Podcasts about nt probnp

Witam Państwa, nazywam się Jarosław Drożdż, pracuję w Centralnym Szpitalu Klinicznym Uniwersytetu Medycznego w Łodzi, skąd nagrywam podcast Kardio Know-How. W tym odcinku kontynuuję omawianie doniesień z tegorocznego kongresu ESC.Najważniejszym postępem w kardiologii w 2025 roku pozostaje, moim zdaniem, badanie DAPA-ACT TIMI-68, pokazujące korzyści z jak najwcześniejszego podania dapagliflozyny w ostrej niewydolności serca, podkreślano tu nie tylko redukcję śmiertelności całkowitej, ale i bezpieczeństwo leczenia już w fazie szpitalnej, a wbrew niektórym komentarzom brak istotności w złożonym punkcie końcowym nie powinien przesłaniać klinicznej wartości wyników. Drugim ważnym tematem kongresu ESC było nowoczesne leczenie kardiomiopatii przerostowej (HCM), której diagnostyka opiera się na obrazowaniu serca i wykluczeniu przyczyn wtórnych, a w wybranych przypadkach także na badaniach genetycznych. Leczeniem pierwszego rzutu w HCM zawężającej są β-blokery, a w przypadku nieskuteczności – werapamil, diltiazem, inhibitory miozyny lub zabiegi redukcji przegrody. Mavacamten poprawia wydolność, NT-proBNP i klasę NYHA, a jego skuteczność potwierdzono w wytycznych ESC 2023 i ACC 2024. Na kongresie ESC 2025 badanie ODYSSEY-HCM nie wykazało korzyści z mavacamtenu w postaci niezawężającej HCM, ale MAPLE-HCM pokazało wyższość aficamtenu nad metoprololem w HCM zawężającej. Aficamten redukował gradient i NT-proBNP, podczas gdy metoprolol nie przynosił poprawy, co może oznaczać przełom w leczeniu. Obecnie β-blokery pozostają terapią pierwszego rzutu, ale inhibitory miozyny stają się realną alternatywą, zmieniając krajobraz leczenia HCM.Szczegółowy TRANSKRYPT do odcinka.Podcast jest przeznaczony wyłącznie dla osób z profesjonalnym wykształceniem medycznym.

When it comes to cardiac disease, early and accurate detection can make all the difference in providing the best patient care. In this episode of the Partner Podcast, Dr. Stacey Hendershott shares her real-world experience with using NT-proBNP testing in both healthy and sick patients—whether for routine screening, investigating new murmurs, or managing complex cases, all with the convenience of point-of-care technology.Sponsored by BionoteResource: bionote.comContact us:Podcast@instinct.vetWhere to find us:Website: CliniciansBrief.com/PodcastsYouTube: Youtube.com/@clinicians_briefFacebook: Facebook.com/CliniciansBriefLinkedIn: LinkedIn.com/showcase/CliniciansBrief/X: @cliniciansbriefInstagram: @clinicians.briefThe Team:Beth Molleson, DVM - HostSarah Pate - Producer & Project Manager, Brief StudioTaylor Argo - Podcast Production & Sound Editing 

CardioNerds (Drs. Rick Ferraro and Georgia Vasilakis Tsatiris) discuss ATTR cardiac amyloidosis with expert Dr. Justin Grodin. This episode is a must-listen for all who want to know how to diagnose and treat ATTR with current available therapies, as well as management of concomitant diseases through a multidisciplinary approach. We take a deep dive into the importance of genetic testing, not only for patients and families, but also for gene-specific therapies on the horizon. Dr. Grodin draws us a roadmap, guiding us through new experimental therapies that may reverse the amyloidosis disease process once and for all.  Audio editing by CardioNerds academy intern, Christiana Dangas. This episode was developed in collaboration with the American Society of Preventive Cardiology and supported by an educational grant from BridgeBio.  Enjoy this Circulation Paths to Discovery article to learn more about the CardioNerds mission and journey.  US Cardiology Review is now the official journal of CardioNerds! Submit your manuscripts here.  CardioNerds Cardiac Amyloid PageCardioNerds Episode Page Pearls: You must THINK about your patient having amyloid to recognize the pattern and make the diagnosis. Start with a routine ECG and TTE, and look for a disproportionately large heart muscle with relatively low voltages on the ECG.  Before you diagnose ATTR amyloidosis, AL amyloidosis must be ruled out (or ruled in) with serum light chains, serum/urine immunofixation, and/or tissue biopsy.  Genetic testing is standard of care for all patients and families with ATTR amyloidosis, and the future is promising for gene-specific treatments. Current FDA-approved treatments for TTR amyloidosis are TTR stabilizers and TTR silencers, but TTR fibril-depleting agents are on their way.  Early diagnosis of ATTR affords patients maximal benefit from current amyloidosis therapies.   TTR amyloidosis patients require a multidisciplinary approach for success, given the high number of concomitant diseases with cardiomyopathy.  Notes: Notes: Notes drafted by Dr. Georgia Vasilakis Tsatiris.  What makes you most suspicious of a diagnosis of cardiac amyloidosis from the typical heart failure patient?  You must have a strong index of suspicion, meaning you THINK that the patient could have cardiac amyloidosis, to consider it diagnostically. Some characteristics or “red flags” to not miss:   Disproportionately thick heart muscle with a relatively low voltages on EKG   Bilateral carpal tunnel syndrome – estimated that 1 in 10 people >65 years old will have amyloidosis   Previously tolerated antihypertensive medications  Atraumatic biceps tendon rupture   Bilateral carpal tunnel syndrome  Spinal stenosis   Concomitant with other diseases: HFpEF, low-flow low-gradient aortic stenosis  How would you work up a patient for cardiac amyloidosis?   Start with a routine ECG (looking for disproportionally low voltage) and routine TTE (looking for thick heart muscle)  CBC, serum chemistries, hepatic function panel, NT proBNP, and troponin levels  NOTE: It is critical to differentiate between amyloid light chain (AL amyloidosis) and transthyretin ATTR amyloidosis, as both make up 95-99% of amyloidosis cases.   Obtain serum free light chains, serum & urine electrophoresis, and serum & urine immunofixation to rule out AL amyloidosis. (See table below)  AL Amyloidosis ATTR Amyloidosis  → Positive serum free light chains and immunofixation (Abnormal M protein) → Tissue biopsy (endomyocardial, fat pad) to confirm diagnosis → Negative serum free light chains and immunofixation (ruled out AL amyloidosis) → Cardiac scintigraphy (Technetium pyrophosphate with SPECT imaging)  What treatment options do we have to offer now for ATTR CM, and how has this compared to prior years?   Before 2019, treatment options were limited outside of cardiac tr...

In this week's issue, Dr. Harlan Krumholz highlights new science with direct clinical implications: a randomized trial showing conduction system pacing outperforms RV pacing in AV block, a pragmatic study suggesting HEPA filtration may modestly lower blood pressure, and long-term data from FLAVOR comparing FFR and IVUS-guided PCI. Also featured are a state-of-the-art review on heart failure therapy implementation, a brief report refining NT-proBNP thresholds for pre–heart failure, and an updated JACC Report Card revealing persistent cardiovascular mortality disparities among Black Americans. The issue closes with reflections on equity, anatomy, and two complex case reports.

Witam Państwa, nazywam się Jarosław Drożdż, pracuję w Centralnym Szpitalu Klinicznym Uniwersytetu Medycznego w Łodzi, skąd nagrywam podcast Kardio Know-How. W tym odcinku przedstawiam nowości opublikowane podczas kongresu HFA ESC 2025. Na tegorocznym kongresie HFA-ESC powrócił temat „wyścigu wszechczasów” – flozyny kontra agoniści GLP-1, który rozpoczął się w 2019 roku wielkim sukcesem badania DAPA-HF. Od tamtej pory flozyny dominują w kardiologii, ale agoniści GLP-1, jak semaglutyd, coraz śmielej wkraczają na tę scenę, co pokazuje choćby badanie SELECT. Najnowsze doniesienia obejmują badanie SOGALDI-PEF (link), gdzie połączenie dapagliflozyny i spironolaktonu skutecznie obniżało NT-proBNP w HFpEF/HFmrEF. Co ciekawe, spironolakton samodzielnie wypadał nawet lepiej niż dapagliflozyna. Z kolei badanie PRAISE-HFrEF analizowało dane 1,5 mln pacjentów z otyłością, cukrzycą i HFrEF, sugerując przydatność GLP-1, choć bez randomizacji wyniki mają ograniczoną wartość. Historia pokazuje, że to właśnie antyaldosteronowy „Spiro” był brakującym elementem Wielkiej Piątki XX wieku – teraz GLP-1 mogą być kandydatem do uzupełnienia nowej generacji terapii. Szczegółowy TRANSKRYPT do odcinka.Podcast jest przeznaczony wyłącznie dla osób z profesjonalnym wykształceniem medycznym.

Witam Państwa, nazywam się Jarosław Drożdż, pracuję w Centralnym Szpitalu Klinicznym Uniwersytetu Medycznego w Łodzi, skąd nagrywam podcast Kardio Know-How. W tym odcinku przedstawiam nowości opublikowane podczas kongresu HFA ESC 2025.  Podczas czerwcowego Kongresu HFA ESC zaprezentowano przełomowe dane nt. terapii genowej nexiguranu ziklumeranu opartej na CRISPR-Cas9, która w badaniach klinicznych fazy 1 wykazała trwałą, >90% redukcję TTR w surowicy u pacjentów z amyloidozą ATTR, zarówno dziedziczną (ATTRv), jak i dziką (ATTRwt). Terapia ta opiera się na pojedynczej infuzji lipidowych nanocząsteczek z tropizmem wątrobowym i nadal jest w fazie badań klinicznych. Przedstawiono także wyniki badania FUTURE-HF, oceniającego wszczepialny czujnik żyły głównej dolnej do zdalnego monitorowania pacjentów z niewydolnością serca. Urządzenie wykazało bezpieczeństwo, wysoką skuteczność techniczną i potencjalną poprawę parametrów klinicznych, w tym NT-proBNP i klasy NYHA. To przykład rosnącej roli nowoczesnych technologii w leczeniu niewydolności serca i potrzeby odejścia od nieskutecznego modelu 1 lekarz – 1 pacjent. Szczegółowy TRANSKRYPT do odcinka.Podcast jest przeznaczony wyłącznie dla osób z profesjonalnym wykształceniem medycznym.

We have covered Low Dose Aspirin (LDA) for pre-natal preeclampsia prevention MANY times before. But here's a good clinical question: Since preeclampsia can also pop-up in the first 6 weeks postpartum (pp), should we continue it in the immediate pp interval? There is a new publication, an RCT, in the AJOG that looked to answer this- and we will highlight that publication in this episode. PLUS, we will briefly summarize a separate publication from the American J Perinatology back in 2023 that also provided some clinical insights on this topic. Listen in for details.1. The association between postpartum aspirin use and NT-proBNP levels as a marker for maternal cardiac health: a randomized-controlled trial; July 2025 (AJOG): https://www.sciencedirect.com/science/article/pii/S00029378250047522. Christenson E, Stout MJ, Williams D, Verma AK, Davila-Roman VG, Lindley KJ. Prenatal Low-Dose Aspirin Use Associated with Reduced Incidence of Postpartum Hypertension among Women with Preeclampsia. Am J Perinatol. 2023 Mar;40(4):394-399. doi: 10.1055/s-0041-1728826. Epub 2021 May 3. PMID: 33940641.3. Mendoza M, Bonacina E, Garcia-Manau P, et al. Aspirin Discontinuation at 24 to 28 Weeks' Gestation in Pregnancies at High Risk of Preterm Preeclampsia: A Randomized Clinical Trial. JAMA. 2023;329(7):542–550. doi:10.1001/jama.2023.0691

With Kevin Damman, University Medical Center Groningen, Groningen - The Netherlands, Floran Sahiti, University Hospital of Wurzburg, Wurzburg - Germany, Joao Pedro Ferreira, University of Porto, Porto - Portugal, Novi Yanti Sari, Siloam Hospitals Group, Jakarta - Indonesia, Marat Fudim, Duke University Medical Center, Durham, NC - USA, Gregorio Tersalvi, Mayo Clinic, Rochester, MN - USA, Jose Luis Morales Rull, University Hospital Arnau de Vilanova, Lleida - Spain and Cornelia Margineanu, Bucharest - Romania. In this episode, we discuss four late-breaking clinical trials presented at the Heart Failure Congress 2025 in Belgrade, Serbia. First, Kevin Damman presents the results of FUTURE-HF, a first-in-human study evaluating the long-term safety, accuracy, and clinical utility of a novel implantable IVC sensor for remote heart failure management. Next, Joao Pedro Ferreira highlights the key findings of SOGALDI-PEF, a crossover trial comparing SGLT2 inhibitor monotherapy versus combination therapy with an SGLT2 inhibitor and a mineralocorticoid receptor antagonist (MRA) in reducing NT-proBNP levels. Third, Marat Fudim reports on the MUSIC-HFpEF phase 1/2a trial, which explores the safety and preliminary efficacy of a novel gene therapy using adeno-associated virus vectors in patients with HFpEF. Finally, Jose Luis Morales Rull shares insights from PREFER-HF, a study assessing the effects of intravenous or oral iron therapy versus placebo in patients with HFpEF and iron deficiency anemia. FUTURE-HF: Long-term safety, accuracy, and utility of a novel implantable IVC sensor for remote HF management - Kevin Damman, University Medical Center Groningen, Groningen, The Netherlands. Host: Floran Sahiti, University Hospital of Wurzburg, Wurzburg, Germany doi: 10.1016/j.jchf.2025.01.019. SOGALDI-PEF: SOdium-Glucose cotransporter 2 inhibitor with and without an ALDosterone AntagonIst for heart failure with preserved ejection fraction – Joao Pedro Ferreira, University of Porto, Porto, Portugal. Host: Novi Yanti Sari, Siloam Hospitals Group, Jakarta (Indonesia).  MUSIC-HFpEF: Gene therapy in Heart Failure with Preserved Ejection Fraction – Marat Fudim, Duke University Medical Center, Durham, NC, USA. Host: Gregorio Tersalvi, Mayo Clinic, Rochester, MN, USA PREFER¬-HF: Effects intravenous iron or oral iron therapy compared to placebo in HFpEF with iron deficiency anemia - Jose Luis Morales Rull, University Hospital Arnau de Vilanova, Lleida, Spain. Host: Cornelia Margineanu, Bucharest, Romania. This 2025 HFA Cardio Talk podcast series is supported by Bayer AG in the form of an unrestricted financial support. The discussion has not been influenced in any way by its sponsor.

Darshan H. Brahmbhatt, Podcast Editor of JACC: Advances, discusses a recently published original research paper on Third-Trimester NT-proBNP for Pre-eclampsia Risk Prediction: A Comparison With sFlt-1/PlGF in a Population-Based Cohort.

