease Detection by Preoperative PSMAPET for Biochemical Recurrence-free Survival in Patients with Otherwise Localized Prostate Cancer and Who are Treated with Radical Prostatectomy.” So, this is a follow-up analysis of a multicenter prospective phase 3 imaging trial. So, could you please tell us more about this abstract where they are using PSMA PET scan in the preoperative localized prostate cancer setting? Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. So, you may recall that the multicenter prospective phase 3 imaging trial that garnered gallium PSMA approval by the FDA was actually based on this study that looked at the intermediate and high-risk patients with prostate cancer undergoing radical prostatectomy and lymph node dissection, and they underwent prior gallium PSMA PET scanning for pelvic nodal metastases prior to surgery. So, this was actually previously reported by Dr. Calais and group. Now they are reporting on Abstract 5088 as a post hoc analysis of the same population and group of patients looking for extraprostatic disease. And the final pathology was also correlated to look at nodal disease in these patients in order to predict biochemical recurrence, so they follow these patients for biochemical recurrence occurrence. So, of the 36% of patients who did undergo radical prostatectomy after they underwent PSMA PET scan, about 41% of them recurred with biochemical recurrence, and 40% of them underwent some kind of salvage therapy or some treatment. What was very interesting was when they looked at the biochemical recurrence-free survival. It was better in those who were PSMA negative, and that recurrence-free survival was easily about 33 months, compared to only about 7.3 months in those who were PSMA-positive scans. Furthermore, the ones who had the longest and the highest biochemical recurrence-free survival, intuitively, were those who were node-negative and PSMA PET-negative, so probably not surprisingly. And that rate was about 46 months—close to 4 years. Whereas those who are node-positive on final pathology and their PSMA PET was also positive, they only had about 3 months of biochemical recurrence-free survival. Dr. Neeraj Agarwal: Very interesting. So, it looks like the PSMA PET scan is predicting biochemical recurrence-free survival in localized prostate cancer settings. So, Jeanny, what is the key takeaway from this trial? Dr. Jeanny Aragon-Ching: I think, Neeraj, the bottom line is that patients with extraprostatic disease that is detected by their preoperative PSMA PET scan does predict strongly a high risk of biochemical relapse, and this can really be an additional tool that clinicians can use to help inform and guide future therapy. Dr. Neeraj Agarwal: Thanks, Jeanny. The research on preoperative PSMA testing and its implications on future treatment strategies in the setting is going to be really interesting to watch in the very near future. Dr. Jeanny Aragon-Ching: Yes, absolutely. I really think we should also discuss Abstract 5072, along those lines, the importance really of radiographic monitoring for disease progression in patients with metastatic hormone-sensitive prostate cancer. Dr. Neeraj Agarwal: Yes, thanks for reminding and this is Abstract 5072. This is a post hoc analysis of the ARCHES trial, titled, “Radiographic Progression in the Absence of PSA Progression in Patients with Metastatic Hormone-sensitive Prostate Cancer.” During the last several years, we have seen many of these agents typically given for gastric resistant prostate cancer moving upfront to the castration-sensitive prostate cancer setting. This is especially true for androgen receptor access targeting agents such as abiraterone, enzalutamide, and apalutamide, all being now approved for patients with metastatic castration-sensitive prostate cancer. What is noteworthy from all these trials, and is reported in Abstract 5072, is the use of imaging studies to evaluate disease progression. So, in Abstract 5072, Dr. Andrew Armstrong and Dr. Arun Azad performed a post hoc analysis of the ARCHES trial to investigate the concordance between radiographic progression and the PSA Progression as defined by PCWG2 criteria, or between radiographic progression and any rise in the PSA above nadir, in patients who were being treated with this novel hormonal therapies, in this case, enzalutamide for metastatic castration sensitive prostate cancer. And as a quick reminder, ARCHES was a phase 3 trial that showed a significant reduction and radiographic progression-free survival and improved overall survival for patients with metastatic castration sensitive prostate cancer treated with enzalutamide plus androgen deprivation therapy (ADT) versus those treated with placebo plus androgen deprivation therapy. So, very interestingly, the findings from this study indicate that 67% of patients on the enzalutamide plus ADT arm did not have [Prostate Cancer Clinical Trials Working Group 2 criteria] PCWG2-defined prostate-specific antigen (PSA) progression at the time of radiographic progression. And discordance was present in the ADT-only arm as well, where they found 42% of patients on the ADT-only arm had radiographic progression but did not have PCWG2-defined PSA progression. Interestingly, this discordance of radiographic disease progression was also seen with any rise in the PSA above nadir. And I personally found this information to be very clinically relevant when we are seeing the majority of patients actually experiencing radiographic disease progression, not experiencing PSA progression at the same time. Dr. Jeanny Aragon-Ching: Yeah, absolutely. I agree with that, Neeraj. So, very interesting data. So, what do you think is the key takeaway message for the clinicians listening to us? Dr. Neeraj Agarwal: I'll make the message very simple. I think the message is that patients with metastatic castration-sensitive prostate cancer need to be monitored for disease progression with periodic scans, and PSA monitoring alone is not sufficient in the majority of these patients. Again, we cannot undervalue the role of periodic imaging studies in these patients so that we can timely diagnose them to have disease progression. Dr. Jeanny Aragon-Ching: I agree with that. Dr. Neeraj Agarwal: Jeanny, the last abstract I would like to mention before we wrap up the podcast is Abstract 4509, the results from the phase1 live SPARC 001 study. So, can you please tell us more about this study titled, “Phase-1 Live SPARC 001: The Study of Belzutifan in Advanced Solid Tumors,” which is an update of the renal cell carcinoma cohort with more than 3 years of total follow up? Dr. Jeanny Aragon-Ching: Thanks, Neeraj. So, while the current therapeutic landscape for patients with metastatic clear cell renal cell carcinoma (RCC) has changed dramatically over the past several years, with significant improvement in patient outcomes. Most patients unfortunately still experience disease progression on current treatments. So, in-depth molecular profiling of clear cell RCC has revealed recurrent loss of function mutations in VHL in actually greater than 90% of patients. So, the VHL protein, as you will recall, is part of the oxygen-sensing pathway, regulating levels of HIF which is hypoxia-inducible factor protein, it's a transcriptional activator that mediates the response to hypoxic conditions. So, HIF-2α is a key oncogenic driver in RCC. So, previous data you may recall from the phase-1 Live SPARC 001 trial was designed to evaluate belzutifan so, this was a novel HIF-2α inhibitor which showed durable anti-tumor activity and acceptable safety profile in patients with metastatic clear cell RCC. So, in Abstract 4509, Drs. Jonasch and Toni Choueiri presented updated results from this trial after more than 3 years of follow-up. Of the 55 patients enrolled 16% of patients remained in treatment. And 62% of patients had discontinued treatment because of, unfortunately, disease progression. The median progression-free survival (PFS) for the total cohort was 14.5 months. And the overall disease control rate was 80%. Forty percent of patients experienced grade 3 treatment-related adverse events with the most frequent ones being anemia and hypoxia. There were no great 4 or 5 treatment-related adverse events. And these results, therefore, show that belzutifan monotherapy continues to show a high rate of disease control and a safety profile in a heavily treated population of patients with metastatic RCC. So, it is great to see that there were no new safety signals. Dr. Neeraj Agarwal: Very nice data indeed. So, Jeanny, what is the key takeaway message here for our listeners? Dr. Jeanny Aragon-Ching: Yeah, I think the message here is that the use of belzutifan monotherapy continues to show efficacy and safety in patients with metastatic clear cell RCC, which have progressed on multiple prior contemporary therapies, and there are phase 3 trials currently underway. Dr. Neeraj Agarwal: Jeanny, any final thoughts before we wrap up the podcast today? Dr. Jeanny Aragon-Ching: Thanks, Neeraj. I think it's a really exciting time to be in genitourinary (GU) oncology, and I'm truly looking forward to seeing some great sessions at the 2022 ASCO Annual Meeting. Dr. Neeraj Agarwal: Thank you, Jeanny, for sharing your insight with us today. It was a great conversation. And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, Arvinas Dr. Jeanny Aragon-Ching: Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, AstraZeneca/MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb , Astellas/Seattle Genetics Travel, Accommodations, Expenses: Dendreon, Algeta/Bayer, Bristol Myers Squibb, EMD Serono, Astellas Pharma Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast expressed their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
SUMMARY--What diuretic do you usually write for during CHF hospitalizations?? If you said furosemide you are not alone One in a study in JACC 2013 looked at HF hospitalizations in 2009 and 2010 – In total 251,472 patients got a loop diuretic during their hospitalization and almost 87% got just furosemide, about 3% only got bumex, while only 0.4 received only torsemide.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038646/#R11 What is the difference between bumetanide and furosemide? Nothing—or at least nothing we care about. No hard outcomes, no patient oriented outcomes. Bumetanide is stronger—An article from 2015 in American Heart Journal states bumetanide is about 40 times stronger than furosemide- thus at times you might have your sphincter tighten when you go to write for 120-160mg of furosemide but feel comfortable writing for 3-4mg of bumex. They also discuss how bumetanide also appears to have a higher more consistent bioavailability at around 80-100% while furosemide seems to range from 10-100% depending on the study. Conclusion: the benefits for bumetanide are there in theory but no hard outcomes that I could find. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346710/ What about torsemide??The bioavailability of torsemide is 76% to 96% and as I mentioned before furosemide hangs out around 10% to 100%. In addition, furosemide bioavailability can decrease by up to 30% with food while torsemide is not affected by food consumption.https://oce.ovid.com/article/00006562-199701000-00009https://pubmed.ncbi.nlm.nih.gov/3709617/ HOWEVER, no patient cares about bioavailability they want to know if they will live longer or live better (patient oriented outcomes)?? First paper- 2001 Nov;111(7):513-20.American Journal of Medicine we have a paper titled“Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure” This was open-label trial of 234 patients who were randomized to torsemide or furosemide and followed for 1 yr. The outcome was heart failure readmissions and it occurred significantly less in the torsemide group, only 17% of the time compared to 32% in the furosemide group. https://pubmed.ncbi.nlm.nih.gov/11705426/ That is almost a 50% relative reduction for heart failure hospitalization at one year! This is an outcome both patients and hospitalist would love to see! Second paper-In 2002- a year later-European Journal of Heart Failure a paper titledTorasemide in chronic heart failure: results of the TORIC studyThis was the published results of the ‘TOrasemide In Congestive Heart Failure (TORIC)' study- It was an open-label, non-randomised, post-marketing surveillance trial. The individuals who were prescribed torsemide on top of their other CHF medications for 12 months had almost a 50% relative reduction in mortality!! That may not seem like a lot but remember this is only 12 months and the outcome was DEATH! In absolute terms roughly 2% of participants died in the torsemide group and 4% died in the furosemide/other diuretic group. PLUS, those in the torsemide group also had an improvement in their NYHA functional heart class.https://pubmed.ncbi.nlm.nih.gov/12167392/ Finally, there is a meta-analysis from 2019 in Journal of Cardiovascular Medicine titledTorsemide versus furosemide and intermediate-term outcomes in patients with heart failure: an updated meta-analysis Which looked at a total of 14 randomized trials and just over 8000 pts and found torsemide to have both fewer heart failure hospitalizations and those individuals taking torsemide were more likely to have an improvement in their new york heart association class but they didnt find a difference in mortality.https://pubmed.ncbi.nlm.nih.gov/30950982/ Currently there is 6000 pt randomized trial that is underway and will be done in august 2023. https://clinicaltrials.gov/ct2/show/NCT03296813 That is it, that is all that I could find!!!! However, with the evidence clearly in favor of torsemide, why have I never even considered it before doing this lecture?? Likely 2 problems 1) It is what we have always done and it is hard to change practice! Furosemide was approved for medical use in 1964.Torsemide was approved in 1993. We as providers get into a rut, the next drug we prescribe is likely to be one of the most recent drugs we prescribed. If you show me the last 10 hypertension medications you prescribed then with almost 90-100% certainty I can guess the next one that you are going to prescribe. 2) There use to be a cost issue when furosemide was generic and torsemide was not. However, now these are both old drugs and per goodrx down here in Florida they only differ by about 1.50$ per month, but we are saving hospitalizations which cost 1000$. A paper from 2000 in Pharmacoeconomics titled “Healthcare costs of patients with heart failure treated with torasemide or furosemide” found torsemide average hospitalization cost per patient each year was $1000 while those in the furosemide group had an average cost of $1500 dollars, and this was back when torsemide wasn't nearly as cheap as it is now. I know I have given you a lot of numbers but a good take away is- Torsemide compared to furosemide has a NNT at 10.5 months to prevent a heart failure hospitalization around 6!!! https://pubmed.ncbi.nlm.nih.gov/10977385/ https://www.medscape.com/viewarticle/771976_8 Even if the number is off a little because of study design flaws like blinding and sample size the evidence does appear to continually point the direction of benefit towards torsemide. Even if you doubled it, a NNT of 12, it is still really good.
This week Norm Scott, a retired NYC DOE teacher, long-time unionist, and blogger, stops by to tell us all about Mulgrewcare, a foiled (or is it?) attempt by the UFT leadership to deprive retirees of their proper, hard-earned benefits OR balance the books after a poorly-executed contract negotiation by collecting their hard-earned money in the form of new, illegal premiums for the same coverage they have always had. We discuss the parallels between Unity's willingness to privatize healthcare and the neoliberal drive to privatize schools, most notably via the charter movement, and much more!Read more of Norm's work at ednotesonline.com
Please join author David Webb and Editorialist Steven Smith as they discuss the original research article “Regular Acetaminophen Use and Blood Pressure in People With Hypertension: The PATH-BP Trial" and the editorial "Acetaminophen-Induced Hypertension: Where Have All the "Safe" Analgesics Gone?" Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm your host today, Dr. Carolyn Lam, associate editor from The National Heart Center in Duke National University of Singapore. And I'm so missing my co-host Dr. Greg Hundley, who can't make it today, but will be back next week. Now, I have the privilege of telling you all about the exciting papers in today's issue, but before I even get there, I need to let you know that coming right up is a discussion you are not going to want to miss. It deals with an issue that we encounter very commonly and perhaps should have questioned many times, but haven't yet. What is it? Well, regular acetaminophen use and its blood pressure effect. Acetaminophen, what we commonly call paracetamol or Tylenol depending where you're coming from, but have we ever stopped to really ask, does this impact blood pressure? We're going to find out more in the path BP trial coming right up, but first here are your summaries. Dr. Carolyn Lam: The first original paper I'd like to tell you about is a study representing additional four years a follow up from the Danish trial. Now recall that Danish was a trial that found that primary prevention ICD implantation was not associated with an overall survival benefit in patients with non-ischemic systolic heart failure, doing a median follow-up of 5.6 years. Although, there was a beneficial effect on all-cause mortality in patients aged 70 years or younger. Now, the current study led by Dr. Lars Køber from Copenhagen University Hospital and colleagues showed that during a median follow up of now 9.5 years, ICD implantation did not provide an overall survival benefit in patients with non-ischemic systolic heart failure. In patients age 70 years or younger, however, ICD implantation was associated with a lower incidence of all-cause mortality, cardiovascular death, and sudden cardiovascular death. Dr. Carolyn Lam: The next original paper reports on pre-specified analyses from the FIGARO-DKD trial assessing the impact of finerenone known on clinically important heart failure outcomes. Now recall that FIDELIO-DKD and FIGARO-DKD, in those trials finerenone, which is a selective nonsteroidal mineralocorticoid receptor antagonist, improved cardiovascular outcomes in patients with albuminuric chronic kidney disease and type two diabetes. In the current study, Dr. Filippatos from Attikon University Hospital in Athens, Greece and colleagues presented the pre-specified analyses of FIGARO-DKD describing novel heart failure related outcomes, which were not previously published in finerenone studies, and these included new onset heart failure. Different outcomes containing first or total hospitalization for heart failure events in the overall population. The results indicated that in patients with chronic kidney disease and type two diabetes on a maximum tolerated dose of renin-angiotensin system inhibitor therapy, fenerenone reduced new onset heart failure and improved heart failure related outcomes irrespective of history of heart failure. This is the first indication that a nonsteroidal mineralocorticoid receptor antagonist may provide benefit in a population with chronic kidney disease and type two diabetes, in which patients with heart failure with reduced dejection fraction or symptomatic NYHA 2-4 were excluded, thus indicating that patients with type two diabetes and chronic kidney disease at risk of heart failure or with early stage heart failure may indeed benefit from fenerenone treatment. Dr. Carolyn Lam: The next original paper shows for the first time, a role of the nuclear receptor Rev-Erb, a key component of the circadian clock in obesity. So, co-corresponding authors, Dr. Song from Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, as well as Doctors Zheng Sun, both from Baylor College of Medicine, and their colleagues used mice with cardiomyocyte specific Rev-Erb deletion that manifested contractile dysfunction, cardiac dilatation, and heart failure. And using these models, authors showed that there was a temporal coordination between clock mediated anticipation and nutrient induced response in myocardial metabolism at multiomic levels. Obesity, together with insulin resistance via a high fat diet, paradoxically improved dysfunction and fatty acid availability from edibles lipolysis in the disrupted circadian mouse model that Rev-Erb knockout. These elegant studies reveal a punitive link between circadian regulation and nutrient induced responses in the heart, potentially helping to explain the obesity paradox. Cardiac molecular chronotropes may, therefore, be involved in human dilated cardiomyopathy. And the implication is that myocardial bioenergetics downstream of Rev-Erb may be a chronotherapy target in treating patients with heart failure. Now, all of this is discussed in an editorial by Dr. Inna Rabinovich-Nikitin and Dr. Lorrie Kirshenbaum from Manitoba, Canada. Dr. Carolyn Lam: The final original paper in today's issue is an important translational paper, in which ZEB2, which is a master regulator of epithelial to mesenchymal transition and is associated with many cancers, has for the first time been identified as a new coronary artery disease associated gene. This was first identified by human Genome-wide Association studies, following which the authors Dr. Quertermous from Cardiovascular Institute Stanford and colleagues used smooth muscle cell specific deletion of ZEB2 in mice, coupled with single cell transcriptomic and epigenetic profiling of smooth muscle cells specific [inaudible 00:07:31] cells, and showed that ZEB2 dramatically alters cell state trajectories of the smooth muscle cells through epigenetic regulation of TGF-β and notch signaling. Lower ZEB2 in smooth muscle cells resulted in atherosclerotic plaques with high risk features. So what are the clinical implications? Well, therapies that specifically regulate smooth muscle behavior can potentially alter the risk of plaque rupture, and may be used to further reduce the risk of myocardial infarction. Existing chemotherapies and additional drugs in development that modulate the epigenetic silencing, such as HDAC inhibitors or hypomethylating agents, may, on the other hand, increase the risk of myocardial infarction. Dr. Carolyn Lam: So very interesting paper. Wraps it up for our original papers, and now onto what else there is in today's issue. There's an On My Mind paper by Dr. Messerli on [entitled] “Why Are We Still Prescribing ACE Inhibitors?” and a Research Letter by Dr. Simon on one-year major cardiovascular events after restrictive versus liberal blood transfusion strategy in patients with AMI and anemia from the reality randomized trial. Well, that's it for the summaries. Thanks for joining. And please hang on tight for this next exciting feature discussion. Dr. Carolyn Lam: For today's feature paper, we are talking about a very familiar medication. Believe it or not, it's just paracetamol, or acetaminophen in its generic term. What we also call Tylenol in the US. And I'm sure this is something that everybody recognizes as one of the first line therapies that we take for chronic pain. It's even over the counter. It's perceived as extremely safe, and in particular, is as having little or no effect on blood pressure. But is that correct? Ah, this paper, I have to tell you audience, really sent chills up my spine. I learned so much from it and I am so, so pleased to have with us the corresponding author, Dr. David Webb from Queens Medical Research Institute in Edinburgh, as well as our editorialists Dr. Steven Smith from University of Florida in United States to discuss this very, very important paper. David, if you don't mind if I start with you, what made you look at this question? It's strikingly important, but seemingly strikingly ignored until your study, so please tell us about that. Dr. David Webb: So paracetamol, or acetaminophen, has a really long history going back to the 1800s, and it replaced a drug that was removed called phenacetin that caused significant toxicity. It didn't really grow in use until about the 1980s, but from then on, it really took off and now it's the most widely used and prescribed analgesic in the world. There have been observational studies, large ones, and small clinical trials that suggested an increase in blood pressure. We undertook a systematic review in 2013 that suggested this really needed to be a topic for a further study, and so we undertook a randomized control trial to answer the question of whether, in hypertensive subjects, paracetamol would increase blood pressure. Dr. Carolyn Lam: Well, thank you for that background. I have to admit, I didn't even know about the origins and that very first paper you talked about, and this is really beautifully summarized as well in, Steve, your beautiful editorial. But before we go there, David, could you tell us about this path BP trial, what you did and what you found? Dr. David Webb: So we were funded by the British Heart Foundation, and we under took a randomized placebo controlled blinded study of one gram of paracetamol given four times a day versus match placebo. And we looked primarily at the gold standard ambulatory blood pressure in patients with hypertension, a third off treatment, and two thirds on treatment, and about a hundred, more than a hundred patients took part in this study. It was a crossover study with washout, and we saw that ambulatory blood pressure compared to placebo treatment increased by five millimeters of mercury, which is substantial. It's very similar to what we see with the nonsteroidal anti-inflammatory drugs, the NSAIDs, which also have effects mediated through prostaglandin metabolism, and that increase of five millimeters of mercury would amount to an increased cardiovascular risk, if sustained, of around 20%. Our study was only for two weeks for practical reasons, but we have no reason to think the effect would not last longer. Dr. Carolyn Lam: And David, just before we carry on, could you clarify a few things? So, these patients did not have pain to enter, and did they have hypertension, and were they on other medications for hypertension? Dr. David Webb: Yeah, so they were patients with hypertension. They had to have an entry average ambulatory blood pressure daytime of more than 135 over 85, but less than 150 over 95, so this is mild to moderate hypertension. A third of them were not treated at the time of the study, but went on to treatment, and two thirds were already on treatment and stayed on their existing treatment. So this is a study in both treated and untreated hypertension, and we saw, although it wasn't powered to look at differences, we saw similar effects in those who were treated and untreated. Dr. Carolyn Lam: So an incredibly important question and Dr. Smith, Steve if I may, you wrote very nicely how the fact that this is individuals with hypertension, but not having an indication of pain and so on. It's really something we needed to look at this question because pain can confound, I suppose, the measurement of blood pressure and so on. So could you tell us a little bit more of why this study is so important and what do you think its impact of the findings will be? Dr. Steven Smith: Sure. Thank you, Carolyn. And first of all, I just say, I appreciate you having me on and getting to discuss this really interesting study by Dr. Webb and his team. I think it's a really interesting study. As you may know now, acetaminophen has been associated with blood pressure increases going back almost half a century now and there have been a number of studies, not all have been particularly strong studies and there's a number of limitations to that literature, and I think I was really fascinated by Dr. Webb's study because they really just asked a simple question and did a well designed, robust study to try to address that question and I think it provided some pretty definitive results. Dr. Steven Smith: As I mentioned in the editorial, despite the fact that acetaminophen has been associated with blood pressure increases in the past, if you go look at Google or whatever, your favorite search engine of choices, you'll find a number of articles right at the top that seem to imply or directly state that acetaminophen is perfectly safe for patients with high blood pressure. And I think that's a concerning thing that the medical information out there is implying or directly stating that acetaminophen is perfectly fine for these patients and so, I'm appreciative with the work that Dr. Webb is doing to try to bring to light some of the risks of acetaminophen Dr. Carolyn Lam: Indeed. And I think it raises a lot of questions that you also so nicely put in your editorial, and maybe this is the chance to ask David directly. For example, what do you think are the implications, in terms of generalizability, in chronic uses of acetaminophen in lower or higher doses in people without hypertension? I mean, this is a big and important issue. What do you think, David? Dr. David Webb: Sorry, Carolyn. Maybe I could start by just sticking to the subjects of the study itself. I think what this tells us, and it's important to recognize that there is very little evidence that paracetamol provides benefit in chronic pain. It's not of any value in low back pain. There seems to be no evidence that it's particularly useful in cancer pain and in a wide range of other forms of pain. The evidence for benefit is very limited, so harms really matter where the benefit is small, and probably most patients with chronic pain are not benefiting from the paracetamol in terms of its analgesic effect. So cautiously trying to withdraw treatment in these patients may well be a benefit in terms of reducing cardiovascular risk. So that's for what patients with hypertension. So beyond hypertension, that's a bit more difficult because we didn't study that, but we looked at a range of blood pressures. Dr. David Webb: And whilst we weren't powered to address this specifically, it looks as though the effects are there for lower blood pressures and for higher blood pressures. So, it would be nice to do the direct study, but it looks as though this might be slightly more general I support. We didn't look at people with chronic pain for practical reasons, but as I say, there's very little evidence that paracetamol is providing a benefit. I always thought that paracetamol was a safe drug. I use it in my hypertension clinic. And I think in my head, this is safer than using a nonsteroidal, but they're less effective and they may be no safer. So I think one needs to inform clinicians and their patients about the relative safety of paracetamol when considering treatment for chronic pain. You asked one other question. In the UK four grams a day as a common dose. It is in many parts of the world as a maximum dose. In the US, FDA has advised reducing to three grams a day as the maximum dose. You can still give four grams a day, but I think that's a helpful recommendation because this is very likely to be a dose dependent effect. So the lower maximum dose will to some extent protect subjects. Dr. Carolyn Lam: And Steve, would you agree with that? What would your take-home message to the audience be, or what do you think are the most important unanswered questions? Dr. Steven Smith: Yeah, it's a great question. If I could piggyback on David's answer, I think one of the really interesting findings from this study is that we see these blood pressure changes even after only two weeks of therapy, so this is not something that requires some chronic, very high dose of acetaminophen to start experiencing these blood pressure changes. Obviously a lot of people are on acetaminophen, as David mentioned all over the world. Many of those patients, of course, are on it for chronic therapy, for example, for osteoarthritis, but a lot take it much more sporadically or for short term use. And I think it's telling that we see these blood pressure changes pretty rapidly after starting therapy. Dr. Steven Smith: As far as unanswered questions go, I think Dr. Webb summarized some of those already, but I guess what I would add is we still lack some clarity on what the ultimate outcomes of these blood pressure changes are. Obviously we know that blood pressure is highly correlated with adverse cardiovascular outcomes, as well as other outcomes, but the data showing an increased cardiovascular risk with acetaminophen is a little bit more murky. And so I do think there's still some question as to how this translates to increased cardiovascular risk, and I totally agree with David that the evidence supporting efficacy of acetaminophen is so weak at this point for most things, it may be a moot point. We may want to just move on from acetaminophen to the extent that we can, because it seems to have some risks, or at least some concern for risks, without a lot of evidence. Dr. Carolyn Lam: Wow. Thank you so much, gentlemen, for this. It's just amazing discussion, but even more so for publishing such an important study and such an elegant editorial in our journal. I think this is one that not only may change practice, but changes my personal perception and things that I'm going to do immediately. Dr. Carolyn Lam: Thank you very much audience. I'm sure you agree. This was incredible. Do tune in again next week for another episode of Circulation On The Run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This podcast discusses the importance of being accurate with NYHA Functional Classification as well as the current study that is focused on NYHA classification.
CardioNerds (Amit Goyal and Daniel Ambinder), join Dr. Anjali Wagle (Internal medicine resident, Johns Hopkins Hospital) and Dr. Nick Smith (Cardiology fellow, Johns Hopkins Hospital) for an important discussion involving a patient with non-ischemic dilated cardiomyopathy and biventricular heart failure who had developed diuretic resistance. They discuss the role for invasive hemodynamic assessment of volume overload, initial strategies in managing a patient with volume overload, the role of guideline directed therapy in the management of patients with recurrent volume overload, and advanced strategies for diuretic resistance. Dr. Nisha Gilotra (Director of the Cardiac Sarcoidosis Program and assistant professor of medicine, Johns Hopkins Hospital) provides the E-CPR for this episode. Audio editing and Approach to Diuretic Resistance infographic by Dr. Gurleen Kaur (Director of the CardioNerds Internship). This episode is made possible with support from Panacea Financial. Panacea Financial is a national digital bank built for doctors by doctors. Visit panaceafinancial.com today to open your free account and join the growing community of physicians nationwide who expect more from their bank. Panacea Financial is a division of Primis, member FDIC. Claim free CME just for enjoying this episode! Disclosures: NoneJump to: Patient summary - Case teaching - References CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Patient Summary - Diuretic Resistance A young woman in her 20s with non-ischemic dilated cardiomyopathy and NYHA class IV ACC stage D biventricular heart failure with an LV ejection fraction of 30-35% on palliative inotropic therapy complicated by cardiogenic cirrhosis and stage IIIb chronic kidney disease presented with acute decompensated heart failure with volume overload. During her hospitalization she exhibited profound signs of diuretic resistance with minimal improvement after increasing inotropes, increasing IV loop diuretics, adding IV thiazides, and trialing continuous IV furosemide. She was given high dose mineralocorticoids, IV acetazolamide, and hypertonic saline paired with IV furosemide and had a durable treatment response. Episode Teaching - Diuretic Resistance Pearls - Diuretic Resistance Diuretic resistance is a complex clinical problem defined as inadequate natriuresis despite an adequate diuretic regimen. However, the practitioner cannot overlook low output heart failure and/or insufficient renal perfusion as the causes for inadequate diuretic response. In cases of inadequate urine output due to low cardiac output, increased inotropic or mechanical support would be the first objective.Confirming adequate cardiac output to support renal perfusion and/or confirming high filling pressures may require invasive hemodynamic assessment.Sodium avidity is most effectively blunted by treating the patient with maximally tolerated guideline directed therapy. This includes but is not limited to a backbone of ARNI (or ACE or ARB), mineralocorticoid receptor antagonists, beta-blockers, and SGLT-2 inhibitors.In cases of advanced diuretic resistance, hypertonic saline paired with high dose IV furosemide can be an effective strategy.In cases of diuretic resistance combined with cirrhosis and heart failure there is a synergistic hyperaldosteronism that can be targeted with higher doses of mineralocorticoid receptors as is seen in the treatment of cirrhosis with ascites. Notes - Diuretic Resistance 1. What is the role for invasive hemodynamic assessment in acute decompensated heart failure? Cases where intracardiac filling pressures are in question: right heart catheterization (RHC) can give insight into the presence and degree of right versus left sided filling pressures.