Forget everything you thought you knew about heart disease. In this eye-opening episode, we dismantle the outdated cholesterol narrative and uncover what's actually behind the rise in cardiovascular dysfunction—from chronic inflammation to insulin resistance, oxidative stress, mitochondrial breakdown, and even spiritual disconnection. We covered:

Hosts Mitsuaki Sawano, MD, and Nobuhiro Ikemura, MD, welcome Yuichiro Mori, MD, MPH, a physician-scientist at Kyoto University, to discuss his ACC.25 poster presentation on biomarker-based pre-heart failure screening using NT-proBNP, conducted in a rural Japanese city in Hokkaido. Drawing from a screening cohort of 1,585 individuals aged 40–74 in Furano, the study integrated NT-proBNP testing into Japan's routine general health checkups. Dr. Mori shares key takeaways from the study and emphasizes how even single-site efforts, when well-structured and strategically communicated, can gain recognition at major global meetings like ACC.

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.

Heart failure is a clinical diagnosis with specific signs. If unsure, N-terminal pro b-type natriuretic peptide (NT-proBNP) levels can help rule it out Differences between brain natriuretic peptide (BNP) and NT-proBNP, and how to apply each of them to your heart failure patients In patients with chronic kidney disease, NT-proBNP levels should be within context of renal dysfunction Serial measurements of NT-proBNP are associated with prognosis, guidance and response to heart failure treatment Only one NT-proBNP test per patient per year is reimbursed; additional tests must be self-funded Host: Dr David Lim | Total Time: 39 mins Experts: Prof Andrew Sindone, Cardiologist A/Prof Ralph Audehm, General Practitioner Register for our fortnightly FREE WEBCASTSEvery second Tuesday | 7:00pm-9:00pm AEDT Click here to register for the next oneSee omnystudio.com/listener for privacy information.

CME credits: 1.25 Valid until: 10-01-2026 Claim your CME credit at https://reachmd.com/programs/cme/ns-mras-and-biomarkers-the-nt-probnp-connection/30064/ Discover the transformative potential of nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs) in optimizing care for patients with the Cardiovascular-Kidney-Metabolic syndrome. Emerging data presented at EASD, HFSA, ASN and AHA, highlight their ability to improve cardiorenal outcomes in the spectrum of the Cardiovascular-Kidney-Metabolic syndrome. By integrating ns-MRAs into individualized treatment plans, healthcare professionals can offer their patients advanced care backed by cutting-edge research.

Welcome to the first episode in a special three-part series of the Diabetes Core Update podcast, focused on heart screening in people with diabetes. Sponsored by Roche, this series explores "heart failure with preserved ejection fraction" (HFpEF), providing primary care clinicians and healthcare professionals with essential insights into screening, diagnosis, and management of this increasingly recognized condition. Episode Summary In this episode, host Dr. Neil Skolnik introduces the growing importance of HFpEF in diabetes care and is joined by two esteemed experts: Rodica Busui, MD, PhD, professor and chief of the division of endocrinology at the Oregon Health and Science University and past president of the American Diabetes Association for Medicine and Science. James Jannuzzi, MD, professor of medicine at Harvard Medical School, staff cardiologist at Massachusetts General Hospital, and senior cardiometabolic faculty at Baim Institute for Clinical Research. The discussion explores: HFpEF Basics: Definition, prevalence, and how it differs from heart failure with reduced ejection fraction (HFrEF). Pathophysiology: The multifactorial causes of HFpEF, including aging, obesity, diabetes, and more. Diabetes and HFpEF: Why HFpEF should be considered a major complication of diabetes alongside atherosclerotic and microvascular diseases. Screening Recommendations: Insights from the 2022 ADA/ACC Consensus Report, emphasizing early detection through biomarkers like NT-proBNP and annual testing for at-risk patients. Key Takeaways Epidemiology: HFpEF affects at least half of heart failure patients and is increasingly prevalent due to aging, obesity, and diabetes. Screening Guidelines: Every person with diabetes, especially those with chronic kidney disease, hypertension, or obesity, should be considered for HFpEF screening. Biomarkers: NT-proBNP thresholds are key tools for early diagnosis, with tailored considerations for obesity and other conditions. Prevention and Collaboration: Effective risk factor management and team-based care can prevent HFpEF progression and improve outcomes. Thank you for joining us on this first of a multipart series on early detection and treatment of heart failure with preserved ejection fraction. In the first part of this series, we focused on basics—epidemiology, pathophysiology, and staging—as well as the critically important new recommendations around screening people with diabetes for heart failure. In the second part of the series, we'll explore treatment strategies for HFpEF. This special edition of Diabetes Core Update is sponsored by Roche.

Ananda Developments Plc (AQSE:ANA) finance director Jeremy Sturgess-Smith takes Proactive's Stephen Gunnion through the latest findings related to MRX1, the company's lead investigative medicinal product. Developed in 2023, MRX1 targets inflammatory conditions such as chemotherapy-induced peripheral neuropathy and endometriosis, and it is also being studied in heart failure. Sturgess-Smith explained how leftover blood plasma samples from earlier research were analysed for NT-proBNP, a critical biomarker for heart failure with preserved ejection fraction (HFpEF). He said, "MRX1 was found to significantly reduce the levels of NT-proBNP in the mice versus the control mice." This, according to him, provides strong translational data to justify advancing to human studies. The results also bolster the company's patent application for MRX1. Ananda is now planning a larger preclinical study to explore additional biomarkers and evaluate MRX1's efficacy. Sturgess-Smith emphasised that the team is beginning to outline steps toward the first human study. Stay tuned for updates on MRX1 and other developments at Ananda. Visit Proactive's YouTube channel for more interviews, and don't forget to like, subscribe, and enable notifications. Relevant Hashtags #AnandaDevelopments #MRX1 #CBDResearch #HeartFailure #InflammatoryConditions #MedicalBreakthrough #Biomarkers #PreclinicalStudies #PharmaceuticalResearch #ProactiveInvestors#ProactiveInvestor s #invest #investing #investment #investor #stockmarket #stocks #stock #stockmarketnews

This week, please join authors Amil Shah and our own Peder Myhre, as well as Guest Editor Allan Jaffe as they discuss the article "NT-proBNP and Cardiac Troponin I, but Not Cardiac Troponin T, Are Associated With 7-Year Changes in Cardiac Structure and Function in Older Adults: The ARIC Study." For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20241202.603271

JACC Associate Editor Muthiah Vaduganathan, MD speaks with author Ambarish Pandey, MD about the LookAHEAD trial published in JACC and presented at AHA. Among adults with T2D and overweight/obesity in the Look Action for Health in Diabetes (AHEAD) trial, an intensive lifestyle intervention targeting weight loss led to sustained reductions in hs-cTnT at 1- and 4-year follow-up, and a rise in NT-proBNP at 1 year that attenuated at 4 years. After accounting for baseline biomarker levels and baseline and changes in risk factors, longitudinal increase in NT-proBNP was associated with higher risk of ASCVD and incident HF. In contrast, increase in hs-cTnT was significantly associated with ASCVD but not incident HF.

In the October 15, 2024 issue of JACC, a study led by Dr. Paul Hayler investigates the use of biomarkers—NT-proBNP, high-sensitive cardiac troponin T, and GDF-15—to assess heart failure risk in patients with atrial fibrillation. The findings reveal that these biomarkers significantly enhance risk stratification, suggesting their potential to identify patients at varying risks for heart failure and improve clinical management.

Explore the fascinating world of muscle as an organ, delving into its roles beyond movement, including its secretory functions and impact on overall health. This episode uncovers the surprising influences muscles have on inflammation, vascular health, and more. Discover how muscles communicate with the body through myokines, manage blood flow, and contribute to heart health.   5 KEY TAKEAWAYS:   1.Muscles as Secretory Organs: Learn how skeletal muscles produce myokines like IL-6 and BDNF, affecting body functions both locally and systemically. 2.Vascular Health and Muscles: Understand how eNOS activity in muscles enhances vascular health through better blood flow and vascular relaxation. 3.Heart Health Insights: Discover the role of NT-proBNP in heart health, produced by the heart under stress and closely linked with muscle function. 4.Muscle Health and Systemic Effects: See how muscle health impacts systemic conditions like diabetes and inflammation through the production of myokines. 5.Nutritional Impacts on Muscle Function: Gain insights into how amino acids like glutamine support muscle function and overall metabolic health.   FEATURED PRODUCT: Boost your muscle health with our advanced formula! Designed to enhance muscle function and support your body's natural processes, this product is perfect for anyone looking to improve their muscular system's overall health and efficiency, as discussed in today's episode. Gut: https://www.mswnutrition.com/products/gut?srsltid=AfmBOoqDiokc4Thnr44DyfkJYjwU-6zhP0aUWyx4Yu2kMccW20vbZfQ0   TIMESTAMPS:   •00:00 START: Introduction to Muscle Health •02:00: Muscles as Secretory Organs •05:00: The Role of eNOS in Muscle Function •10:00: Heart Health and Muscle Interaction •15:00: Systemic Effects of Healthy Muscles •20:00: Nutritional Strategies for Muscle Support   RESOURCES:   1.Myokines and Muscle Function: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710002/ 2.eNOS and Vascular Health: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8774925/ 3.Heart Stress and BNP: https://my.clevelandclinic.org/health/diagnostics/22629-b-type-natriuretic-peptide 4.Nutritional Influence on Muscles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019684/  

The following question refers to Section 5.1 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.The question is asked by University of Colorado internal medicine resident Dr. Hirsh Elhence, answered first by advanced heart failure faculty at the University of Chicago and Co-Chair for the CardioNerds Critical Care Cardiology Series Dr. Mark Belkin, and then by expert faculty Dr. Biykem Bozkurt.Dr. Bozkurt is the Mary and Gordon Cain Chair, Professor of Medicine, Director of the Winters Center for Heart Failure Research, and an advanced heart failure and transplant cardiologist at Baylor College of Medicine in Houston, TX. She is former President of HFSA, former senior associate editor for Circulation, and current Editor-In-Chief of JACC Heart Failure. Dr. Bozkurt was the Vice Chair of the writing committee for the 2022 Heart Failure 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. /*! elementor - v3.23.0 - 25-07-2024 */ .elementor-toggle{text-align:start}.elementor-toggle .elementor-tab-title{font-weight:700;line-height:1;margin:0;padding:15px;border-bottom:1px solid #d5d8dc;cursor:pointer;outline:none}.elementor-toggle .elementor-tab-title .elementor-toggle-icon{display:inline-block;width:1em}.elementor-toggle .elementor-tab-title .elementor-toggle-icon svg{margin-inline-start:-5px;width:1em;height:1em}.elementor-toggle .elementor-tab-title .elementor-toggle-icon.elementor-toggle-icon-right{float:right;text-align:right}.elementor-toggle .elementor-tab-title .elementor-toggle-icon.elementor-toggle-icon-left{float:left;text-align:left}.elementor-toggle .elementor-tab-title .elementor-toggle-icon .elementor-toggle-icon-closed{display:block}.elementor-toggle .elementor-tab-title .elementor-toggle-icon .elementor-toggle-icon-opened{display:none}.elementor-toggle .elementor-tab-title.elementor-active{border-bottom:none}.elementor-toggle .elementor-tab-title.elementor-active .elementor-toggle-icon-closed{display:none}.elementor-toggle .elementor-tab-title.elementor-active .elementor-toggle-icon-opened{display:block}.elementor-toggle .elementor-tab-content{padding:15px;border-bottom:1px solid #d5d8dc;display:none}@media (max-width:767px){.elementor-toggle .elementor-tab-title{padding:12px}.elementor-toggle .elementor-tab-content{padding:12px 10px}}.e-con-inner>.elementor-widget-toggle,.e-con>.elementor-widget-toggle{width:var(--container-widget-width);--flex-grow:var(--container-widget-flex-grow)} Question #33 A 63-year-old man with a past medical history of hypertension and type 2 diabetes mellitus presents for routine follow-up. He reports feeling in general good health and enjoys 2-mile walks daily. A review of systems is negative for any symptoms. Which of the following laboratory studies may be beneficial for screening?ANT-proBNPBCK-MBCTroponinDC-reactive proteinENone of the above Answer #33 ExplanationThe correct answer is A – NT-proBNP.This patient is at risk for HF (Stage A) given the presence of risk factors (hypertension and type 2 diabetes mellitus) but the absence of signs or symptoms of heart failure.Patients at risk for HF screened with BNP or NT-proBNP followed by collaborative care, diagnostic evaluation, and treatment in those with elevated levels can reduce combined rates of LV systolic ...

In today's VETgirl online veterinary CE podcast, we're going to review a study by Morey et al out of University of Missouri entitled “N-terminal brain natriuretic peptide, cardiac troponin-I, and point-of-care ultrasound in dogs with cardiac and noncardiac causes of nonhemorrhagic ascites.”

CardioNerds Dr. Josh Saef and Dr. Tommy Das join Dr. Omkar Betageri, Dr. Andrew Geissler, Dr. Philip Lacombe, and Dr. Cashel O'Brien from the Maine Medical Center in Portland, Maine to enjoy an afternoon by the famous Portland headlight. They discuss a case of a patient who presents with obstructive cardiogenic shock. Dr. Bram Geller and Dr. Jon Donnelly provide the Expert CardioNerd Perspectives & Review segment for this episode. Dr. Maxwell Afari, the Maine Medical Center cardiology fellowship program director highlights the fellowship program. Audio editing by CardioNerds Academy Intern, student doctor Tina Reddy. This is the case of a 42 year-old woman born with complicated Tetralogy of Fallot repair culminating in a 29mm Edwards Sapiens (ES) S3 valve placement within a pulmonary homograft for graft failure who was admitted to the cardiac ICU for progressive cardiogenic shock requiring vasopressors and inotropic support. Initial workup showed lactic acidosis, acute kidney injury, elevated NT-proBNP, and negative blood cultures. TTE showed at least moderate biventricular systolic dysfunction. She was placed on furosemide infusion, blood cultures were drawn and empiric antibiotics initiated. Right heart catheterization demonstrated elevated right sided filling pressures, blunted PA pressures with low PCWP, low cardiac index, and low pulmonary artery pulsatility index. Intracardiac echocardiography (ICE) showed a large mass within the ES valve apparatus causing restrictive valve motion with a low gradient across the pulmonic valve in the setting of poor RV function. Angiography revealed a large filling defect and balloon valvuloplasty was performed with immediate hemodynamic improvement. Blood cultures remained negative, she was gradually weaned off of inotropic and vasopressor support, and discharged. Despite empiric treatment for culture negative endocarditis and ongoing anticoagulation, she was readmitted for recurrent shock one month later at which time the pulmonic mass was revisualized on ICE. A valve-in-valve transcatheter pulmonary valve (29mm ES S3) was placed to compress what was likely pannus, with an excellent hemodynamic result and no visible mass on ICE. US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here. 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! Case Media Pearls - Obstructive Cardiogenic ShocK Tetralogy of Fallot is the most common cyanotic defect and can lead to long term complications after surgical repair including chronic pulmonary insufficiency, RV dysfunction, residual RVOT obstruction and branch pulmonary artery stenoses. Chronic RV failure may be more indicative of a structural defect and therefore require interventional or surgical management. Valve thrombosis, infective endocarditis and obstructive pannus formation should be considered in the differential of a patient with obstructive shock with a prosthetic valve. Bioprosthetic pulmonic valve obstruction may be effectively managed with balloon valvuloplasty in patients who present in acute extremis but TCPV will likely provide a more lasting result. While valvular gradients are typically assessed via echocardiography, invasive hemodynamics can serve as a critical adjunctive tool in its characterization. Show Notes - Obstructive Cardiogenic ShocK Notes were drafted by Drs. Omkar Betageri, Philip Lacombe, Cashel O'Brien, and Andrew Geissler. What are the common therapies and management for Tetralogy of Fallot? Tetralogy of Fallot is the most common cyanotic defect in children beyond the age of one year Anatomic Abnormalities: Anterior and Superior deviation of the conal septum creating a SubAo VSD and encroachment on the RVOT.

Commentary by Dr. Candice Silversides

NT-proBNP （解説）心臓血管研究所 循環器内科 心不全担当部長　加藤祐子氏（ききて）防衛医科大学校教授　　池脇克則氏

Join Dr. Joel Kahn on this episode of Heart Doc VIP as he delves into the fascinating world of biomarkers, specifically focusing on one called BNP (B-type natriuretic peptide) or NT-proBNP. Biomarkers play a crucial role in providing diagnostic and prognostic information in clinical care, as well as in the realm of life insurance panels. Discover what BNP is and how it functions within the body, along with the conditions that can lead to elevated levels of this biomarker. Dr. Kahn expertly guides us through the evaluation process when abnormal results are observed, shedding light on the significance of such findings for patients' health.  Moreover, in this episode, Dr. Kahn introduces a special supplement known as MitoQ, which shows promising potential in helping to lower BNP levels. If you're intrigued to learn more about MitoQ, you can find it at (https://shop.drjoelkahn.com/mitoq-pure-60-capsules.html). Once again, we extend our gratitude to our sponsor, healthycell.com, and invite you to take advantage of the exclusive 20% discount with the code KAHN during checkout. Tune in to this informative and empowering episode to stay ahead in your journey to a healthier heart!

The following question refers to Section 5.1 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. The question is asked by Keck School of Medicine USC medical student & CardioNerds Intern Hirsh Elhence, answered first by Greater Baltimore Medical Center medicine resident / Johns Hopkins MPH student and CardioNerds Academy House Chief Dr. Alaa Diab, and then by expert faculty Dr. Biykem Bozkurt. Dr. Bozkurt is the Mary and Gordon Cain Chair, Professor of Medicine, Director of the Winters Center for Heart Failure Research, and an advanced heart failure and transplant cardiologist at Baylor College of Medicine in Houston, TX. She is former President of HFSA, former senior associate editor for Circulation, and current Editor-In-Chief of JACC Heart Failure. Dr. Bozkurt was the Vice Chair of the writing committee for the 2022 Heart Failure 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. Question #17 A 63-year-old man with CAD s/p CABG 3 years prior, type 2 diabetes mellitus, hypertension, obesity, and tobacco use disorder presents for routine follow-up. His heart rate is 65 bpm and blood pressure is 125/70 mmHg. On physical exam, he is breathing comfortably with clear lungs, with normal jugular venous pulsations, a regular rate and rhythm without murmurs or gallops, and no peripheral edema. Medications include aspirin 81mg daily, atorvastatin 80mg daily, lisinopril 20mg daily, and metformin 1000mg BID. His latest hemoglobin A1C is 7.5% and recent NT-proBNP was normal. His latest transthoracic echocardiogram showed normal biventricular size and function. Which of the following would be a good addition to optimize his medical therapy?   A DPP-4 inhibitor B Dihydropyridine calcium channel blocker C SGLT2 inhibitor D Furosemide Answer #17 Explanation The correct answer is C: SGLT2 inhibitor. This patient is at risk for HF (Stage A) given absence of signs or symptoms of heart failure but presence of coronary artery disease and several risk factors including diabetes, hypertension, obesity, and tobacco smoking. At this stage, the focus should be on risk factor modification and prevention of disease onset. Healthy lifestyle habits such as maintaining regular physical activity; normal weight, blood pressure, and blood glucose levels; healthy dietary patterns, and not smoking have been associated with a lower lifetime risk of developing HF. Multiple RCTs in patients with type 2 diabetes who have established CVD or are at high risk for CVD, have shown that SGLT2i prevent HF hospitalizations compared with placebo. The benefit for reducing HF hospitalizations in these trials predominantly reflects primary prevention of symptomatic HF, because only approximately 10% to 14% of participants in these trials had HF at baseline. As such, in patients with type 2 diabetes and either established CVD or at high cardiovascular risk, SGLT2i should be used to prevent hospitalizations for HF (Class 1, LOE A). The mechanisms for the improvement in HF events from SGLT2i have not been clearly elucidated but seem to be independent of glucose lowering. Proposed mechanisms include reductions in plasma volume, cardiac preload and afterload, alterations in cardiac metabolism, reduced arterial stiffness,

Commentary by Dr. Candice Silversides

CME credits: 1.25 Valid until: 27-03-2024 Claim your CME credit at https://reachmd.com/programs/cme/nt-probnp-during-screening-in-the-study-of-vericiguat-in-participants-with-heart-failure-with-reduced-ejection-fraction-victoria-trial-insights-into-outcomes-and-vericiguat/15289/ In this program, expert faculty discuss data presented at the 2023 ACC Congress in a concise, informative, on-demand format. This format extends the congress analysis to a broader audience with greater detail than what is available in abstracts. Rapid advances from the meeting require well-planned educational programming to bridge knowledge, competence, and performance gaps.

The following question refers to Section 8.1 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.  The question is asked by Western Michigan University medical student & CardioNerds Intern Shivani Reddy, answered first by Brigham & Women's medicine resident and Director of CardioNerds Internship Dr. Gurleen Kaur, and then by expert faculty Dr. Prateeti Khazanie. Dr. Khazanie is an Associate Professor and Advanced Heart Failure and Transplant Cardiologist at the University of Colorado. She was an undergraduate at Duke University as a B.N. Duke Scholar. She spent two years at the NIH in the lab of Dr. Anthony Fauci and completed a dual MD-MPH program at Duke Medical School. When she started residency, she thought she was going to be an ID doctor, but she fell in love with cardiology at Stanford where she was an intern, resident, and then chief resident. She went back to Duke for her general cardiology and advanced heart failure/transplant fellowships as well as research training at the DCRI. Dr. Khazanie joined the University of Colorado in 2015 as a health services clinician researcher with a focus on improving health equity and bioethics in advanced heart failure care. She mentors medical students, residents, and fellows and is a faculty mentor for the University of Colorado Cardiology Fellows “House of Cards” mentoring group. She has research funding from the NIH/NHLBI K23, NIH Ethics Grant, and Ludeman Center for Women's Health Research. Dr. Khazanie is an author on the 2022 ACC/AHA/HFSA HF Guidelines, the 2021 HFSA Universal Definition of Heart Failure, and multiple scientific statements. 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 #11 A 64-year-old woman with a history of chronic systolic heart failure secondary to NICM (LVEF 15-20%) s/p dual chamber ICD presents for routine follow-up. She reports several months of progressive fatigue, dyspnea, and peripheral edema. She has been hospitalized twice in the past year with acute decompensated heart failure. Efforts to optimize guideline directed medical therapy have been tempered by episodes of lightheadedness and hypotension. Her exam is notable for an elevated JVP, an S3 heart sound, and a III/VI holosystolic murmur best heard at the apex with radiation to the axilla. Labs show Na 130 mmol/L, Cr 1.8 mg/dL (from 1.1 mg/dL 6 months prior), and NT-proBNP 1,200 pg/mL. ECG in clinic shows sinus rhythm and a nonspecific IVCD with QRS 116 ms. Her most recent TTE shows biventricular dilation with LVEF 15-20%, moderate functional MR, moderate functional TR and estimated RVSP of 40mmHg. What is the most appropriate next step in management? A Refer to electrophysiology for upgrade to CRT-D B Increase sacubitril-valsartan dose C Refer for advanced therapies evaluation D Start treatment with milrinone infusion Answer #11 Explanation The correct answer is C – refer for advanced therapies evaluation. Our patient has multiple signs and symptoms of advanced heart failure including NYHA Class III-IV functional status, persistently elevated natriuretic peptides, severely reduced LVEF, evidence of end organ dysfunction, multiple hospitalizations for ADHF, edema despite escalating doses of diuretics, and progressive intolerance to GDMT. Importantly, the 2018 European Society of Cardiology revised definition of advanced HF focuses...

The following question refers to Section 7.6 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.  The question is asked by premedical student and CardioNerds Intern Pacey Wetstein, answered first by Baylor College of Medicine Cardiology Fellow and CardioNerds Ambassador Dr. Jamal Mahar, and then by expert faculty Dr. Nancy Sweitzer. Dr. Sweitzer is Professor of Medicine, Vice Chair of Clinical Research for the Department of Medicine, and Director of Clinical Research for the Division of Cardiology at Washington University School of Medicine. She is the editor-in-chief of Circulation: Heart Failure. Dr. Sweitzer is a faculty mentor for this Decipher the HF Guidelines series. 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 #9 Mr. Flo Zin is a 64-year-old man who comes to discuss persistent lower extremity edema and dyspnea with mild exertion. He takes amlodipine for hypertension but has no other known comorbidities. In the clinic, his heart rate is 52 bpm and blood pressure is 120/70 mmHg. Physical exam reveals mildly elevated jugular venous pulsations and 1+ bilateral lower extremity edema. Labs show an unremarkable CBC, normal renal function and electrolytes, a Hb A1c of 6.1%, and an NT-proBNP of 750 (no prior baseline available). On echocardiogram, his LVEF is 44% and nuclear stress testing was negative for inducible ischemia. What is the best next step in management? A Add furosemide BID and daily metolazone B Start empagliflozin and furosemide as needed C Start metoprolol succinate D No change to medical therapy Answer #9 Explanation The correct answer is B – start empagliflozin and furosemide as needed. The patient described here has heart failure with mildly reduced EF (HFmrEF), given LVEF in the range of 41-49%. In patients with HF who have fluid retention, diuretics are recommended to relieve congestion, improve symptoms, and prevent worsening HF (Class 1, LOE B-NR). For patients with HF and congestive symptoms, addition of a thiazide (eg, metolazone) to treatment with a loop diuretic should be reserved for patients who do not respond to moderate or high-dose loop diuretics to minimize electrolyte abnormalities (Class 1, LOE B-NR). Therefore, option A is not correct as he is only mildly congested on examination, and likely would not require such aggressive decongestive therapy, particularly with normal renal function. Adding a thiazide diuretic without first optimizing loop diuretic dosing would be premature. The EMPEROR-Preserved trial showed a significant benefit of the SGLT2i, empagliflozin, in patients with symptomatic HF, with LVEF >40% and elevated natriuretic peptides. The 21% reduction in the primary composite endpoint of time to HF hospitalization or cardiovascular death was driven mostly by a significant 29% reduction in time to HF hospitalization, with no benefit on all-cause mortality. Empagliflozin also resulted in a significant reduction in total HF hospitalizations, decrease in the slope of the eGFR decline, and a modest improvement in QOL at 52 weeks. Of note, the benefit was similar irrespective of the presence or absence of diabetes at baseline. In a subgroup of 1983 patients with LVEF 41% to 49% in EMPEROR-Preserved, empagliflozin, an SGLT2i, reduced the risk of the primary composite endpoint of cardiovascular death or hospitalization f...

Découvrez dans ce podcast les éléments clefs à savoir concernant l'insuffisance cardiaque en MG avec Dr Olivier A. cardiologue à Nancy. A la fin de cet épisode, vous aurez revu : 1) Pourquoi la FEVG est devenue le mode de classification de l'Insuffisance cardiaque (IC) 2) Comment repérer l'insuffisance cardiaque en MG ? 3) Que faire avec le BNP ou NT-proBNP ? 4) Quel bilan de 1ère intention et dans quel délai adresser au cardiologue ? 5) Quelle est la quadrithérapie de base de traitement de l'IC ? 6) Qu'apportent les iSGLT2 dans l'IC ? 7) Quelles mesures hygiéno-diététiques conseiller aux malades ? Guideline.care : Le DPC n'a jamais été aussi simple : formations video courtes en ligne avec fiches de synthèses, ordonnances types, calculateurs de scores médicaux en accès illimités ! Taux de satisfaction des médecins sur guideline.care > 9,6/10 ⭐️⭐️⭐️⭐️⭐️