Como usar a classificação de NYHA?
Valsartan, also known as Diovan, is an angiotensin II receptor blocker (ARB). It is used for treating NYHA class II to IV heart failure along with both treating and managing hypertension. Another common indication is for both STEMI and NSTEMI patients. Typical initiation dosing for heart failure, STEMI and NSTEMI is 20 mg twice daily with titrations up to 160 mg twice daily. When initiating treatment for hypertension the range begins at 80-160 mg po every day up to a max dose of 320 mg per day. Valsartan works by blocking AT2 from the AT1 receptor and is considered to be more efficient than ACEs along with having less side effects such a cough. Some common side effects are orthostatic hypotension, dizziness, and lightheadedness. Common monitoring parameters for valsartan are blood pressure, blood pressure urea, pregnancy, and electrolytes. Patients should avoid salt substitutes containing potassium. There is a black box warning for fetal toxicity because drugs that affect the renin-angiotensin system can cause injury/death to the fetus. Go to DrugCardsDaily.com for my episode show notes which will contain a drug summary, quiz, and a link to FREE drug card sheets. SUBSCRIBE on Spotify or Apple Podcasts or search for us on your favorite place to listen to podcasts. I will go over the Top 100-200 Drugs as well as throwing in some recently released drugs that peak my interest. Also, if you'd like to say hello, suggest a drug, or leave any constructive feedback on the show I'd really appreciate it! Leave a voice message at anchor.fm/drugcardsdaily or message us through twitter @drugcardsdaily --- Send in a voice message: https://anchor.fm/drugcardsdaily/message
Nils Christian og Anders lærer deg NYHA-klassifikasjon ved hjelp av en case. Du møter Geir Daniel (80 år) som har hypertensjon, diabetes type 2 og kjent hjertesvikt. Han har følt seg mer slapp de siste par månedene, har økende hevelse i beina og han klarer ikke lenger å gå opp trappene til leiligheten sin uten å ta pauser. Finn frem MedEasy-appen og løs casen sammen med Nils Christian og Anders.
I denne episoden fortsetter anestesilege Anders å hjelpe Nils Christian med å sortere begrepet hjertesvikt som var tema i forrige ukes case «tights og tungpust». De repeterer definisjonen av hjertesvikt, gjennomgår ulike måter å sortere hjertesvikt på, og terper ekstra på praktisk bruk av NYHA-kalkulator i møte med hjertesviktpasienter.
Dr Carolyn Lam: Welcome to Circulation on the Run! Your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, we got double features today. Now, the first one's all about fruit and vegetables. Now, before you switch off, this is a very important one, okay? So, listen on. And the second is on the EMBRACE heart failure trial. Now, this was a late breaker, very important, more data on empagliflozin, that SGLT2 inhibitor. So really, really fun discussions coming right up. But first, can I dig into one of the papers that I'm really dying to tell you about? Dr. Greg Hundley: Absolutely. Dr Carolyn Lam: Okay. This is all about the diagnostic performance of high-sensitivity cardiac troponin T strategies, that super hot topic. We know that European data support the use of low high sensitivity troponin measurements or a 0/1 hour algorithm for myocardial infarction or to exclude MACE among emergency department patients with possible acute coronary syndrome. However, there's really very modest U.S. data to validate these strategies. This study today from Dr. Allen and colleagues from University of Florida, really evaluated the diagnostic performance of an initial high sensitivity cardiac troponin T measure below the limit of quantification. And that is six nanograms per liter, a 0/1 hour algorithm, and their combination with heart scores for excluding MACE in a multi-site U.S. cohort. And this is the largest prospective multi-site U.S. study of high sensitivity troponin T strategies to date. Dr. Greg Hundley: Wow, Carolyn you've really piqued my interest. So what did they find? Dr Carolyn Lam: Okay. And initial high sensitivity, cardiac troponin T below that level of quantification of six nanograms per liter was associated with a negative predictive value of 98.3% for 30-day MACE. Okay. That was that value itself. Now the 0/1 hour algorithm rolled out 57.8% of patients with a negative predictive value of 97.2% for 30-day MACE. The addition of a low-risk heart score to that initial high sensitivity troponin T level below that six nanogram per liter and the 0/1 hour algorithm improved the negative predictive value for 30-day MACE to 99% and 98.4% respectively. Dr. Greg Hundley: Wow. Carolyn, it looks like a really comprehensive analysis of the high sensitivity troponin. So tell us what are the clinical implications of this study? Dr Carolyn Lam: So these data seem to imply that when used without a risk score and initial high sensitivity troponin T below six nanograms per liter, or a 0/1 one hour algorithm, may not have sufficient sensitivity or negative predictive value to exclude 30-day MACE in the U.S emergency department patients. But the addition of that low-risk heart score to those measures improves the negative predictive value, but rolls out fewer patients. And so in totality, these results suggest that in the U.S. Emergency departments, adding a risk score to either of these strategies really increases their safety. Dr. Greg Hundley: Boy, great new information in our journal. Well, Carolyn, I'm going to switch to the world of basic science and start to evaluate in this next paper, the regulation of cellular signatures in children with dilated cardiomyopathy, and the work comes to us from Dr. Stephanie Dimmeler from Goethe University in Frankfurt. So Carolyn, Stephanie's team performed single nuclei RNA sequencing with heart tissues from six children with dilated cardiomyopathy. One was age 0.5, 1.75 and another at 5, 6, 12, and then 13 years of age. And they did this to gain insight into age and disease-related pathophysiology, pathology, and molecular fingerprints. And the goal was to gain further insight into dilated cardiomyopathy, which is a leading cause of death in children with heart failure. Dr Carolyn Lam: Cool. So what did they find Greg? Dr. Greg Hundley: Right, Carolyn. So, the number of nuclei in fibroblast clusters increased with age in dilated cardiomyopathy patients, a finding that was consistent with an age-related increase in cardiac fibrosis quantified by cardiovascular magnetic resonance imaging. Dr. Greg Hundley: Now Carolyn, fibroblast of the dilated cardiomyopathy patients over six years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans and a switch in thrombospondin isoforms and signatures for fibroblast activation. Additionally, Carolyn, a population of cardiomyocytes with a high pro-regenerative profile was identified in infant dilated cardiomyopathy patients, but was absent in those children that were greater than six years old. And this cluster in these infants showed high expression of cell cycle activators, such cyclin D family members increased glycolytic metabolism and any oxidative genes and alterations in beta adrenergic signaling genes. Dr Carolyn Lam: Wow. That sounds like a magnificent and elegant study. Could you boil it down to the take home messages? Dr. Greg Hundley: You bet. Carolyn. Great question. So two points first, infants with a predominantly regenerative cardiomyocyte profile, may preferentially receive treatment strategies to support cardiac regeneration while patients with a pattern associable with cardiac fibrosis may benefit from an early anti-fibrotic therapy to avoid diastolic dysfunction. And second, despite the impracticality of performing these large cohort studies in children with dilated cardiomyopathies, tailored pharmacological treatment is possibly realistic. For example, based on the expression of beta adrenergic signaling genes. Dr Carolyn Lam: Oh wow. That is super cool. That's Circulation for you, publishing these amazing basic science papers with very big clinical implications. Well, I've got another basic science paper for you and this time I've learned a new word actually. It's called O-GlcNAcylation. I should get you to say it after me. I had to get our editor-in-chief Joe Hill to teach me to say that, O-GlcNAcylation. So, cardiomyopathy from diverse causes is marked by increased O-GlcNAcylation. Now, in this paper, co-corresponding authors, Dr. Anderson and Umapathi from Johns Hopkins University provide a new genetic mouse model to control myocardial O-GlcNAcylation independent of pathological stress. Their data actually provided evidence that excessive O-GlcNAcylation caused cardiomyopathy, at least in part due to defective energetics. Enhanced O-GlcNAcase activity was well-tolerated. And conversely, attenuation of O-GlcNAcylation was beneficial against pressure overload induced pathological remodeling in heart failure. Dr. Greg Hundley: Interesting, Carolyn. So what are the clinical implications of these findings? Dr Carolyn Lam: Well, the data really provide new proof of concept that excessive O-GlcNAcylation is sufficient to cause cardiomyopathy, and they also suggest that attenuation of this excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy. Dr Carolyn Lam: Shall we go on and sort of wrap up on what else is in this issue? Because I'd like to talk about highlights from the Circulation family of journals that Sarah O’Brien really beautifully summarizes, talking about everything from Circulation: Arrhythmia & Electrophysiology, to [Circulation:] Cardiovascular Quality & Outcomes. It's just a beautiful piece where we get all the highlights. Must read. There's also a Perspective piece by Dr. Gillis on Rhythm Control in Atrial Fibrillation: Is Earlier the Better?, and that discusses the EAST-AFNET 4 and early AF trials. Dr. Greg Hundley: Very good, Carolyn. Well, from the mailbox, professors Pan and Liu exchange letters regarding a prior response to a letter regarding the article Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program. Also, Dr. Arbus-Redondo has an EKG challenge entitled, Dual Chamber Pacemaker after Sinus Node Dysfunction and an Enlarged Right Atrium. Is it what it seems? Dr. Greg Hundley: And then finally, Dr. Corrado has a very nice Research Letter, entitled, Serial versus Single Cardiovascular Screening of Adolescent Athletes. Dr. Greg Hundley: Well, Carolyn, I'm dying to hear about fruits and vegetables. How about we get onto those featured discussions? Dr Carolyn Lam: Cheeky, cheeky, Greg. Here we go. Dr Carolyn Lam: Oh, I'm so excited about today's featured discussion because it's about my favorite thing, fruits and vegetables. Okay, wait a minute, everybody. Before you start rolling your eyes, this is a really important one. Have you ever asked yourself, what is the optimal intake levels of fruit and vegetables for maintaining long-term health? Well, guess what? We're about to find out and I'm so pleased to have the first author of today's feature paper, Dr. Wang Dong, and he's from Harvard medical school and Brigham Women's Hospital. We also have our Associate Editor, Dr. Mercedes Carnethon from Northwestern University and our Associate Editor who is also the editorialist to this paper, Dr. Naveed Sattar from University of Glasgow. So welcome, everyone. Dr. Wang, please tell us what you did in this study and what were your main results? Dr. Wang Dong: Thank you, Carolyn. So, basically, in this study, we analyzed the data from two long running cohort study. That is the Nurses' Health Study and Health Professional Follow-Up Study. So these two study includes more than 100,000 participants who had been followed for up to 30 years. And we also include a meta-analysis that includes in total 26 studies and about two million participant from 29 countries, and had countries around the world. So, basically, the major finding from this study is, of course, the intake of fruits, vegetable is inversely associated with the risk of death from all cause and the different kinds of cause-specific mortality. And we have a very interesting finding that is intake of about five servings per day, that can be translated into two serving of fruits and three servings of vegetables per day, was associated with the lowest risk of total mortality. So that's an optimal intake level for fruits and vegetable. Dr. Wang Dong: And another important finding from this study is, not all foods that some people consider to be fruits and vegetables can offer the same health benefits. For example, in this study, we found that starch vegetables such as peas and corn, and some fruits juice and potatoes are actually not associated with any benefit in terms of longevity. On the other hand, if you look at green living vegetables such as spinach, kale, and fruits that's orange color fruits and vegetables, that's rich in beta-carotene and vitamin C such as citrus fruits and berries, carrots they're associated with a substantial reduction in the risk of total mortality. That's a major finding from this paper. Dr Carolyn Lam: Oh, I just love it. I mean, just like such wholesome, beautiful findings from a wonderful study. Now, if I could ask you, cause I think the first thing everyone's going to say is, okay, these are associations. I mean, what'd you do about the residual risks? Could you maybe describe how you try to address some of these things like, is taking in fruits and vegetables just a surrogate for people who, I don't know, exercise more, for example? Dr. Wang Dong: Yeah. So in original data analysis, we actually have extensive data collection of all kinds of foods, lifestyle, risk factors, medication use, any health-related variables. So we carefully adjust for a large number of confounding factors. So actually another thing I want to point out, most all of these health-related lifestyle factors actually are inverse confounding factors in this kind of analysis. So when you adjust for other confounding factors, it's tend to attenuated your inverse association. So the review from confounding actually wouldn't be a major explanation for this association. Dr Carolyn Lam: Oh, that's great. And by the way, I think I misspoke. I'm not sure if I said residual confounding or residual risk just now, but you absolutely read me right, that I meant residual confounding. So thanks. Now that we've got that out of the way, if I could ask Mercedes, please. I mean, ah, another fruits and vegetables paper, I mean, what made this one different that we said we have to have it at Circulation. Dr Mercedes Carnethon: Well, thanks so much, Carolyn. And thank you Dong, for your team's outstanding work. I know what excited me about it was the demonstration of something that we have adopted into our lexicon, that one needs five fruits and vegetables. So I was excited to see you quantify it. In particular, the question I have for you is, did you see that these patterns of association of fresh fruit and vegetable intake were consistent across the age range and in both sexes? Dr. Wang Dong: Yes, of course. In total, this acts as a stratification variable. So basically, in our original data analysis, we did the analysis in the Nurses' Health Study, which all the participants are women, and in the Health Professional Follow-Up study, in which all the participants are men, would be analyzed separately and we found very consistent results in both cohorts. Then will be the meta-analysis to meta-analyze the results from these two cohorts. It comes out age, actually if you look at the paper, I think in one of the supplemental table, with the age stratified analysis, to look at the a better association if it still holds in different age group. And we did found that the results is pretty consistent in different age groups. And also, I would point out this meta-analysis provides further support to show that this results is generalizable in different people with different social economic status, demographics status also from different background. Dr Mercedes Carnethon: Thank you so much, Dong. it brings me to what Naveed wrote about in his editorial, that food is medicine and I just really loved that and loved the implications of that. So, I don't know, Naveed, if you've got some comments to make? Questions? Dr Naveed Sattar: Yeah, thanks Mercedes. No, I really love this as well because clearly the cardiovascular community, we do lots of trials. Lots of us are nihilists and just look at trials, but actually it's hard to do trials in the food and the dietary area, but these data are very consistent. I think there are multiple potential mechanisms that may explain this. We all have to eat every day, so it's a big part of our lives. Increase fiber intake, increase potassium, micronutrients, food displacement, the more fruit and veggies you eat, the less you'll eat of other things that perhaps are not as protective. And actually, part of the motivation to write an editorial was to put all that into context in terms of mechanisms. And particularly fiber, I think we underestimate the importance of fiber, but then it was also to discuss, well, if this is true, how do we help people make the changes? Dr Naveed Sattar: And at the level of policy, at the level of high risk groups, and my own particular favorite is really communicating dietary change in the clinic. And one of the things I often try, and we put this in a kind of headline figure in the editorial, was actually getting people to try to undergo the palate test or the retraining their palates. I have lots of patients, who, would you believe, in the west of Scotland, never really eat fruit and veg, and I really pushed them to say, "Look, would you please try? And it might take a few weeks for you to retrain your palate". And lots of people come back saying, "Ah, you're correct. And my God, now I like banana and I now like salad." Dr Naveed Sattar: So actually, there's lots of tips that we can do to help people increase from their average of two to three intake, which is the vast majority of population, to four to five, but it's a gradual process and it requires good communication with our patients and to compel them that these changes might take time, but that if they make these changes, they can get to a point where they really enjoy eating fruit and veg and all the multiple health benefits that come, which this paper has now showed, Mercedes. Dr Naveed Sattar: I think for me, that was the real nub of this. Dr Carolyn Lam: Naveed, I just love the way you express it. And indeed, everyone take up that editorial and look at that beautiful figure. I love the colorful fruits and vegetables on top because it also reminds us, and this paper shows, we are not talking about potato chips, and was it those, corn and peas. But, you know, we're talking about nutrition and fiber and the good stuff. Oh, this is just amazing. I wish we could go on forever, but we have a double feature this issue. And I just want to end by saying, thank you, thank you all of you, for being on the show today. It was such an important topic and I really loved the discussion as I'm sure the audience did. Thank you. Dr Mercedes Carnethon: Thank You. Dr Naveed Sattar: Thanks very much. Dr. Wang Dong: Thank you so much. Dr Carolyn Lam: I am so pleased to have with us today, a friend, a deeply admired colleague and the corresponding author of today's feature discussion, Dr. Mikhail Kosiborod from Saint Luke's Mid America Heart Institute. Dr Carolyn Lam: Welcome, Mikhail. And thank you for publishing this beautiful paper on EMBRACE heart failure with us. I know that this was presented as a late-breaking trial at the Heart Failure Society of America meeting, and it's a very much anticipated paper, but maybe I could start with it's all about SGLT2 inhibitors these days. So please tell us how does EMBRACE add to this accumulating knowledge that we have on SGLT2 inhibitors and heart failure? Dr. Mikhail Kosiborod: Well, first of all, Carolyn, thanks so much for publishing our trial in Circulation. And you're right, SGLT2 inhibitors have been taking the world of cardiometabolic medicine and heart failure by storm over the past few years. EMBRACE is a very unique trial because it really, took this world of rapidly developing technology in heart failure and heart failure monitoring, and coupled it with one of the hottest topics in heart failure today in terms of drug management, which is the advent of SGLT2 inhibitors and the emergence SGLT2 inhibitors as a efficacious therapy, not just for prevention of heart failure, but also treatment of heart failure. Because as you know, pulmonary artery pressure and hemodynamic status are one of the strongest predictors of patient outcomes, both in terms of symptoms, hospitalizations, and deaths in heart failure. And we know actually that monitoring and intervening on elevated pulmonary pressure in this patient population may lead to hospitalizations and possibly even death. Dr. Mikhail Kosiborod: But up until recently, it's been very difficult to monitor pulmonary pressures and to use them as an outcome in heart failure trials, because you will have to use invasive monitoring, essentially a right heart catheterization to get that data. Well, now we can actually have this implanted sensors like CardioMEMS, which are the sensors that we use in EMBRACE-HF trial. So, the question we wanted to ask is, we know SGLT2 inhibitors in DAPA-HF and EMPEROR-Reduced trials, clearly reduce the risk of cardiovascular death and hospitalization for heart failure, worsening heart failure, but the mechanisms have been hotly debated. Is there a possibility these agents can actually have an impact on hemodynamic status and pulmonary pressures? And that's the key central question that we tried to address and EMBRACE-HF trial by using this novel technology at the time, now it's been around for a few years, to noninvasively measure pulmonary pressures and use it as a primary outcome in our trial. Dr Carolyn Lam: Mikhail, first of all, hats off, it was a very, very clever idea to look at these patient populations who already have CardioMEMS right, and then perform this randomized trial. I mean, when I saw this, I was like, "Aw, man, how come I didn't think of that? That's just like so clever, but it's just so Mikhail to be ahead of the curve." But I'd like to remind the audience, this was a prospective randomized trial, the pre-specified outcomes, right? So maybe you could describe that in a greater detail and then the results. Yeah. Dr. Mikhail Kosiborod: Absolutely. Well, Carolyn, first of all, once again, thank you very much. You're being very kind. We do think it was a very novel clever idea and that you're absolutely correct, as this was very rigorously designed, randomized, double blind placebo controlled investigating trial within this study and 10 sites in United States. And the patients had to have heart failure, either with reduced or preserved ejection fraction, about half-and-half actually, as it turned out to be once it's all said and done with the trial. Because they had to have implanted CardioMEMS for clinical indication previously, they were quite advanced in terms of their heart failure. So more than half of the patients were in NYHA class III or IV, they had elevated brain natriuretic peptide levels, they had hybrid symptoms as you would expect. And essentially the patients were screened, and if they were eligible, randomized to use a empagliflozin-placebo in a double-blind fashion. Dr. Mikhail Kosiborod: And they were monitored actually for a couple of weeks prior to randomization to get a baseline pulmonary artery diastolic pressure. They were then treated for 12 weeks with empagliflozin, 10 milligrams a day, or a matching placebo. And we were measuring pulmonary pressure twice a day, every day for the 12 week treatment period, and then at the end of the treatment period, the treatment was stopped, but we actually continued to measure pulmonary pressure for one additional week again, twice a day, every day. So we actually saw what happened for one week after the treatment was stopped. And, as I mentioned before, the patient population was quite advanced from a heart failure standpoint. These were patients that were adequately managed with guideline-directed medical therapy for heart failure. Of course, about half of those patients have, have HFpEF. Did I mention before was the standard of care is not a thoroughly defined? Dr. Mikhail Kosiborod: And essentially what we observed was quite remarkable, which is average pulmonary artery diastolic pressure at baseline was about 22 millimeters of mercury across the patient population, and in patients treated with empagliflozin, there was quite a rapid reduction in pulmonary artery diastolic pressure that we saw almost immediately within one week as compared with placebo. And that divergence of curves in terms of pulmonary artery diastolic pressure continued over the entire 12-week treatment period. And by the end of the treatment period, there was nearly two millimeter of mercury difference in favor of empagliflozin, with lower pulmonary artery diastolic pressure in patients with empagliflozin compared with placebo. And also interestingly, even after the treatment was stopped for an additional week, those curves continued to diverge, with even greater lowering of pulmonary artery diastolic pressure in patients that received empagliflozin. So, I think to our knowledge, this is the first evidence from a randomized clinical trial, randomized double blind placebo controlled clinical trial, that SGLT2 inhibitors, in this case, empagliflozin, have essentially direct the congestion effect towards a lower pulmonary artery pressure rapidly and with effect amplified over time. Dr Carolyn Lam: Yes. Congratulations and beautifully present it there. Now, if I could ask a few more questions now, because the things will come up there. What happened to the diuretic dose? Is this depend on diuretic dose? Are there any subgroups that appeared to benefit more? Dr. Mikhail Kosiborod: No, excellent question, Carolyn. So first of all, we monitored average daily furosemide equivalent dose continuously throughout the trial, and what we observed was that there was no difference in diuretic dose, essentially, between the two groups from a loop diuretic management standpoint. Now, remember this patients are getting frequent pulmonary pressures with diuretics being adjusted all the time. But if you look at what happens over time, that's one of the figures in the paper you see essentially the flat lines in both groups. And coupling that with the fact that pulmonary pressures continue to diverge for another week after the treatment was stopped, at least in my mind, suggests that this hemodynamic benefits as we observed with empagliflozin as compared with placebo was lowering of pulmonary pressures is likely not simply due to diuretic effect. It just cannot be explained only by diuretic effect. I think these findings are very much in line with the analysis that we had in DAPA-HF trial with the analysis that recently were published from EMPEROR-Reduced, showing that you just can't explain what you see with heart failure benefits with SGLT2 inhibitors simply by diuresis. Dr Carolyn Lam: Fascinating. Well, how about the question of diabetes? Dr. Mikhail Kosiborod: Yes. So in terms of subgroups, that you mentioned, we did do subgroup analysis. Now I will say that the subgroup analysis have to be interpreted with a great deal of caution in this trial, because the entire trial had about 65 patients, so it's a small trial. It was really powered to look at the entire patient population and look at the primary end point of the diastolic pressure. Nevertheless, as I mentioned before, we had half-and-half reduced and preserved EF and we did not see a statistically significant heterogeneity in the treatment effect when we look at patients with reduced to preserved EF, so that hopefully both for outcome trials in preserved EF heart failure, we'll see, of course, what happens with that. And in terms of diabetes we saw a bit greater effect in patients with diabetes as compared to patients without diabetes, in terms of pulmonary artery pressure reduction. Dr. Mikhail Kosiborod: But again, I would just strongly caution interpretation of those subgroups because certainly when we look at clinical outcomes in those DAPA-HF and EMPEROR-Reduced, we see no such difference. We see that the benefits, right, the hard clinical outcomes, benefits, are quite consistent regardless of diabetes status. I will say one other thing, which I think is really important. If you look at the pulmonary artery pressure trajectory in patients treated with placebo in EMBRACE-HF, you see that they actually go up over time. And this is in patients that have frequent monitoring of blood pressures, our own guideline-directed medical therapy are closely watched by predominantly heart failure cardiologists and their teams to make sure that they're well-managed. And despite that, you see this increase in pulmonary pressure over time, and that's just another reminder to us that heart failure is a progressive disease despite best available therapy. Dr. Mikhail Kosiborod: These patients deteriorate over time, which is why treatment, novel advancements, treatments like SGLT2 inhibitors and their effective implementation is just so important because we know the benefits occur very early. We saw one week here, when we start seeing separation of curves, certainly see a significant difference by 12 weeks with pulmonary pressure. But of course we know with clinical outcomes, we see within a few weeks of randomization, already a significant benefit in reducing CV death and hospitalization for heart failure, both in DAPA-HF and EMPEROR-Reduced trials. So I think that's a critical point for clinicians to keep in mind at the time of the death. Dr Carolyn Lam: Mikhail, those are just such important and practical take-home messages. Thank you again. In the last minute though, I just really, really have to go back to that very clever method. Could I just pick your brain? I mean, it's like a very clever population. This CardioMEMS population that maybe what's in the future plans? Give us a sneak peek! Dr. Mikhail Kosiborod: Well, Carolyn, very insightful as always. I really think of it as a novel platform for drug development and heart failure. I think this is the proof of concept. This is really the first time we did something in the heart failure space was with monitoring of pulmonary pressures that shows that drugs that work for hard clinical outcomes actually do something meaningful on hemodynamics. We've struggled for such a long time in heart failure to have a good surrogate endpoints that would be reflective of clinical outcomes. This may be it. It may be one of them. And I think EMBRACE-HF is a good concept proving study that can say, if you have a compound and you think that compound may be effective for heart failure. So of course the congestion is so important that we know correlates so well with clinical outcomes Dr. Mikhail Kosiborod: When we started to trial all the way back to late 2015, very few patients had this device. It's not lots of patients have this device. And testing novel treatments to try to understand will there promise in heart failure, and even making go-no-go decisions, in terms of drug development, I think is starting to become a potential future development, which we should at least seriously consider in the heart failure space. Dr Carolyn Lam: Wow, Bravo. And Mikhail, I mean. Okay, audience, listen, you heard it right here. This is amazing. Thank you once again for publishing with us and congratulations on the beautiful paper. Dr Carolyn Lam: And from Greg and I, thank you audience for joining us again today, you've been listening to Circulation on the run. Tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association 2021.
In this episode, Dr. Stephen Greene, of the Duke Clinical Research Institute, breaks down a recent study he led comparing the sensitivity of NYHA class versus patient-reported outcomes for capturing changes in disease state among patients with HFrEF.
Paul J. Wang: Welcome to the monthly podcast, On the Beat for Circulation, Arrhythmia and Electrophysiology. I'm Dr. Paul Wang, editor-in-chief with some of the key highlights from this month's issue. In our first paper, Bruce Wilkoff and associates evaluated antibacterial envelope cost effectiveness compared to standard of care infection prevention strategies in the US healthcare system. Decision tree model was used to compare costs and outcomes of the antimicrobial envelope used adjunctive to standard of care infection prevention versus standard of care alone over a lifelong time horizon. The analysis was performed from an integrated payer provider network perspective. Infection rates, antimicrobial envelope effectiveness, infection treatment costs and patterns, infection related mortality and utility estimates were obtained from the WRAP-IT study. Life expectancy and long-term costs associated with device replacement, follow-up, and healthcare utilization were sourced from the literature. Costs and quality life adjusted years were discounted at 3%. An upper willingness-to-pay threshold of $100,000 per quality adjusted life year was used to determine cost-effectiveness in alignment with the American College of Cardiology and American Heart Association practice guidelines and as supported by the World Health Organization and contemporary literature. The base case incremental cost-effectiveness ratio (ICER) of the antibacterial envelope compared with standard-of-care was $112,603 per quality-adjusted life year. The ICER remained lower than the threshold in 74% of iterations in the probabilistic sensitivity analysis and was most sensitive to the following model inputs: infection-related mortality, life expectancy, and infection cost. The authors concluded that the absorbable antibacterial envelope was associated with a cost-effectiveness ratio below contemporary benchmarks in the WRAP-IT patient population, suggesting that the envelope provides value for the US healthcare system by reducing the incidence of CIED infection. In our next paper, Peter Loh and associates in this study aim to investigate the feasibility and safety of single pulse irreversible electroporation (IRE) pulmonary vein (PV) isolation in patients with atrial fibrillation (AF). Ten patients with symptomatic paroxysmal or persistent AF underwent single pulse IRE pulmonary vein isolation under general anesthesia. Three-dimensional reconstruction and electroanatomical voltage mapping of the left atrium and pulmonary veins were performed using a conventional circular mapping catheter. Pulmonary vein isolation was performed by delivering nonarcing, nonbarotraumatic 6 ms, 200 Joule direct current IRE applications via a custom nondeflectable 14-polar circular IRE ablation catheter with a variable hoop diameter (16–27 millimeters). A deflectable sheath was used to maneuver the ablation catheter. A minimum of 2 IRE applications with slightly different catheter positions were delivered per vein to achieve circular tissue contact, even if pulmonary vein potentials were abolished after the first application. Bidirectional pulmonary vein isolation was confirmed with the circular mapping catheter and a post ablation voltage map. After a 30-minute waiting period, adenosine testing was used to reveal dormant pulmonary vein conduction. All 40 pulmonary veins could be successfully isolated with a mean of 2.4 IRE applications per pulmonary vein. Mean delivery peak voltage and peak current were 2154 volts and 33.9 amperes. No pulmonary vein reconnections occurred during the waiting period and adenosine testing. No periprocedural complications were observed. The authors concluded that in 10 patients in this first in-human study, acute bidirectional electrical pulmonary vein isolation could be achieved safely using single pulse IRE ablation. In our next paper, Christian Sohns and associates studied the relationship between left ventricular ejection fraction (LVEF) New York Heart Association (NYHA) class on presentation and the end points of mortality and heart failure (HF) admissions in the CASTLE-AF study population. Furthermore, predictors for LVEF improvement were examined. The CASTLE-AF patients with coexisting heart failure and AF (n=363) were randomized in a multicenter prospective controlled fashion to ablation (n=179) versus pharmacological therapy (n=184). Left ventricular function in NYHA class were assessed at baseline after randomization and at each follow-up visit. In the ablation arm, a significantly higher number of patients experienced an improvement in their LVEF to greater than 35% at the end of the study (odds ratio, 2.17; P
Nyha Shree: An entrepreneur who pursued option D to find herself. As the Co-founder and CMO of conversational commerce platform, Jumper.ai, Nyha helps bridge the gap between e-commerce and brick and mortar retail. In this week’s ep, we hear from Nyha as she reflects on her indecisive adulthood, how we can get ok with pursuing option D and the ‘aggressive’ commentary inflicted on hard-working women.Discover more:Connect with Nyha on LinkedIn: https://www.linkedin.com/in/nyhashree/ - Learn more about Jumper.ai: https://jumper.ai - Follow us on Instagram: https://www.instagram.com/thepeersproject/ - See acast.com/privacy for privacy and opt-out information.
This week’s episode includes author John McMurray and Associate Editor Brendan Everett as they discuss the effect of dapagliflozin on outpatient worsening of patients with heart failure and reduced ejection fraction. TRANSCRIPT BELOW: Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Well, Carolyn, I hear you might have an interesting feature paper? Dr Carolyn Lam: Oh, yes. I think everyone's going to look forward to this one, because we cannot get enough of the DAPA-HF study. This is another very important prespecified analysis, looking at the effect of dapagliflozin on outpatient worsening of patients with heart failure with reduced ejection fraction. Very important stuff coming right up, but first, I've got two papers looking at congenital heart disease that I'd like to share with you, Greg. Have you got your coffee? Dr Greg Hundley: Yeah, I do. Let's get going. Dr Carolyn Lam: Well, as you know, the mechanisms of congenital heart disease associated right ventricular dysfunction are not well-understood. And so, in this first paper, Dr Reddy from Stanford University and colleagues assessed lipid peroxidation, a potent form of oxidative stress, as well as mitochondrial function and structure, in right ventricular myocardium, collected from patients with and without right ventricular failure. And what they found, was that right ventricular failure was characterized by increased oxidation of membrane phospholipids, known as lipid peroxidation and its products, such as 4-hydroxynonenal, or 4-HNE. Now, 4-HNE binds to metabolic and mitochondrial proteins, and was associated with decreased myocardial energy generation and mitochondrial structural disruption with increasing severity of right ventricular hypertrophy and right ventricular failure. Mechanistically, the authors showed that 4-HNE was sufficient to decrease energy generation by inhibiting electron transport chain complex activities and mitochondrial dynamics. Dr Greg Hundley: Dr Carolyn, a lot of mechanism here. So clinically, what are the implications? Dr Carolyn Lam: I thought you'd ask. Well, since standard heart failure therapies, such as ACE inhibitors and beta blockers, are ineffective in the treatment of right ventricular failure, developing therapies focusing on new targets, such as what we talked about, the lipid peroxidation, could improve right ventricular function in congenital heart diseases by improving mitochondrial energy generation and cardiomyocyte survival. Dr Greg Hundley: Ah, very interesting, Carolyn. Dr Carolyn Lam: Thank you. The next paper, also very interesting, this time focusing on Tetralogy of Fallot, the most common cyanotic congenital heart disease. Now, this is from Dr Marijon from Hôpital Européen Georges-Pompidou in France and colleagues who highlighted, first, that sudden cardiac death represents an important mode of death in these patients with Tetralogy of Fallot, yet data evaluating the ICDs in these patient population, really, has remained scarce. And so, they use the nationwide French registry to include 165 patients with Tetralogy of Fallot with an ICD initiated in 2010 by the French Institute of Health and Medical Research. 63%, by the way, of these ICDs, were used for secondary prevention. Dr Greg Hundley: Ah, Carolyn, I can't wait to see. What did they find? Dr Carolyn Lam: So during a median follow-up of 6.8 years, 47% of patients received at least one appropriate ICD therapy. The annual incidence of the primary outcome was 10.5% overall, 7.1% in the primary prevention, and 12.5% in the secondary prevention cohorts, respectively. 43% of patients presented with at least one ICD complication, and, importantly, QRS fragmentation was the only predictor of appropriate ICD therapies. So, even before you asked me, Greg, the take home message is, patients with Tetralogy of Fallot and an ICD, experience high rates of appropriate therapies, including those implanted for primary prevention. The considerable long-term burden of ICD-related complication, however, underlines the need for careful candidate selection. A combination of easy-to-use criteria, including QRS fragmentation, might improve our risk prediction. Dr Greg Hundley: Oh, very nice summary, Carolyn. Learned a lot there. Well, I'm going to steer us to two other papers in the issue, and the first one is from the world of basic science, and it's from Dr John Cooke from the Houston Methodist Research Institute. So Carolyn, the angiogenic response to ischemia restores perfusion, so as to preserve tissue. Something we all know. A role for mesenchymal to endothelial transition in the angiogenic response is controversial, and this study utilized a murine model of hindlimb ischemia and an in vivo Matrigel plug assay, together with lineage tracing studies and single-cell RNA sequencing, to examine the transcriptional and functional changes in fibroblasts in response to ischemia, to determine if resident fibroblasts contribute to angiogenesis. Dr Carolyn Lam: Ah, it's so interesting. Do fibroblasts contribute to angiogenesis? What did they find, can't wait? Dr Greg Hundley: Yeah, Carolyn. So, in both mice and human-isolated fibroblasts, these author studies indicated the presence of subsets of tissue fibroblasts, which seemed poised to contribute to the angiogenic response. And the expansion of these subsets with ischemia was dependent upon activation of innate immune signaling, and this signaling contributed to recovery of perfusion and preservation of ischemic tissue. Really interesting findings. Didn't suspect the fibroblasts as being the contributors here. Dr Carolyn Lam: Very nice, Greg. Thank you. You've got another one. Dr Greg Hundley: Yes. So the next study is from Professor Phillips Tsao from Stanford University School of Medicine. Well, Carolyn, this is a genome-wide association study, and it's from the Million Veteran Program, testing 18 million DNA sequence variants in patients with abdominal aortic aneurysms. In the study, they identified 7,642 cases and 172,172 controls in veterans of European ancestry, with independent replication and another study in 4,009 72 cases and 99,858 controls. Dr Carolyn Lam: Wow. Dr Greg Hundley: So it's nice, they have a replication study. The authors then use Mendelian randomization to examine the causal effects of blood pressure on abdominal aortic aneurysms. And they examine the association of abdominal aortic aneurysm risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and lastly, derived a genome-wide polygenic risk score to identify a subset of the population at greater risk for disease. Dr Carolyn Lam: Wow. So a GWA study with replication to identify those at risk for abdominal aortic aneurysms in huge cohorts. What did they find? Dr Greg Hundley: Well, Carolyn, this study was managed by one of our experts in GWA studies, Dr Wendy Post, and through GWAs, the authors identified 14 novel loci, and there were already 10, so it brings the total number of significant abdominal aortic aneurysm loci to 24. So a new finding there. And in their Mendelian randomization analysis, they demonstrated that a genetic increase of 10 millimeters of mercury in diastolic blood pressure, as opposed to systolic blood pressure, likely had a causal relationship with the future development of abdominal aortic aneurysms. They observed that 19 of those 24 aortic aneurysm risk variants associate with aneurysms in at least one other vascular territory. And then lastly, a 29 variant polygenic risk score was strongly associated with abdominal aortic aneurysms, independent of family history and smoking risk factors. So Carolyn, in conclusion, the authors in this study identify novel abdominal aortic aneurysm genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of abdominal aortic aneurysms, independent of their family history. And their data suggests that perhaps extending current screening guidelines to include testing for those with high polygenic abdominal aortic aneurysm risk, would significantly increase the yield of many of our current screening algorithms, as you know, that predominate based on smoking and age. Dr Carolyn Lam: Wow. Very, very impressive and convincing data. Thanks, Greg. Let me tell you about other papers in today's issues. There's a research letter by Dr Tiburcy on inhibition of prolyl-hydroxylase domain enzymes, and how that protects from reoxygenation injury in the engineered human myocardium. There's another research letter from Dr Ohbe, entitled, The Risk of Cardiovascular Events after a Spouse's ICU Admission. And, one more from Dr Ganatra, on chimeric antigen receptor T cell therapy-associated cardiomyopathy in patients with refractory or relapsed non-Hodgkin lymphoma. Dr Greg Hundley: You know, Carolyn, our research letters, they really pack a punch. Such very interesting research, in a nice concise format. I've got some other publications. So first, there's an On My Mind piece from our own Charlie Loewenstein, and also Dr Solomon from Boston, Massachusetts, involving, Severe COVID-19 as a Microvascular Disease, does endothelial exocytosis drive COVID-19? And next, there's a case series entitled, ECMO Therapy for Cardiac Lymphoma, and it's from Dr Oscar Cingolani. And then finally, Carolyn, a very nice ECG challenge from Dr Bansal, related to identifying the location of an AV block. Well, Carolyn, I'm really excited to get onto your feature discussion. Dr Carolyn Lam: Let's go, Greg. Today's feature discussion looks at a prespecified analysis of DAPA-HF. My goodness, I don't think we can get enough of the data from DAPA-HF, and we have none other than be corresponding author, Dr John McMurray from University of Glasgow, to discuss this exciting paper, as well as our associate editor, Dr Brendan Everett from Brigham and Women's Hospital in Boston, Massachusetts. So John, today's feature paper, all about outpatient worsening of heart failure. Could you please start by defining what we meant by that, and why is it so important? Dr John McMurray: Our interest in this actually started back when we did PARADIGM and we had collected, in a not very systematic way, information about episodes of outpatient worsening, so by that, I mean episodes of worsening symptoms and signs, not leading the patient to go to the emergency department or be admitted to hospital. The sort of worsening that a patient might tell you about in your outpatient clinic, say they're a bit more breathless or they've got a bit more ankle swelling, and you do something about it. And that's the critical part. You decide to increase their dose of diuretic, add another drug. And in PARADIGM, we find that those episodes, first of all, were quite common, and secondly, and most importantly, we're actually prognostically very significant. They were associated with worse outcomes. So in that HF, we decided that we would collect these more systematically, we would try and define them a little bit more robustly, so we would require the investigator to report worsening signs and symptoms, and we also wanted evidence that additional treatment had been given and then that had been sustained for at least a month, because, as you know, diuretic dose can increase and decrease. Then we prespecified, as you said, Carolyn, that we would then incorporate those manifestations of worsening, as an additional component to our primary composite endpoint, which was cardiovascular death, heart failure hospitalization, worsening of heart failure requiring intravenous therapy, so an urgent visit for that, that would often be in an emergency department, and then in addition to that, this further manifestation of worsening as the extra component to this broader composite outcome that we hoped would encompass the whole range of worsening of heart failure that a patient might experience. Dr Carolyn Lam: Thanks so much, John, and you actually preempted my question of how it differed from the original primary outcome that included urgent heart failure visits, intravenous diuretic use, but not these nuance outpatient intensification of heart failure therapy that I really salute you for prospectively collecting information on. So could you summarize what you found, please? Dr John McMurray: Well, first comment to make, Carolyn, is that we included those urgent visits requiring intravenous therapy, because, as you know, in the U.S., I think there is a move to try and avoid admission and to treat patients in the ambulatory care setting or non-ward setting. Although, I have to say, as it turned out, those episodes of worsening were very infrequent. There was, I think, 33 in total in DAPA-HF, compared to almost 600 of the other episodes of worsening. The ones that we almost feel at a brainstem reflex level when we see patients in our clinics. So what did we find? Well, we find that when you add those episodes of worsening, then, of course, you considerably increase the proportion of patients who have, from what you might call, the most trivial manifestation, worsening the events we just talked about, all the way through to the very worst, in other words, death, from cardiovascular causes, in fact, so much so, that by about two years of follow-up, the Kaplan-Meier rate for that expanded composite endpoint was about 33%. And, as you know, Carolyn, we're talking about a trial that enrolled patients who were very well-treated by conventional standards and who, by and large, had mild symptoms, but 70% were NYHA class II. And yet, within two years, if you take into account all of these different manifestations of worsening, we had about one-in-three people in the placebo group that deteriorates, and we reduced the risk of deterioration with dapagliflozin, we reduced the instance of that expanded composite endpoint by 27%, and that was a highly statistically significant result. And if you like numbers needed to treat, then for that expanded very broad composite endpoint, the number needed to treat over the median follow-up of 18.2 months, was only 16. And by the way, we did confirm that those outpatient worsening events were prognostically significant as well. Dr Carolyn Lam: Very good. Brendan, could I bring you in on this? It's got such great implications, maybe you could share a little bit about what the editors thought when we saw this paper? Dr Brendan Everett: One of the key things that the editors thought when they reviewed this, was the fact that, as you pointed out, you collected these outpatient worsening episodes prospectively across the trial and did so in a very rigorous and systematic way. And I think for those of us who take care of patients with heart failure, which of course is most cardiologists, these kinds of episodes where your patient calls you and their weight's gone up, or where they've gotten a little more short of breath, then you, over the phone, intensify their diuretic regimen, are incredibly common, and, of course, bothersome to the patient and challenging for the clinician who's caring for the patients too. So I think, in that sense, it's a really important paper. That was the other aspect, I think, that the editors were interested in. But the impact, the clinical impact on day-to-day care of patients with heart failure, was substantial. The other part that I found intriguing, because of course, when you're caring for individual patients, you don't have a sense, necessarily, of what these episodes mean in a broader population for those patients' overall risk of bad outcomes. So you mentioned it right at the end when you were speaking a moment ago, about the association of these outpatient intensifications of oral diuretic therapy and their association with future bad outcomes within the trial. Could you tell us a little bit about what those were and why they ended up seeming so important, both to patients and to you as the trialist? Dr John McMurray: We write about these being common, in fact, in the placebo group in DAPA-HF. I think it was 14% of patients had one of those episodes of outpatient worsening. And again, as you correctly identified, in the majority of cases, the therapeutic intervention by the physician, was simply to increase the dose of diuretic, although, actually about 40% of people also, at some point, had the addition of another drug. So, in terms of the significance of those events, in PARADIGM, we find that they appeared to be associated with almost the same impact on mortality as being admitted to hospital with worsening heart failure. But in fact, in DAPA-HF, where we collected more of these events, so maybe we collected, perhaps, the more severe cases in DAPA where we collected them systematically, we find that the prognostic impact wasn't quite as large. So for example, if you were admitted to hospital with heart failure during DAPA-HF, then you were six-times more likely, subsequently, to die in that rather short follow-up period, than if you had no manifestation of worsening. On the other hand, if you had an outpatient episode of worsening, then it was around a three-fold higher risk of death than if you had no manifestation of worsening. So, my take home from this was that these episodes really do matter to patients. Not only, of course, do they matter because it means the patient doesn't feel so good, but they matter because that patient suddenly is on a different prognostic trajectory, and you can change that by intervening. So these events are common, they're prognostically bad news, and fortunately, we can reduce them. And maybe the last thing to say, which I also didn't mention, I apologize, was that, of course, if you look at that expanded endpoint, as you can imagine, because there's so many events now, you see the effect of treatment very, very quickly. So by day 27 after randomization, in other words, by day 27 after starting dapagliflozin, we had a statistically significant reduction in the occurrence of that comp standpoint, that then remained significant thereafter. Dr Brendan Everett: Thanks, John. I had one other question that I hope doesn't take us too far into the weeds, but I think as a clinician, when you care for these patients, you try to intensify their outpatient therapy, and when that seems to fail, the patient then becomes admitted to the hospital. And I thought it was very interesting and thoughtful the way that you approach that problem, in other words, you have potentially, of this composite endpoint, you have the outpatient worsening that comes first, and then it's followed, in many cases, by a hospitalization for heart failure. How did you tease those two apart? And what analyses did you do to make sure that what you were really measuring was the effect of the outpatient intensification, rather than really just a prelude to a hospital? Dr John McMurray: Very good question, Brendan. So, obviously, we were concerned about the possibility of double counting, so we did a primary analysis in which we built in a blanking window. So, for example, if you had an episode about outpatient and you or I increased the patient's oral therapy, but within 30 days, they were admitted to the hospital, then in our analysis, that patient only counted once, and the event that counted was the hospital admission, not the outpatient episode of worsening. And then, as I said, we did a number of sensitivity analyses where we adjusted the length of that blanking period, because we recognized, obviously, that some people, that episode of outpatient worsening that you intervene for, your intervention may not work and they may still get hospitalized. So we try to, as you obviously identified when you read our manuscript, we tried to counter that by not double counting episodes of outpatient worsening that were closely adjacent to the hospital admission. Dr Carolyn Lam: Could I end with just one quick question? You've published many times with us at Circulation, and I'd like to think that that's from a very good experience with us, with working with us, and I've noticed even in this discussion, it's just so interesting the exchange. And so, John, could you say a few words about publishing in Circulation, and why do it? Dr John McMurray: Well, obviously it's our leading cardiovascular journal. As I was being trained as a fellow, it was every fellow's aspiration to publish a paper in Circulation. So reputationally, obviously, it's very, very important. But why do I like Circulation other than that? Well, first of all, you handle papers quickly and efficiently. I think you're very fair. I really like the reviews. So I would say one of the greatest frustrations most authors, and certainly I know that from my own experience, is when you get poor reviews. I don't think I get those from Circulation, so you obviously have a much higher quality review. I like the way the editors give you guidance about the manuscript and how to respond to the reviewers. That's really, really helpful, because sometimes you think, "Well, that reviewer’s comment doesn't make sense. Do I have to really do that?" But often, your replies to me, come with guidance about how to handle the different reviewers’ comments. So, all in all, it's fair. I would say that's always important. Everybody will not get every paper accepted, but I think you get a very fair response from Circulation. It's good. It's thoughtful. So, that's fine. Dr Carolyn Lam: Thank you so much, John. I'm sure I'm speaking on behalf of Brendan as well, and kudos to him because obviously he managed this paper so well. Thank you, audience, for joining us today on Circulation on the Run. So don't forget to tune in again next week. Dr Greg Hundley: This program is copyright the American Heart Association.
CardioNerds (Amit Goyal & Daniel Ambinder) join University of California San Diego (UCSD) cardiology fellows (Harpreet Bhatia, Dan Mangels, and Quan Bui) for a relaxing beach bonfire in the beautiful city of San Diego! They discuss a challenging case of post-transplant cardiac allograft vasculopathy. Dr. Hao (Howie) Tran provides the E-CPR and program director Dr. Daniel Blanchard provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident Richard Ferraro with mentorship from University of Maryland cardiology fellow Karan Desai. Jump to: Patient summary - Case media - Case teaching - References The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus. We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director. CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademySubscribe to our newsletter- The HeartbeatSupport our educational mission by becoming a Patron!Cardiology Programs Twitter Group created by Dr. Nosheen Reza Patient Summary A man in his late 20s with a past medical history of orthotopic heart transplant, presents with one-week of progressive lower extremity edema and dyspnea with NYHA class IV symptoms. 5 years prior, he underwent orthotopic heart transplant for arrhythmogenic right ventricular cardiomyopathy. Subsequently, he has had multiple episodes of rejection or recurrent graft dysfunction. On presentation, he was normotensive and borderline tachycardic. Exam revealed elevated JVP, decreased breath sounds, and pitting edema. Labs demonstrated leukocytosis, acute kidney injury, and elevated pro-BNP. TTE demonstrated LVEF 35%, apical akinesis, and grade III diastolic dysfunction (all similar to prior). He was initially diuresed and RHC/EMB was performed to evaluate for rejection. Early in his course, the patient unfortunately suffered a PEA arrest with ROSC was quickly achieved after 1 minute of CPR. He was intubated and cannulated for VA ECMO. EMB demonstrated ISHLT Grade 1R cellular rejection and he was ultimately listed for re-transplant. Shortly thereafter, the patient received an OHT. His pathology demonstrated intimal thickening of all his coronaries, consistent with coronary artery vasculopathy, felt to be the major contributor to his presentation. Case Media ECG Episode Schematics & Teaching Click to enlarge! The CardioNerds 5! – 5 major takeaways from the #CNCR case 1. What is CAV? CAV stands for cardiac allograft vasculopathy. Within the transplanted heart, CAV is the proliferation of vascular smooth muscle and intimal thickening in the epicardial coronary arteries and microvasculature leading to diffuse narrowing. CAV is common, present in greater than 30% of patients at 5 years post-transplant. It is a significant contributor to post-transplant mortality after the first year. CAV, in contrast to typical atherosclerotic lesions, is diffuse and concentric while atherosclerosis tends to be focal with eccentric luminal narrowing and heterogenous plaque composition. Patients s/p OHT can still develop typical coronary artery disease,
Commentary by Dr. Ronald Witteles
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In part one of a series on "Single Payer & COVID-19," Rachel Madley explains what a single payer healthcare system would look like in New York and how the New York Health Act (NYHA), if passed, could help solve some of the problems caused by COVID-19. Rachel refers to the current NYHA bills, A5248 and S3577. The Assembly Bill has passed for four years and the Senate Bill needs one more co-sponsor. Rachel Madley's presentation was part of "COVID-19 Escalates Demands for System Change," a virtual town hall held by Physicians for a National Health Program-NY Metro and the Campaign for NY Health. The town hall can be viewed in full at vimeo.com/401517736. Rachel is a fourth year biomedical research PhD student at Colombia and a student fellow with the PNHP-NY metro chapter. She has written multiple articles, including in the New York Times, about how Medicare for All would benefit patients, providers, and medical researchers. The "Single Payer & COVID-19" series is being produced by HMM correspondent Spencer.