Please join author Subodh Verma and Guest Editor Christopher Granger as they discuss the article "Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial." 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-host. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Peder Myhre: And I'm Dr. Peder Myhre, social media editor and doctor at Akershus University Hospital at University of Oslo in Norway. Dr. Carolyn Lam: Peder, I am so excited to be discussing this issue. So many great articles and a feature discussion coming up on the SGLT2 inhibitor, empagliflozin. And do you think it's got effects on left ventricular remodeling in people without diabetes? Very interesting question. Dr. Peder Myhre: That is so interesting, Carolyn. I can't wait to hear this discussion. Dr. Carolyn Lam: Yep, I agree, but we got to wait till we discuss the other papers in today's issue. I want to go first. So we know that non-vitamin K oral anticoagulants, or NOACs, they've become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation. But, what is the effectiveness and safety of NOACs in patients on dialysis? That is hemodialysis. The AXADIA-AFNET 8 study sought to test the hypothesis that apixaban would be non-inferior to vitamin K antagonists in these very patients undergoing hemodialysis. Dr. Peder Myhre: Oh wow. This is really a gap of knowledge that we've been waiting to hear more about. NOACs in patients with hemodialysis. Tell us about this trial, Carolyn. Dr. Carolyn Lam: Sure. So this is from corresponding author, Dr. Reinecke, and colleagues, from University of Munster in Germany. And it's an investigator initiated prospective randomized open-blinded outcome assessment of 97 patients with atrial fibrillation on chronic hemodialysis randomized to either apixaban 2.5 mg BID, or a vitamin K antagonist, aiming for an INR between 2 and 3. Over a median follow-up time of 429 days for apixaban, and 506 days for the vitamin K antagonist, the composite primary safety outcome of first, major bleeding, clinically relevant, non-major bleeding, or all cause death, occurred in 46% of patients on apixaban, and 51% of patients on the vitamin K antagonist. That would be a hazard ratio of 0.91, with a p for non-inferiority being 0.157. How about the primary efficacy outcome? While this was a composite of ischemic stroke, all cause death, myocardial infarction, or deep vein thrombosis, and/or pulmonary embolism, and that occurred in 21% of patients on apixaban and 31% of patients on the vitamin K antagonists. Again, no difference when there was testing. So, in summary, Peder, there were no differences in the safety or efficacy observed between apixaban and vitamin K antagonists in patients with atrial fibrillation on chronic hemodialysis. Of note, however, even receiving oral anticoagulations, these patients remain at very high risk of cardiovascular events. So these data really support the consideration of apixaban for prevention of cardiovascular complications in patients with atrial fibrillation on chronic hemodialysis, but larger studies are definitely needed. Dr. Peder Myhre: Oh wow, Carolyn, that is so clinically relevant. And the next paper is also a clinically relevant paper. And it comes to us from the SPRINT authors. And to remind you, the SPRINT study was a study of intensive systolic blood pressure lowering compared to standard blood pressure lowering. And the results demonstrated that there was a robust reduction in both heart failure endpoints and all cause mortality. And in this sub-study that comes to us from corresponding author Jarett Berry from University of Texas Tyler School of Medicine, these authors look at the mechanisms through which intensive blood pressure lowering reduces the risk of these endpoints. And given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure, and strong association that has been observed between hypertension and levels of cardiac troponin and NT-proBNP, the authors hypothesized that intensive systolic blood pressure lowering would decrease levels of high sensitivity cardiac troponin T and NT-proBNP. Dr. Carolyn Lam: Cool. That's interesting. So how did they do this, and what did they find? Dr. Peder Myhre: So, as expected, Carolyn, the authors found that increases in troponin and NT-proBNP from baseline to 1 year were associated with a higher risk of heart failure and death. And there were really no significant interaction by treatment assignment. But let's look at the changes in troponin. And these results showed that randomization to intensive blood pressure lowering versus standard blood pressure lowering resulted in a significant 3% increase in cardiac troponin T level over 1 year follow up, and a higher proportion of participants with more than 50% increase, and that's with an odds ratio of 1.47. And Carolyn, in contrast, NT-proBNP decreased by 10% in intensive blood pressure arm. And these patients had substantially lower probability of increasing more than 50% in NT-proBNP, with an odds ratio of 0.57 compared to the standard arm. And now, to the most interesting part of this analysis, Carolyn, the association of randomized treatment assignment on changes in troponin was completely attenuated after accounting for changes in eGFR during the follow up, whereas the association of treatment with NT-proBNP changes were completely attenuated after adjusting for changes in systolic blood pressure. So Carolyn, the authors highlight in their discussion the importance of non-cardiac factors influencing variation in cardiac biomarkers, and raise questions about the potential role of cardiac troponin T as a surrogate marker for heart failure or death in blood pressure lowering studies. Dr. Carolyn Lam: Wow, very interesting. Thanks, Peder. Can I tell you now about a preclinical study? Very interesting, because it shows that cardiac inflammation and hypertrophy are regulated by a heart-brain interaction. Dr. Peder Myhre: Wow, Carolyn, a heart-brain interaction. I'm excited to hear more about this. Please explain. Dr. Carolyn Lam: I'd love to, but first some background. Interleukin-1 beta, now that is a pro-inflammatory cytokine that causes cardiac hypertrophy and heart failure. I need to familiarize you with this, the nucleotide-binding domain leucine-rich containing family, pyrin domain-containing-3, NLRP3 for short, which is an inflammasome, which is a cytosolic multiprotein complex that mediates active interleukin-1 beta production. Okay? So you know these terms, and now I want to tell you about the study. This is an elegant series of experiments performed by co-corresponding authors, Dr. Higashikuni, from University of Tokyo, and Dr. Sata, from Tokushima University Graduate School of Medicine, and their colleagues. They first showed that genetic disruption of the NLRP3 inflammasome resulted in significant loss of interleukin-1 beta production, cardiac hypertrophy, and contractile function during pressure overload. Next, a bone marrow transplantation experiment revealed an essential role of NLRP3 inflammasome in cardiac non-immune cells in myocardial interleukin-1 beta production and the cardiac phenotype. It was extracellular ATP released from sympathetic nerve terminals that induced the hypertrophic changes of cardiac cells in an NLRP3 and interleukin-1 beta dependent manner in vitro. And finally, depletion of ATP release from sympathetic efferent nerves, or ablation of cardiac afferent nerves, or a lipophilic beta-blocker, all reduced cardiac extracellular ATP, and inhibited the NLRP3 inflammasome activation, the interleukin-1 beta production, and the adaptive cardiac hypertrophy during pressure overload. So all of this suggests that controlling the neuronal brain signals might have therapeutic potential for the treatment of hypertensive heart disease. Neat, huh? Dr. Peder Myhre: Oh, that is so interesting. The heart and brain interaction. And, Carolyn, we're going to stay in the field of preclinical science. And now we're going to talk about another field that is really interesting, and that is regeneration of cardiomyocytes. Because, Carolyn, developmental cardiac tissue holds remarkable capacity to regenerate after injury, and consists of regenerative mononuclear and deployed cardiomyocytes. Whether reprogramming metabolism promotes persistence of these regenerative mononuclear and deployed cardiomyocytes that enhance cardiac function in repair after injury is unknown. Therefore, these researcher, led by corresponding author, Mohsin Khan, from Temple University School of Medicine, investigated whether the RNA binding protein, LIN28a, which is a master regulator of cellular metabolism, plays a role in cardiac repair following injury. Dr. Carolyn Lam: Wow. That is always, always interesting, regeneration and repair following injury. So what did the authors find? Dr. Peder Myhre: Well, Carolyn, through a number of elegant experiments, the authors made the following key findings. For the first time, they documented a role for RNA binding protein LIN28A in regulating cardiomyocyte turnover in the postnatal and adult heart. And LIN28a overexpression promotes cardiomyocyte cell cycle activity during postnatal development and extends cardiac regenerative ability of the mammalian heart to postnatal day 7. And in the adult heart, the authors could demonstrate that LIN28a drives new myocyte formation, augmenting cardiac structure and function after myocardial injury. And Carolyn, I'm sure you're going to ask the clinical implications of this study. Dr. Carolyn Lam: Indeed. Dr. Peder Myhre: And that is that these results may suggest a novel translational role for LIN28a based strategy to replenish cardiomyocytes in the adult heart after injury. Dr. Carolyn Lam: Very nice, Peder. Thank you. Also in the issue is a Research Letter by Dr. Bick on interleukin-6 receptor polymorphism attenuates clonal hematopoiesis mediated coronary artery disease risk among many individuals in the UK Biobank. There's also Cardiology News by Tracy Hampton, where she highlights few really interesting things, like aging cardiomyocytes accumulate new genetic mutations that was published in Nature Aging, cytokines promote tissue repair after a heart attack in mice, and that was published in Science, and scientists identifying molecular alterations in a failing heart at a single cell resolution, which was published in Nature. Dr. Peder Myhre: And there are a couple of other papers also in this issue, Carolyn. And there's first, an exchange of letters by Drs. Halushka, Lu, and Mayr, regarding the article "Circulating MicroRNA-122-5p is Associated with a Lack of Improvement in Left Ventricular Function after TAVR and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles." And finally, we have an "On My Mind" piece by doctors Monda and Limongelli entitled "An Integrated Sudden Cardiac Risk Prediction Model for Patients with Hypertrophic Cardiomyopathy." Dr. Carolyn Lam: Oh, nice. Nice full issue. Thank you, Peder. Let's go to our feature discussion now. Shall we? Dr. Peder Myhre: Let's go. Dr. Greg Hundley: Welcome listeners to this feature discussion on January 24th. And we have with us Dr. Subodh Verma, from St. Michael's University in Toronto, Canada. And a guest editor, Dr. Christopher Granger, from Duke University in Durham, North Carolina. Welcome gentlemen. Well, Subodh, we will start with you. Can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address? Dr. Subodh Verma: First, my great pleasure to be here, and thank you very much for the opportunity to discuss this paper with your viewers. As you know, SGLT2 inhibitors have been truly transformative therapies. From a heart failure perspective, we know that they prevent incident heart failure in people with diabetes who have vascular disease or risk factors. They also have been shown to treat prevalent heart failure in people with heart failure and either a reduced, mildly reduced, or preserved ejection fraction independent of glycemic status. And really, these have been the basis of very strong recommendations to use these agents in the prevention of heart failure in people with diabetes, and also in the treatment of prevalent heart failure in people with and without diabetes. Now, the fact that these drugs have such broad effects in people with heart failure has led to a theory that maybe these drugs could be introduced earlier on in the natural history of heart failure in people who neither have diabetes nor have significant heart failure, the so-called sort of stage A or stage B patient. But there really have been no clinical trials evaluating this question. There've been a lot of translational randomized trials that have provided some mechanistic insights about LV remodeling in people with diabetes or in people with prevalent heart failure. And we hypothesized that maybe the first step to evaluate whether SGLT2 inhibitors may have favorable effects on cardiac remodeling in people without diabetes or without heart failure would be to conduct a randomized double-blind control trial looking at indices of left ventricular remodeling in a population that I've just described. Dr. Greg Hundley: Very nice, Subodh. So you've started us into your study design. Maybe describe that a little more fully, and then who was included in your study population? Dr. Subodh Verma: So EMPA-HEART 2 CardioLink was a multi-center double-blind placebo control randomized trial in which we studied the effects of empagliflozin, an SGLT2 inhibitor, at a dose of 10 mg per day versus placebo in people who did not have type 2 diabetes or significant heart failure. We included people who were adults between the age of 40 and 80 who met 1 of 2 entry criteria. Either they had to have one major criteria, which was an increase in left ventricular mass index by specific echo criteria or MRI criteria, or they could have increased LVH as identified by ECG or by intraventricular septal or posterior wall thickness. They could also get in if they had resistant hypertension, hypertension despite being on 3 antihypertensive agents, or the second strata was entry through 2 minor criteria, which included a history of myocardial infarction, a GFR between 30 or 60, or evidence of overweight or obesity. Dr. Greg Hundley: And how many subjects did you randomize? Dr. Subodh Verma: So we randomized, of the 318 that we screened, 169 were randomized to receive empagliflozin 10 mg or a placebo. Patients had a baseline cardiac MRI done, and then the exposure was 6 months. They had a follow-up MRI at the end of 6 months. And the primary outcome measure was a 6-month change in left ventricular mass index from baseline to 6 months between the two groups. Dr. Greg Hundley: Very nice. And so , Subodh, can you describe for us now, what did you find? What were your study results? Dr. Subodh Verma: So, first and foremost, what we found in terms of baseline characteristics was that we enrolled a population of people with a mean age of around 60 with a BMI of around 30 kg/m2, predominantly men, about 80% or so were men. These were patients who did not have significant heart failure. The NT-proBNP at baseline was around 50 pg/mL. The eGFR was around 80 mL/minute, and the vast majority of these patients actually had a history of hypertension. Of course, none of them had diabetes by definition. The hemoglobin A1C was around 5.8%. Now what we found was, despite the fact that we went after patients who we thought would be enriched for a baseline increase in LV mass indices, the baseline LV mass index was mildly elevated, was around 63 g/m2. And over the course of 6 months, we did not find any significant difference in terms of LV mass regression between the placebo and empagliflozin groups. In fact, the adjusted treatment effect was minus 0.30 g/m2, which was not statistically significant. No other differences were found in terms of other indices of a remodeling, including left ventricular and diastolic or end systolic volume indices or in terms of left ventricular ejection fraction. There was a 2% increase in ejection fraction, and the p-value for that was 0.07, but really was not statistically significant. Dr. Greg Hundley: And very nice. And realizing that women may have smaller LV masses, any stratified analysis that evaluated effects on men versus women? And then what about, perhaps in the higher quartile versus lower quartile, of age? Dr. Subodh Verma: Right. So, Greg, we actually did look at various subgroups and covariates, including gender, including age. And age or gender did not really influence the overall result that we obtained. There was really a neutral result in empagliflozin, irrespective of these 2 covariates. We also looked at baseline blood pressure, baseline NT-proBNP, LV mass indices, the presence or absence of heart failure, chronic kidney disease. So for the covariates that we have evaluated over a short term of 6 months in this relatively low risk population, we did not find any heterogeneity the result, per se. Dr. Greg Hundley: Very good. Well, Subodh, thank you so much for that beautiful presentation. And listeners, now we're going to turn to our guest editor, Dr. Chris Granger. And Chris is an expert in the field of heart failure. Also, a lot of familiarity with HFpEF, which sounds a little bit, we're looking at precursors. We don't have HFpEF yet, but maybe trying to inhibit this from happening using empagliflozin. How do you put these results in the context with other studies that have emphasized utilizing SGLT2 inhibitors in patients with sort of a preserved ejection fraction and absence of diabetes? Dr. Christopher Granger: Yeah. Well thanks, Greg. And again, congratulations, Subodh, to your study. And I think you framed some of the context here as these drugs, the SGLT2 inhibitors, as being transformative, which I think is exactly right. And it's such a fascinating story. Right? These drugs, which we thought originally, with their cause of glucose spilling in the urine, and a modest decrease in blood glucose, might have a role for modestly improving glucose control in diabetes. And low and behold, they've turned out to be one of the great stories I think in recent, across all of medicine, in terms of their consistent and substantial improving clinical outcomes for patients with heart failure, with diabetes and cardiovascular disease, and now even kidney protection, and much broader implications. And their well tolerated, and they don't have dose titration. So there's some practical appeal to this class of drugs in terms of their benefits, in terms of clinical outcomes. But we're left with having this amazing evidence-based generated without really understanding why are these drugs so effective? And what are they doing? And you've provided, I think, an important piece to the puzzle. We did have the data from patients with diabetes and heart failure, with diabetes and left ventricular hypertrophy, that there is a modest reduce in LV mass with SGLT2 inhibitors. And what you've shown is that for patients that with mild LVH, with risk for LVH, that we simply don't see a substantial reduction in LV mass with the use of these drugs. So I think that provides this evidence that that's not a major cause of benefit, at least in this earlier phase of development of heart failure. And I think it really underscores the fact that there's a lot of work to do still to understand. We know that the renal effects are obvious place that these drugs have such an important benefit. And then the linkage of renal disease and cardiac performance is one of the areas, I think, that's a very exciting aspect of a probable contribution of the mechanism of these drugs. But I think in the end, we're left with still not really understanding why these drugs are so beneficial. But understanding that, I think, will be important, both for opening new avenues of targeting pathways, as well as being able to tell the clinical community, okay, you have these important benefits, but people do want to also know why are we seeing these benefits. Dr. Greg Hundley: Very nice. Well, listeners, we're going to turn back to Dr. Verma here. Subodh, what do you see is the next study to be performed in this sphere of research? Dr. Subodh Verma: Well, first, my thanks to Professor Granger, Chris, for handling this paper and for his very thoughtful comments. And he's absolutely right. We have such wonderful clinical data, and these results, of course, should not in any way take away from the importance of using empagliflozin or other SGLT2 inhibitors in the prevention of heart failure in people with diabetes, or in the treatment of HFpEF or HFrEF. But we're struggling with trying to understand what is the dominant mechanism of action here. And, in the previous precursor to EMPA-HEART 2, we did EMPA-HEART 1 in people with diabetes, and we saw a modest effect that was statistically significant of reduction in LV mass index. And we did not see this, of course, in a lower risk population without diabetes. And that tells me that remodeling may be occurring to a modest effect, it may require a longer time to actually show its benefits, but that this is unlikely a dominant sort of mechanism through which these drugs are working. And I do share Chris's thoughts that one of the key mechanisms of benefit that needs to be further explored is looking at the renal cardiac axes. We know that these drugs are profoundly renal protective, and that the benefits may actually be secondary to improvements in renal hemodynamics, improvements in renal function. And I think that is a population that needs to be, that's a mechanism that needs to be studied further. So I think the next generation of translational mechanistic studies need to really tease out the renal cardiac axes, maybe tease out populations that are at risk but have more significant left ventricular hypertrophy, maybe evaluate patients for a longer duration of treatment, or select people who truly have significant hypertension at baseline. I think those are groups and questions that need further exploration. And, of course, the translational science needs to be also studied in the context of larger completed clinical trials, where biomarkers are currently available and they can be linked, of course, to the outcomes in those trials. So those are some of my thoughts as to where the field could move towards. Dr. Greg Hundley: Very nice. And Chris, do you have anything to add? Dr. Christopher Granger: Subodh, I think that was a great summary. And I might just make a comment on the other end of the spectrum. That is, we have these drugs and the evidence of their benefit, and yet they're grossly underused in the populations that have proven to have benefit. Now it takes some time to educate, to get people familiar with, and get them to integrate these treatments into practice, but there's an enormous opportunity, and I think there is a linkage here. I think when people understand the mechanism, and when they're thoughtful about how these drugs may be working, that that really helps to make the case that the drug should be used, and that people are on board with using them. So I think there's this linkage here, there's the need to both better understand mechanism, and there's the need to have systems of care where these treatments are integrated to provide the benefit that's been so clearly shown in the randomized trials. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Subodh Verma, from St. Michael's University in Toronto, and our guest editor, Dr. Chris Granger, from Duke University in Durham, North Carolina, for bringing this paper highlighting that among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, that SGLT2 inhibition with empagliflozin did not, did not, result in a meaningful reduction in LV mass index after 6 months. Well, on behalf of Carolyn, Peder, 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.