OAP, orthopnée, crépitants aux bases, NYHA, soins intensifs, ICS ou ICFEP, inhibiteurs enzyme de conversion, bétabloquants, diurétiques (Lasilix et furosemide), Spironolactone, VNI C-PAP, éducation régime hygiène et réadaptation cardiaque à l'effort. sources : https://www.has-sante.fr/upload/docs/application/pdf/2012-04/points_critiques_ic_web.pdf
In this episode we explore Heart Failure. Learning outcomes include:Knowledge:1) Defining heart failure and an appreciation of the common aetiologies2) NYHA classification with respect to assessment of symptoms 3) Understanding the medical and non-pharmacological therapies for heart failure and appreciating when device therapies may be warranted4) An awareness of conditions that may mimic heart failure 5) Complexities of managing HF in older multimorbid patientsSkills:1) Identify heart failure symptoms 2) Interpreting N-terminal pro-B-type natriuretic peptide (NT pro-BNP) results3) Identifying which patients require urgent referral to hospitalAttitudes:1) The importance of comorbidities and to create individualised care plans, including patient education2) Appreciating the role of the multi-disciplinary team in the management of heart failure3) Recognising how heart failure may impact the quality of life of a patient4) Appreciating the psychological impact of heart failure on patients5) Respecting patient choice regarding prognostic therapiesShow notes are available to view and download at www.thehearingaidpodcasts.org.uk for more detail and curriculum mapping against Foundation, CMT, GPVTS, Geriatric Registrar, ANP and NHS Knowledge Skills Framework (KSF) programmes.Presented by: Dr Iain Wilkinson and Dr Jo Preston, Consultant Geriatricians and the Contributing Faculty: Dr Shahbaz Roshan - Consultant Geriatrician, Lindsay Ip - Psychologist, Kaler Jasvinder Singh - Cardiovascular Pharmacist, NasaMarie Emode & Silapiya Smith - Heart Failure Clinical Nurse Specialists CPD log available at https://goo.gl/forms/2yxYn1F0dZ07ICE33
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. This week's issue provides much long awaited healthcare resource utilization and cost implications in the MOMENTUM 3 randomized controlled trial of a magnetically levitated cardiac pump in advanced heart failure. All of this coming right up after these summaries. The first original paper this week provides important mammalian data on the acute effects of phosphodiesterase type 1 inhibition on the heart. Now phosphodiesterase type 1, or PDE1, is known to hydrolyze cyclic AMP and cyclic GMP in the heart. However, what's important to understand is that data from rodents may not be applicable to humans because rodents express mostly the cyclic GMP favoring PDE1A isoform, whereas human hearts predominantly express PDE1C isoform which has a balanced selectivity for cyclic AMP and cyclic GMP. In today's paper, first author Dr Hashimoto, corresponding author Dr Kass from Johns Hopkins University School of Medicine and colleagues, determined the acute effects of PDE1 inhibition on PDE1C expressing mammals, dogs and rabbits, in normal and failing hearts. They found that selective inhibition of PDE1 with ITI-214 induced positive inotropic, lusitropic, chronotropic, and arterial vasodilatory effects in dogs and rabbits. These effects occurred via cyclic AMP modulation and were observed in failing hearts. ITI-214 contractile increase was insensitive to beta adrenergic blockade or heart rate increase, but inhibited in vivo by adenosine receptor inhibition. Furthermore, isolated myocytes revealed differences between PDE1 and PDE3 inhibition. Wherein PDE3 inhibition, augmented beta receptor agonism and calcium transients, whereas PDE1 inhibition enhanced function without calcium increase. These findings have important clinical implications for ITI-214 which has completed phase 1 trials and may provide a novel therapy for heart failure. We know that macrophages are involved in foam cell formation in atherosclerotic plaques, but our next paper tells us we may now have a way to therapeutically modify this. Co-corresponding authors Dr Wei and Schober from Ludwig Maximilian's University Munich elucidated the role of microRNA generating enzyme Dicer in macrophage activation during atherosclerosis. They showed that Dicer deletion in macrophages accelerated atherosclerosis in mice, along with enhanced inflammatory response and increased lipid accumulation in lesional macrophages. In vitro, alternative activation was limited, whereas lipid filled foam cell formation was exacerbated in Dicer deficient macrophages due to impaired mitochondrial fatty acid oxidative metabolism. MicroRNA biogenesis promoted the degradation of fatty acids by mitochondrial respiration in macrophages, which in turn reduced intracellular lipid storage and limited atherosclerosis. Thus, reducing foam cell formation in atherosclerotic arteries by enhancing energy metabolism through microRNA mediated fatty acid oxidation may be a promising approach for the treatment of atherosclerosis. The next study evaluates how aortic stiffening relates to resting cerebral blood flow and cerebral vascular reactivity in older adults. First and corresponding author Dr Jefferson from Vanderbilt Memory and Alzheimer's Center and her colleagues studied participants free of clinical dementia, stroke, or heart failure, including 155 older adults with normal cognition and 115 mild cognitive impairment. They found that greater thoracic aortic stiffening quantified by cardiac magnetic resonance was associated with lower cerebral blood flow in cognitively normal older adults. Aortic stiffening was associated with reduced resting cerebral blood flow in the presence of preserved reactivity and associated vasodilatory capacity, particularly among participants without hypertension. ApoE4, a well-known genetic susceptibility risk factor for Alzheimer's disease, modified the results with stronger effects among carriers in the temporal lobes, where Alzheimer's disease pathology is known to first evolve. In summary, greater aortic stiffening related to lower regional cerebral blood flow and higher cerebral vascular reactivity in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer's disease. Understanding the association between higher aortic stiffness and compromised brain health, including cerebral hemodynamics, may allow for earlier detection and targeted interventions to prevent or mitigate the onset of more serious cerebral vascular damage associated with greater aortic stiffening. Aortic valve replacement for aortic stenosis is usually timed according to the development of symptoms, but could the timing be too late once irreversible myocardial scar has developed? Co-first authors Drs Musa and Treibel, corresponding author Dr Greenwood from University of Leeds and their colleagues found that in patients with severe aortic stenosis, focal myocardial fibrosis determined by cardiac magnetic resonance imaging was present in over 50% of patients and was associated with a two-fold higher late mortality. Focal scar was independently associated with all cause and cardiovascular mortality, after both surgical and transcatheter aortic valve replacement. In severe aortic stenosis, late gadolinium enhancement appears to be a useful biomarker of left ventricular remodeling, and its presence is associated with worse long-term outcomes following aortic valve intervention. Thus, in severe aortic stenosis, late gadolinium enhancement may be a useful biomarker of left ventricular remodeling, and its presence may be associated with worse long-term outcomes following aortic valve intervention. The next study suggests that endogenous factor Xa activity may be irrelevant pharmacodynamic marker to guide Edoxaban dosing in future. First author Dr Yin, corresponding author Dr Giugliano from TIMI Study Group, Brigham and Women's Hospital in Boston, and their colleagues, describe the value of endogenous factor Xa activity as a pharmacodynamic marker, linking Edoxaban concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial. They showed that the extent of inhibition of endogenous factor Xa activity was influenced by Edoxaban dosing and clinical characteristics, and was associated with both antithrombotic benefit and risk of bleeding. The implications are that this approach of linking endogenous factor Xa activity to clinical outcomes may be used to guide dose selection in future clinical trials, to monitor patients in certain clinical scenarios, or to define the doses of oral factor Xa inhibitors in patients who require precise anticoagulation therapy. The next paper describes a novel multi-protein complex that plays a critical role in regulating cardiomyocyte survival. First author Dr Zhang, corresponding author Dr Yan from University of Rochester School of Medicine and Dentistry and colleagues, showed that phosphodiesterase 1C is activated by transient receptor potential canonical channel-3 derived calcium, thereby antagonizing adenosine A2 receptor cyclic GMP signaling and promoting cardiomyocyte death or apoptosis. Targeting these molecules individually, or in combination, may represent a compelling therapeutic strategy for potentiating cardiomyocyte survival. The final paper demonstrates a molecular link between two well-recognized biomarkers of fibrosis, Galectin-3 and Osteopontin. First author Dr Shirakawa, corresponding author Dr Sano from Keio University School of Medicine and their colleagues, showed that Osteopontin was almost exclusively produced by Galectin-3 high CD206 positive macrophages, which specifically appear in the infarct myocardium after a myocardial infarct. The interleukin-10-STAT3 Galectin-3 axis was essential for Osteopontin producing reparative macrophage polarization after myocardial infarction, and these macrophages contributed to tissue repair by promoting fibrosis and clearance of apoptotic cells. These results therefore suggest that Galectin-3 may contribute to reparative fibrosis in the infarct myocardium by controlling Osteopontin levels. And that brings us to the end of this week's summaries, now for a feature discussion. Left ventricular assist devices have truly revolutionized our management of advanced heart failure. In fact, these devices have allowed us to keep patients not just as a bridge to transplantation, but as destination therapy. The devices get better and better but also more and more expensive, and the problem is, that places a lot of strain on our healthcare systems. A lot of us are crying out for information on the cost effectiveness of these newer devices, and guess what? We have answers this week with our featured paper. I am delighted to have with us the first and corresponding author Dr Mandeep Mehra from Brigham and Women's Hospital in Boston, Massachusetts, as well as our senior editor Dr Biykem Bozkurt from Baylor College of Medicine in Houston, Texas. Hello, Mandeep and Biykem! I am so pleased to be talking about a subject really close to all our hearts. Mandeep, could you start by maybe sketching out the actual issue, and maybe reminding our audience what's the difference between the different types of left ventricular assist systems that you compared. Dr Mandeep Mehra: The era of left ventricular assist devices took a major therapeutic shift when we recognized that we could usher in continuous flow devices. These are devices that generate no peripheral pulse, they do not have systole and diastole. And these devices are small in profile, have very few moving parts, and there are several commercially available devices, two in the United States and up to three worldwide, that bear these characteristics. The HeartMate II device, which is a continuous flow device that flows blood in an axial format. The HeartWare, or HVAD device, which is a centrifugal flow pump, where the blood comes in and then is ejected at a 90 degree angle. The Jarvik 2000 pump that is still used in some areas, in many regions experimentally, and then the new kid on the block, the HeartMate 3 device, which is a centrifugal flow pump with some very unique technological characteristics. Dr Carolyn Lam: Nice! And now drumroll, please tell us what you found in your brilliant study this week. Dr Mandeep Mehra: First, I'd like to remind the audience that the MOMENTUM 3 trial which randomized patients to the HeartMate II versus the HeartMate 3 device, was called MOMENTUM 3 and was a two-year study. We presented the pivotal two year trials results in 366 randomized patients earlier this year in The New England Journal of Medicine, and this study showed that the HeartMate 3 was superior on the primary endpoint when compared to the HeartMate II. The primary endpoint was survival, free of a disabling stroke, or the need to replace the pump surgically for a pump malfunction. And much of that, Carolyn, was driven by the need for replacement of the pump because the HeartMate 3 pump has some unique features that reduce its proclivity for pump thrombosis. The HeartMate 3 pump is a frictionless pump. It's completely, magnetically, dynamically, born in the rotor. It has wider blood flow paths, so we don't see hemolysis with this pump. And this pump also has an artificial intrinsic pulse that has been created, that pulsates the pump in a 40 beats per minute configuration. So this was the primary trial result, and one of the lucky foresights that we had when we designed the trial was to embed, prospectively, economic analysis within this trial. We recognized that the cost effectiveness related issues and cost configurations with these devices would become very, very important as we scale into today's day and age of healthcare transformation. And the paper that is being presented in Circulation this week, really speaks to the health resource utilization and cost outcomes between the two devices. We found that the HeartMate 3 pump is actually a cost minimization device, and what that means, Carolyn, is that we have become very used to thinking of new technology as providing incremental costs. So we think that, "Oh, well, what incremental costs should society bear for the benefits as we allocate new technology?" And in this particular trial, what we found is that while the costs of the pump itself, the HeartMate II and the HeartMate 3, were kept the same, which means its operational implant costs were the same, pretty much. We found that the HeartMate 3 pump was associated with a reduction in healthcare resource utilization over two years and with a marked decrease in cost. And in fact, our estimate of cost reduction was in the range of about 65 thousand dollars less, compared to the HeartMate II, in favor of the HeartMate 3. Dr Carolyn Lam: Wow, Mandeep, first of all, congratulations on these remarkable findings. Biykem, I really have to bring you in here. What do you think of the implications of this? Dr Biykem Bozkurt: First, I would like to congratulate the authors for a very innovative approach. As Mandeep has stated, they prospectively collected very challenging billing data from the hospitals, and then also did a very complex analysis including the VRG, as well as looking at payer reimbursements for public versus private. And did a variety of subgroup analysis, which I thought was quite helpful in sorting out that perhaps the cost effectiveness was concurrent both from the Medicare, the public, as well as the private, or regardless of the intent for destination versus bridge to transplant. Probably the most important concept when you look at these close analysis is incremental cost effectiveness ratio, per quality of adjusted life year gained. Now, I do realize the current analysis doesn't allow us to infer the ICER benefit or the incremental cost effectiveness, which I think the investigators are planning to do with a thousand and more patients over a course of two years, which is going to be probably the more definitive. But as it currently stands, with what is provided by Dr Mehra and his colleagues is, we're probably reaching that sweet spot of what is construed as the cost effectiveness ratio of a cost. Let's say 100 thousand dollars over the course of a year, then I would like to ask Mandeep whether on the prediction will reach that threshold of less than 100 thousand dollars. Because the former studies, looking at the ICER ratios, or incremental cost effectiveness ratios for the DT destination therapies, usually we select somewhere around 200 thousand dollars. And I know that usually that is seen as a prohibited cost, and there was a discussion whether we would be able to reduce the cost by about half, either doing index admission and add subsequent hospitalizations. With the data Dr Mehra and his colleagues have shown, it looks like the re-hospitalization cost is about, approximately half, or reduced by 50%. Mandeep, any thoughts on that, on that sweet spot? Dr Mandeep Mehra: Yeah. I think, Biykem, you have articulated this extraordinarily well. And for the audience, since it's worldwide, I'd like to place a few things in perspective on how to think of economic modeling. First of all, the point I would make is that this is the first prospectively collected data that we have in the field, and as you pointed out, it was very, very difficult to pull this data together and is still very complex. But let's just think about what ICER really is. It all starts with what we consider to be health utility. For example, Carolyn, Biykem, and me less so, would have a health utility of 1.0, 1.0 means a perfect health utility number. And I know, Carolyn, you and Biykem are absolutely perfect so you would be a 1.0, I probably am not a 1.0. But a patient with advanced heart failure has a health utility of about .4, so that's only 40% of what is perfect. And when we place ventricular assist devices, whether you place the HeartMate 3 or the HeartMate II, the health utility actually jumps up to about .7. So it's not perfect yet, but it moves all the way up there. The incremental cost effectiveness ratios of implanting a device over time are calculated based on this health utility benefit, compared to the population of advanced heart failure. And the best current estimates of the HeartMate II are that ICER is about 200 thousand dollars, per quality adjusted life years gained, and this has been done by creating what's known as Markov modeling. A lot of that, by the way, is conjecture, it's not real information. It is predicted information, so one has to take that data with a grain of salt. Here in this health resource analysis for MOMENTUM 3, we actually looked at actual data. There are some estimates used in this analysis as well, where we did not have accurate billing forms available, but we focused on those things where we had very clear knowledge of the cost of outcomes. For example, we did not look at the costs of outpatient follow-up care. We mainly looked at the cost differences of hospitalizations. And what we essentially found here is that just looking at hospitalizations and differences between the two devices, the cost differential, whether it's Medicare which is public [inaudible 00:20:14], or whether it's commercial. It ranges somewhere between 50 to 65 thousand dollars of difference between the two devices. Now, if you assume that the ICER for the HeartMate II is accurately at about 200 thousand, and you reduce that ICER by about 50 to 60 thousand, the ICER would naturally come into the range of what you would consider to be about 135 thousand to 150 thousand dollars per quality adjusted life years gained for the HeartMate 3, compared to an advanced heart failure population. Once we look at it from that perspective, as Biykem pointed out, we are getting closer and closer to the societal norms. At one time-point, society used to think of a quality adjusted life years gained cost of 50 thousand dollars as something that would be acceptable to society, and this was seemingly based on the threshold for what dialysis provides in benefit. And now, we recognize that we have to really expand that to somewhere around 100 thousand more logically, or between 100 and 150 thousand for some technologies. The important thing I would say to you is that, that is society dependent. So what the United States considers to be a reasonable ICER, say 100 to 130 thousand dollars per quality adjusted life years gained, may not be the same that Great Britain would look at, or Sweden would look at, or another country would look at. And each country actually creates their own economic value propositions, and this will have to be taken into account as we think about this data as well. Dr Carolyn Lam: How cleverly and clearly articulated, thank you so much Mandeep. Just one last question for both you and Biykem, what do you think this implies for moving to less and less advanced heart failure with these left ventricular assist device systems? Biykem? Dr Biykem Bozkurt: It's an ever-expanding field, and as these devices are becoming smaller, lower profile with lesser complications and more affordable, probably the utilization will likely increase as we have been seeing. As you know, even the percutaneous non-durable device used, as well as our mechanical circulatory support durable devices are definitely increasing utilization. And thus, one may wonder not only the bridge to transplantation, but the destination therapy portfolio, or bridge to decision portfolio, may really increase as these devices become safer and more affordable. Dr Carolyn Lam: Wow, that's amazing. How about you, Mandeep, what do you think? Dr Mandeep Mehra: Carolyn, I couldn't have said it any better than what Biykem articulated. I do think that at least in the United States, as we reach the thresholds of cost effectiveness that we as a society accept, we will start to see a lot more widespread utilization, particularly for lifelong therapy or so-called destination therapy. I completely agree with that. I think that moving the needle to the less sicker population is still challenging, because there are complications with these devices that make that slightly difficult. There was a trial called the REVIVE-IT trial that was stopped midstream largely because of concerns about pump thrombosis, and that trial was looking at taking these devices to a less sick NYHA class 3 population and was stopped midstream. Now that the HeartMate 3 has pretty much resolved the issue of pump thrombosis, and even show a halfing in stroke rates with this device over two years, I think that that portfolio of evidence needs to be reopened. I would caution though, that until we have confirmatory randomized data in those less sick populations, the use to that population should still stay restricted. Dr Carolyn Lam: I don't think anyone could have said it better than both of you. Thank you so much for this very insightful and balanced conversation. Thank you so much for listening today. You were listening to Circulation on the Run, and don't forget to tune again next week.
Paul Wang: Welcome to the monthly podcast “On The Beat”, for Circulation: Arrhythmia and Electrophysiology. I am Dr. Paul Wang, Editor-in-Chief, with some of the key highlights from this month's issue. We'll also hear from Dr. Suraj Kapa, reporting on new research from the latest journal articles in the field. In our first article, Adetola Ladejobi and associates studied 1,433 patients, between 2000 and 2012, who were discharged alive after sudden cardiac arrest. A reversible and correctable cause was identified in 792 patients, or 55%. A reversible cause for sudden cardiac arrest was defined as significant electrolyte or metabolic abnormality, evidence of acute myocardial infarction or ischemia, recent initiation of antiarrhythmic drug, or illicit drug use, or other reversible circumstances. Of the 792 sudden cardiac arrest survivors, due to reversible or correctable cause, 207 or 26% of the patients received an ICD after their indexed sudden cardiac arrest. During a mean follow-up of 3.8 years, 319 or 40% of patients died. ICD implantation was highly associated with a lower all-cause mortality, p < 0.001, even after correcting for unbalanced baseline characteristics. In subgroup analyses, only patients with sudden cardiac arrest, were not associated with myocardial infarction, extracted benefit from the ICD, p < 0.001. The authors concluded that in survivors of sudden cardiac arrest, due to a reversible and correctable cause, ICD therapies associated with lower all-cause mortality, except if the sudden cardiac arrest was due to myocardial infarction. Further prospect of multi-center randomized control trials will be needed to confirm this observation. In our next study, Carlo Pappone and associates, studied 81 patients with persistent atrial fibrillation, randomized to undergo high density electrophysiological mapping, to identify repetitive regular activities, before modified circumferential pulmonary vein ablation, or modified circumferential pulmonary vein ablation alone. The primary endpoint was freedom from arrhythmia recurrence at one year. In the 81 patients with persistent atrial fibrillation, there were 479 regions exhibiting repetitive regular activities in these patients, or 5.9 repetitive regular activities per patient. There were 232 regions in the mapping group, which consisted of 41 patients, and 247 regions in the control group, consisting of 40 patients. Overall, 39% of the repetitive regular activities were identified within pulmonary veins, whereas 61% were identified in non-pulmonary vein regions. Mapping-guided ablation resulted in higher arrhythmia termination rate, as compared to conventional strategy, 61% vs. 30%, p < 0.007. Total RF duration, mapping, and fluoroscopy times were not significantly different between the groups. No major procedure related adverse events occurred. After one year, 73% of the mapping group of patients were free of recurrences, compared to 50% of the control group, p = 0.03. The authors concluded that targeted ablation of regions showing repetitive regular activities provided adjunctive benefit in terms of arrhythmia freedom at one year in treatment of patients with persistent atrial fibrillation. These findings should be confirmed by additional larger randomized multi-centered studies. In the next article, Maciej Kubala and associates examine repolarization abnormalities in 40 patients with arrhythmogenic right ventricular cardiomyopathy, comparing extent and location of abnormal T-waves of one millimeter or greater in depth, downsloping elevated ST segment in two or more adjacent leads to the area and location of endocardial bipolar and unipolar, and epicardial bipolar voltage abnormalities. They found an abnormal unipolar right ventricular endocardial area of 33.4% with presence in eight patients without negative T-waves. Patients with negative T-waves extending beyond V3, seen in 20 patients, had larger low bipolar and unipolar endocardial areas, and larger epicardial low bipolar areas, compared to those with negative T-waves limited to leads V1 to V3. ECG localization of negative T-waves regionalized to the location of substrate. Patients with downsloping elevated ST segment, all localized to leads V1, V2 had more unipolar endocardial abnormalities involving outflow in mid-right ventricle, compared to patients without downsloping elevated ST segment. The authors concluded that in arrhythmogenic right ventricular cardiomyopathy, abnormal electric current areas were proportional to the extent of T-wave inversion on the 12 lead electrocardiogram. Marked voltage abnormalities can exist without repolarization changes. Downsloping elevated ST segment patterns in V1 and V2 occurs with more unipolar endocardial voltage abnormalities, consistent with more advanced trans neural disease. In the next manuscript, Teresa Oloriz and associates examine the timing and value of program stimulation after catheter ablation for ventricular tachycardia. They performed 218 program ventricular stimulations six days after ablation in 210 consecutive patients, 48% with ischemic cardiomyopathy in the median left ventricular ejection fraction of 37%. After ablation, ICDs were programmed according to NIPS results. Class A were noninducible, Class B non documented inducible VT, and Class C documented inducible VT. Concordance between the programmed ventricular stimulation at the end of the procedure and at six days was 67%. The positive predictive value and negative predictive value were higher for the programmed ventricular stimulation at day six. Ischemic patients and those with preserved ejection fraction showed the highest negative predictive value. Among noninducible patients at the end of the procedure, but inducible at day six, 59 patients had VT recurrence at one year follow-up. Recurrences were 9% when both studies were noninducible. There were no inappropriate shocks, incidents of syncope with 3%, none harmful. The rate of appropriate shocks per patient per month according to NIPS was significantly reduced, comparing the month before and after the ablation. The authors concluded that programmed ventricular stimulation at day six predicts VT recurrence. In the next study, Tor Biering-Sørensen and associates examined ECG global electrical heterogeneity, GEH, in its longitudinal changes, are associated with cardiac structure and function, in their Atherosclerosis Risk and Community study, ARIC, consisting of 5,114 patients, 58% which were female and 22% African Americans. Using the resting 12-lead ECGs, and echocardiographic assessments of left ventricular ejection fraction, global strain, left ventricular mass index, end diastolic volume index, end systolic volume index at visit five. Longitudinal analysis included ARIC participants with measured GEH at visits one to four. GEH was quantified by spatial ventricular gradient, the QRST angle, and the sum of the absolute QRST integral. Cross sectional and longitudinal regressions were adjusted for manifest subclinical cardiovascular disease. Having four abnormal GEH parameters was associated with a 6.4% left ventricular ejection fraction decline, a 24.2 gram/meter square increase in left ventricular mass index, a 10.3 milliliter/meter square increase in left ventricular end diastolic volume index, and a 7.8 milliliter/meter square increase in left ventricular end systolic index. All together, clinical and ECG parameters accounted for approximately one third of the left ventricular volume in 20% of the systolic function variability. The associates were significantly stronger in patients with subclinical cardiovascular disease. The QRST integral increased by 20 millivolts/meter second for each three year period participants who demonstrated left ventricular dilatation at visit five. Sudden cardiac death victims demonstrated rapid GEH worsening, while those with left ventricular dysfunction demonstrated slow GEH worsening. The authors concluded that GEH is a marker of subclinical abnormalities in cardiac structure and function. In the next manuscript, Takumi Yamada and associates studied 19 patients with idiopathic ventricular arrhythmias, originating in the parietal band in 14 patients, in the septal band in 5 patients. Among 294 consecutive patients with right ventricular arrhythmia origins, parietal band and septal band ventricular arrhythmias exhibited a left bundle branch block, with left inferior in 12 patients', superior in 2 patients' axes, in left or right inferior axis pattern in four and one patients respectively. In Lead 1, all parietal band ventricular arrhythmias exhibited R-waves, while septal band ventricular arrhythmias often exhibited S-waves. A QS pattern in lead AVR, in the presence of a knock in the mid QRS were common in all infundibular muscle ventricular arrhythmias. During infundibular muscle ventricular arrhythmias, a far-field ventricular electrogram, with an early activation, was always recorded in the His bundle region, regardless of the location of ventricular arrhythmia regions. With 9.2 radiofrequency applications in a duration of 972 seconds, catheter ablation was successful in 15 of the 19 patients. Ventricular arrhythmias recurred in four patients during a fallout period of 43 months. In the next paper, Uma Mahesh Avula and associates examine the mechanisms underlying spontaneous atrial fibrillation, in an Ovine model of left atrial myocardial infarction. The left atrial myocardial infarction was created by ligating the atrial branch of the left anterior descending artery. ECG loop recorders were implanted to monitor atrial fibrillation episodes. In seven sheep, Dantrolene, a Ryanodine receptor blocker, was administered in vivo, during the observation period. The left atrial myocardial infarction animals experienced numerous episodes of atrial fibrillation during the eight day monitoring period, that were suppressed by Dantrolene. Optical mapping showed spontaneous focal discharges originating through the ischemic/normal-zone border. These spontaneous focal discharges were calcium driven, rate dependent, and enhanced by isoproterenol, but suppressed by Dantrolene. In addition, these spontaneous focal discharges initiated atrial fibrillation-maintaining reentrant rotors anchored by marked conduction delays at the ischemic/normal-zone border. Nitric oxide synthase one protein expression decreased in ischemic zone myocytes, or NADPA oxidase in xanthine oxidase enzyme activities in reactive oxygen species increased. Calmodulin aberrantly increased, Ryanodine binding to cardiac Ryanodine receptors in the ischemic zone. Dantrolene restored the physiologically binding of Calmodulin to the cardiac Ryanodine receptors. The authors concluded that atrial ischemia causes spontaneous atrial fibrillation episodes in sheep, caused by spontaneous focal discharges that initiate re-entry. Nitroso redox imbalance in the ischemic zone is associated with intensive reactive oxygen species production, and altered the Ryanodine receptor responses to Calmodulin. Dantrolene administered normalize the Calmodulin response and prevents left atrial myocardial infarction, spontaneous focal discharges in atrial fibrillation initiation. In the next study, Wouter van Everdingen and associates examine the use of QLV for achieving optimal acute hemodynamic response to CRT with a quadripolar left ventricular lead. 48 heart failure patients with left bundle branch block were studied. Mean ejection fraction 28%, mean QRS duration 176 milliseconds. Immediately after CRT implantation, invasive left ventricular pressure volume loops were recorded during biventricular pacing, with each separate electrode at four atrial ventricular delays. Acute CRT response, measured as a change in stroke work compared to intrinsic conduction, was related to the intrinsic interval between the Q on the electrocardiogram and the left ventricular sensing delay, that is the QLV, normalized for the QRS duration, resulting in QLV over QRS duration in the electrode position. QLV over QRS duration was 84% and variation between the four electrodes was 9%. The change in stroke work was 89% and varied by 39% between the electrodes. In univariate analysis, an anterolateral or lateral electrode position in a high QLV to QRS duration ratio had a significant association with a large change in stroke work, all P less than 0.01. In a combined model, only QLV over QRS duration remained significantly associated with a change in stroke work, P less than 0.5. However, a direct relationship between QLV over QRS duration in stroke work was only seen in 24 patients, while 24 other patients had an inverse relation. The authors concluded that a large variation in acute hemodynamic response indicates that the choice of stimulated electrode on the quadripolar electrode is important. Although QLV to QRS duration ratio was associated with acute hemodynamic response at a group level, it cannot be used to select the optimal electrode in the individual patient. In the next study, Antonio Pani and associates conducted a multi-centered prospective study evaluating the determinance of zero-fluoroscopy ablation of supraventricular arrhythmias. They studied 430 patients with an indication for EP study and/or ablation of SVT. A procedure was defined as zero-fluoroscopy when no fluoroscopy was used. The total fluoroscopy time inversely was related to number of procedures previously performed by each operator since the study start. 