It's another session of CardioNerds Rounds! In these rounds, Dr. Loie Farina (Advanced Heart Failure and Transplant Fellow at Northwestern University) joins Dr. Jane Wilcox (Chief of the Section of Heart Failure Treatment and Recovery at Northwestern University) to discuss the nuances of HFpEF diagnosis and management. Dr. Wilcox is also the Associate Director of the T1 Center for Cardiovascular Therapeutics in the Bluhm Cardiovascular Institute and Director of the Myocardial Recovery Clinic at Northwestern University. Dr. Wilcox is a prolific researcher, clinician, and thought leader in Heart Failure and we are honored to have her on CardioNerds Rounds! Notes were drafted by Dr. Karan Desai. Audio editing by CardioNerds Academy Intern, student doctor Akiva Rosenzveig. This episode is supported with unrestricted funding from Zoll LifeVest. A special thank you to Mitzy Applegate and Ivan Chevere for their production skills that help make CardioNerds Rounds such an amazing success. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. Case details are altered to protect patient health information. CardioNerds Rounds is co-chaired by Dr. Karan Desai and Dr. Natalie Stokes.  Speaker disclosures: None Challenging Cases - Atrial Fibrillation with Dr. Hugh Calkins CardioNerds Rounds PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes - Antithrombotic Management with Dr. Deepak Bhatt Case #1 Synopsis: A woman in her 80s with a history of HFpEF presented with worsening dyspnea on exertion over the course of a year but significantly worsening over the past two months. Her other history includes prior breast cancer with chemotherapy and radiation therapy, permanent atrial fibrillation with AV node ablation and CRT-P, and CKD Stage III. She presented for an outpatient RHC with exercise to further characterize her HFpEF. Her echo showed normal LV size, no LVH, LVEF of 50%, decreased RV systolic function, severe left atrial enlargement, significantly elevated E/e' and mild MR. Right heart catheterization showed moderately elevated bi-ventricular filling pressures at rest but with passive leg raise and Stage 1 exercise the wedge pressure rose significantly. We were asked to comment on management. Case #1 Takeaways Amongst the things that were discussed were the role of specific therapies in symptomatic patients with HFpEF. In patients with HFpEF and documented congestion, they will require diuretic therapy for symptomatic relief. But in addition to diuretic therapy, we discussed starting HFpEF-specific therapies. Amongst, those specific therapies mineralocorticoid receptor antagonist (MRA) and sodium-glucose co-transporter 2 (SGLT2) inhibitor. In multiple trials that have included patients with HFPEF, SGLT2i have reduced the risk of hospitalization. This includes the EMPEROR-PRESERVED Trial (see the CardioNerds Journal Club discussion on the trial) in which nearly 6000 patients with NYHA Class II-IV symptoms, EF > 40% and elevated NT-proBNP with a prior HF hospitalization within the past 12 months were randomized to Empagliflozin or placebo. The primary outcome – death from CV causes or hospitalization for Heart Failure – was significantly lower in the SGLT2i arm (13.8% vs 17.1%, 95% CI 0.69-0.90, P 45% to receive either spironolactone or placebo. The primary endpoint (death from CV cause, aborted cardiac arrest, or hospitalization for HF) was not statistically different between treatment arms. Of note, however, there were concerns for regional differences which is outlined well in this NEJM Evidence piece. Case #2 Synopsis: A woman in her 70s with history of hypertension, obesity,