289 procedures, or 67%, were zero-fluoro. Multi-variable analyses identified as predictors of zero-fluoro was the 30th procedure for each operator, as compared to procedures up to the ninth procedure, the type of arrhythmia, AVNRT having the highest probability of zero-fluoro, the operator, and the patient's age. Among operators, achievement of zero-fluoro varied from 0% to 100%, with 8 operators, or 23%, achieving zero-fluoro in 75% of their procedures. The probability of zero-fluoro increased by 2.8% as the patient's age decreased by one year. Acute procedural success was obtained in all cases. The authors concluded that the use of 3D mapping completely avoided the use of fluoroscopy in most cases, with very low fluoro time in the remaining, and high safety and effectiveness profiles. In the next paper, Demosthenes Katritsis and associates examine the role of slow pathway ablation from the septum as an alternative to right-sided ablation. Retrospectively, 1,342 undergoing right septal slow pathway ablation for AV nodal reentry were studied. Of these, 15 patients, 11 with typical and 4 with atypical AVNRT, had a left septal approach following unsuccessful right sided ablation, that is, the righted left group. In addition, 11 patients were subjected prospectively to a left septal only approach for slow pathway ablation, without previous right septal ablation, that is, left group. Fluoroscopy times in the right and left group, and the left groups were 30.5 minutes and 20 minutes respectively, P equals 0.6. The rate of [inaudible 00:18:24] current delivery time for comparable, 11.3 minutes and 10.0 minutes respectively. There are no additional ablation lesions at other anatomical sites in either group, and no cases of AV block were encountered. Recurrence rate for arrhythmias in the right and left group was 6.7% and 0% in the left group, in the three months following ablation. The authors concluded that the left septal anatomical ablation of the left inferior nodal extension is an alternative to ablation of both typical and atypical AV nodal reentry when ablation at the right posterior septum is ineffective. In our next study, Mark Belkin and associates reported prior reports of new-onset device-detected atrial tachyarrhythmias. Despite the clear association between atrial fibrillation and the risk of thromboembolism, the clinical significance of new-onset device-detected atrial tachyarrhythmias and thromboembolism remains disputed. The authors aim to determine the risk of thromboembolic events in these patients. Using the Ovid Medline, Cochrane, SCOPUS databases to identify 4,893 reports of randomized control trials, perspective or retrospective studies of pacemaker and defibrillator patients reporting the incidence of device detected atrial tachyarrhythmias. The authors examine 28 studies, following a total of 24,984 patients. They had an average age of 69.9 years and a mean study duration of 21.8 months. New-onset device-detected atrial tachyarrhythmias was observed in 23% of patients. Among nine studies, consisting of 8,181 patients, reporting thromboembolism, the absolute incidence was 2.1%. Thromboembolic events were significantly greater among patients with new-onset device-detected arrhythmias, with a relative risk of 2.88, compared to those who had less than one minute of tachyarrhythmias, 1.77 risk ratio. The authors concluded that new-onset device-detected atrial tachyarrhythmias is common, affecting close to one quarter of all patients with implanted pacemakers and defibrillators. In our last paper, Sanghamitra Mohanty and associates performed a meta-analysis systematically evaluating the outcome of pulmonary vein isolation with and without thermoablation in patients with atrial fibrillation. For pulmonary vein ablation alone, only randomized trials conducted in the last three years reporting single procedure success rates, off antiarrhythmic drugs at 12 months or greater follow-up were included. In the PVI plus FIRM group, all public studies reporting a single procedure off antiarrhythmic drug success rate with at least one year follow-up were identified. Meta-analytic estimates were derived, using the DerSimonian and Laird Random-effects Models, and pooled estimates of success rates. Statistical heterogeneity was assessed using the Cochran Q test and I-square. Study quality was assessed with the Newcastle-Ottawa Scale. 15 trials were included, 10 with PVI plus FIRM, with 511 patients, non-randomized perspective design, and 5 pulmonary vein isolation-only trials, consisting of 295 patients, all randomized. All patients in the pulmonary vein only trials had 100% non paroxysmal atrial fibrillation, except for one study, and no prior ablations. About 24% of the PVI plus FIRM patients had paroxysmal atrial fibrillation. After 15.9 months of follow-up, the off antiarrhythmic drug pooled success was 50% with FIRM plus PVI, compared to 58% in the PVI alone. The difference in the effect size between the groups was not statistically significant. No significant heterogeneity was observed in this meta-analysis. The authors concluded that the overall pooled estimate did not show any therapeutic benefit of PVI FIRM over PVI alone. That's it for this month, but keep listening. Suraj Kapa will be surfing all journals for the latest topics of interest in our field. Remember to download the podcast On The Beat. Take it away, Suraj. Suraj Kapa: Thank you, Paul, and welcome back to “On The Beat”. Again, my name is Suraj Kapa and I'm here to review with you articles across the cardiac electrophysiology literature that were particularly hard hitting in the month of February. To start, we review the area of atrial fibrillation, focusing on anticoagulation. Reviewing an article published in this past month's issue of the Journal of the American Heart Association, by Steinberg et al., entitled Frequency and Outcomes of Reduced Dose Non-Vitamin K Antagonist Anticoagulants, results from ORBIT AF II. The ORBIT AF II registry, also called the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, is a prospective national observational registry of AF patients. The author sought to describe the frequency, appropriateness, and outcomes of patients prescribed reduced doses of NOACs in the community practice. They reviewed the records of almost 8,000 patients receiving NOACs and noted that the vast majority, nearly 84%, received a standard dose of NOACs, consistent with the U.S. FDA labeling. While only 16% received a reduced dose, only 43% of these were consistent with labeling instructions. Those who received reduced dose NOACs inappropriately more often tended to be younger and have, interestingly, lower overall bleeding risks scores. Furthermore, compared with those appropriately receiving dosing, patients receiving inappropriately reduced dose NOACs had a higher unadjusted rates of thromboembolic events and death. These data are important to understand, in that, discussion with patients, that inappropriate reduction of NOACs does not necessarily offer appropriate protection against long-term risk of thromboembolic events. Thus, close attention must be paid to consideration of the use cases and instructions for use. While the registry cannot get into the details of why the dose was reduced in the spectrum of patients, it does highlight the fact that this continues to be a problem in general practice. Further data is needed to understand what leads to inappropriate dose reduction, which could include factors such as patient preference, or physician education. Staying within the realm of anticoagulation and understanding individual needs, we next review an article published in this past month's issue of Circulation, by Nielsen et al., entitled Female Sex Is a Risk Modifier Rather Than a Risk Factor for Stroke in Atrial Fibrillation. Should we use a CHA2DS2-VA score rather than CHA2DS2-VASc? In this review, the authors sought to evaluate whether female sex is truly an overall risk factor, as opposed to a risk modifier. Using three nationwide registries, they identified patients with nonvalvular atrial fibrillation between 1997 and 2015, and they calculated two sets of scores. The first score, they termed a CHA2DS2-VA score, calculated for men and women with follow-up of one year in the Danish National Patient Registry. They wanted to calculate the risk based on this pseudo-value method. They then reviewed female sex as a prognostic factor by inclusion as an interaction term on the CHA2DS2-VA score, to calculate overall thromboembolic risk. Amongst over 200,000 patients with atrial fibrillation, almost half of whom are women, they noted that the mean CHA2DS2-VA score, where sex is excluded, was a tad higher in women than men, namely 2.7 vs. 2.3. However, women had an overall higher one year thromboembolic rate of 7.3 vs. 5.7 per 100 person-years. Interestingly, with a CHA2DS2-VA score of zero, the absolute risk of thromboembolism was equal amongst men and women, around .5%. Once overall points increased above one, however, women exhibited a higher stroke risk. This interaction was statistically significant. Thus, the authors indicated that female sex is a risk modifier for stroke in patients with atrial fibrillation, rather than a risk factor. The terminology is important to consider. Essentially, what they are noting is that at the lower risk level, female sex, in and of itself, is not something that necessarily puts somebody in the higher risk cohorts. Instead, at higher risk levels, because of other factors, a woman may have a higher overall risk of stroke than men. Thus, stroke risk is accentuated in women, who would have been eligible for oral anticoagulating treatment anyway, on the basis of a CHADS score above one. These data highlight the importance of thinking about the fact that at the lower risk score level, female sex alone might not be sufficient to say that a patient has reached the CHA2DS2-VASc score of one and above. But, really, you need an overall CHA2DS2-VA score, or a risk score, inclusive of at least two other risk factors to indicate that now, being a female is going to modify the risk and further accentuate it. Now, one thing to note is, these data are very consistent with the guidelines. The European guidelines indicates that female sex alone, which in the CHA2DS2-VASc score would confer a risk score of one, should not, by itself, construe the need to put somebody on anticoagulation. However, it's important to highlight that these data show that at a CHA2DS2-VASc score of one in females, they should really be construed as equivalent to a CHA2DS2-VASc score of zero in men. Using the CHA2DS2-VA score, where sex is excluded, but considering that women overall have a higher incidence of stroke at any given CHA2DS2-VA level above one, will help better counsel women about the importance of being on anticoagulants. The next article we review relates to long-term risk related to atrial fibrillation, published in February's issue of Heart Rhythm, by Nishtala et al., entitled Atrial Fibrillation and Cognitive Decline in the Framingham Heart Study. While there's much out there about the potential long-term role of cognitive decline in atrial fibrillation patients, longitudinal research investigating the relationship is relatively sparse. Thus, the authors sought to investigate the association between atrial fibrillation and cognitive performance, cross-sectionally and longitudinally. They chose patients within the Framingham study who are dementia and stroke-free at the time of baseline neuropsychological assessments. They evaluated atrial fibrillation status as a two level variable, namely prevalent atrial fibrillation vs. no atrial fibrillation in cross-sectional analyses. And they also separated into prevalent atrial fibrillation at baseline, interim development of atrial fibrillation, and those who didn't develop any atrial fibrillation in longitudinal analysis. They studied 2,682 participants in the Framingham Heart study, including original and offspring cohorts. They noted that a baseline of about 4% had diagnosed atrial fibrillation. Prevalent AF was noted to be significantly associated with poorer attention. Interestingly, sex differences were noted, with men performing worse on test of abstract reasoning and executive function than women. They noted that prevalent atrial fibrillation was significantly associated with the longitudinal decline in executive function, in both the original cohorts, as well as interim atrial fibrillation being significantly associated with longitudinal decline in executive function of the offspring cohorts. Thus, they noted that atrial fibrillation is associated with a profile of long-term change in cognitive function. The importance of these data are to further highlight the potential contribution of atrial fibrillation to cognitive decline. While the exact mechanisms remain to be fully elucidated, the question of how to get ahead of the cognitive decline associated with atrial fibrillation is further put out by these data. Whether the relationship between atrial fibrillation and cognitive decline is due to recurrent thromboembolic events vs. the therapies used vs. other factors such as humid anatomic factors resulting in poor brain perfusion, are relatively unclear. Certainly it is also possible that atrial fibrillation simply reflects a process associated with other factors that might lead to cognitive decline. However, again, further mechanistic studies and potential treatment interventions to mitigate the risk of cognitive decline are still needed. Speaking of this, we next review a paper published in the European Heart Journal this past month, by Friberg and Rosenqvist, entitled Less Dementia with Oral Anticoagulation in Atrial Fibrillation. Speaking of treatments to avoid long-term cognitive decline, the authors sought to evaluate if oral anticoagulant treatment might offer protection against long-term dementia risk in atrial fibrillation. These retrospective registry studies of patients with the hospital diagnoses of atrial fibrillation and no prior diagnosis of dementia in Sweden, including patients between 2006 and 2014. The study included a total of 444,106 patients over 1.5 million years. They noted that patients who were on anticoagulant treatment at baseline were associated with a 29% lower risk of dementia than patients without anticoagulant treatments. Thus, there is an overall 48% lower risk on treatments with the appropriate anticoagulation. There is no difference on whether Warfarin or the newer oral anticoagulants were used. Thus, the authors concluded that the risk of dementia is higher without oral anticoagulant treatment in patients with atrial fibrillation, suggesting that early initiation of anticoagulant treatment in patients with atrial fibrillation could be of value to preserve long-term cognitive function. This relates directly back to the previous paper, which focused more on the epidemiologic risk, while this paper focuses on elements that might construe mechanism or treatment options. Many authors have concluded the incredible importance of early recognition of the need for anticoagulant initiation in patients with atrial fibrillation. While the exact mechanism of cognitive decline and dementia in atrial fibrillation remains to be completely elucidated, certainly recurrent thromboembolic events that might be relatively silent as they occur, but result in a long-term cumulative risk might be helped by placing patients on anticoagulants. This becomes another reason to counsel patients on the importance of long-term anticoagulant therapy. Certainly, the limitations of these studies, however, are the retrospective nature and the fact that there might be some subtle differences that may not be otherwise able to be construed from retrospective registry data regarding the relative role of anticoagulants in truly protecting against long-term cognitive decline. However, the data are certainly provocative. Continuing within realm and discussing outcomes associated atrial fibrillation, we next review an article by Leung et al., entitled The Impact of Atrial Fibrillation Clinical Subtype on Mortality, published in JACC: Clinical Electrophysiology this past month. The author sought to investigate the prognostic implications of a subtype of atrial fibrillation, paroxysmal or persistent, on long-term prognosis. They sought to evaluate differences in mortality between paroxysmal or persistent atrial fibrillation amongst 1,773 patients. They adjusted for comorbid diseases associated with atrial fibrillation, as well as CHA2DS2-VASc score. In the study, a total of about 1,005 patients or about 57% had persistent atrial fibrillation. Over the follow-up period, about 10% of those with paroxysmal atrial fibrillation and 17% of those with persistent atrial fibrillation died. They noted that persistent atrial fibrillation, after correcting for other comorbidities, was independently associated with worse survival. Thus, they concluded that persistent atrial fibrillation is independently associated with increased mortality in the long term. These data are relevant in that they highlight that persistent atrial fibrillation in its nature might construe an overall higher risk cohort. It remains to be fully understood what are the true mechanistic differences between persistent and paroxysmal atrial fibrillation. Overall, however, the community grossly agrees that persistent atrial fibrillation likely suggests a higher degree of atrial myopathy. If we believe this, then it is reasonable to believe that the risk associated with this specific form of atrial fibrillation might result in higher long-term harm. Of course, these data are subject to the same limitations of all retrospective data. Namely, these persistent atrial fibrillation patients might have received different therapies or been more sick to start with that cannot be construed by comorbidities alone. Furthermore, these data do not necessarily get to the point of whether treating atrial fibrillation in the persistent patient more aggressively necessarily reduces the risk equivalent to that of paroxysmal patients. Thus, further understanding is needed to understand how to use these data to reduce this mortality difference. Continuing within the realm of epidemiology of atrial fibrillation, we next review an article published in this past month's issue of Circulation, by Mandalenakis et al., entitled Atrial Fibrillation Burden in Young Patients with Congenital Heart Disease. It is assumed that patients with congenital heart disease are vulnerable to atrial fibrillation because of multiple factors. These include residual shunts, hemodynamic issues, atrial scars from previous heart surgery, valvulopathy and other factors. However, there's limited data on the overall risk of developing atrial fibrillation and complications associated with it, especially in children and young adults with congenital heart disease. Furthermore, these children and young adults with congenital heart disease have never been compared with overall risk and control subjects. The authors use the Swedish Patient and Cause of Death Registries to identify all patients with diagnoses of congenital heart disease born from 1970 to 1993. They then matched these patients with control subjects from the Total Population Register in Sweden. They noted amongst almost 22,000 patients with congenital heart disease and almost 220,000 matched control subjects that 654 patients amongst the congenital heart disease cohort developed atrial fibrillation, while only 328 amongst the larger control group developed atrial fibrillation. The mean follow-up overall was 27 years. They noted the risk of developing atrial fibrillation was almost 22 times higher amongst patients with congenital heart disease than control subjects. They noted the highest risk with a hazard ratio of over 84 was noted in patients with conotruncal defects. Furthermore, at the age of 42 years, over 8% of patients with congenital heart disease had a recorded diagnosis of atrial fibrillation. Interestingly, heart failure was a particularly important complication in patients with congenital heart disease and atrial fibrillation, with over 10% of patients developing atrial fibrillation and [inaudible 00:38:20] congenital heart disease developing a diagnosis of heart failure as well. These data are important in that they help in counseling the importance of close follow-up of patients with congenital heart disease and their long-term risk of other complications. Even if patients might be perceivably well managed, incident atrial fibrillation might increase risk of stroke in these patients. It is further important to note that many of these patients cannot be evaluated according to traditional risk or evaluations. Thus, it is important to consider whether or not a patient should be treated with anticoagulation once they develop atrial fibrillation. The high risk of overall atrial fibrillation incidents, particularly in patients with more complex congenital defects, needs to be taken into consideration when advising on the frequency of follow-up. It is important to further note that we must think of this overall risk as the minimum possible risk, namely, counseling a congenital heart disease patient that up to one in ten of them may develop atrial fibrillation by the age of 42 years, is likely the minimum amount. The reason for this is many patients, due to either lack of follow-up or lack of sufficient monitoring, and the asymptomatic nature of atrial fibrillation in many patients might have not been diagnosed. Implications or treatments remain to be seen, and whether or not there are methods to reduce the overall risk of atrial fibrillation is unclear. However, engaging congenital heart disease experts and advising patients, especially at younger ages, on the importance of close electrocardiographic monitoring for a potential atrial fibrillation risk is critical. Next within the realm of atrial fibrillation, we switch to the topic of ablation. And review an article by Pallisgaard et al., published in this last month's issue of European Heart Journal, entitled Temporal Trends in Atrial Fibrillation Recurrence Rates After Ablation, between 2005 and 2014: a nationwide Danish cohort study. Ablation has been increasingly used as a rhythm control strategy for patients with atrial fibrillation. Over this time, we have all noted evolution in both the experience and the techniques used. Thus, the authors sought to evaluate whether recurrence rate of atrial fibrillation has changed over the last decade. They included all patients with first-time AF ablation done between 2005 and 2014 in Denmark. They then evaluated recurrent atrial fibrillation based on a one year follow-up. They included a total of 5,425 patients undergoing first-time ablation. They noted, interestingly, that the patient median age increased over time, and the median AF duration prior to ablation decreased over time. However, the rates of recurrent atrial fibrillation decreased from 45% in 2005 to 31% in the more recent years of 2013, 2014. With the relative risk of recurrent atrial fibrillation almost being cut in half. They noted that female gender, hypertension, atrial fibrillation duration more than two years, and cardioversion with one year prior to ablation were all associated with an increased risk of recurrent atrial fibrillation, regardless of year. These data, again, are retrospective and thus must be taken in the context of that consideration. However, they highlight that it is possible either our selection of appropriate patients for atrial fibrillation ablation or our techniques have improved overall success. The fact that atrial fibrillation ablation is still a relatively young field, with evolving approaches and evolving techniques, needs to be taken into consideration when advising patients on success rates. Using data from many years prior to informed discussion today is fraught with potential error, especially as our catheter design and mapping system use and understanding of appropriate lesion set changes. Of course, some criticism is required as well. While the patients included were relatively older in more recent years, the total AF duration prior to ablation decreased over the years. This suggests that patients are being ablated earlier than they were in the early days of atrial fibrillation ablation. There is some data out there to suggest that earlier ablation for atrial fibrillation might result in a lower long-term recurrence rate. Thus, this might account for some of the difference. However, it is unlikely that it accounts for all of it, given the degree of reduction in overall risk of occurrence. Staying within the trend of talking about changes in techniques for atrial fibrillation ablation, we next review an article published in this past month's issue of Heart Rhythm, by Conti et al., entitled Contact Force Sensing for Ablation of Persistent Atrial Fibrillation: A Randomized, Multicenter Trial. Contact force sensing is one of the newer techniques being used to optimize the success rates for atrial fibrillation ablation. It is generally felt that understanding when one is in contact will optimize atrial fibrillation ablation outcomes by ensuring the physician knows each time they are in contact, and also potentially reducing complications by avoiding excessive contact. Thus, the authors designed the TOUCH AF trial to compare contact force sensing-guided ablation vs. contact force sensing-blinded ablation. They included a total of 128 patients undergoing first-time ablation for persistent atrial fibrillation, and thus randomized them to a situation where the operator was aware of the contact force vs. blinded to the contact force. While the force data was hidden in the blinded cohort, it was still recorded on the backend. In all patients, wide antral pulmonary vein isolation plus a roof line was performed, and patients were followed at 3, 6, 9, and 12 months, with clinical visits, ECGs, and 48-hour Holter monitoring. The primary endpoint was cumulative radio frequency time for procedures, and atrial arrhythmia is greater than 30 seconds after three months is considered a recurrence. They noted that average force was higher in the contact force-guided arm than contact force-blinded arm, though not statistically significant, with an average of 12 grams in the latter and 14 grams in the former. Interestingly, the total time of ablation did not differ between the two groups. Furthermore, there was no difference in the single procedure freedom from atrial arrhythmia, computing to about 60% in the contact force-guided arm vs. the 63% in the contact force-blinded arm. They did notice, however, that lesions with associated gaps were associated with significantly less force and less force-time integral. The authors concluded from this, the contact force-guided ablation did not result in significant decrease in total radio frequency time or 12-month outcomes in terms of freedom from atrial arrhythmias. These data are important to help guide us in terms of thinking about how the tools we use, as they change, actually alter outcomes. Sometimes we may perceive benefits based on logical thinking that's knowing more about what is happening when we are performing a procedure should optimize that procedure. However, this is not necessarily always the case, and thus highlights the importance of randomized trials to directly compare different situations, such as awareness of contact force vs. lack of awareness of contact force. The relevance of these particular articles is that when we compare catheters with different designs, it does not necessarily highlight the importance of the force number itself. Namely, comparing a contact force catheter vs. non-contact force catheter implicates use of essentially two completely different catheters. To understand the incremental utility of force in making decisions, it is important to consider the same catheter, but simply with awareness or lack of awareness of the actual force number. One of the limitations, however, is that individuals who might have been trained on using the same force sensing catheter might have some degree of tactile feedback and understanding of the amount of force being applied to the tip of the catheter, based on having been repeatedly exposed to contact force numbers during use of said catheter. Thus, there might be a difference in being blinded to contact force in early stage operators than in later stage operators who might have been trained based on repeated feedback. Thus, it's difficult to conclude, necessarily, that contact force is not offering mental benefit. In fact, there's a fair chance that it does. However, offering a skeptical viewpoint to help guide the importance of continually evolving technology in actually improving outcomes is important. Finally, within the realm of atrial fibrillation, we review an article published by Pathik et al., in this past month's issue of Heart Rhythm, entitled Absence of Rotational Activity Detected Using 2-Dimensional Phase Mapping and the Corresponding 3-Dimensional Phase Maps in Human Persistent Atrial Fibrillation. Current clinically used phase mapping systems involve 2-dimensional maps. However, this process may affect accurate detection of rotors. The authors sought to develop 3-dimensional phase mapping technique that uses a 3D location of the same basket electrodes that are used to create the currently available 2-dimensional maps. Specifically, they wanted to determine whether the rotors detected in 2D phase maps were present in the corresponding time segments and anatomical locations in 3D phase maps. They used one minute left atrial atrial fibrillation recordings obtained in 14 patients, using the basket catheter, and analyzed them offline, using the same phase values, based on 2-dimensional vs. 3-dimensional representations. They noted rotors in 3.3% using 2D phase mapping, 9 to 14 patients demonstrated about 10 transient rotors, with a mean rotor duration of about 1.1 seconds. They noted none of the 10 rotors, however, were seen at the corresponding time segments and anatomical locations in 3D phase maps. When looking at 3D phases maps, 4 of the 10 corresponded with single wavefronts, 2 of 10 corresponded with simultaneous wavefronts, 1 of 10 corresponded with disorganized activity, and 3 of 10 had no coverage by the basket catheter at the corresponding 3D anatomical locations. These data are important, in that they highlight the importance of when we consider reflecting 2-dimensional systems in a 3-dimensional world of atrial fibrillation. The role of ablating rotors is still in question. However, it is still an important question, and it requires continued study. The best way of identifying a rotor, knowing a rotor is a rotor, and understanding where the rotor is, are going to be critical to further evaluating whether actual ablation of these rotors has any relevance to long-term atrial fibrillation ablation. The truth is, that we need to be sure that we are properly identifying all the rotors in order to help guide whether or not we are actually being successful in ablating atrial fibrillation. The importance of the study is in reflecting whether 2-dimensional representations of the 3-dimensional geometry is sufficient to reflect what is actually happening in that 3-dimensional geometry. These authors suggest that it is not. One of the limitations, however, might be that when we wrap a 2-dimensional framework into 3 dimensions and perform additional post-processing, this might result in some degree of attenuation of the data. However, it does highlight the importance for continued rigorous evaluation of current approaches to phase mapping. Several articles have been published in recent months as well, about different single processing techniques to evaluate whether or not a rotor is, in fact, a rotor and to help optimize identification of them. The jury is still out on whether or not targeted ablation of rotors will, in fact, improve overall long-term atrial fibrillation ablation outcomes. The limitations might not necessarily be that rotors are not an appropriate target, but that we just don't understand entirely where rotors are, based on limited single processing options, or based on limitations of anatomical localization. Next, delving into the realm of ablation at large, we review an article by Iwasawa et al., published in this past month's issue of Europace, entitled Trans Cranial Measurement of Cerebral Microembolic Signals During Left-Sided Catheter Ablation with the Use of Different Approaches - the Potential Microembolic Risk of a Transseptal Approach. The authors note the importance of considering microemolization in subclinical brain damage during catheter ablation procedures. They evaluated microembolic signals detected by transcranial Doppler during ablation of supraventricular or ventricular arrhythmias with the use of either a transseptal or a retrograde approach. The study set was small, only including 36 patients who underwent catheter ablation. They noted in about 11 patients left-sided ablation was done with transaortic approach, and in 9 patients a transseptal approach was used. The other 16 patients were not included, as they only had right-sided ablation. The total amount of microembolic signature, based on transcranial Doppler were counted throughout the procedure and then analyzed offline. There is no significant difference in number of radio frequency applications, total energy delivery time, total application of energy, or total procedure time between the different groups. However, they did note that the mean total number of microembolic signals was highest in those undergoing transseptal approach to left-sided ablation. It was significantly lower in those having retrograde aortic approach, and lowest in those having right-sided only ablation. Interestingly, many of the microembolic signals were detected during the transseptal puncture period, and then during the remainder of the procedure there was relatively even distribution of emboli formation. A frequency analysis suggested that the vast majority of microembolic signals are gaseous, in particularly Group 1 and Group 3, though only 91% in Group 2. No neurological impairment was observed in any of the patients after the procedure. Recently, there's been a lot of focus on the potential long-term risk of cognitive impairments due to microembolic events in the setting of ablation. At least one recent paper in ventricular arrhythmias and several recent papers in atrial fibrillation ablation have suggested a fairly high risk of incidence cerebral emboli noted on MRI post ablation. While these results do not necessarily get at MRI lesions, they do suggest microembolic events. And what is most interesting, they look at microembolic events that occur throughout the entire ablation period with different approaches. Interestingly, there is a massive spike in overall microembolic signals during the transseptal puncture period, and relatively even distribution throughout ablation, irrespective of application of radio frequency or not. Furthermore, while nearly all microembolic signals are gaseous, based on frequency analysis, with retroaortic approach or in those having right-sided only ablation, significantly less seem to be due to gaseous events in those having a transseptal approach. It is known that there's possible damage to the internal dilation system when exposing it to transseptal needles or wires. Thus, one has to wonder whether some of the embolization could be from material associated with the actual transseptal puncture, either from portions of the punctured septum itself, or perhaps from the plastic material that which is being pushed transseptally. These data still need to be considered and we have yet to see what the long-term applications of these kinds of findings are. It may be possible that while transseptal approach seems to offer more instant microembolic signals, if the long-term risk is no different, does it really matter? However, these findings are provocative in the sense that they highlight potential significant differences and the risk of silent cerebral damage, based on the approach we use to ablation. Changing gears, we next focus on the role of devices. And the first paper review is in the last month issue of JACC: Heart Failure, by Gierula et al., entitled Rate Response Programming Tailored to the Force Frequency Relationship Improves Exercise Tolerance in Chronic Heart Failure. The authors sought to examine whether the heart rate at which the force frequency relationship slope peaks can be used to tailor heart rate response in chronic heart failure patients with cardiac pacemakers, and to see whether this favorably influences exercise capacity. They performed an observational study in both congestive heart failure and healthy subjects with pacemaker devices. They then evaluated in a double-blind, randomized, controlled crossover study, the effects of tailored pacemaker rate response programming on the basis of a calculation of force frequency relationship based on critical heart rate, peak contractility, and the FFR slope. They enrolled a total of 90 patients with congestive heart failure into the observational study cohorts, and 15 control subjects with normal LLV function. A total of 52 patients took part in the crossover study. They noted that those who had rate response settings limiting heart rate rise to below the critical heart rate were associated with greater exercise time and higher peak oxygen consumption, suggesting the tailored rate response program can offer significant benefit, particularly in congestive heart failure patients. The importance of this trial is in that it highlights the importance of thoughtful decision-making in programming devices, and that group decision-making involving exercise physiologists, alongside pacemaker programming, and involving our congestive heart failure specialists might be the most critical in optimizing the approach to programming. It might be that more aggressive measures are needed in congestive heart failure patients to decide on what optimal programming is, than it is in otherwise normal patients. Staying within the realm of devices, we next focus on a publication by Sanders et al., published in this past month's issue of JACC: Clinical Electrophysiology, entitled Increased Hospitalizations and Overall Healthcare Utilization in Patients Receiving Implantable Cardioverter-Defibrillator Shocks Compared With Antitachycardia Pacing. The authors sought to evaluate the effect of different therapies and healthcare utilization in a large patient cohorts. Specifically comparing antitachycardia pacing with high voltage shocks. They used the PROVIDE registry, which is a prospective study of patients receiving ICDs for primary prevention in 97 U.S. centers. They categorized these patients by type of therapy delivered, namely no therapy, ATP only, or at least one shock. They then adjudicated all ICD therapies, hospitalizations, and deaths. Of the 1,670 patients included, there was a total follow-up of over 18 months. The vast majority, 1,316 received no therapy, 152 had ATP only, and 202 received at least one shock. They noted that patients receiving no therapy and those receiving only ATP had a lower cumulative hospitalization rate and had a lower risk of death or hospitalization. The cost of hospitalization was known to be significantly higher for those receiving at least one shock than for those receiving only ATP therapy. They noted no difference in outcomes or cost between patients receiving only ATP and those without therapy. Thus, the authors concluded that those receiving no therapy or those receiving only ATP therapy had similar outcomes, and had significantly reduced hospitalizations, mortality, and costs compared to those who received at least one high voltage shock. The relevant findings from this study is similar to prior studies that suggest that any shock over follow-up is associated with potential increase in long-term mortality. The difficulty in assessing this, however, is the fact that it might be that those who have VT that can be appropriately ATP terminated, might be at a somewhat lower risk than those who need to be shocked to get out of their VT. Thus, the presumption of needing a shock to restore normal rhythm might suggest a higher risk cohort, it cannot be gleaned from traditional evaluation of morbid risk factors. This is why the importance of considering how devices are programmed and whether or not a patient who has received shocks can be reprogrammed to offer ATP only therapy to terminate those same VTs, needs to be taken into consideration. How to best tailor this therapy, however, is still remaining to be determined, though more and more clinical trials are coming out to suggest in terms of optimal overall population-wide programming for devices. Staying with the realm of devices, we next review an article by Koyak et al., in this past month's issue of Europace, entitled Cardiac Resynchronization Therapy in Adults with Congenital Heart Disease. Heart failure is one of the leading causes of morbidity and mortality amongst patients with congenital heart disease. But there's limited experience in the role of cardiac resynchronization therapy amongst these patients. Thus, the authors sought to evaluate the efficacy of CRT in adults with congenital heart disease. They performed a retrospective study on a limited number of 48 adults with congenital heart disease who received CRT, amongst four tertiary referral centers. They have defined responders as those who showed improvement in NYHA functional class or improvement in systemic ventricular ejection fraction. The median age at CRT implant was 47 years, with 77% being male. There was a variety of syndromes included. They noted that the majority of patients, nearly 77%, responded to CRT, either by definition of improvement of NYHA functional class, or systemic ventricular function, with a total of 11 non-responders. They noted that CRT was accomplished with a success rate comparable to those with acquired heart disease. However, the anatomy is much more complex and those technical challenges in achieving success o