This week, please join authors Svati Shah and Senthil Selvaraj as well as Guest Editor and Editorialist Manuel Mayr as they discuss the article "Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF" and the editorial "SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism." Dr. Carolyn Lam: Welcome to Circulation On 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 Pauley Heart Center at VCU Health Richmond, Virginia. Dr. Carolyn Lam: In today's feature paper, we will be talking about the metabolomic profiling of the effects of dapagliflozin in heart failure, and this is from the DEFINE-HF trial. It's just such a cool paper with a lot of insights you have to hear from the authors. But, before we get there, let's talk about some of the other papers in today's issue. Shall we, Greg? Dr. Greg Hundley: You bet, Carolyn. Well, how about if I go first? Dr. Carolyn Lam: Please. Dr. Greg Hundley: Thank you, Carolyn. My first paper comes to us from Professor Paulus Kirchhof from the Universitäres Herzzentrum in Hamburg. Carolyn, in the randomized EAST-AFNET 4 study, so the early treatment of atrial fibrillation for stroke prevention, these trial investigators demonstrated that systematic initiation of early rhythm control reduced adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. However, the effectiveness and safety of early rhythm control in patients with multiple cardiovascular comorbidities is not known. Carolyn, in this study, it was a prespecified sub-analysis of the EAST-AFNET 4 trial and it compared the effectiveness and safety of early rhythm control with usual care stratified into patients with high CHA2DS2-VASc scores of greater than or equal to 4. Dr. Carolyn Lam: Nice. Okay. Important question, what did they find? Dr. Greg Hundley: Right, Carolyn. Quite a bit of data in this study, so let's walk through it carefully. First, in regards to the study population, the EAST-AFNET 4 randomized 1093 patients with CHA2DS2-VASc scores of greater than or equal to 4, these were predominantly women, 61% female, and then also 1,696 patients with CHA2DS2-VASc of less than four, and these were predominantly men, so only 37% women. Now let's get to the date. Early rhythm control reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening heart failure or for acute coronary syndrome in patients with high CHA2DS2-VASc scores of greater than 4, but not in patients with CHA2DS2-VASc scores of less than 4. Second, now Carolyn, the primary safety outcome, so death, stroke, or serious adverse events of rhythm control therapy, was not different between study groups in patients with high CHA2DS2-VASc scores of greater than 4, but occurred more often in patients with low CHA2DS2-VASc scores randomized to early rhythm control. Now Carolyn, life threatening events or death were not different between the groups. When female sex was ignored for the creation of high and lower groups, the interaction P was not significant for the primary efficacy outcome, but remained significant for the primary safety outcome. Dr. Carolyn Lam: Oh, you are right. A lot of interesting data here. What's a take home message? Dr. Greg Hundley: Right, Carolyn. So the take home message is the following. Patients with recently diagnosed atrial fibrillation and multiple cardiovascular comorbidities should be considered to have priority access to early rhythm control to reduce cardiovascular outcomes, and a specific trial of early rhythm control in these patients is really needed as a next step. Dr. Carolyn Lam: Oh, thank you, Greg. The next paper focuses on arrhythmogenic right ventricular cardiomyopathy, which we know is characterized by a high propensity to life threatening arrhythmias and progressive loss of heart muscle. More than 40% of reported genetic variants linked to arrhythmogenic right ventricular cardiomyopathy, or ARVC, reside in a gene called plakophilin-2, or PKP2. In today's paper, Dr. Delmar and Lundby from NYU Grossman School of Medicine and University of Copenhagen, respectively, and their colleagues, described a comprehensive characterization of the ARVC molecular landscape using a multidisciplinary approach including human samples from ARVC patients with PKP2 mutations and left ventricular ejection fraction above 45%, as well as PKP2-deficient murine and human induced pluripotent stem cell-derived cardiomyocytes. They studied all of these with comprehensive proteomics and functional analysis. Dr. Greg Hundley: Wow, Carolyn, another great study in circulation combining both preclinical murine models as well as data from human subjects. So, what did they find? Dr. Carolyn Lam: Precisely, Greg. Here's what they found. Loss of nuclear envelope integrity and subsequent DNA damage is a key substrate in the molecular pathology of AR VC. The authors further showed transcriptional down regulation of proteins of the electron transcript chain as an early event in the molecular pathophysiology of the disease prior to an ejection fraction falling below 45%. This associates with increased oxidant production, with the clinical message being, therefore, that the authors propose therapies that limit oxidant formation may be a possible intervention to restrict DNA damage in ARVC. Dr. Greg Hundley: Very nice, Carolyn. Okay, our next paper comes from Dr. Donald Lloyd-Jones from Northwestern University, the Feinberg School of Medicine. Carolyn, you can tell the change in inflection of my voice because it's time for another Carolyn's quiz. Carolyn, open-ended question. Can you remind us of life's essential eight? Dr. Carolyn Lam: Oh boy, Greg. It's like asking me to name the dwarfs. I know I'm going to forget one, but here you go. Diet, exercise, cholesterol, weight, smoking, sugar must be there, diabetes, blood pressure. You see, I got seven. What's the eighth? Dr. Greg Hundley: Yeah. Remember seven dwarfs, Sleepy. Dr. Carolyn Lam: Sleep. Dr. Greg Hundley: Very good. Great job, Carolyn. Dr. Carolyn Lam: Thank you. Dr. Greg Hundley: Recently, the American Heart Association recently published an updated algorithm for quantifying cardiovascular health, the Life's Essential 8 score. In this study, the investigative team quantified US levels of cardiovascular health using the new score. They included non-pregnant, non-institutionalized individuals aged 2 through 79 years who were free of cardiovascular disease from the National Health and Nutrition Examination Surveys that were conducted between 2013 and 2018. Now, for all participants, they calculated the overall cardiovascular health score, and it ranged from 0, which is really low, to 100, which is the highest, as well as the score for each component. And Carolyn, yes, you are very close. Remember the eight? Diet, physical activity, nicotine exposure, sleep duration, body mass index, blood lipids, blood glucose, and blood pressure, and they used published American Heart Association definitions of these. The cardiovascular health scores were assessed across strata of age, sex, race, ethnicity, family income, and depression. Dr. Carolyn Lam: Okay, Greg. What did they find? Dr. Greg Hundley: Right, Carolyn. There were 23,400 plus participants, representing 201,728,000 adults and 74 million children. The overall mean cardiovascular health score was 64.7 among adults using all eight metrics, and it was 65.5 for the three metrics available of diet, physical activity, and BMI among the children and adolescents that were aged 2 through 19 years. Now, for the adults there were significant differences in mean cardiovascular health scores by sex, age, and racial ethnic group. Mean scores were lowest for diet, physical activity, and the BMI metrics. There were large differences in mean scores across demographic groups for diet, nicotine exposure, blood glucose, and blood pressure. In children, diet scores were low, 40.6, and were progressively lower in higher age groups. Large differences were also noted in mean physical activity and BMI by sociodemographic group. Carolyn, this study basically identifies wide ranges of scores across multiple domains of the essential eight, and thus, this new Life's Essential 8 score helps identify large group and individual differences in cardiovascular health. Additionally, overall, cardiovascular health in the US population remains well below optimal levels, and there are both broad and targeted opportunities to monitor, preserve, and improve cardiovascular health across the life course in both individuals, as well as the population at large. Dr. Carolyn Lam: Wow. Thanks, Greg. Truly really interesting. Everyone's going to have to pick up that paper and all the other papers in this issue, because there's also an In Depth paper by Dr. Whelton on “Harmonization of the ACC/AHA and ESC/ESH Blood Pressure Hypertension Guidelines, Comparisons, Reflections, and Recommendations. There's a Research Letter by Dr. Munshi on the accurate classification of cardiomyopathy etiology by chromatin accessibility. Dr. Greg Hundley: Carolyn, I have got to report an exchange of letters from Professor Sun and Weng regarding the article, “Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture.” And then Carolyn, lastly, there's a Perspective piece from Professor Vidal-Petiot entitled, “Thresholds for Hypertension Definition, Treatment Initiation, and Treatment Targets: Recent Guidelines at a Glance.” Well, Carolyn, how about we get on to that feature discussion? Dr. Carolyn Lam: Yes, let's go Greg. Wow, we have a star stud cast for today's feature discussion, and on a star studied topic, if I may. It's on the SGLT2 inhibitors, this time in the DEFINE-HF study and really going into the mechanism of action of SGLT2 inhibitors. Now, that's one question I personally get all the time. How do these things work? Today's paper brings us one step closer, for sure, in the understanding. I'm so grateful to have the first author, Dr. Senthil Selvaraj from University of Pennsylvania, as well as the corresponding author of the paper, Dr. Svati Shah, associate editor, as well as the corresponding author from Duke Molecular Physiology Institute. We also have Dr. Manuel Mayr who was both the guest editor and editorialist for this paper, and Dr. Mayr is from Kings College London, British Heart Foundation Center. Welcome, everyone. Senthil, get us started here. The DEFINE-HF study, just a quick summary, what that was about and then what you did, what you found. Dr. Senthil Selvaraj: Absolutely. Good morning, everyone, or maybe good evening for your time, Carolyn, but we were very excited about this study and the ability to do targeted metabolomic profiling in DEFINE. This audience is well familiar with the fact that SGLT2 inhibitors are foundational therapy in heart failure reduced ejection fraction, and the interesting thing is, despite a lot of literature, we still don't know why. Whether it relates to change in inflammation or endothelial function, but given the mechanism of action, metabolism is sort of at its core. So in this study we sought to identify metabolic pathways that were associated with dapagliflozin treatment using this targeted metabolomics platform in which we assayed 63 metabolites, acylcarnitine, which are markers of fatty acid oxidation, several amino acids, and ketone-related metabolites. To do this, we studied 234 participants from DEFINE, which is a 12-week placebo-controlled trial of dapagliflozin in this population, and we perform principal components analysis for dimensionality reduction techniques. In this study, briefly we found that, first, our principal components analysis yielded 13 different factors that accounted for the substantial proportion in the variation of the data, and that two in particular, ketone-related metabolites and short acylcarnitines in factor 6, as well as medium-chain acylcarnitines in factor 7 were differentially associated with dapagliflozin treatment. Specifically, there were increases in several ketone-related metabolites and short acylcarnitines, as well as several medium-chain acylcarnitines, really speaking to, potentially, changes in fatty acid as well as ketone biology with dapagliflozin treatment. The second aim of our study was to look at changes in metabolites and changes in endpoint studying DEFINE, which included NT-proBNP as well as KCCQ scores. We found that dicarboxylate long-chain acylcarnitines and aromatic amino acids really related to worsening heart failure endpoints there. So, a lot to impact, a lot that we found, and appreciative about the opportunity. Dr. Carolyn Lam: Oh, wow. Thank you so much for that amazing summary. Svati, I've heard you speak so many times on metabolomics on our calls, but this is really so important. First, I think the question is, congratulations for thinking ahead of time to collect the samples and to do all of this. Congratulations on that. Could I ask if you went in with any specific hypothesis or were you surprised by these findings, Svati? Dr. Svati Shah: Yeah, Carolyn, thank you so much. It was such a pleasure to work with Senthil on this and I really want to highlight what an incredible early career investigator he is. He's really going to set the metabolism world on fire. I also wanted to say thank you to the PI of the clinical trial, the parent clinical trial DEFINE-HF Mikhail Kosiborod, who did the really hard work of collecting the samples along with the clinical trial itself. To me, what's really cool is to be able to take a clinical trial like this with really important clinical outcomes well adjudicated and to be able to dig into the mechanism at a metabolic level of what might be going on with SGLT2 inhibitors. Going into this, Carolyn, we suspected that ketone-related biology was at play. There have been studies in other populations, non-HFrEF populations, that have shown that SGLT2 inhibitors have what appears to be beneficial impacts on ketone biology and induced ketosis. So, going into this, we suspected that this ketone pathway was going to come up. I think what's exciting is, not only did we find that the ketone pathway was differential modified by dapagliflozin, but that it wasn't at the level of severe ketosis that we would be concerned about. And then secondly, we found pathways of fatty acid oxidation. Some related to the effects of the medication and some related to changes in functional outcome. So it really enhanced beyond what we already knew about ketone biology, expanded our understanding of potential mechanisms of SGLT2 inhibitors, and expanded this into the HFrEF space, Carolyn. Dr. Carolyn Lam: Oh, that's so nice. I'm bursting with questions, but I really, really have to ask Dr. Manuel Mayr, first, could you put these findings into context for us and tell us what they mean clinically? Dr. Manuel Mayr: Yeah, Carolyn. First of all, I want to join you in congratulating the authors to this important study. As Svati mentioned, previous studies have reported effects of SGLT2 inhibitors on ketone bodies, but the present study really adds to the literature because it uses the state of the art metabolomic techniques. It uses a technique called mass spectrometry, but they also have a rating of, I think, in total, 63 metabolites in over 200 patients. Mass spectrometry is becoming increasingly important for cardiovascular precision medicine because we can use it in clinical trials to provide an unbiased assessment of metabolites and proteins. So it's a very versatile technology. I think this study really adds to the rapidly growing literature that SGLT2 inhibition is a principle of unloading the failing heart from metabolic stress. Dr. Carolyn Lam: Wow, I really like that and your editorial is just beautiful. I love that you say, "After the serendipitous findings of improved heart failure outcomes with SGLT2 inhibitors, mechanisms were postulated, but studies, such as the one we're discussing, are needed to really uncover what's the real thing." Now, I know this may sound really oversimplified and so on, but I'd really love for Senthil or Svati to just bear with me as I ask, what are you going to say to people who go, "Okay, then we should just be downing ketones," Or, "We should be Working on the fatty acid parts of it," Or taking conclusions like that. What would you say to something like that? Dr. Senthil Selvaraj: I'm happy to go first. It's a really wonderful question and I do think that this study raises the question of whether we should be exogenously increasing ketone levels to provide some sort of benefit. I would say the jury's still out there. I think it's a hot topic right now. But there are also differences between how we raise key tone levels, whether you do that endogenously in the body, or whether you give something like a ketone supplement, so exogenous ketone supplementation. And I think that there are completely different physiologies there. So more to come. I think there are a lot of studies in this space. The ketogenic diet is something that I'm often asked as well, whether that might provide benefit to heart failure. There are a lot of ways that I can, but one thing that we need to be mindful of is the fact that it will reduce glycogen stores as well, which may impact exercise capacity. So, we need more data. I would say the other thing that we found in our studies, while they were increased in ketone levels and markers of fatty acid oxidation with dapagliflozin treatment, we aren't necessarily sure that those mediate the benefits of SGLT2 inhibitors. DEFINE has important clinically relevant endpoints, but it is not an event-based trial. And so we don't know and we can't link the changes in metabolites with changes in outcomes quite yet. Dr. Svati Shah: Carolyn, just to add to the wonderful response that Senthil just gave, I think we do have to be careful. We don't know whether these are direct effects of SGLT2 inhibitors or whether these are related to the caloric loss that we know happens with these medications. I think it's important to point out that we're looking in the blood, we don't actually know what's happening at the tissue level, so we do have to be a little bit careful. We have made inferences that this is reporting on substrate fuel selection in the heart, but we also suspect that skeletal muscle and other organs are heavily involved in some of the pathways we're seeing. So I just wanted to make those important caveat to the epidemiologic work that we do. Dr. Carolyn Lam: And those are so important, so thank you Senthil and Svati. Manuel, I'd love to invite your thoughts because you did sort of point out some of these points in your editorial. Could you maybe discuss a bit of those and raise any questions, perhaps? Dr. Manuel Mayr: Yes. I think Svati and Senthil have nicely mentioned already that these measurements are performed in plasma. So the changes in plasma could be due to, for example, increased production in the liver due to decreased consumption in other tissues. So I guess the next step would be, and I would be really interested on what the authors want to pursue, is to provide direct evidence for the energetic hypothesis, that really the heart is consuming these keto bodies and what type of measurements could be performed to provide direct evidence in humans for these metabolic hypothesis. Dr. Senthil Selvaraj: That's a really great question, Manuel. There was a really nice study that was published about a year or two ago in Science in which the authors did coronary sinus sampling. So really to get arterial venous gradients, measure substances in the arterial system as well as the coronary sinus venous system and get extraction. I think that that study would be very interesting to understand. You take patients on SGLT2 inhibitors, those who are not, and to understand what is the heart chewing on. Obviously more invasive than some other approaches, but other studies that I think would be really interesting in those space would be flux studies and stable isotope studies. Again, as Svati really nicely mentioned, these are systemic physiology snapshots whenever we do less localized techniques like that, but they're still very important because heart failure is a systemic process. Dr. Carolyn Lam: Anything to add, Svati? Dr. Svati Shah: No, I think you said it beautifully. I'll just say on the sort of epidemiologic side, to be able to link this to harder outcomes, DEFINE-HF wasn't really designed to be able to do that. So as we expand our understanding of SGLT2 inhibitors, understand different populations, and to link these pathways to more objective outcomes, I think, will be really useful, also. Dr. Carolyn Lam: Indeed. Manual, in your editorial, you actually discuss some of your own work, which may be the ones that Senthil is actually talking about. What is your view? Dr. Manuel Mayr: Well, I think I'm very excited that beyond fatty acid metabolism and glucose metabolism, ketones have extracted increasing attention. Ketone body metabolism, I think, has long been underappreciated. We still need to understand to what extent it really acts as a fuel and that it can help to overcome the energy deficit that creates heart failure. I think, as mentioned by Svati and Senthil, we need more studies in this area, and of course other trials are ongoing where they're going to measure, for example, the phosphocreatine to ATP ratio by using phosphor-NMR spectroscopy. So we get direct evidence whether there really is an energetic improvement upon SGLT2 inhibition. I think this will be studies to look forward to and to add to the growing literature that metabolism is important as a therapeutic target for heart failure. Dr. Carolyn Lam: Oh, such exciting times. You mentioned the EMPA-VISION trial in your editorial. I think I'm trying to tell everybody, you have to pick up the paper and the editorial. You're going to learn so much. This is so cool. Thank you so, so much all of you for being on this podcast, for sharing your thoughts. I'm sure everyone has learned a lot and enjoyed it just as I have. On behalf of Greg and I, thank you for being here, thank you for joining us today, and don't forget to tune in again next week. Thank you. 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 week, please join authors Mikhail Kosiborod and Christian Schulze and Editorialist Stefan Anker as they discuss the original articles "Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial" and "Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients With Acute Decompensated Heart Failure (EMPAG-HF)" and the editorial "SGLT2 Inhibitors: From Antihyperglycemic Agents to All-Around Heart Failure Therapy." 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 Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam:             I'm so excited about the feature discussion this week. It is a paired feature along with their editorial and it's all focused on SGLT2 inhibitors. The first, results from the EMPULSE trial, Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure; and the second, the EMPAG-heart failure trial, The Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients with Acute Heart Failure. Incredibly important topics, incredibly important discussion. Wait up for it. We're just going to tell you a little bit more about two other original papers in today's issue, and I'm going to go first, Greg. Is that okay? Dr. Greg Hundley:           You bet. Dr. Carolyn Lam:             Now, really interesting topic here. We have strong evidence supporting the effective blood pressure and cardiovascular disease risk lowering properties of healthy diet such as the DASH diet, Mediterranean diet, and so on and so on. But what about the diet consumed by a fifth of the entire world's population? The Chinese cuisine. Interestingly, today's paper addresses just that. This is from authors, Dr. Wu, from Peking University Clinical Research Institute and colleagues who performed a multicenter patient and outcome assessor blind randomized feeding trial among 265 participants with baseline systolic blood pressure of 130 to 159 in four major Chinese cuisines. And these are the Shandong, Huaiyang, Cantonese, and Szechuan cuisines, and here's how they did it. After a seven day run in period on a control diet matching the usual local diets, participants were randomized to continue with the control diet or the cuisine based Chinese heart healthy diet for another 28 days. The primary outcome was systolic blood pressure. The study developed the first heart healthy Chinese diet that fits Chinese food culture and emphasizes its palatability by involving master shifts in developing the recipes. Dr. Greg Hundley:           Oh wow. Carolyn, this is really interesting, especially one fifth of the world's population in studying a heart healthy diet. So did it work? I can't wait to hear the results. Dr. Carolyn Lam:             Well, the change in systolic and diastolic blood pressure from baseline to the end of the study in the control group was five millimeters mercury and 2.8 millimeters mercury reduction, respectively. The net difference of change between the two groups in systolic and diastolic blood pressure were a reduction of 10 and almost four millimeters mercury, respectively. The effect size did not differ among cuisines, and so in summary, with a patient and assessor blind randomized feeding trial, this study really demonstrated that the blood pressure lowering effect of the Chinese heart health diet could indeed be substantial, and importantly, be compatible with medications while palatable and affordable in Chinese adults with high blood pressure, and so these results support the idea that food is medicine and will give many patients with high blood pressure the confidence to adopt heart healthy diets in their lifestyle treatment. Dr. Greg Hundley:           Wow, Carolyn, that is really an interesting article. So many of these articles today could all be features in and of themselves. That was just outstanding. Well, my next paper comes to us from the world of preclinical science, and it's from Dr. Sean Wu from Stanford University School of Medicine. So Carolyn, immune checkpoint inhibitors are monoclonal antibodies that are used to activate the immune system against tumor cells. Now, despite their therapeutic benefits, immune checkpoint inhibitors have the potential to cause immune mediated adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Now histologically, patients with immune checkpoint inhibitor of myocarditis have lymphocytic infiltrates in the heart implicating T-cell mediated mechanisms. However, the precise pathologic immune subsets and molecular changes in immune checkpoint inhibitor myocarditis are unknown. Dr. Carolyn Lam:             Wow. So insights into the etiology of these immune checkpoint associated myocarditis cases must be very important. So what did they find? Dr. Greg Hundley:           Right, Carolyn? So clonal cytotoxic, TEMRA CD8+ cells were found to be significantly increased in the blood of patients with immune checkpoint inhibitor myocarditis corresponding with an analogous increase in effector cytotoxic CD8+ cells in the blood and hearts of PD-1 deficient mice with myocarditis. These expanded effector CD8+ cells had unique transcriptional changes, including upregulation of the chemokines CCL5, CCL4, and CCL4L2, and they may serve as attractive diagnostic therapeutic targets for reducing life threatening cardiac immune related adverse events in immune checkpoint inhibitor treated cancer patients, and Carolyn, just like so many of our articles, there's a very nice accompanying editorial by Professor Gianluigi Condorelli that also offers an update on current research pertaining to non-systemic steroid therapy to treat immune mediated myocarditis. Well, Carolyn, how about we jump to some of the other articles in the issue? Dr. Carolyn Lam:             Oh, you bet, Greg. There's an exchange of letters between Drs. Madias and Knops regarding the article “Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in Transvenous and Subcutaneous Implantable Defibrillators: The Analysis of All Appropriate Therapy in the PRAETORIAN Trial.” Dr. Greg Hundley:           And also in the mail bag, Professor Mark has a Research Letter entitled “Effect of Empagliflozin on Kidney Biochemical and Imaging Outcomes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction, The SUGAR-DM-HF Study,” and our own Tracy Hampton has several synopses from articles published elsewhere in our piece on cardiovascular news. Well, how about we get onto that feature forum discussion, two papers, two editorialists. I can't wait. Dr. Carolyn Lam:             Me too. Let's go, Greg. Dr. Greg Hundley:           Welcome, listeners to this July 26th feature forum discussion. So remember, listeners, for forum discussions, we have several manuscripts that focus on a singular topic and we bring together the authors, our associate editors, and also an editorialist, and today, I want to introduce, we have with us Dr. Mikhail Kosiborod from Mid America Heart Institute in Kansas City, Missouri, Dr. Christian Shults from University Hospital Jena in Germany, Stefan Anker from Charité in Berlin, Germany, and our Associate Editors, Brendan Everett from Brigham and Women's Hospital in Boston, Massachusetts, and Justin Grodin from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentleman, and we'll start with you, Mikhail. Could you describe for us the background information that went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Mikhail Kosiborod:   Well, thanks very much, Greg. The background for the study, which was the secondary analysis of the EMPULSE trial was patients that are hospitalized with acute decompensated heart failure represent a very high risk group. We know that they have high risk of death and hospitalizations, and we also know that they have very poor health status that's very high burden of symptoms, physical limitations, and poor quality of life, and so addressing those treatment goals, trying to reduce the risk of clinical events like death and hospitalizations and improve the symptoms and physical limitations in this patient population are very important treatment goals. Now we previously demonstrated in the main results of the EMPULSE trials that using empagliflozin initiating empagliflozin SGLT2 inhibitor in this patient population as compared with placebo provided a significant total clinical benefit, which was a composite of total death, repeat hospitalizations for heart failure, or a change in a Kansas City cardiomyopathy questionnaire, which is a kind of a gold standard measure of patient's health status. What we tried to do in a much more granular fashion in this study is to understand the effects of empagliflozin as compared with placebo on this very important outcome, the Kansas City cardiomyopathy questionnaire, and we actually evaluate all of the key domains and composite symptoms, physical limitations, as well as quality of life. Dr. Greg Hundley:           Very nice, and Mikhail, can you describe for us what study population specifically, and then what was your study design? Dr. Mikhail Kosiborod:   Well, this was a population of patients that were hospitalized with heart failure and that EMPULSE was unique in its design because first of all, previous SGLT2 inhibitor trials mostly focused on patients with chronic heart failures that were in an outpatient setting, including prior trials of empagliflozin, and EMPULSE really focused on acutely hospitalized patient population, but it included patients regardless of ejection fraction. So as they were hospitalized with decompensated heart failure and reduced or preserved ejection fraction. They were enrolled regardless of if they had type 2 diabetes, they were enrolled essentially, regardless of kidney function, only patients with EGFR of less than 20 were excluded, and also importantly, was this study and a unique feature of the study in particular was that we enrolled patients whether they had acute de novo heart failure. That means that was a new diagnosis of heart failure that was bad enough for them to be hospitalized or worsening chronic heart failure requiring hospitalization. So it was really an all-comer trial for patients acutely hospitalized for heart failure. So we had just over 500 patients and they were randomized in the hospital. After a brief period of stabilization, we use empagliflozin, 10 milligrams daily or placebo and treated for 90 days, and the primary outcome at 90 days was a total clinical benefit that I described that was a composite, hierarchical composite of total death hospitalizations, repeat hospitalizations for heart failure and changing KCCQ. In this study, again, we focused predominantly on KCCQ, trying to understand the effects on health status, again, symptoms, physical limitations, and quality of life. Dr. Greg Hundley:           Excellent. And Mikhail, what were your study results? Dr. Mikhail Kosiborod:   Well, what we observed, a couple of things. One is we first examined the effects of empagliflozin on the primary endpoint across the range of KCCQ and baseline, and what we found was that regardless of the degree of symptomatic impairment and baseline, empagliflozin was consistent in providing them total clinical benefits that I described previously, and then kind of shifting to what I think is the most interesting findings, the effects of empagliflozin versus placebo on KCCQ, what we found was that as you would imagine in this population of patients that were acutely hospitalized with heart failures, that had very poor health status, very low KCCQ at baseline, and within the first 90 days, which was observation period, both groups of patients had substantial improvements in KCCQs. As one would expect after acutely decompensated episode of heart failure and treatment in a hospital, everyone got better. But patients treated with empagliflozin had significantly greater improvement in KCCQs than those that were treated with placebo, and that was first of all, a very substantial difference between the two groups. It was more than five points in favor of empagliflozin already at 15 days and was highly statistically significant, and it was maintained throughout the 90 day treatment period. So the fact that we saw both a clinical meaningful and statistically significant improvement in just 15 days, I think is a very important clinical message, and then finally, I guess what I will mention is these benefits of empagliflozin while main outcome we looked at was KCCQ total symptoms, we're focusing on the symptoms, but it was consistent when we looked at physical limitations as well as quality of life. So really, all key domains of KCCQ were impacted in a similar way. Dr. Greg Hundley:           Very nice. So in acute heart failure, marked symptomatic improvement after the administration of the SGLT2 inhibitor empagliflozin at 10 milligrams per day. Well, now listeners, we're going to turn to our associate editor, Dr. Brendan Everett, and Brendan, again, you have many papers come across your desk. What attracted you to this particular manuscript? Dr. Brendan Everett:      Well, thanks, Greg, and I think this manuscript caught my eye because of the importance of the clinical question, and Mikhail outlined why I think that was really relevant. So we understand that this class of medications or SGLT2 inhibitors have important effects on outcomes like re-hospitalization in patients with heart failure, and what was particularly striking about this paper is that it took patients rather than those with chronic heart failure, but as Mikhail mentioned, enrolled a patient population that was actually in the hospital, and I think this was an important frontier for this particular question about when to start the SGLT2 inhibitor and what kind of benefits there might be. Furthermore, I think the fact that they did not select the population based on ejection fraction was particularly striking, and of course, I think is remarkable, but now old news, they did not select on the presence or absence of diabetes as well. And so those three components really attracted me to the paper. I also think the outcome is one that really is valuable and worth exploring, and specifically, I'm talking about how patients feel on the medication after a hospitalization for heart failure. Appropriately, we focused on re-hospitalization for heart failure and cardiovascular death in prior trials in this space, and I think we need to embellish those findings or further deepen those findings with a perspective on how patients actually feel when they get the medication, and of course, it goes without saying that what's particularly important here also is that it was a randomized placebo controlled trial, and so the results have some element of internal validity that I think is really important. So those were the things, Greg, that really attracted my attention as I read the paper for the first time. Dr. Greg Hundley:           Thank you so much, Brendan. Well, listeners, we've got a second paper today and we're next going to hear from Dr. Christian Shults, and he also is focusing on really another aspect of the administration of empagliflozin in patients with acute heart failure and that pertains to the renal function of the patients. So Christian, could you describe for us the background pertaining to your study and what was the hypothesis that you were intending to address? Dr. Christian Schulze:     Thanks, Greg. Well, it's great to introduce all study here in this running. So our study impacted those in acute decompensated heart failure. The impact HF trial was a study based on the hypothesis that we wanted to test, whether empagliflozin has effects in acute decompensated heart failure, and we focused on the patient population that was not addressed in EMPULSE, patients that came to the ER and needed to be treated right away, and we wanted to know and this was our main hypothesis, but are the diuretic and [inaudible 00:17:11] effects of the SGLT2 inhibitor on this case, empagliflozin, actually had an impact on diuretic regimens and kidney functions since this is one of the main end points that limits treatment, and also is one of the outcomes of patients with acute decompensated heart failure in the hospital. Dr. Greg Hundley:           Very nice. And so Christian, what study design did you implement and who was included in your study population? Dr. Christian Schulze:     So we also used the randomized two arm study design. We included patients with acute decompensated heart failure independent of left ventricular ejection fraction. Patients needed to have an NT-proBNP of more than 500. The average NT-proBNP in fact was 4,300 in our entire patient population, and we included patients within 12 hours of presentation. So many of these patients have been recruited in the ER, they presented two hour cardiology heart failure service, and then were immediately randomized to the trial in the two arms, and we tested not 10 milligrams of empagliflozin. We actually tested 25 milligrams of empagliflozin based on in-house data that 25 milligrams potentially had a stronger diuretic effect compared to 10 milligrams. Dr. Greg Hundley:           And what did you find? Dr. Christian Schulze:     So we followed patients for five days. It was a relatively short period of time. It was designed to address the in-house phase of patients with acute decompensated heart failure. The mean duration of stay was 6.3 days in the hospital so this was exactly the time that we wanted to test. We had a 30 day endpoint for safety issues, and what we could see is that patients on 25 milligrams on empagliflozin on top of standard diuretic regimens and medical care had 25% higher diuretic outputs compared to patients in the placebo group. We also found no differences in markers of renal injury dysfunction, and could in fact confirm that after 30 days, patients in the empagliflozin group had a better EGFR compared to patients in the placebo group. On top, we saw a more rapid decrease in body weight and also a more profound decrease in NT-proBNT values. Dr. Greg Hundley:           And Christian, just for our listeners to put a little bit of this in perspective, what was the range of serum creatinine for the patients that were enrolled in your study? Dr. Christian Schulze:     So the main EGFR in the entire population was around 60 and the creatinine values were around 107 on average in the entire cohort. So this is a very typical population. We had around 30% of the population with de Novo heart failure, around 20 to 30% of the population was pre-treated for preexisting heart failure. So very typical population of patients with heart failure presenting to the emergency room. Dr. Greg Hundley:           And did you have any kind of lower level EGFR cutoff, I mean, for enrollment into this study? Dr. Christian Schulze:     So when we designed the trial, we actually still had the sub classification of diabetes or impaired glucose or homeostasis as an inclusion criteria. We dropped it before we started the trial because the data came out that this is actually, in fact, not a critical issue for patients with heart failure. So diabetes was not a subgroup in our trial and the lower limit of EGFR was actually a thoroughly defined protocol. Dr. Greg Hundley:           Very nice. Well, listeners, now we're going to turn to our second associate editor, Dr. Justin Grodin from University of Texas Southwestern Medical Center in Dallas, Texas, and Justin, similar to Brendan, and you see many papers come across your desk and so what attracted you to this particular paper by Christian and his colleagues? Dr. Justin Grodin:            Well, Greg, I think first and foremost, and I think very similar to Brendan, but I think what's always striking is if I may just take a step back, decompensated heart failure in the United States is the number one cause for hospitalization among Medicare beneficiaries. So I think really, the brunt and really the truly public health message of the disease is very important in the applicability, and even though that decompensated heart failures is one of the most common things that we ever encounter when we practice, internists, cardiologists, et cetera, we have very, very little clinical trial guidance that tells us how to decongest individuals when they're hospitalized with swelling and heart failure and a lot of these individuals can be quite ill, and we have some clinical trial data, but largely, we have a lot of negative studies or inconclusive studies in this space. So certainly, what drew me to this trial was definitely that context, and obviously, based on the mechanistic data with SGLT2 inhibitors, I think one of the natural questions, which Christian addresses, is that we know that up front, they do augment natriuresis. So I think it's very compelling to marry those two together because this is what many of us that use these medications regularly have been asking is whether or not they would have some efficacy in that regard, and then another thing that caught my eye and me as a cardiorenal investigator was, just as Christian highlighted, was we have a clinical trial that randomly assigned individuals, really that were ill and many of whom were not stabilized within 12 hours of presentation, and we're talking about patients that are coming into the hospital at all times during the day in and I think that's very remarkable that we have something with standard... We have a study with standardized assessments where we're really trying to ask a very practical, pragmatic question, which is do these therapies lower the sodium balance in individuals with decompensated heart failure, and I think what's important is largely, we've got a lot of medications that supplement loop diuretics, which are the class of drugs that the majority of us use, and we have a lot of other therapies that we use that really have very little data or poor data that guide us such as thiazide diuretics, carbonic and hydrase inhibitors, mineralocorticoid receptor antagonists, and so here, we have a clinical trial that asks a question that's on many people's minds. And then we do have very compelling, at least short term pragmatic and mechanistic data that does tell us that these individuals do have a greater natriuretic effect when empagliflozin is used as an adjunct to standardized loop diuretic therapy. So it's a very practical clinical question, and I think what's very important, and we could debate probably all day about the implications of GFR change and kidney function change while we're decongesting somebody with diuretics, but I think what's reassuring to all the clinicians is we really didn't see an effect on kidney function despite a greater natriuretic effect or enhanced diuretic effect, if you will, with the use of empagliflozin. Dr. Greg Hundley:           Very nice. Well, thank you, Justin. Listeners, now we have an editorialist and as you know, editorialists really help us put the scientific presentation of an original manuscript into the perspective of really the global theme of a topic, and we have Stefan Anker from Berlin, and Stefan, can you describe for us how do we put these two manuscripts and results that we've heard about really in the context now of moving forward with the use of SGLT2 inhibitors in the management of patients with acute decompensated heart failure? Dr. Stefan Anker:            Thank you so much. Really, I think these two papers, on the one hand, enhance our certainty about early use, and on the other hand, possibly show us that there might be even more to achieve by, on the one hand, moving even earlier with the application of SGLT2 inhibitors or possibly consider the higher dose. Now let's take one step back. These drugs were developed in type two diabetes and the first successful trial was the [inaudible 00:25:42] outcome trial. Many people have forgotten that this trial tested two doses and not only one, the 10 and the 25 milligram dose, and of course, with the success for improving kidney outcomes and heart failure hospitalization outcomes, we move forward into these two specialist areas, on the one hand, broadening it to the non-diabetic communities, but on the other end, narrowing it by focusing on the 10 milligram dose regardless of whether there is [inaudible 00:26:12]. And we basically now learn A, to use these drugs even earlier than we did in the big trials and we can now be sure to start their use in the hospital, and if you take the average change in quality of life results seen, you actually get a better result for the patient on quality of life when you start earlier than when you start late in the ambulatory studies where basically, in the chronic setting, maybe you have one and a half to two points difference. Here, you now have four and a half points in the study shown by Mikhail, and of course, it's also good to know that you can start this in any type of patient, regardless of their quality of life. The impact study from Christian, they basically moved it now even earlier, moving into the hospital space is possible based on EMPULSE. Moving it into the acute admission space is at least a consideration now based on what Christian here has shown. And he is actually addressing the one question I hear very often in my presentations about SGLT2 inhibitors, what about this 25 milligram dose? Is there a place for this in cardiology as well, and a possible place is shown here, not only that this is a safe thing to do, but also you get urinary output. Of course, we may in the future, want to see this compared, directly compared to the 10 milligram dose, but of course, the world is not created in one day, but needs more than one and so really, I think these two studies, on the one hand, address an important issue, when to start using them. On the other hand, show us a little bit of a glimpse to the future. Dr. Greg Hundley:           Very nice, Stefan, and listeners, we get to take advantage of having these authors, editors, and editorialists together and ask them what they see as the next study to be performed in this sort of sphere of research. So Mikhail, we'll start with you. In 30 seconds or less, what do you see as the next study to be performed in this arena of research? Dr. Mikhail Kosiborod:   I think, Greg, what we've learned recently, including from the EMPULSE trial, we have this population of patients in a hospital with heart failure's a huge issue as Justin mentioned, and until recently, we had very little [inaudible 00:28:31] for them beyond the usual kind of decongestion with loop diuretics and trying to make them feel better, but you look at outcome data. It really was a dearth of effective therapies that have meaningful impact on important outcomes. Now that's changing, SGLT2 inhibitors is one example. There are some other recent examples in this patient population, like a firm HF and iron deficient patients with heart failure. But the bottom line is it's no longer kind of a desert, if you will, of positive trials. We now have something we can do and I think what this proves is that we need to actually invest more, both in terms of resources and time to really do what we we're being able to do in other areas of heart failure and those patients with chronic, half and half where we can start developing pillars of therapy that can actually truly improve outcomes with this patient population and there is a lot going on that makes me optimistic that's going to be the case in the coming years. Dr. Greg Hundley:           Very nice. And Brendan? Dr. Brendan Everett:      Well, I think both trials mentioned today really pushed our understanding of this population forward. I think the biggest clinical question that I face when I'm caring for these patients is that we have four, at least, guideline directed therapies, right? We have beta blockers, we have ARBs, ACE inhibitors and ARNIs. We have mineral receptor antagonists and we have SGLT2 inhibitors. So which do we use in what order and how do we start them, and what kind of parameters do we use to guide us if we're limited either by renal function or by blood pressure or by some other factor. And we often, if not always, have one of those constraints that we're dealing with and so I would say the next step for me is trying to sort out which of these therapies and what order ought to be our highest priority for patients with acute decompensated heart failure as we move quickly from the acute decongestion stage towards discharge and a chronic therapy that will then be followed as an outpatient over the ensuing days and months. Dr. Greg Hundley:           Very nice. And Christian. Dr. Christian Schulze:     Thank you again, and Brandon pointed out very nicely. I mean, we have good evidence now for chronic heart failure treatment. We have the four columns of heart failure medical therapy. Questions that remain open is what do we do with all these patients that are now guideline medicated, come to the hospital with an acute decompensation? Should we carry on with the medication? Should we terminate and in particular, should be carry on with full dose, 50% dose of SGLT2 inhibitors, and the next question is, what dose should we use, in fact, for SGLT2 inhibitors? Is it in group effects or is sotagliflozin comparable to empagliflozin, and then is there a role for a step by scheme that we initially have in high dose therapy that we then downgrade to 10 milligrams on the chronic heart failure treatments, and then of course, quality of life is very important. We should ask this question also in this patient population that is early on treated, do we see benefits that carry on in the outpatient setting and do we see an effect of early treatment on long term benefits? Dr. Greg Hundley:           Justin? Dr. Justin Grodin:            Well, I would have to agree with all of my colleagues here on this call. I think all have raised really good points, but I think one very simple, and I'll echo some of Brendan's statements, but one very simple question is we know that when we decongest people and initiate a negative salt balance in the hospital for decompensated heart failure, we cause neurohormonal activation and there are a lot of downstream untoward effects from chronic decongestive therapies, and I think one of the more compelling things is we still yet have defined what is the best way to decongest individuals with swelling or volume overload in the hospital. Here, we have compelling studies with SGLT2 inhibitors for quality of life and really, the way patients feel. And this is really what's important to them, and then something very pragmatic to clinicians and let's make people pee more, but I think one of the compelling questions, and I don't know if it will be answered, is we have a lot of choices for supplemental therapies and different diuretic strategies when patients come in the hospital for decompensated heart failure, and I do think that these studies do move the needle with SGLT2 inhibitors. I think that's abundantly clear, but we still don't know what is the best way to dry out my patient or make my patient pee so that they feel better, but I do think that these studies do at least set the stage that there's some compelling advantages to SGLT2 inhibitors. Dr. Greg Hundley:           And then lastly, Stefan. Dr. Stefan Anker:            Thank you. Besides the detailed points mentioned by many, and Christian, totally support 25 versus 10 milligram, how long 25 milligram, if at all in the future. Besides this, I'm interested in the big picture question. So what about the post myocardial infarct congestion/heart failure situation, and there will be two trials in the next 18 to 24 months that report on this, and my pet kind of area is actually to treat heart failure where nobody thinks it is heart failure, and what I mean is for instance, advanced cancer patients, cardiac wasting cardiomyopathy. So the heart failure in sick cancer patients, and indeed, we are planning to do exactly that now in a study focusing on hospice care patients to really improve the quality of life, the very thing focus here on the EMPULSE trial. Dr. Greg Hundley:           Well, listeners, we want to thank our authors, Dr. Mikhail Kosiborod from Mid America Heart Institute in University of Missouri, and Christian Shults from the University Hospital in Jena, Germany. Also, our associate editors, Dr. Brendan Everett from Brigham and Women's Hospital in Boston, and Dr. Justin Grodin from University of Texas Southwestern in Dallas, Texas, and also, our editorialist, Dr. Stefan Anker from Charité in Berlin, Germany for bringing us these two manuscripts pertaining to two randomized clinical trials regarding the administration of the SGLT2 inhibitor, empagliflozin in acute heart failure, demonstrating first, marked improvement in heart failure symptoms and health related quality of life. And second, in those with estimated GFRs greater than 30 mls per minute, an augmentation of natriuresis in the setting of the co-administration of diuretics without deterioration in renal function. Well, on behalf of 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, 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.

A new paper entitled, “Impaired Vagal Activity in Long-COVID-19 Patients” sheds light on the vagus nerve's involvement in Long-COVID-19. COVID-19 is divided into three phases of infection: 1. “Acute COVID-19” (signs and symptoms of COVID-19 infection up to 4 weeks). 2. “Ongoing symptomatic COVID-19” (from 4 weeks up to 12 weeks). 3. “Post-COVID-19 syndrome” (signs and symptoms persist beyond 12 weeks). Click here to learn more about the Hedberg Institute Membership. Study Methods 30 Long-COVID-19 patients were compared to 20 control subjects who never had COVID-19. 21 patients were classified based on their experience while having COVID-19 as mild/moderate and 9 as severe/critical. 7 patients had no/negligible functional limitations, 6 had slight functional limitations, and 17 had moderate/severe functional limitations. No significant differences were found among study subjects and controls regarding gender, demographics, medical history, drug use, and vital signs. However, previous studies have shown that females are more affected by Long-COVID-19. Heart rate variability was measured through ECG. Heart rate variability parameters are controlled by the parasympathetic nervous system. The sympathetic nervous system promotes inflammation through catecholamines and beta-adrenergic stimulation in contrast to the parasympathetic nervous system which is anti-inflammatory. COVID-19 causes an imbalance between these two systems, thus driving inflammation and a procoagulative state. Study Findings Heart rate variability was found to be lower in the Long-COVID-19 patients. Left ventricular ejection fraction was lower in Long-COVID-19 patients. When SARS-CoV-2 comes into contact with the eye, it may reach the central nervous system via the trigeminal nerve. And when the virus contacts the nasal mucosa, it may reach the brain through the olfactory nerve. It may also travel to the central nervous system via the vagus nerve from the respiratory system, the heart, the digestive system, the kidneys, bladder, uterus, and testicles. This occurs through neuronal retrograde transport to the axonal terminal. SARS-CoV-2 has been detected in the vagus nerve, thus persistent damage to this nerve could explain impairment of the parasympathetic nervous system in Long-COVID-19 patients. SARS-CoV-2 can also invade the brain through a dysfunctional blood-brain barrier, which has been damaged by cytokine storm. SARS-CoV-2 binds to the ACE2 receptor found in the respiratory airway, lung, vascular endothelia, kidney cells, and small intestine. ACE2 receptors are also found in neurons and glia in the brainstem regions responsible for cardiovascular function and regulation. SARS-CoV-2 neuronal invasion drives epinephrine and norepinephrine from the adrenal gland known as the “catecholamine surge” which causes cardiovascular, lung, and brain injury. NT-proBNP levels were found to be increased in Long-COVID-19 patients, which reflects myocardial strain due to increased vascular pressure. This persistent myocardial strain may drive the dysautonomia, or it could be due to increased ischemia and inflammation. D-dimer can have prolonged elevation in Long-COVID-19 patients, which can lead to increased thromboembolic complications. Dysautonomia, neurotropsim, inflammation, and the persistence of a procoagulative state with an elevated myocardial strain may explain vagus nerve impairment in these patients. However, the authors state, “...it remains unclear whether dysautonomia associated with Long COVID-19 directly results from post-infectious immune-mediated processes or from the autonomic-virus pathway.” The authors call for research on evaluation of cholinergic nerve fiber damage in Long-COVID-19 patients to confirm impaired vagal activity. How to improve vagus nerve function? I have patients do a variety of exercises throughout the day such as singing, humming, gargling with water,