Dr Wong: Welcome to the monthly podcast, "On The Beat, for Circulation: Arrhythmia, and Electrophysiology." I'm doctor Paul Wong, editor in chief, with some of the key highlights from this month's issue. We'll also here from Dr. Suraj Kapa reporting on new research from the latest journal articles in the field. In our first article, Mathew Daly and associates examine whether a high-resolution, 9 French, infrared thermography catheter can continuously image esophageal temperatures during atrial fibrillation catheter ablation. The infrared temperature catheter was inserted nasally or orally into the esophagus, adjacent to the left atrium. Endoscopy was performed within 24 hours to document esophageal injury. Thermal imaging showed that 10 out of 16 patients experienced one or more events where the peak esophageal temperature was greater than 40 degrees centigrade. Three patients experienced temperatures greater than 50 degrees centigrade and one experienced greater than 60 degrees centigrade. Analysis of temperature data from each subject's maximal thermal event revealed high radius, 2.3 degrees centigrade per millimeter and rates of change 1.5 degrees centigrade per second, with an average length of esophageal involvement of 11.0 millimeters. Endoscopy identified three distinct thermal lesions, all in patients with temperatures greater than 50 degrees centigrade, all resolving within two weeks. The authors concluded that infrared thermography, high-resolution mapping of esophageal temperatures during catheter ablation may be performed. Esophageal thermal injury occurs with temperatures greater than 50 degrees centigrade, and was associated with large spacial-temporal gradients. In our next article, Nitesh Sood and associates reported on the real-world incidence and predictors of perioperative complications in transvenous lead extractions involving ICD leads in the NCDR ICD registry. Lead extraction was defined as removal of leads implanted for greater than one year. Predictors of major perioperative complication for all extraction procedures, 11,304, and for high voltage leads, 8,362, or 74% across 762 centers were analyzed, using univariate and multivariate logistic regression. Major complications occurred in 258, or 2.3% of the extraction procedures. Of these, 258 procedures with a complication, 41 or 16% required urgent cardiac surgery. Of these, 14 or 34% died during surgery. Among the total 98, or 0.9% deaths reported, 18 or 0.16% of the total occurred during extraction. In multivariate, logistic regression analysis of all extractions, female sex, admission other than electively for the procedure, three or more leads extracted, longer implant duration, dislodgement of other leads, patients' clinical status, requiring lead extraction, such as infection or perforation, were associated with increased risk of complications. For high voltage leads, smaller lead diameter, a flat versus round coil shape, in greater proximal surface coil area, were multivariate predictors of major perioperative complications. The rate of major complications and mortality with transvenous lead extraction is similar in the real world compared to single center studies from high volume centers. There remains a significant risk of urgent cardiac surgery with a very high mortality, and planning for appropriate cardiothoracic surgical backup is imperative. In our next paper, Bence Hegyi and associates, have reported on the repolarization reserve in failing rabbit ventricular myocytes, and the role of calcium and beta-adrenergic effects on delayed and inward rectifier potassium currents. The authors measured the major potassium currents, IKr, IKs, IK1, and their calcium and beta-adrenergic dependence in rabbit ventricular myocytes, in chronic pressure, in volume overload, induced heart failure, and compared them to age-matched controls. The authors made a number of observations. One, action potential duration was significantly prolonged only at lower pacing rates, 0.2 to 1 Hertz, in heart failure under physiological ionic conditions and temperature. Two, beat to beat variability of action potential duration was also significantly increased in heart failure. Three, both IKr and IKs were significantly regulated in heart failure under action potential clamp but only when cytosolic calcium was not buffered. Four, CaMKII inhibition abolished IKs upregulation in heart failure, but did not affect IKr. Five, IKs response to beta-adrenergic stimulation was also significantly diminished in heart failure, and, six, IK1 was also decreased in heart failure regardless of calcium buffering, CaMKII inhibition or beta-adrenergic stimulation. These observations changed when cytosolic calcium was buffered. The action potential prolongation in heart failure was also significant in higher pacing rates. The authors concluded that in heart failure, calcium dependent up regulation of IKr and IKs counter-balances the reduced IK1, maintaining the repolarization reserve, especially at higher heart rates. In physiologic conditions, unlike conditions of strong cytosolic calcium buffering. Under beta-adrenergic stimulation, reduced IKs responsiveness, severely limits the integrated repolarizing potassium current in repolarization reserve in heart failure, increasing the arrhythmia propensity. In the next paper, Christopher Piorkowski and associates report on the feasibility of a combined endo-epicardial catheter approach for mapping the ablation of atrial fibrillation. The authors studied 59 patients with permanents pulmonary veins isolation and had further symptomatic recurrences of paroxysmal atrial fibrillation, persistent atrial fibrillation, or atrial tachycardia. These patients underwent repeat ablation using bi-atrial endo- and epicardial mapping and ablation. Identification of arrhythmia substrates and selection of ablation strategy were based on sinus rhythm voltage mapping. In all patients, endo-epicardial mapping ablation were feasible using standard technologies of catheter access, three dimensional mapping, and radiofrequency ablation. Epicardial mapping and ablation did not add procedural risk. Exclusively, epicardial low voltage substrate were found in 14% of patients. For the first time, novel epicardial conduction abnormalities located in the epicardial fiber network were described in human patients, 19% of the cohort. Epicardial ablation was needed in 80% of the patients. Over 23 months of follow up, freedom from arrhythmia recurrence was 73%. The authors used continuous monitoring and three months blanking period. Freedom from ATR of greater than two minutes was defined as the primary end-point. The authors concluded that endo-epicardial mapping ablation was feasible and safe. Epicardial ablation increases transient mortality of ablation lesions. Further studies will be needed to demonstrate reproducibility and long-term outcomes, and how the technique compares to other methods. In the next article, Michael Wolf and associates examined the long-term results of substrate modification for ablation of ventricular tachycardia using substrate elimination, targeting local, abnormal ventricular activities, or LAVA, post-myocardial infarction. They reported on 159 consecutive patients undergoing first ablation, age 65, 92% with ICDs, 54% with storms, and 73% with appropriate shocks. LAVA were identified in 92% and VT was inducible in 73%. Complete LAVA elimination after ablation was achieved in 64% and non-inducibility was achieved in 85%. During a median follow-up of 47 months, single procedure, ventricular free survival was 55%, 10% storms, and 19% shocks. The ventricular arrhythmia free survival was 73% after one year and 49% after five years. Complete LAVA elimination was associated with improved outcomes, ventricular arrhythmia free survival of 82% at one year and 61% at five years. The subgroup treated with multi-electrode mapping and real-time image integration had improved ventricular arrhythmia free survival, 86% at one year and 65% at four years. Repeat procedures were also performed in 18% of patients. The outcomes improved, 69% ventricular arrhythmia free survival during a median follow-up of 46 months. In a single center study, substrate modification, targeting LAVA for post myocardial infarction ventricular tachycardia resulted in a substantial reduction in ventricular tachycardia storm and ICDs shocks with up to 49% of patients free of arrhythmias at five years after a single procedure. Complete LAVA elimination, multi-electrode mapping, and real-time integration were associated with improved ventricular arrhythmia free survival. In the next paper, Jean-Baptiste Gourraud and associates examined the safety and feasibility of transvenous lead extraction in adults with congenital heart disease over a 20 year period at a single center. The authors reported on 71 transvenous lead extraction procedures in 49 patients with adult congenital heart disease, mean age 38 years in which a total of 121 leads were extracted. The primary indication for extraction were infection in 48%, lead failure in 31%. A laser sheath was required in 46% and a femoral approach in 8%. Complete transvenous lead extraction was achieved in 92% of the leads. 49% of the patients had transposition of the great arteries. In multivariate analysis, lead duration was predictive of transvenous lead extraction failure. No perioperative death or pericardial effusion was observed. Subpulmonary, atrioventricular valve regurgitation increased in eight patients, five of whom had TGA and were independently associated with ICD leak or valvular vegetation. After a median of 54 months of follow up after the first lead extraction, three deaths occurred independently from lead management. The authors concluded that despite complex anatomical issues, transvenous lead extraction can be achieved successfully in most adult congenital heart disease patients using advanced extraction techniques. Subpulmonary AV valve regurgitation is a prevalent complication, particularly in patients with transposition of the great arteries. In the next paper, Gabriela Orgeron and associates examined the incidence of ventricular arrhythmias and follow-up in ARVC patients grouped by the level of indication for ICD placement, based on the 2015 International Task Force Consensus Statement Risk Stratification Algorithms for ICD Placement in arrhythmogenic right ventricular dysplasia/cardiomyopathy. In 365 of arrhythmogenic right ventricular dysplasia/cardiomyopathy patients, the authors found that the algorithm accurately differentiates survival from any sustained VT/VF among the four risk groups, p < 0.001. Patients with a Class I indication had significantly worst survival from VT/VF than patients with a Class IIa indication or a Class IIb. However, the algorithm did not differentiate survival free from VF or V flutter between patients with Class I and Class II indications. Adding Colter results, less than 100 PVCs per 24 hours to the classification, helps differentiate the risk. Patients with a high PVCs burden, greater than 1000 PCVs per 24 hours had a poor survival from both VT/VF and VF and V flutter. In the next paper, Takeshi Kitamura and associates studied eight patients that had bi-atrial tachycardia, a rare form of atrial macroreentrant tachycardia, in which both atria form a critical part of the circuit and were mapped using an automatic, high resolution, mapping system. 708 patients had a history of persistent atrial fibrillation, including septal or anterior left atrial ablation before developing bi-atrial tachycardia. One of the patients had a history of atrial septal path closure with a massively enlarged right atrium. The authors found that 9 atrial tachycardias, with a median cycle length of 334 milliseconds had three different types. Three were peri-mitral and peri-tricuspid reentrant circuit, three utilized the right atrial septum in a peri-mitral circuit, and three utilized only the left atrium and the left right atrial septum. Catheter ablation successfully terminated eight of the nine bi-atrial tachycardias. The authors found that all patients who developed bi-atrial tachycardia had an electrical obstacle on the intraseptal left atrium, primarily from prior ablation lesions. In our next paper, Kwang-No Lee and associates randomized 500 patients with paroxysmal atrial fibrillation to one of two strategies after pulmonary vein isolation. One, elimination of non-PV triggers in 250 patients, group A, or, two, step-wise substrate modification using complex fractionated atrial electrogram or linear ablation until non-inducibility of atrial tachyarrhythmias was achieved, 250 patients in group B. Recurrence of atrial tachyarrhythmias was higher in group B compared to group A. 32% of patients in group A experienced at least one episode of recurrent atrial tachyarrhythmia after the single procedure, compared to 43.8% in group B. P-value of 0.012 after a median follow-up of 26 months. Competing risk analysis showed that the cumulative incidence of atrial tachycardia was significantly higher in group B compared to group A (p= 0.007). The authors concluded that elimination triggers as the end-point of ablation in paroxysmal atrial fibrillation patients decreased long-term recurrence of atrial tachyarrhythmias compare to non-inducibility approach achieved by additional empiric ablation. In our final paper of the month, Roland Tilz and associates reported on 10 year outcome after circumferential pulmonary vein isolation using a double lasso and three dimensional electro anatomic mapping technique. From 2003 to 2004, 161 patients with symptomatic drug refractory paroxysmal atrial fibrillation underwent electro-anatomical mapping guided circumferential pulmonary vein isolation. The procedure end-point was absence of pulmonary vein spikes thirty minutes after isolation, after a single procedure and a median follow up of 129 months, stable sinus rhythm was present in 32.9% of patients based on Holter-ECGs and telephonic interviews. After multiple procedures, mean 1.73 and median follow up of 123.4 months, stable sinus rhythm was seen in 62.7% of patients. Progression towards persistent atrial fibrillation was observed in 6.2%. The authors concluded that although the 10-year single procedure outcome in patients with paroxysmal atrial fibrillation was low, 32.9%, it increased to 62.7% after multiple procedures and the progression rate to persistent atrial fibrillation was remarkably low. That's it for this month but keep listening. Suraj Kapa will be surveying all journals for the latest topics of interest in our field. Remember to download the podcast, "On the beat." Take it away Suraj. Dr Kapa: Thank you Paul, and welcome back everybody to Circulation’s “On the Beat”, where we'll be discussing hard hitting articles across the electrophysiology literature. Today, we'll be reviewing 22 separate articles of particular interest, published in January 2018. The new year saw plenty of articles that are of particular interest either for the future of our field of for present management of our patients. First, within the realm of atrial fibrillation, we'll review several articles within the realm of anticoagulation and left atrial appendage occlusion. The first article we'll review is by Yong et al in the American Heart Journal, volume 195, entitled "Association of insurance type with receipt of oral anticoagulation in insured patients with atrial fibrillation: A report from the American College of Cardiology NCDR PINNACLE registry." In this publication, the author sought to evaluate the effect of insurance type on the appropriate receipt of anticoagulant therapy, specifically looking at warfarin versus NOACs. They reviewed retrospectively over 360,000 patients and found significant differences in appropriate prescription of anticoagulants, irrespective of which anticoagulant was considered. Medicaid patients received less appropriate anticoagulant prescription than those who were privately insured on Medicare or military insured. Furthermore, those on military or private insurances had a higher rate of NOAC prescription than those with Medicare. Furthermore, there was an even wider disparity in NOAC use than warfarin use amongst differently insured patients. These data are important in that they highlight potential variability in appropriate management of patients based on insurance type. Of course, there are many issues that might impact this, such as health care access or available pharmacy coverage of specific medications. Furthermore, the authors do not dive into the impact on outcomes based on the therapy availability. The next article we'll review is by Jazayeri et al, entitled "Safety profiles of percutaneous left atrial appendage closure and lysis: An analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database from 2009 to 2016" published in the Journal of Cardiovascular Electrophysiology in volume 29 issue 1. Here, the authors sought to evaluate the overall safety profiles of procedures performed with different percutaneous left atrial appendage occlusion devices, including LARIAT and WATCHMAN. They review 356 unique reports and compared outcomes pre- and post- approval of the WATCHMAN device. The look at the specific composite outcome of stroke, TIA, pericardiocentesis, cardiac surgery, and death. They noted that this composite outcome occurred more frequently with WATCHMAN than with LARIATs, and this is irrespective of pre- or post- approval status. These findings highlight the importance of postoperative monitoring in evaluation of overall outcomes. The reason by which there was more frequent negative outcomes in the WATCHMAN than LARIATs need to be considered. Obviously there's several limitations in the MAUDE database, similar with all large databases. However, it does highlight the importance of considering the mechanisms or sure decision making necessary, not just amongst patients and their providers but amongst operators of the staff or amongst physicians and industry executives. To determine how to optimize devices going forward. Speak of left atrial appendage occlusion devices and the potential future of these, we next review an article by Robinson et al, entitled "Patient-specific design of a soft occluder for the left atrial appendage" published in nature biomedical engineering, in volume two in the year 2018. Robinson et al used 3D printing to create a soft, immunocompatible, biocompatible, endocardial implant to occlude the left atrial appendage. They use the individual CT of an in vivo pig to three D print using a specialized material, a left atrial appendage occlusion device, and demonstrated feasibility of achieving adequate occlusion. This paper is important and is one of the initial [inaudible 00:22:03] to how three D printing may be used to optimize patient care. In fact, three D printing has the potential to overturn medical manufacturing and device development. Anatomy tends to be more often patient-specific than not. That's one size fits all implant designs may not be optimal, and resulting exclusion or inadequate occlusion amongst many patients. Decide of three D printable patient specific rapidly prototype soft devices that are biocompatible and hemocompatible, holds the potential to revolutionize the occlusion. Staying in the field of left atrial appendage occlusion, we next review an article by Lakkireddy et al entitled "left atrial appendage closure and systemic homeostasis: The LAA homeostasis study" published in JACC. The authors sought to evaluate the effect of epicardial-versus endocardial left atrial appendage occlusion on systemic homeostasis, including effects on neuro-hormonal profiles of patients. They performed a prospective, single center, observational study, including 77 patients, about half of whom received endocardial versus epicardial device. Interestingly, they noted that the epicardial left atrial appendage occlusion cohort exhibited significant decrease in blood adrenaline, noradrenaline and aldosterone levels. Those are not seen with endocardial devices. Internal epicardial devices are associated with increases in adiponectin and insulin levels as well as a decrease in free fatty acids and consistently lower systemic blood pressure. These data suggest a significant difference in the effect of epicardial versus endocardial closure left atrial appendage on neurohormonal profile. The authors propose several mechanisms for these findings but not the exact mechanisms as yet unclear. Several factors potentially could lead to these findings. One is that epicardial ligation may result in more total ischemia of the left atrial appendage than endocardial closure. Another potential mechanism maybe that the presence for material in the pericardial space versus in the bloodstream may have different effects on neuro-hormonal profile. However, these significant differences in outcomes highlight the importance of considering whether all approaches of left atrial appendage occlusion are considered equal. Many flaws of this study is that it's observational and not randomized. Does it possible those receiving epicardial closure may have been perceived to be lower risk for epicardial puncture, in this, as result, had better long-term outcomes. Changing gears now but staying within the realm of atrial fibrillation, we next review elements for cardiac mapping and ablation. The first article we review is one that has received significant press, published by Marrouche et al entitled "Catheter ablation for atrial fibrillation with heart failure" in the New England Journal of Medicine, volume 378. It is well recognized that morbidity and mortality are higher in heart failure patients who also have atrial fibrillation. Marrouche et al published the results of the CASTLE-AF trial, which attempted to determine if catheter ablation [inaudible 00:24:46] better outcomes among patients with heart failure and atrial fibrillation. They randomized 179 patients to ablation and 184 to medical therapy, which consisted of either rate or rhythm control. Inclusion criteria were those with NYHA class II to IV heart failure, LVEF of 35% or less, and an ICD. The primary endpoint was a composite where the death from many causes or hospitalizations for worsening heart failure. They noted over a median of three as a follow up, the end-point was reached in 28.5% of the ablation group and 44.6% of the medical therapy group, accounting for a significant hazard ratio of 0.62. Furthermore, fewer patients that in the ablation group died from any cause, were hospitalized for worsening heart failure, or died from cardiac causes. These data made a big splash because they're highly supportive of the premise that catheter ablation may be beneficial in some patients with atrial fibrillation and heart failure, often beyond that of medical therapy alone. One major strength of this paper is that the actual AF burden was tracked by the ICD, so we know for sure whether or not the procedure was successful and how controlled the atrial fibrillation was. One thing to note however, is that subgroup analysis suggest that those with more symptomatic heart failure, namely NYHA class III to IV, not benefit as much from ablation. Furthermore, it's also important to note that the five years expected mortality in patients was higher than predicted in the CASTLE-AF trial, however overall these trials highly suggest that the potential benefit that ablation may hold over conventional medical therapy. Extrapolation to comparison with the utility of interventions such as biventricular pace with AV node ablation, however, remains to be considered. Next, we review an article by Chugh et al entitled "Spectrum of atrial arrhythmias using ligament of Marshall in patients with atrial fibrillation" published in Heart Rhythm volume 15, issue 1. They reviewed the spectrum of presentations associated with arrhythmogenesis attributed to the ligament of Marshall, amongst patients with atrial fibrillation. They demonstrate that nearly a third of those patients, ligament of Marshall associated arrhythmias had a pulmonary vein ligament connection, that variously required ablation, the left lateral ridge, the mitral annulus, or alcohol ablation. In addition, they noted about a quarter of patients had atrial tachycardia attributable to the ligament, and the remaining had periatrial reentry requiring either ablation or alcohol injection of the ligament to attain a conduction block. The relevance of this publication, albeit it is of a small number of patients and a small center, lies in highlighting on the right mechanisms by which the ligament of Marshall may contribute to arrhythmogenesis. Namely, can include direct venous connections, inhibition to inaudibility to attain mitral block, and directly attributed atrial arrhythmias. Recognition of the various ways and situations under which the ligament of Marshall may play a role in arrhythmogenesis in atrial fibrillation patients, may optimize physician decisions to look for identify and target the ligaments. What is not as well understood however is the frequency with which ligament of Marshall plays a significant role in arrhythmogenesis in atrial fibrillation. Moving gears, we next review an article by Pathik et al entitled "Transient rotor activity during prolonged three-dimensional phase mapping in human persistent atrial fibrillation" published in a special issue of JACC Clinical Electrophysiology, that focus on atrial fibrillation specifically, in volume 4 issue 1. Pathik et al sought to validate three-dimensional phase mapping system for persistent atrial fibrillation. Commercially available rotor mapping systems project the heart into two dimensions based on a three-dimensional catheter. Instead, Pathik et al used a combination of basket catheters along with the non-left atrial surface geometry to construct three D representations of phase progression. Amongst 9 out of 14 patients, they identified 34 rotors, with all these rotors being transients. Of particular interest, the rotors were only seen in areas of high electric density, where internal electric distances were shorter. They also noted the single wave front is also the most common propagation pattern. The importance of this publication lies in considering two things. First is the three dimensional representation of rotor position and the feasibility of this, and the second is really the high electro-density necessary to observe for others. This has been one of the main problems in rotor analysis, namely what the spacial and temporal density is, that is required to identify rotors, especially given how transient they often are. The presence of rotors does not necessarily mean they're ablation targets in all patients. However, the question still remains regarding the optimal approach to mapping rotors, it needs to be remembered that rotors actually are meant to represent three dimensional scrollway phenomena, that cannot necessarily always be reflected in traditional two D mapping schema. Furthermore, to be remembered that when we claim three-dimensional mapping, this just reflects a two-dimensional surface being wrapped in three dimensions to reflect overall internal surface geometry but it does not take into account transmural activation. Thus, taking into account all these elements it should be remembered as sometimes, it is possible that a rotor might exist but it's just not evident based on the two-dimensional representation or a two-dimensional representation that looks like a rotor may in fact not be a rotor when you consider it in a three-dimensional media. Our last article within the realm of cardiac mapping and ablation we will consider is by Zghaib et al, entitled "Multimodal examination of atrial fibrillation substrate: Correlation of left atrial bipolar voltage using multielectrode fast automated mapping, point by point mapping, and magnetic resonance imaging intensity ratio", published in JACC Clinical Electrophysiology, in the same volume as the previous article. The authors sought to compare fast automated mapping with multiple electrodes versus point by point mapping and correlate with weighed gadolinium enhancement as seen by MRI, termed the image intensity ratio. We all recognize that bipolar voltage is critical to recognizing and evaluating substrate. It's traditionally used in decay regions of substrate in both the atrium and ventricles. However, whether a newer automated approach used to characterize substrate perform equally well in comparison with traditional point to point mapping is still unknown. Thus, the authors in 26 patients perform cardiac MRI and mapping endocardial using both voltage mapping techniques. They noted that for each unit increase in image intensity ratio on MRI, in other words, increasing late enhancement, there was 57% reduction of bipolar voltage. They also noted that the bipolar voltage using other fast elevating mapping or point by point was significantly related with actual differences in calculated voltage, becoming more dissimilar in the extreme of high and low voltage areas. The relevance of this publication is highlight in the potential utility of fast automated mapping in creating accurate voltage maps. The correlation of voltage values with image-intensity ratios suggest the utility of either approach. In turn, correlation with MRI suggest a pathologic correlate for all of these findings. However, whether substrate characterization guide ablation carries incremental benefit remains to be seen. Changing gears but staying in the realm of atrial fibrillation, we next review elements of risk stratification and management. The first article we review is by Friedman et al, entitled "Association of left atrial appendage occlusion and readmission for thromboembolism amongst patients with atrial fibrillation undergoing concomitant cardiac surgery", published in JAMA, volume 319, issue four. Friedman et al sought to evaluate whether surgical left atrial appendage occlusion let to a reduction in long-term thromboembolic risk in a large database of Medicare recipients. They included the primary outcome as readmission for thromboembolism, including stroke, TIA, or systemic embolism, in up to three years of follow-up. With secondary end-points including hemorrhagic stroke, all-cause mortality, and a composite end-point of all outcomes. Amongst more than 10,000 patients, there were almost 4,000 patients receiving surgical occlusion of left atrial appendage. Surgical occlusion was associated with a reduction in thromboembolic risk, OR of 6%, all cause mortality, 17 versus 24%, and the composite end-point, 21 versus 29%. However, interestingly, surgical occlusion was only associated with reduction in thromboembolic risk compared with no occlusion amongst those discharged without anticoagulation and those discharge with it. Namely, the thromboembolic risk reduction was primarily seen in those where the surgical occlusion, those who were sent home without any sort of anticoagulation. These data suggest that surgical occlusion leads to reduction of thromboembolic risk overall. As any large database based study, there are massive flaws in the database itself. Namely, we're relying on the coding of hospitals and operators. To know exactly what was done and what happens latter. However, these data are hypothesis generating. One key element is the fact that surgical left atrial appendage occlusion was only superior in reducing thromboembolic risk amongst those discharged without anticoagulation. This raises the question as why. Was left atrial appendage completely closed in these patients? In which case, they may be at further increased risk or that the operators felt that there is a high risk for other reasons that cannot be cleaned from an administrative datasets? While the data support consideration of the benefit of left atrial appendage occlusion in a surgical manner, a kin to what has been seen in papers on WATCHMEN and other approaches, and how is the critical nature of randomized trials in this regard. We next review an article published in JAMA Cardiology, volume three issue one by Inohara et al, entitled "Association of atrial fibrillation clinical phenotypes with treatment patterns and outcomes: A multicenter registry study." Traditionally classification of AF has depended largely on factors such as the nature of AF, paroxysmal versus persistent, LA size, and other factors such as extend of the late enhancement. Inohara et al sought to evaluate whether cluster analysis could better define heterogeneity of AF in the population. They included an observational cohort of almost 10,000 patients admitted to 124 sites in the United States in the ORBIT-AF registry. Outcome was a composite major address cardiovascular and neurological events or major bleeding. Amongst these patients, they identified four clusters, including one those with lower rates of risk factors and comorbidities than other clusters, two, those with AF at younger ages and with comorbid behavior disorders. Three, those with AF with tachycardia-bradycardia type syndromes and had devices for sinus node dysfunction, and four, those with AF with other risk factors such as a coronary disease. Those in the first cluster had significantly lower risks of major events. All clusters were noted to have symptom dissociation to specific clinical outcomes. These data are interesting and highlight the highly heterogeneous nature of classifying risk attributable to atrial fibrillation. When broad datasets associated atrial fibrillation with specific outcomes. Maybe suggest an attribution to all patients with atrial fibrillation. However, this single relationship was specific to the outcomes suggest the limitation of applying outcome as approach to understand atrial fibrillation impacts and outcomes, namely depending on clusters that may take into account patient age or comorbidities, it may be irrelevant in discriminating patient outcomes than the traditional paradigm in the same paroxysmal versus persistent or depending on the left atrial size. These data also highlight the importance of considering the inclusion criteria in randomized trials of atrial fibrillation before stripling real world outcomes to patients who don't fit within that trial. Next, we will be reviewing an article by Chou et al entitled "Relationship of aging and incident comorbidities to stroke risk in patients with atrial fibrillation," published in JACC, volume 71 issue two. Chou et al sought to evaluate the effect of aging and evolving instant comorbidities to stroke risk in patients with atrial fibrillation. Many large database studies or trials where added baseline CHADSVASC score and the then ensuing follow up period to define risk over time of ischemic stroke. The authors hypothesized that as patients age, develop new comorbidities that would change the score, may be more predictable of long-term outcomes than the score itself. They included over 31,000 patients who do not have comorbidities to CHADSVASC aside from age and sex but had atrial fibrillation. They didn't calculate a delta score defined as the difference between the baseline and follow up scores. The mean baseline score was 1.29 with an increase in 2.3 during follow up, with an average delta of one. The score may not change over follow up in 41% of patients. Interestingly, significantly more patients had a delta CHADSVASC of one or more and develop ischemic stroke than non-ischemic stroke. The delta CHADSVASC was shown to better predictor of ischemic stroke than either baseline or follow up CHADSVASC score. This data suggest that additive shifts in the CHADSVASC score over time may be more predictive of stroke risk than the actual score itself. These findings are thoughtful and logical. They indicate the potential impact of continued aging or acquisition identification of new comorbidities. In some patients, potential discovery or new comorbidities or follow-up; for example, hypertension and coronary artery disease may lead to reclassification of stroke risk. That is important to maintain close follow up of atrial fibrillation patients, and not to show a continued need or lack of need of anticoagulation on the basis of a baseline evaluation. This also holds relevance single center long-term outcomes in patients specific scores. Whether is acquisition of new comorbidities or presence of baseline comorbidities or predict a long-term score, should we consider when assessing the need for anticoagulation, particularly in perceived initially low risk cohorts who go on to develop ischemic stroke. Lastly, within the realm of atrial fibrillation, we review an article by Hussain et al, entitled "Impact of cardiorespiratory fitness on frequency of atrial fibrillation, stroke, and all-cause mortality" published in the American Journal of Cardiology, volume 121 issue one. Hussain et al review the effect of cardiorespiratory fitness on overall outcomes and incidence of atrial fibrillation and outcomes amongst patients with atrial fibrillation. Amongst over 12,000 individuals prospectively followed up after treadmill exercise test, they noted 1,222 had a incidence of AF, 1,128 developed stroke, and 1,580 died. For every 10% increase in functional layover capacity, there was a 7% decrease in risk of incident AF, stroke, or death. Similarly, in those who developed AF, stroke was lower in those with higher functional aerobic capacity. These findings support the notion known to other areas of cardiovascular disease that better cardiorespiratory fitness is associated with better outcomes, in this case to stroke, incident AF, or mortality. Furthermore, even on the presence of AF, those with better functional capacity had a lower risk of stroke. These data highlight the continued importance of counseling patients on the benefits of physical fitness even in the setting of already present AF. Moving on to a different area of electrophysiology, we review the realm of ICD pacemakers and the CRT. The first article review is by Sze et al entitled "Impaired recovery of left ventricular function in patients with cardiomyopathy and left bundle branch block" published in JACC volume 71 issue 3. Patients with left bundle branch block and cardiomyopathy are known to respond to CRT therapy. Thus the investigators sought to evaluate whether guideline medical therapy in patients with reduced LVEF and left bundle branch block, afford a beneficial first line approach therapy. The reason for this currently guidelines suggest waiting at least three months before consideration of CRT has had as some patients may recover on guideline directed medical therapy without the need for device implantation. They review patients with a LVEF of less or equal than 35% and baseline ECG showing left bundle branch block. In evaluating left ventricular ejection fraction at follow up of three to six months. They excluded patients with severe valvular disease, and already present cardiac device, an LVAD, or heart transplant. Among 659 patients meeting criteria, they notice 74% had a narrow QRS duration of less than 120 whereas 17% had QRS duration greater than 120, and the remainder had a QRS duration greater 120 but was not left bundle branch block. The mean increase in the left ventricular ejection fraction on guideline directed medical therapy was in those with a narrow QRS duration and least in those with left bundle branch block, 8.2%. Furthermore, when comparing mean LVEF improvement, those with on versus non-on guideline directed medical therapy, there was virtually no difference in rates of recovery. Furthermore, composite end-point of heart failure hospitalization mortality was highest in those with left bundle branch block. These data suggest that those with bundle branch block and cardiomyopathy received less overall benefit from guideline directed medical therapy over the three to six months follow up period. Whether this is due to already more severe myopathic process to start with or due to the CRT is unclear. However, it may suggest that in some patients, left bundle branch block may benefit from inclusion of CRT early in their disease course as known the significant number of patients up to three to six months guideline directed medical therapy with insufficient DF recovery may then benefit from CRT. As well as intervening earlier may result in better outcomes, especially knowing the high and term raise mortality in heart failure hospitalization remains to be seen. A trial studying early implantation of CRT on these patients may be relevant. The next article review is by Gierula et al entitle "Rate-response programming tailored to the force-frequency relationship improves exercise tolerance in chronic heart failure" published in JACC Heart Failure, in volume six, issue two. The authors sought to evaluate whether tailored rate-response programming improved exercise tolerance in chronic heart failure. The double blinded, randomized, control, crossover study, they compared the effects of tailored programming on the basis of calculated force-frequency relationship, defined as including critical heart rate, peak contractility, and the slope, multidimensional programming and exercise time and maximal oxygen consumption. They demonstrate amongst 98 enrolled patients that rate-response settings limiting heart rate raise to below the critical heart rate led to create exercise timing and higher peak oxygen consumption. These data suggest that personalizing rate-response therapies may improve exercise time and oxygen consumption values in patients with heart failure and pacing devices. The main limitation of the study is that the number of patients was small, 90, and then the number of patients crossing over was even smaller, 52. However, highlights the potential of working closely between device programmers and consideration of individual's characteristics and their exercise needs in determining optimal programming strategy. Finally, within the realm of devices, we review an article by Hawkins et al, entitled "Long-term complications, reoperations, and survival following cardioverter defibrillator implant" published in Heart, volume 104 issue three. Hawkins et al sought to evaluate the long-term complications and risk of reoperation associated with defibrillator implantations in a large [inaudible 00:41:56] population of 300,410 patients, they noted over a 30-month follow up period there was a 12% reoperation rate within the year of implant. This is most prominent for CRT devices, with a risk of 18% in one year post-implant. Furthermore, CRT had the highest rate of early complications, with device complexity, age, or the presence of atrial fibrillation being significantly associated with complication risk. Mortality also increased over time from 5% within the first year to nearly a third after five years. However, younger patients exhibited five years survival similar to the general population with a progressive decline of this as older patients were considered. These findings highlight several critical issues. First, they report a high one year reoperation rate for a variety of reasons. This finding highlights the importance of considering protocols to minimize the need for reoperation. Furthermore, they note the higher rate amongst CRT patients, with seems logical given the likely longer associated procedural risk and need for more leads. Finally, the impact of age on expectant survival are to be taken into consideration with the device and the life-saving potential of the defibrillator. Moving on to cellular electrophysiology, review one article by Zhang et al, entitled "Reduced N-type calcium channels in atrioventricular ganglion neuron are involved in ventricular arrhythmogenesis" published at the journal of the American Heart Association, in volume seven issue two. Zhang et al reported a rat model of ventricular arrhythmogenesis and characterized the role of atrioventricular ganglion neurons in risk of arrhythmogenesis as well as the mechanism for this risk this model relates in humans to the attenuated cardiac vagal activity in heart failure patients, which is known to relate to their arrhythmic risk. The demonstrated reduced N-type calcium channel in these AV ganglion neurons, which project innervating systems to the myocardium, resulting in increased risk of PVCs, and increased susceptibility to induction of ventricular arrhythmias with programmed stimulation. The relevance of the intrinsic cardiac nervous system arrhythmogenesis has become increasingly prominent as methods to study it have improved. Understanding the direct and most relevant inputs may facilitate better understanding of risk of arrhythmias in patients. In the case of this study by Zhang et al, the critical finding is that disorder of the atrioventricular ganglion neurons may lead to increased susceptibility for ventricular arrhythmogenesis. Clinical relevance includes consideration of effects on this specific ganglion when performing ablation on for other conditions, and potential long-term effect on arrhythmogenic risk, as well as potentially relevant functional explanations for arrhythmogenesis. Moving on to the genetic channelop, these are considered two separate articles. The first one by Bilmayer et al, entitled "ExomeChip-Wide analysis of 95,626 individuals identified ten novel loci associated QT and JT intervals" published in Circulation: Genomic and Precision Medicine, in volume 11 issue 1. This whole exome study reviewed several novel loci that modified the QT and JT intervals. They include over 100,000 individuals and identified ten novel loci not previously reported in the literature. This increases the number of known loci that impact from ventricular portal adjacent by nearly one third. These loci appear to be responsible for myocyte and channel structure and interconnections that internally impact the ventricular repolarization. While long QT syndrome be characterized amongst the known genes in 75% of affected individuals, that also means one fourth long QT syndrome cannot be characterized based on known genes impacting ventricular repolarization. The identification of novel loci or novel that may be affect repolarization kinetics to unique means are critical to define novel therapies as well as in genetic counseling the patients in potential effects on family members when screening them for potential disease risk. These findings should assess an opportunity for further studying the mechanisms by which these loci modulate QT and JT intervals and the potential contribution to phenotypic risk. The second paper within this realm we review is by Zumhagen et al, entitled "Impact of presynaptic sympathetic imbalance on long QT syndrome by positron emission tomography" published in Heart, volume 104. The authors sought to evaluate by a PET scan the impact of sympathetic heterogeneity on long-QT syndrome risk. Amongst 25 patients with long-QT syndrome, including long-QT type I and II, and 20 ostensibly healthy controls, they noted that regional retention in disease were similar between affected patients and controls. However, regional washout rates were higher in the lateral left ventricles in patients with long-QT syndrome. Internal global washout rates were associated with greater frequency of clinical symptoms. That's there seem to be some relationship between regional and global sympathetic heterogeneity, particularly during washout, with overall risk in long-QT syndrome patients. These findings report the notion for sympathetic imbalance, partly mediating the risk attributable to long-QT syndrome. The findings on PET suggest regional imbalance of presynaptic cathecholamine and reuptake and release, being one mechanisms. This was most prominent in long-QT I patients who also often drive most benefit from left sided sympathectomy. The novelty of these findings is in the potential role of imaging to determine basic contributors to congenital long-QT syndrome in given patients. The larger prospect of size would really need to be evaluated this further. Moving on to the realm of ventricular arrhythmias, we review three different articles. The first one, by Hamon et al, entitled "Circadian variability patterns predict and guide premature ventricular contraction ablation, procedural disability, and outcomes" published in Heart Rhythm, volume 15 issue one. Hamon et al sought to evaluate whether circadian variability of PVC frequency can predict optimal drug response intraprocedurally during PVC ablation. One of the main problems of PVC ablation is when PVC are infrequent and tend to disappear during the procedure, achieving procedural success or attaining sufficient frequencies of PVCs to map becomes very difficult. Next, they use Holter monitoring in the ambulatory stripe to define three groups. Those of higher PVC burden during faster heart rates, those with higher PVC burden during slower heart rates, and those with no correlation between their PVCs burden and their heart rate. More than half the one hundred and one patients included a high burden of PVCs at fast rate while 40% had no correlation between the two and 10% had higher burden in slower heart rates. Almost one third of patients taken for ablation have infrequent PVCs during a procedure, while the best predictor of this being a low ambulatory PVC burden of less than 120 per hour. Isoproterenol infusion was only useful in lessening PVCs in those with PVCs associated with fast heart rates. The isoproterenol washout or phenylephrine where used with those associated with slower heart rates. Interestingly, not a single drug was effective in inducing PVCs in those with infrequent PVCs that have not heart rate correlation in the ambulatory stages. They noted that outcomes ablates were similar amongst those with higher heart rate associated PVCs and non-heart rate correlated PVCs previously responded to a drug. But, [inaudible 00:48:08] noted only a 15% success rate from ablation in infrequent PVCs in patients who lacked correlation between PVC burden and heart rate and who were unresponsive to drug previously. These data are important highlighting the potential for further defining idiopathic PVC ablation needs and likelihood of success based on ambulatory data, by correlating PVC burden with heart rate and their circadian variability, it's possible to predict likelihood specific intraoperative drugs working when dealing with infrequent intraprocedural PVCs. Furthermore, the finding of lack of correlation with slower or fast heart rate in terms of PVC burden is associated with the poor success rate unless those PVCs are drug responsive. Highlights the potential benefit of performing preoperative antiarrhythmic drug testing to get likelihood of ablation success in this patients. The next article we review is by Lee et al, entitled "Incidence and significance of the lesions encountered during epicardial mapping and ablation of ventricular tachycardia in patients with no history of prior cardiac surgery or pericarditis" published in Heart Rhythm, volume 15 issue one. Lee et al sought to determine the frequency of pericardial lesions, impeding mapping in patients without prior surgery, operative procedure, or pericarditis, in other words virgin hearts. Amongst 155 first time attempts of access, 8% had pericardial lesions. The only clinical predictor was the presence of severe renal impairment. In addition, no patients with supposedly normal hearts had a lesions. Notably, those with a lesion had more frequent impairment in mapping and lower overall success rates; there were similar complication rates as those without the lesions. These data are relevant in highlighting the ease of mapping of pericardial access may not always be present, even when dealing with inversion of pericardial space. A lesion may be present in patients, particularly with severe renal disease. Advising patients of this possibility prior to the procedure and considering that epicardial access may be impaired in a fair number of patients, even the absence of prior history of surgery, epicardial access or pericarditis isn't important. The final article we'll review within the realm of ventricular arrhythmias is by Kumar et al, published in Journal of Cardiovascular Electrophysiology, volume 29 issue one, entitled "Right ventricular scar-related ventricular tachycardia in nonischemic cardiomyopathy: Electrophysiological characteristics, mapping, and ablation underlying heart disease." Kumar et al sought to evaluate the substrate and outcomes associated with right ventricle scar related ventricular tachycardia ablation in nonischemic patients at large, but particularly in those with neither stroke or coronary artery disease as potential explanations for this scar. They reviewed 100 patients consecutively over half of whom had ARVC and the remainder was sarcoid or RV scar of unclear origin. Those with RV scar of unknown origin tend to be older compared to the ARVC patients, and had more severe LV dysfunction compared with saroid patients. However, the scar distribution extend was similar within all these groups. Furthermore VT/VF survival was higher in those with RV scar of unknown origin. The velocity of survival free or death or cardiac transplant and VT/VF survival seen in sarcoid patients. These data suggest that close to one third of patients, RV scar related VT may have VT of unknown cause. Total outcome was superior overall to those with defined myopathic processes. What's most interesting is, over follow up, none of those with RV scar of unknown origin develop any further findings to reclassify them as sarcoid or ARVC. It is possible this group reflects some mild form of either disease however. Again, the exact pathophysiologic process remains unclear. These findings may help in counseling patients who are in long-term expected outcomes from ablation intervention. The final article we'll review this month is within the realm of other EP concepts that may be broadly applicable, published by van Es et al, entitled "Novel methods for electrotissue contact measurement with multielectrode catheters", published in Europace, volume 20 issue one. In this publication, the authors sought to evaluate the potential utility of a novel measure on evaluating electro tissue contact. With multielectrode catheters it is known that one of the problems with assessing contact is a contact force that cannot be used. Electro with coupling index is often used but even this has fragile problems, especially when you get into high impedance areas, that can be affected by surrounding ion impedance structures. Due to the fact that measuring contacts forces challenging in such multielectrode catheters, the authors measure electric interface resistance by applying a low level electrical field, pushing neighboring electrodes. They compared the effectiveness of assessing contact by this approach without using contact force in a poor side model. They know that this measure was directly correlated with contact force in measuring tissue contacts. These findings support a role for aversion of an active electrode location and determining tissue proximity and contact-based on the coupling between the electrodes on multipolar catheters in the tissue. These findings may be highly useful when there is a variety of catheters where contact force cannot be implemented. Further studies on the methods and cutoff to establish tissue proximity on the end of contact will be also needed. To summarize, however, as a term was brilliant here that was not well explained, active electrical location is actually a phenomenon that occurs in nature. This is seen in deep sea fish, which actually have multiple electrodes oriented around its body. They emit a small electrical field that results in a general impedance field surrounding the fish. This essentially is the way of visualizing the world around them. Perturbations based on proximity to different structures, whether they are live or death, and based on whether they are live or death, results in changes in the perturbations of this resistive fields, resulting in proximity determination by the fish. Several individuals are looking into potential applications of this to understanding tissue proximity when using catheters in the body. This consideration of impedance is fundamentally different than the traditional measure impedance were used by traditional generator. I appreciate everyone's attention to this key and hardening articles that we've just focus on or this past month of cardiac electrophysiology across literature. Thanks for listening. Now back to Paul. Dr Wong: Thanks Suraj, you did a terrific job surveying all journals for the latest articles on topics of interesting in our field. There's not an easier way of staying in touch with the latest advances. These summaries and the list of all major articles in our field for month can be downloaded from the Circulation: Arrhythmia and Electrophysiology website. We hope that you find the journal to be the go to place for everyone interested in the field. See you next month.
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Today's feature paper is going to cause us to rethink the way we prognosticate patients with pulmonary arterial hypertension following their initial management. Think you know the hemodynamic variables? Well, stay tuned for this discussion coming right up after these summaries: Our first original paper this week shows for the first time the predictive value of coronary artery calcification progression for coronary and cardiovascular events in a population base study. Authors Dr. Erbel and Lehmann from University Hospital Essen in Germany and their colleagues evaluated several progression algorithms between CTs performed at baseline and after a mean of five years for the risk prediction of coronary and cardiovascular events in a population base cohort of more than 3,200 participants initially free from cardiovascular disease. The authors found that coronary artery calcification progression added some predictive value to the baseline CT and risk assessment, and even when the five-year risk factors were taken into account. However, the progression yielded no additional benefit when the five-year coronary artery calcification results were taken into account instead of the baseline coronary artery calcification results. Double zero coronary artery calcification scans in a five-year interval meant an excellent prognosis, which was better than the prognosis for incident coronary artery calcification after five years. Thus, the authors concluded that sophisticated coronary artery calcification progression algorithms may be unnecessary and clinicians can instead rely on the most recent risk and coronary artery calcification assessment. The next paper demonstrates for the first time cell-specific effects of Smad3 signaling in the infarcted myocardium. Now, in the infarcted heart, Smad3 signaling is known to be activated in both cardiomyocytes and the interstitial cells. In the current paper, co-first authors, Doctors Kong and Shinde, corresponding author Dr. Frangogiannis from Albert Einstein College of Medicine in New York, and their colleagues hypothesized that cell-specific actions of Smad3 may regulate, repair, and remodeling in the infarcted myocardium. In order to dissect the cell-specific Smad3 actions in myocardial infarction, these authors generated mice with Smad3 loss specifically in activated fibroblasts or in cardiomyocytes. They found that fibroblast-specific Smad3 activation played a critical role in repair following myocardial infarction by restraining fibroblast proliferation and contributing to scar organization by stimulating integrin synthesis. On the other hand, cardiomyocyte-specific Smad3 signaling did not affect acute ischemic injury, but triggered nitrosative stress and induced matrix metalloproteinase expression in the remodeling myocardium, thereby promoting cardiomyocyte death and contributing to systolic dysfunction. In summary therefore, these authors demonstrated the cellular specificity of Smad3-dependent actions that stimulate distinct cellular responses in fibroblasts versus cardiomyocytes in the healing myocardial infarction. The implications are that nonspecific therapeutic targeting of Smad3 signaling in pathologic conditions may interfere with both detrimental and beneficial actions. On the other hand, design of interventions with specific cellular targets may be needed for the development of safe and effective therapies. Good news from the next paper! Genetically predetermined high blood pressure and its complications may be offset by healthy lifestyle. Well, at least, to some extent. First author, Dr. Pazoki, co-corresponding authors Dr. Elliott from Imperial College London and Dr. Tzoulaki from University of Ioannina in Greece aimed to investigate the extent to which lifestyle factors could offset the effect of an adverse blood pressure genetic profile as well as its effects on cardiovascular disease risk. To do this, they constructed a genetic risk score for high blood pressure using 314 published blood pressure loci in more than 277,000 individuals without previous cardiovascular disease from the UK Biobank study. They scored participants according to their lifestyle factors including body mass index, healthy diet, sedentary lifestyle, alcohol consumption, smoking, and urinary sodium excretion levels measured at recruitment. They examined the association between tertiles of genetic risk and tertiles of lifestyle score with blood pressure levels and incident cardiovascular disease. They found that adherence to a healthy lifestyle was associated with lower blood pressure regardless of the underlying blood pressure genetic risk. Furthermore, adherence to a healthy lifestyle was also associated with lower risk of myocardial infarction, stroke, and the composite cardiovascular disease at all levels of underlying blood pressure genetic risk. Healthy compared to unhealthy lifestyle showed a 30%, 31%, and 33% lower risk of cardiovascular disease respectively among participants at low, middle, and high genetic risk groups. Thus, these results strongly support population-wide efforts to lower blood pressure and subsequent cardiovascular disease risk through lifestyle modification. The final paper is an aggregate report from two large randomized trials, which demonstrate for the first time that more potent antiplatelet therapy further lowers venous thromboembolism risk relative to aspirin alone. First author Dr. Cavallari, corresponding author Dr. Bonaca, and colleagues from the TIMI Study Group in the Brigham and Women's Hospital ascertained and characterized symptomatic venous thromboembolism events in more than 47,600 patients randomized in the TRA 2°P-TIMI 50 and PEGASUS-TIMI 54 trials. They evaluated risk of symptomatic venous thromboembolism over time, independent risk factors for venous thromboembolism, and the efficacy of more intensive antiplatelet strategies at reducing venous thromboembolism risk. They found that the rate of venous thromboembolism in patients with atherosclerosis was 0.3% per year while on treatment with at least one antiplatelet agent. This risk increased independently with the number of symptomatic vascular territories. Furthermore, more intensive antiplatelet therapy with Vorapaxar and Ticagrelor in this case reduced the risk of venous thromboembolism. These data suggested a relationship between atherosclerosis burden and venous thromboembolism risk. The data also support the inclusion of venous thromboembolism as a prospective endpoint in long-term secondary prevention trials evaluating the risks versus benefits of antiplatelet therapies in patients with atherosclerosis. Well, that wraps it up for our summaries. Now for our feature discussion. For our feature discussion today, we are talking about pulmonary arterial hypertension. We've learned so much from registries about prognostication of pulmonary arterial hypertension at the time of diagnosis. But these registries have only provided limited insight into the impact of therapies on long-term outcomes and how we're supposed to use variables after initiation of therapy to determine prognosis. Well, that gap is being filled by today's paper in circulation. I'm so pleased to have the first and corresponding author with us, Dr. Jason Weatherald from University of Calgary, as well as Dr. Kelly Chin, associate editor from UT Southwestern, to discuss this very important paper. Jason, congratulations on this paper. Could you tell us a bit more about what you did and why you did it, and what's exciting about what you found? Dr. Jason Weatherald: This is a study that started during my research fellowship last year when I was spending time in Paris with the group of Professor Olivier Sitbon and Marc Humbert. We started this study based on some other recent papers showing the importance of pulmonary arterial compliance, and some smaller studies that emphasized the importance of hemodynamic variables after treatment initiation and the prognostic importance of that. We wanted to look at the relative importance of pulmonary arterial compliance as well as the stroke volume in the cardiac index in newly diagnosed patients. We looked at a 10-year cohort from the French registry of patients who had right heart catheterizations at baseline and then after treatment initiation. We looked at prognostic variables, both at baseline and at the first follow-up after initial treatment. The interesting result is that we found that actually pulmonary arterial compliance is not the most important prognostic variable, but it seemed that the stroke volume index, which was calculated from the cardiac index and the heart rate, was the most significant independent predictor of long-term survival from the hemodynamic perspective. Dr. Carolyn Lam: Kelly, could you help point out why this is so important in clinical practice? You see a lot of these patients. In what way did this paper make you think differently about them? Dr. Kelly Chin: I think there's a couple different areas that really struck me. The first one was, as you mentioned in the introduction, the importance of post treatment values versus baseline values. This is not to say that the baseline values aren't important because it does still associate with survival and it's very important when choosing therapy, but as PAH therapies have become more effective, we would hope to see that the baseline severity matters less and that, indeed, seems to be what we're seeing here. That also reinforces the importance of serial reassessment to see how your patient is doing and make further decisions for therapy. The second key finding, I think, is what Jason was just talking about with which hemodynamic measures do we really want to be keeping a close eye on? Here's where, in the stepwise analysis, they found that the right atrial pressure and then, the surprising one, the stroke volume index were the key measures that were associated. Interestingly, cardiac index fell out of that model. That isn't to say that cardiac index wasn't associated with outcome. It was a predictor in the univariate analysis. But I think when you step back and you think about the comparison between those two, if you have a patient who's maintaining their cardiac index only by becoming tachycardic, they're probably not doing nearly as well as a patient who has a normal heart rate and a normal stroke volume index. I think this really struck me as something, "Hey, when I'm in the cath lab, I probably need to be thinking about this and reporting it out, so everybody's seeing it right there on the report", which is not something we've been doing. Dr. Carolyn Lam: Thanks Kelly. That makes so much sense. What I really appreciated about the paper as well is that they gave us practical thresholds through their receiver operating characteristic analyses. Just for everyone to know, the threshold value for stroke volume index was 38 mils per minute per meter square, right? And the right atrial pressure threshold was 9 mils of mercury. These are sort of very important, 38 and 9, and practical to keep in mind. Really appreciate that Jason. The other thing that struck me is these are just very much saying that right ventricular function is important. Is it not, Jason? Dr. Jason Weatherald: Yeah, I agree. I think that's one of the interesting insights from the study is that we focused mostly on the cardiac index, but it can be misleading in certain patients like Kelly said who perhaps do respond to therapy by increasing the cardiac index but predominantly through increased heart rate. That can be somewhat misleading if you don't really step back and look at it. What I found interesting, too, is that when we looked at subgroups of patients who, in the clinic, you generally think are low risk patients who had good six-minute walk distance, very few symptoms NYHA functional class I or II, and had a cardiac index above the current recommended target of 2.5, that there was almost a third of patients with a low stroke volume index in that category and that seemed to be the majority of patients who died over long-term follow-up within five years. I think that's really telling about the importance of right ventricular function and just looking at the cardiac index itself can perhaps mislead you if you don't take all of those other factors into consideration. Dr. Carolyn Lam: Yeah, that's just such a great point and important. That even those classified that we would not have picked up as high risk are the usual measures that we look at. If you look at stroke volume index, they still distinguish those who do better than those who do worse. This is something that was also highlighted, I think, in the accompanying editorial, Kelly, that you invited by Lewis Rubin from New York. Kelly, what do you think are the real take home messages from this? Dr. Kelly Chin: I think he does make a big point that the functional status of the right ventricle is a primary goal of therapy, and that we should definitely be paying attention to it and that there's more than one way to do this. There's the hemodynamic measurements, there's also exercise capacity and functional class, which really do associate with how well the right heart is functioning, both at rest and exercise. I think he also comes back to the serial measurements and the importance of reassessment. Dr. Carolyn Lam: Yeah, as you had also so elegantly summarized earlier. But, a quick question to both of you. What do we do now about other measures of right heart function? I mean, magnetic resonance imaging seems to be used increasingly for this. Where does this fall in? And what does this say about the routine clinical parameters that we usually look at, like six-minute walk? Jason? Dr. Jason Weatherald: I have a couple points on that. Number one, I fully agree and our results are really in keeping with the previous smaller studies looking at cardiac magnetic resonance and showing the importance of the stroke volume on imaging. From personal experience, although MR is wonderful, there's a good population of patients who don't really tolerate MR, especially for serial measurements, and there's other contraindications, so I think hemodynamics will continue to fill an important role and are still useful in the patient where you can't figure out exactly what's going on and why they're getting worse. At this point, I think it's complementary and certainly I think there's some centers in many countries that don't have cardiac MR widely accessible, especially for serial follow-ups, so I think they're really complementary and that our results support imaging studies. I would say the next thing about the study is that, in the multi variable models that exercise distance, the six-minute walk distance and functional capacity remained independent predictors, so I think, it just highlights the importance and the robustness of these measures, even though NYHA functional class is subjective, it remains a very powerful predictor at baseline and during follow-up. To me, it speaks to the importance of looking at multiple parameters and coming to a multidimensional assessment of risk and PAH and not focusing on one particular variable for making decisions in the clinic. Dr. Kelly Chin: I definitely agree with the multidimensional look at a patient function and heart and catheterization. What I was going to say was I also liked, Jason, the use of "complementary" when talking about catheterization and MRI. I see MRI filling a similar niche to echo for many patients. I think if you get an echo and it looks great, heart size is good, heart function is good, I don't see a whole lot of reason to add an MRI, too. We're always routinely doing catheterizations, at least early post treatment, to reassess. But I do see a role for MRI in some of our patients who are doing not well at all, but we're not quite sure if they're doing poorly enough that it's time for transplant, and I'm trying to decide if the RV is growing or not. It's clearly big, but is it getting bigger each six months that we're looking at it? Sometimes MRI just seems to provide so much more precision than we can get with echo and certainly you're not getting any of those types of measures off of your catheterization. Dr. Carolyn Lam: Maybe one last question Jason. It's so interesting. What is the future? What are the gaps that you're looking to fill at the moment? Dr. Jason Weatherald: Ideally, I think it would be a noninvasive way to look at the right ventricle that is cheap, reproducible, and gives us the same confidence that invasive hemodynamics do. Although I find echo is indispensable and MRI is very useful, I think at the end of the day, we all go back to the right heart catheterization and we need to find something that can replace that, but give us the same confidence in what we think we're measuring and that it reflects treatment changes and clinical worsening. Dr. Carolyn Lam: And Kelly, what do you think should be next steps? Dr. Kelly Chin: I have to say I really liked this study. I thought it moves us forward in assessment of prognosis for this population of patients in a really big way. It was large and included a large number of measures that were done very carefully. You always want to see replication. But, what I'd also like to see is the other forms of pulmonary arterial hypertension. You know this focused mainly on the idiopathic PAH patients, so what happens in connective tissue disease, and also what happens late after treatment, because I think we sometimes see a little bit of a different phenotype in patients that we've treated for many years and sometimes hemodynamics have improved, but in different ways than what we see early on with initial therapies. Dr. Carolyn Lam: You've been listening to Circulation on the Run. Tune in again next week.
This episode covers Chapter 81 of Rosen’s Emergency Medicine. This one is mint! Heart failure is one of those must-know-about presentations, you WILL see this in the ED. Define Cardiac index Preload Afterload Describe: How compliance changes the relationship between end diastolic pressures and volume the Frank-Starling relationship Pousseils Law and LaPlaces Law List 3 CV and 4 Neurohormonal physiologic compensatory mechanisms in CHF List the 5 most common disease processes resulting in HF and briefly describe the contribution of each Describe the different classifications of heart failure: Acute vs. Chronic HF Systolic vs. Diastolic dysfunction Right vs. Left sided HF High-output vs. Low-output HF Describe the NYHA function HF Classes and the Killip Classification List 10 common precipitants of acute HF List 6 historical predictors of acute HF and 6 clinical features of acute HF List 5 CXR and 5 ECG findings of HF What is the role of BNP in HF? Describe the primary management goals in acute HF Describe the mechanism of action of NIPPV in HF. Who needs to be intubated? When is it contraindicated? Describe the pharmacologic treatment strategy for: Acute pulmonary edema + adequate perfusion Acute pulmonary edema + hypotension How do nitrates work in acute pulmonary edema? What is the dose? List 10 treatment options for chronic HF
This episode covers Chapter 81 of Rosen’s Emergency Medicine. This one is mint! Heart failure is one of those must-know-about presentations, you WILL see this in the ED. Define Cardiac index Preload Afterload Describe: How compliance changes the relationship between end diastolic pressures and volume the Frank-Starling relationship Pousseils Law and LaPlaces Law List 3 CV and 4 Neurohormonal physiologic compensatory mechanisms in CHF List the 5 most common disease processes resulting in HF and briefly describe the contribution of each Describe the different classifications of heart failure: Acute vs. Chronic HF Systolic vs. Diastolic dysfunction Right vs. Left sided HF High-output vs. Low-output HF Describe the NYHA function HF Classes and the Killip Classification List 10 common precipitants of acute HF List 6 historical predictors of acute HF and 6 clinical features of acute HF List 5 CXR and 5 ECG findings of HF What is the role of BNP in HF? Describe the primary management goals in acute HF Describe the mechanism of action of NIPPV in HF. Who needs to be intubated? When is it contraindicated? Describe the pharmacologic treatment strategy for: Acute pulmonary edema + adequate perfusion Acute pulmonary edema + hypotension How do nitrates work in acute pulmonary edema? What is the dose? List 10 treatment options for chronic HF
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Carolyn: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Today, we will be discussing an interesting Danish nationwide cohort study on the return to the workforce following first hospitalization for heart failure, but first here's your summary of this week's journal. The first paper addresses a common question asked by patients who have survived an aortic dissection. Will this happen to me again? First author, Dr. Isselbacher, and corresponding author, Dr. Lindsay, and investigators of the International Registry of Aortic Dissection investigated this in the largest systematic analysis to date of patients presenting to hospital with a recurrent aortic dissection. In this large registry, the authors identified 204 patients with recurrent aortic dissection and compared these to 3624 patients in the registry with an initial aortic dissection. They found that patients with recurrent dissection were more likely to have Marfan syndrome, but not bicuspid aortic valve. Descending aortic dimensions were greater in those with recurrent dissections than those with only an initial dissection, and this was independent of the sentinel dissection type. In multivariable analysis, the diagnosis of Marfan syndrome was independently predictive of a recurrent aortic dissection with a hazards ratio of 8.6. Furthermore, they found that the patient's age at the time of first dissection correlated with the anatomic pattern of aortic involvement. In younger patients, dissection of the proximal aorta tended to be followed by dissection of the distal aorta, whereas the reverse was true among older patients suggesting divergent mechanisms of disease. In summary, therefore, this study shows that recurrent aortic dissection while in common does occur and in fact affected 5% of those in this registry. The data really illustrate the importance of syndromic forms of aortic dissection and suggest that occurrence of a recurrent dissection should raise suspicion of a genetic etiology of aortic disease. The next study provides pre-clinical data suggesting that counteracting increased hepcidin may be a therapeutic target for treatment of intracerebral hemorrhage. In this study from first author, Dr. Xiong, corresponding author, Dr. Yang, and colleagues from Xinqiao Hospital, the Third Military Medical University in China, parabiosis and intracerebral hemorrhage mouse models were combined with in vitro and in vivo experiments to investigate the roles of hepcidin in brain iron metabolism after intracerebral hemorrhage. Hepcidin in an important iron regulatory peptide hormone that controls cellular iron efflux. The authors found that increased hepcidin-25 was found in the serum and astrocytes after intracerebral hemorrhage. In hepcidin-deficient mice with intracerebral hemorrhage, there was improvement in brain iron efflux and protection from oxydative brain injury and cognitive impairment, whereas, the administration of human hepcidin-25 peptide in these mice aggravated the brain injury and cognitive impairment. In vitro studies showed that increased hepcidin inhibited intracellular iron efflux in brain microvascular endothelial cells, but this phenomenon was rescued by a hepcidin antagonist. Additionally, toll-like receptor 4 signally pathway increased hepcidin expression, whereas, a toll-like receptor 4 antagonist decrease brain iron levels and improve cognition following intracerebral hemorrhage. In summary, the study showed that increased hepcidin expression caused by inflammation prevented brain iron efflux and aggravated oxidative brain injury and cognitive impairment, thus, counteracting increased hepcidin maybe a mechanistic target to promote brain iron efflux and attenuate oxidative brain injury following intracerebral hemorrhage. The next basic science paper provides fascinating insights into the similarities between advanced atherosclerotic lesions and tuberculous granulomas, both of which are characterized by a necrotic lipid core and a fibrous cap. First author Dr. Clement, corresponding author Dr. Mallat, and colleagues from the University of Cambridge Addenbrooke's Hospital in United Kingdom looked at the C-type lectin receptor 4E which has been implicated in the events leading to granuloma formation in tuberculosis. The authors hypothesized that the same C-type lectin receptor 4E may be involved in the formation of atherosclerotic lesions as well. They addressed this hypothesis by examining the impact of receptor activation on macrophage functions in vitro and on the development of atherosclerosis in mice. They showed that C-type lectin receptor 4E was expressed within human and mouse atherosclerotic lesions and was activated by necrotic lesion extracts. The receptor signaling in macrophages inhibited cholesterol efflux and induced endoplasmic reticulum stress responses leading to the induction of proinflammatory mediators and growth factors. Furthermore, repopulation of LDL receptor-deficient mice with C-type lectin 4E receptor-deficient bone marrow reduced lipid accumulation, endoplasmic reticulum stress, macrophage inflammation, and proliferation within developing arterial lesions that's significantly limiting atherosclerosis. In summary, this paper shows that C-type lectin receptor 4E orchestrates major pathophysiologic events during pluck development and progression, and thus, provides a mechanistic explanation for the close association between necrotic lipid core formation and the development of inflammatory advanced atherosclerotic lesions. The last paper examined the impact of optimal medical therapy in the dual antiplatelet therapy or DAPT study. In this paper from first author, Dr. Resor, corresponding author, Dr. Mauri, from the Brigham and Women's Hospital in Boston and colleagues, authors sought to assess the impact of optimal medical therapy use on long term patient outcomes and on the treatment benefit and risk of continued dual antiplatelet therapy, and they did this using data from the DAPT study which was a randomized placebo control trial comparing 30 versus 12 months of final prudent therapy on the background of aspirin after coronary stenting. Optimal medical therapy was defined as a combination of statin, beta blocker, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker used in patients with an ACC/AHA class 1 indication for each medication. Endpoints included myocardial infarction, major adverse cardiovascular and cerebral vascular events or MACE, and GUSTO moderate or severe bleeding events. Of 11,643 randomized patients with complete medication data, 63% were on optimal medical therapy. Between 12 and 30 months, continued final prudent therapy reduced myocardial infarction compared to placebo in both groups and had consistent effects on the reduction in MACE, and an increased bleeding regardless of the optimal medical therapy status. In other words, the P for interaction was nonsignificant for these comparisons. Importantly, patients on optimal medical therapy had lower rates of myocardial infarction, MACE, and bleeding compared to patients not on optimal medical therapy. Rates of stent thrombosis in death did not differ. The take home message is therefore, that more emphasis on the use of optimal medical therapy after coronary stenting is needed, but the decision to continue dual antiplatelet therapy beyond 12 months should be made irrespective of the optical medical therapy status. Those were your summaries. Now, for our feature paper. Our feature paper today discusses a really important, but frankly, often neglected outcome in heart failure, and that is return to the workforce following first hospitalization for heart failure, and I'm really pleased to have the first and last author of this really special Danish paper, Dr. Rasmus Rorth and Dr. Soren Kristensen, both from the University of Copenhagen, here to join me today. Hello, gentlemen. Soren: Hello and thank you for having us, Carolyn. Rasmus: Hello. Carolyn: As a very special third guest, we actually have editorialist, Dr. Martin Cowie from Imperial College London as well. Hi, Martin. Martin: Hi, Carolyn. Nice to be part of the conversation. Carolyn: This is going to be so fun. Let's get straight into this. Rasmus, maybe you could start by telling us. This return to work concept is hardly addressed in guidelines, it's so important, and yet, you are one of the first if not the first to take a look at it. What inspired you to do this? Rasmus: First of all, we are very inspired to work with heart failure because heart failure is a common costly, disabling, and deadly disease, and furthermore, information on young patients with heart failure is vast. We know that they have a high hospitalization rate and a low mortality rate compared to all the patients. We also know from some of the big trials that young heart failure patients report low quality of life. Therefore, we wanted in this study to examine return to work for a number of reasons. First of all, it gives off some information of the patient's performance basis and we get some information of their quality of life and mental status, and one more reason that is not that common for us as clinicians to think about is also for society, the economic burden these patients play in the society, and all of these reasons inspired us to get into this exciting field. Carolyn: I really appreciated that you did this because the patients that I see here in Asia are on average 10 years younger than the heart failure patients that have been seen in other European registries and so on, so it is a very, very important aspect because my heart failure patients are often the sole breadwinners of families here. Could you, maybe, Soren, share with us what are those unique resources that you manage to look at this in such detail in the Danish registries? Soren: The unique quality in Denmark is that you have the unique identifying numbers for all the citizens of Denmark and these numbers are not only used in the health systems. They're also used for administrative registries for tax paying and for state funds and pensions. We were able to link information from the hospital discharge registries with information on tax paying and whether or not people are getting pensions. In that way, we could follow all patients who stayed in Denmark at least to see whether or not they were receiving any funds, any pension, or sick leave money, or things like this from the state, or whether they upheld a position. That's what makes the Danish system a bit unique, that we have this ability to track the patients across all the fields of society and also that we have a public health system which all patients are included in, and the private sector is negligible in Denmark. Carolyn: Wow. Listening to that is making all epidemiologist everywhere really drool. That is such a precious system to look at this. What were your main findings, Rasmus? Rasmus: Maybe I should explain a bit about the setting. This is a nationwide-based study starting where we identify the patient with the first heart failure hospitalization, 18 to 60 years in the period from 1997 to 2012, and we followed them onwards. In our primary analysis, we only included patients in the workforce, that means either employed or available for the labor market at time hospitalization. That is the setting of the study. Carolyn: Could you share your main findings and your take home messages? Rasmus: Our primary outcome of this study is that after one year, 25% of the patients did not return to the workforce and we had a low mortality, only 7% died. Carolyn: Twenty-five percent didn't return to the workforce? Rasmus: Yeah, and keeping in mind, Carolyn, these are patients in the workforce at their first hospitalization and also young patients. Our take home patient from this paper is that patient in the workforce at heart failure hospitalization had a low mortality for the high risk of [inaudible 00:13:41] from the workforce at one year of followup. Furthermore, we look at some association effect associated with returning to work, and we found that young age, male sex, and high level of education were associated with high likelihood of returning to work. Carolyn: Martin, you wrote just a beautiful editorial. I have to say I was chuckling and enjoying it as I read it. I could hear your voice in it. What do you make of these results in the interpretation? Martin: I was really pleased to see something published by this really important topic that is largely ignored, and as you said in your introduction, the guidelines, if you read them you'll think that nobody of working age ever develops heart failure. There's no mention at all about return to work. There's no mention of the kind of urgent need to be able to provide people with the counseling about the heart failure and how it might impact their work, and also, no interaction, no mention of interaction with employers to tell them, "Yes, this person have this condition, but actually, could do their job or stay in the same job," or "How we can help support them?" I think this article which is so good to see graded publish in Circulation and I think we have to see it in the context of other occupational rehabilitation work which shows that if you don't get people back to work quite quickly after a major event in their lives, then you'll never get them back, and that's got huge consequences for them in their mental health, their economic, social, family, and never mind the healthcare system. It's really nice to see this work and I hope many people read it and quote it. Carolyn: Martin, you've been to Asia. You know that our patients are strikingly young, but I wonder, do you think these results are extrapolatable outside of Denmark? Martin: I think this comment and not an editorial, Denmark, of course, is a relatively small country. It's wealthy. It's different from the states, but it's very different from Asia as you say, so lots of heart failure patients in Asia are young, of working age, and quite often, their families depend on them. I think the tactics may have to be different to different countries, but the general principles are the same that we, as a heart failure team, as heart failure doctors, have to think about the person not just in terms of the left atrium and left ventricle, or even of the whole body function, but actually, what is their role in their family, what are they trying to achieve in life, how can we support them about way, because otherwise, we're really failing our patient. I think, in Asia even more than in some wealthy, rich countries where there's a lot of safety nets, it's really important. I'd be interested in your comment, Carolyn, on what you think we can do to improve right across the world in terms of occupational rehab. Carolyn: First, I think it begins with awareness and that's why I just wanted to tell Soren and Rasmus how much I enjoyed this paper and I will be citing it because I think it's so important especially in the younger heart for the community, but can I ask you, Soren or Rasmus, have these findings changed your practice in any way or to be even more provocative, do you think that maybe return to work should be a benchmark to evaluate heart failure programs? Rasmus: Martin also points out that, first of all, we need to shed light on this hidden fact of heart failure, and afterwards, I think it's also a very good policy metrics to use in the future to see how our patients do. Carolyn: Are there efforts in Denmark to improve this as a yardstick? Soren: I'm quite sure that, by large, it's not really registered who is working, who is not working there. There's not much attention to it. We're all focusing very much on the performance of the patient of the NYHA class and so on, so I think we should put more emphasis on this issue and we should, as Martin also added, that we should discuss with the patients if they could change their job or their positions in some ways to better cope if they lost some of their performance, because we're both think and we both agree with Martin that it's a huge quality of life to be able to maintain your job in one way or the other, and we should definitely put more focus on that, but I'm afraid to say that I don't think we put much focus on it in Denmark at this time, but hopefully, we will. Martin: I think you're right, the attitude have to change across the world, don't they, and they start with the heart failure team and the patients because I think most doctors and nurses and patients assume diagnosis of heart failure, that means really nothing can be the same again, but we really should be trying to return people to their optimal function, and I'm sure we can do a lot more, but perhaps, we need to upscale the workforce and knowing about the key things about occupational counseling, and maybe also [inaudible 00:18:30] interact with employers a little bit more without patient's permission to give them the confidence to have this person re-enter the workforce in a supported way because I'm sure the employers value many of these people and would be pleased to see them still in the workforce. Rasmus: Exactly. I even think that could be like a fair way of trying to help the patient by relieving them from their job, which is actually will be a big mistake for some patients [inaudible 00:18:54] as a physician to help them with making sure they don't have to return to their job and fill out the statements and everything, but this may not be the best for the patient. Martin: Exactly. Carolyn: Gentlemen, I have enjoyed this conversation so much. Thank you for taking the time to discuss this very important paper. You've been listening to Circulation on the Run. Tune in next week for more.
Dr. Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore. Today we will be discussing the first multinational study looking at per-cutaneous device closure of peri-valvular leaks, a topic I'm certain you'll recognize as rapidly developing in cardiology, but first, let me fill you in on the highlights of this week's journal. The first paper is a translational study telling us that when transfusing stored red blood cells for hemorrhagic shock, cold transfusing hemopexin and heptoglobin may be beneficial. This study is from first author Dr. Graw, and corresponding author Dr. Zapol and colleagues from the anesthesia center for critical care research at Massachusetts General Hospital and Harvard Medical School. These authors reasoned that erythrocytes undergo progressive deleterious changes during storage. Such that, the transfusion of long-stored, packed red blood cells increases plasma levels of cell-free hemoglobin and heme. These are toxic breakdown products of hemolyzed erythrocytes. Now, mammals usually synthesize the scavenger proteins: heptoglobin and hemopexin, which bind these toxic extracellular hemoglobin and heme, respectively. The authors therefore, tested the concept of cold transfusion of heptoglobin and hemopexin along with stored red blood cells in their murine remodel of hemorrhagic shock. They first showed that resuscitation with long-stored, packed red blood cells produced a higher mortality, higher plasma hemoglobin levels, hemoglobinuria, kidney injury and diffused tissue inflammation, compared to resuscitation with fresh, packed red blood cells. However, when resuscitating hemorrhagic shock with stored red blood cells co-infused with either exogenous human hemopexin or heptoglobin, there was an increased survival and decreased tissue inflammation. Furthermore, co-infusion of heptoglobin with the stored red blood cells, prevented hemoglobinuria and kidney injury. These animal model data warrant further assessment in clinical conditions of severe hemolysis. The next study suggests that sickle cell disease, although primarily a blood disease, may also be considered a vascular disease. This is a paper from co-authors Dr. Ranque and Menet from the University Paris Descartes in France, and describe results from the CADRE study. That is, the heart arteries and sickle cell study, which is the World's largest ongoing cohort of sickle cell disease that prospectively recruited more than 3,700 patients with sickle cell disease and 950 healthy controls from Cameroon, Ivory Coast, Gabon, Mali, and Senegal. The authors found that mean carotid femoral pulse wave velocity was lower in patients with sickle cell disease, compared to controls and lower in specific hemoglobin phenotypes compared to others. Augmentation index, corrected for heart rate, also increased more rapidly with age in the patients with sickle cell disease, compared to controls, and was higher in patients than in controls. Both carotid femoral pulse wave velocity and augmentation index were independently associated with the glomerular filtration rate and osteonecrosis. Augmentation index was also associated with stroke, pulmonary hyper-tension and priapism. Whereas, carotid femoral pulse wave velocity was also associated with microalbuminuria. These findings really under-score the association between sickle cell disease and vascular abnormalities and complications. The prognostic value of these vascular indexes will be assessed during the follow-up of these patients. The next paper is a basic science paper suggesting that after sudden cardiac arrest, normalizing calcium cycling, may be a novel approach to improved post-arrest myocardial function. This paper is from co-corresponding authors Dr. Woods, from the Palo Alto Medical Foundation and Dr. Ashley from Stanford University in California. These authors developed a rodent model of cardiac arrest using ECMO resuscitation. They used a genetically encoded calcium sensor in a novel fiber optic catheter imaging system to observe calcium-induced calcium release in-vivo before and after resuscitation. They then isolated cardiomyocytes from this model and assessed a mechanical load and calcium cycling simultaneously, using the micro-fiber carbon technique. The main finding was of potentiation of calcium-induced calcium release in the post-arrest situation that began in-vivo and was mediated by activation of the calcium calmodulin kinase 2 or CaMKII. Since they also observed that oxidated stress and aldehydic adduct formation were high post arrest, they further tested a small molecule activator of aldehyde dehydrogenase type 2, known as Alda-1, which reduced oxidative stress, restored calcium and c CaMKII homeostasis and improved cardiac function in post-arrest outcomes in-vivo. These findings are significant for their potential translational application in post-sudden cardiac arrest, a condition which is really known to have a high mortality. The next study reports the results of the DOCTORS Study, standing for Does Optical Coherence Tomography Optimized Results of Stenting. This paper is from Dr. Meneveau from the University Hospital Jean Minjoz and colleagues. The DOCTORS Study is the first randomized control trial testing optical coherence tomography via OCT guided PCI to standard fluoroscopy guided PCI in 240 patients with non-ST-elevation and acute coronary syndromes. The first finding was that OCT results directly impacted physician decision making, leading to a change in procedural strategy in half of the cases in the OCT guided group. The primary end-point of functional results of PCI, as assessed by post-PCI, FFR, was modestly improved in the OCT guided group compared to fluoroscopy alone. This improvement appeared to be explained mostly by optimization of the stent expansion. The benefit was obtained at the cost of a longer procedural and fluoroscopy time and more contrast use, but without an increase in peri-procedural myocardial infarction or kidney dysfunction. These findings of the DOCTORS study add to the accumulating body of evidence supporting a potential benefit of OCT to guide PCI procedures in acute coronary syndrome. Additional prospective studies with clinical endpoints are warranted. These issues are discussed in an excellent accompanying editorial by Dr. Wijns and Dr. Pyxaras. This brings us to the end of our summaries. Now for our feature paper. Our featured paper today discusses a problem that we've actually created and that is para-valvular leaks following surgical valve replacement, and we're specifically discussing the role of percutaneous device closure exploring the first multi-national experience form the United Kingdom and Ireland and I'm here with first author, corresponding author as well, Dr. Patrick Calvert from Papworth Hospital in the United Kingdom. Welcome Patrick. Dr. Calvert: It's a great pleasure to be here, thank you for inviting me. Dr. Lam: Joining us also is Dr. Dharam Kumbhani, associate editor from UT Southwestern, hi. Dr. Kumbhani: Hi Carolyn, thanks for having me. Dr. Lam: Let's get straight into this. It's a problem we've created. How common is it? Why should we care about talking about perivalvular leaks? Dr. Calvert: You know Carolyn, this is actually quite a common problem. The series we know from previous publications around 5-17% of surgical valves develop leaks. We know in the early experience of TAVR that there was quite a problem with leak, although more recent iterations that's less of a problem. There's a lot of patients out there that have this problem. It's a difficult problem to treat because these are, by definition, high-risk patients and re-operation is not such an inviting thought for them to have. This is something that needs may be a different solution than re-operation. Dr. Lam: Could you tell us what makes your series special? Dr. Calvert: Yes, so let's talk about the other series first of all. We had a fabulous series published in 2001 from the Mayo Clinic. That was a single center of excellence where they are really great at doing the procedure, but they gave us great insight of a master class, really if you like, if I had to do the procedure. What is different about our paper is that it's like a real-world experience. It's all the centers that contributed in the United Kingdom and Ireland. It's 20 centers over an 11 year period, in total 308 procedures. It's, if you like, a warts-and-all approach to it. It think that's one way it's a little different. I think another way that it definitely stands out is that we are fortunate enough in Europe to have licensed or CE-mark, a number of oblong devices that are a little different in shape. What we do know about these holes is, they tend to be crescentic in shape or at least longer then they are wide. The problem is, if you try to put a circular device in an oblong hole, it's not going to work. Dr. Lam: Which types of perivalvular leak are you talking about here? Dr. Calvert: We have approximately 50/50 split between the aortic surgical valve and the micro-surgical valve. Then, about 5% were TAVIs or TAVRs. Then we had a small number of pulmonic valves and one or two around angioplastic rings, so that's the proportions. We had about 57% mechanical valves and 37% bio-prosthetic valves. Dr. Lam: Wow, first congratulations. That is really important information. I can already imagine. I see those patients too. Dharam, as an interventional cardiologist. What is your take on it. Especially this mention of the oblong devices? They are not FDA approved, so they won't be in the United States, but what did you think of that, managing this paper? Dr. Kumbhani: I think this is a very tricky subset of patients to treat. As Patrick and his group have shown, that the rates of success can be very high. As you point out, we don't have all the devices that they have in the U.S. A lot of us who do this use more circular devices but they're flexible. The feeling is that they tend to fit in with whatever geometry of the leak is. I do think it would be interesting, and probably more appropriate to have devices that are shaped like these holes are. As Patrick mentioned, they're usually crescentic, or certainly not round. Dr. Lam: As a non-interventional cardiologist, I didn't realize it was very intricate. Tell us about your main findings. Dr. Calvert: Our principle findings, and what I think is the most important thing is that, if you're going to do this procedure, you have to achieve a leak at the end of the procedure, or at least in the months that follow-up, that is mild or less. In our series, we showed that those patients that had that, they were independently associated with less deaths and less major adverse cardiovascular events. It's a very clear dichotomy between those groups. Of course there's all sorts of reasons why you might be able to achieve a good result in a patient, but we know that if you can do it, those patients will be very much better than the others. In our paper we achieved that in around 75% of patients and they did much better than the others. That is a principle finding. There were another of other factors that were associated independently with death and those also included NYHA classification at follow up, but also creatinine baseline. As I've already eluded to, this is a high-risk chord of patients and there are conventional risk factors that will pre-dispose whether someone's going to do well or not. That's what came out in the multi-variable analysis. Dr. Lam: Very important clinically. Take home message from your point? Dr. Kumbhani: I think one of the interesting findings was that only 16% of these PVLs were closed for hemolysis. The vast majority of them were done for symptomatic causes. That probably speaks to the dictum that it's the smaller PVLs that cause hemolysis. I don't know if you have a handle, based on your experience, on that? Dr. Calvert: When we designed the series, a number of years ago ... When you design a registry you look at the things you're going to collect. Then when you've written the paper you think, "I just wish I had collected some more data." That's one of those things we really wish we looked ... It's fascinating. We do this procedure together and one of the things we're terrified about is taking a big leak, getting rid of heart failure and creating hemolysis. Dr. Kumbhani: Exactly. Dr. Calvert: We all have had personal experiences of that happening. Dr. Kumbhani: Yes. Dr. Calvert: The data we collected, collected patients who had new hemolysis, requiring transfusion. Therefore, all I can tell you from our series is, that was really quite a small ... It was only 2 or 3% of people who had new hemolysis. Dr. Kumbhani: After the closure? Dr. Calvert: After the closure. Of course, about 16 or 17% had hemolysis going into it. It doesn't really tell us any information about what happened to those, unfortunately. Dr. Kumbhani: One other interesting thing that I wanted to point out. If you look at the PCIs registry, all of, there are about 120 hospitals in it. Is that correct? Dr. Calvert: That's approximately correct, yes. Dr. Kumbhani: You had 20 centers that were doing this? Dr. Calvert: Yes. Dr. Kumbhani: 1 in 6 is doing these in a competent fashion, the PVL closures. I think, as you pointed out, the series are usually single institutions that really specialize in this in the U. S. I think the experience may be a little more consolidated. If you want to just comment on that finding alone? The second thing is, is there something different about the intervention training procedure in the U.K. that allows for more interventionists to be comfortable doing this? Dr. Calvert: I think that's a really great question. I think there's a little to pick apart behind that. I think the first thing to say is that, although there were 20 centers that contributed cases, some of those centers would have definitely had proctors come in to do the cases. This is the entire learning curve. This is every case that has contributed in the U.K. It's watching our learning curve and the lot. There will be a number of centers that have been heavily proctored coming in. One thing that's really nice about the U.K., it's a small country. Particularly in this structural community, most people know each other. If you've got a problem, you ring up your friend down the road and say, "You've done a few of these, come and give us a hand." We get that and I do that too, so that's great. I think the second thing to say, and I think it's important to say this, our cousins in America are fantastic at doing this procedure. I think they have to be because although the devices are malleable, and they will squash because as we both know, it doesn't matter what the device looks like at the end provided it plugs the hole and is not interfering with the leaflets and it's not falling out. That's fine. I do believe that the oblong devices are more likely to get a good closure. I think therefore, you're less likely to be having to put in 2 or 3 devices in the same sitting. I think that's technically demanding for ... I think it probably is a little more straight forward with the oblong devices. I think it is important to say for the record, that there's nothing in this paper that is scientifically proven the oblong devices are better. They trend in their right but, it is a fact of the series of oblong devices. Once they're available, it was 72% and for the total it's about 2/3. It's not a scientific comparison but, we've got these good results with these devices. Dr. Kumbhani: It would not be a fair comparison but in your database, are you able to do some kind of propensity analysis looking at the oblong versus the other devices? Comparing ventricle leak for example or hemolysis? Dr. Calvert: We don't have enough breakdown data on hemolysis unfortunately. I think I just need to be careful what I say because a lot of the authors came up with hypotheses about things. I looked at the data and I think when we subgroup too much, it became too small to read to give any careful answers. Dr. Kumbhani: I see. Dr. Calvert: I think what would be really fascinating, is when we pool data with other countries because I know there are other countries that are looking at this as well. We might get more information, but that's something we have on the horizon so what this space. Dr. Kumbhani: That's good. Dr. Lam: That is fantastic. Thank you Patrick. Thank you Darrin. Seriously, I'm floored. I learned so much from this and I really enjoyed this conversation. Thank you very much, and to the listeners out there, don't forget you've been listening to Circulation on the Run. Join us next week for more highlights and features.
Commentary by Dr. Valentin Fuster
Joining Doug is John B. Rhea, Chairman of the New York City Housing Authority. Now in its 75th year, the NYHA provides affordable housing in a safe and secure living environment for low and moderate- income residents throughout the five boroughs.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 07/19
Überlegene Offenheitsraten der Arteria mammaria interna gegenüber Vena-saphena-magna-Transplantaten sind angiographisch valide. Ziel der vorliegenden Untersuchungsreihe war, Outcome und klinischen Benefit von Patienten mit bilateralem ITA(BITA-)und solchen mit einfachem ITA(SITA-)Bypass im mittelfristigen postoperativen Verlauf zu verifizieren. 1.378 Patienten, die sich zwischen 01/97 und 08/99 einer isolierten aortokoronaren Bypassoperation unterzogen hatten, wurden retrospektiv untersucht. Das Follow-up betrug 4,0 bis 6,6 Jahre (im Mittel 5,3 Jahre). 716 Patienten erhielten einen BITA-Bypass, 662 einen SITA-Bypass sowie zusätzlich Vena-saphena-Transplantate. Wir analysierten Mortalitätsrate, Freiheit von Re-Operationen und Interventionen wie PTCA/Stent, die Inzidenz kardialer Ereignisse sowie die Lebensqualität in Relation zu patientenspezifischen Risikofaktoren. Der Prozentsatz weiblicher Patienten war in der BITA- wie auch in der SITA-Gruppe signifikant niedriger (BITA-Gruppe: 115 weibliche und 601 männliche Patienten, SITA-Gruppe: 150 weibliche und 512 männliche Patienten; p < 0,01). Das mittlere Alter (BITA: 69,2 Jahre, zwischen 42,7 und 88,6 Jahren, SITA: 71,0 Jahre, von 47,3 bis 91,6 Jahren) war nicht signifikant unterschiedlich. Die Prävalenz von Diabetes mellitus (26,0% vs. 25,9%,n.s.)wie auch der mittlere BMI (27,4 vs. 27,0; n.s.) waren in beiden Gruppen vergleichbar. Mittelfristig (im Mittel 5,3 Jahre nach dem Eingriff) profitieren Patienten mehr von einem Doppelmammaria-Bypass als von der Verwendung nur einer A. mammaria interna als Graft. Die kardial bedingte Mortalität und die Zahl der erforderlichen Re-Operationen waren nach der Verwendung von BITA-Transplantaten im Vergleich zum Einsatz von SITA-Transplantaten auf weniger als die Hälfte reduziert. Auch wurden kardiologische Eingriffe wie PTCA und Stentanlage bei Patienten mit BITA-Transplantaten seltener erforderlich, jedoch waren die Unterschiede nicht statistisch signifikant. Klinische Symptome (Einordnung in NYHA- und CCS-Klassifikationen)wurden durch die Anlage eines Doppelmammaria-Bypasses selten beeinflusst. Weitere Studien über einen längeren Nachuntersuchungszeitraum werden erforderlich sein, um endgültig zu klären, ob die Verwendung beider Aa. mammariae internae als Transplantate tatsächlich die Langzeitüberlebensrate verbessern kann und die gegenwärtige Begeisterung für diese Vorgehensweise weiterhin berechtigt ist.
Mathematik, Informatik und Statistik - Open Access LMU - Teil 02/03
Clinical trials often judge the efficacy of a new treatment by comparing the survival patterns of patients who are randomly assigned to undergo the new or a standard/placebo treatment. Usually, the entire groups are analyzed, although certain subgroups of patients may react differently to the new treatment than others. Some patients taking the new treatment might benefit from it (the positive responders) while others may be harmed by it (the negative responders). We applied a newly developed responder identification method (Kehl&Ulm, 2003) on the doubleblinded placebo controlled European Myocardial Infarction Amiodarone Trial (EMIAT). The method, which is based on bump hunting, proceeds to find the so called predictive factors, which describe positive and negative trends in survival in special subgroups of patients, solely due to Amiodarone. Factors found to be predictive were: age, previous infarction, beta-blocker treatment, onset, NYHA classification, and sex. Negative responders to Amiodarone, i.e. patients taking Amiodarone who survived shorter than a similar group under placebo, were patients who were older than 65 years, have had a previous infarction, and were not on beta-blockers. Positive responders to Amiodarone, (longer survival time), were male patients who were not negative responders, had NYHA classification greater than or equal to two, and onset greater than one. Further studies are needed to investigate this hypothesis.
To characterize the determinants of circulating levels of adrenomedullin (AM), the plasma levels of this peptide were measured in 58 patients with end-stage renal disease on hemodialysis, Predialysis plasma levels of AM were more than twice as high in patients on hemodialysis as compared to controls. In hemodialysis patients with heart failure (NYHA classes II-IV) or hypertensive HD patients plasma levels of AM were significantly higher than in patients with end-stage renal disease only. Plasma levels of AM were clot altered immediately by hemodialysis but decreased significantly 14-20 h after hemodialysis, AM plasma levels before hemodialysis and 14-20 h after hemodialysis were correlated with the corresponding mean arterial pressure.
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