This week, please join author Ratika Parkash and Editorialist Sean D. Pokorney as they discuss the article "Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients with Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial" and the editorial "The Evidence Builds for Catheter Ablation for Atrial Fibrillation and Heart Failure." 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 Centre and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature discussion, oh, so exciting. We enter the month of June, and it pertains to heart failure and atrial fibrillation. And we are going to learn a little bit more from the RAFT-AF trial, involving randomizing patients to ablation and rhythm control, as opposed to just settling for rate control for patients with AFib. But before we do that, how about we grab a cup of coffee and start with some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I absolutely would. And I will start by asking everyone a question. Could a single high-sensitivity cardiac troponin T level, below the limit of detection of six nanograms per liter, exclude an acute myocardial infarction? Well, you are going to find out because, remember that data for excluding AMI with a single high-sensitivity cardiac troponin level relies largely on the limit of detection, which is really a threshold of five nanograms per liter, which cannot be reported in the United States, per the FDA, because there, only the lowest reportable concentration is allowed, which is the limit of quantitation of six nanograms per liter. Dr. Carolyn Lam: So, today's authors Dr. Sandoval from Mayo Clinic and colleagues, very cleverly sought to determine whether a single high-sensitivity cardiac troponin T level below the limit of quantitation of six nanograms per liter could indeed identify patients at low risk for AMI. Dr. Greg Hundley: Very interesting, Carolyn. So we have the limit of quantitation and then the limit of detection. This is really intriguing. And of course, cardiac troponin T, as cardiologists, we receive a lot of requests for consults on this. So, what did this study find, Carolyn? Dr. Carolyn Lam: A total of over 85,000 patients were first evaluated in the CV data marked biomarker cohort, amongst which 29% had a baseline high-sensitivity cardiac troponin T level below this limit of quantitation of six nanograms per liter. Among 11,962 patients with this baseline high-sensitivity cardiac troponin below six nanogram per liter and serial measurements, only 1.2% developed acute myocardial injury, resulting in a negative predictive value of 98.8% and a sensitivity of 99.6%. Dr. Carolyn Lam: In an adjudicated cohort, among those with a non-ischemic electrocardiogram, only 0.2% had myocardial infarction or death at 30 days. So in summary, Greg, this is the largest study evaluating a single high-sensitivity cardiac troponin T level below this limit of quantitation of six nanograms per liter to identify patients at low risk for AMI. Dr. Carolyn Lam: And indeed, the present study demonstrates that a single high-sensitivity cardiac troponin level below six nanogram per litter is a safe and rapid method to identify a substantial number of patients at very low risk for acute myocardial injury and infarction. Dr. Greg Hundley: Oh wow, Carolyn, really informative study. Well, Carolyn, my next study comes from the world of preclinical science. And Carolyn, vascular smooth muscle cell phenotypic switching contributes to cardiovascular diseases. And epigenetic regulation is emerging as a key regulatory mechanism with the methylcytosine dioxygenase Tet2, acting as a master regulator of the smooth muscle cell phenotype. Dr. Greg Hundley: The histone acetyltransferases, HATs p300, and CBP are highly homologous and often considered to be interchangeable. And their roles in smooth muscle cell phenotypic regulation are not known. So Carolyn, these authors led by Dr. Kathleen Martin from Yale University School of Medicine assessed the roles of p300 and CBP in human vascular smooth muscle cells with knockdown in inducible, smooth muscle specific knockout mice, and in samples of human intimal hyperplasia. Dr. Carolyn Lam: Cool, Greg. So what did they find? Dr. Greg Hundley: Right, Carolyn. So, they found that p300 and CBP serve non-redundant and opposing function in vascular smooth muscle cell phenotypic switching and coordinately regulate chromatin modifications through distinct functional interactions with Tet2 or HDACs. And Carolyn, targeting specific histone acetyltransferases therefore may hold therapeutic promise for future cardiovascular disease interventions. Dr. Carolyn Lam: Oh, that's great, Greg. Well, to round it all up, there are some other papers in today's issue. There's a Research Letter from Professor Zhang, entitled “Single Nucleus Transcriptomics: Apical Resection in Newborn Pigs Extends the Time-Window of Cardiomyocyte Proliferation and Myocardial Regeneration.” There's also a Research Letter from Dr. Vaduganathan, entitled “Estimating the Benefits of Combination Medical Therapy in Heart Failure with Mildly Reduced and Preserved Ejection Fraction.” Ah, that's such a cool issue. Now, let's go on to our feature discussion. Shall we, Greg? Dr. Greg Hundley: You bet, and learn a little bit more about rhythm versus rate control in patients with heart failure and atrial fibrillation. Dr. Carolyn Lam: Our feature discussion today is about the long-awaited results of the RAFT-AF trial, and that is the randomized ablation-based rhythm control versus rate control trial in patients with heart failure and atrial fibrillation. Thank you so much, Dr. Ratika Parkash for joining us today as the first and corresponding author from Queen Elizabeth II Health Sciences Center in Canada, as well as Dr. Sean Pokorney, the editorialist from Duke University. Dr. Carolyn Lam: I am so, so excited to be discussing this paper. I really meant it. You know, as a heart failure cardiologist, we've been waiting for these results and trying to understand everything in context. So maybe, Ratika, could you please start off by telling us about the RAFT-AF trial and what you found? Dr. Ratika Parkash: Thank you, Carolyn. I'm happy to be able to talk about this study on behalf of the RAFT-AF investigators and my co-PI, Dr. Anthony Tang. So the trial... First of all, the rationale for the study, I think many of us, as heart failure or heart rhythm specialists, understand that in the past, we've done many trials looking at rate versus rhythm control, the AFFIRM trial being the largest, and then of course, specifically in heart failure patients, the AF-CHF trial, both of which were negative in reducing cardiovascular events and mortality in patients with or without heart failure, in terms of a rate to rhythm control. Dr. Ratika Parkash: One of the issues with those trials is that the form of rhythm control was antiarrhythmic drugs. So we have learned that catheter ablation is superior to antiarrhythmic drugs in maintaining sinus rhythm. And based on that premise, we decided to go forward with the RAFT-AF study. Dr. Carolyn Lam: That's great, Ratika, so thanks. And what were the results? Dr. Ratika Parkash: The main finding, so the primary outcome of the study was mortality and heart failure events. Heart failure events was defined as a heart failure hospitalization or any escalation of heart failure therapy that was done in the outpatient settings, including the use of intravenous Lasix in an emergency department setting. Dr. Ratika Parkash: So the main findings were that ablation-based rhythm control was not statistically significant in reducing mortality and heart failure events over rate control in patients with atrial fibrillation and heart failure. The study included patients both with preserved ejection fraction, as well as reduced eject fraction. And we did stratify based on ejection fraction at the entry point into the trial. The hazard ratio was 0.71 and the 95% confidence interval just crossed unity, ranging from 0.49 to 1.03 with a P value of 0.066. Dr. Carolyn Lam: Oh, ouch. So, thank you. And again, truly, congratulations on a very, very important trial. Sean, I said it before, I'll say it again, really, really loved your editorial. Could you put these findings in the context of... Maybe, start with even the most recent guidelines, the 2022 ACC/AHA/HFSA heart failure guidelines, which I believe gives catheter ablation a class 2A recommendation. Maybe, start from there, and how does this fall in place? Dr. Sean Pokorney: Yeah, no, absolutely. I think, first of all, it's a really important trial and it's great to have this additional data. I do think, as you said, that it's important to understand the context. We now have several recent guidelines that have commented on the role of catheter ablation in patients with heart failure. Dr. Sean Pokorney: You mentioned the most recent heart failure guidelines. We also have additional AFib guidelines and we have the 2019 AHA/ACC/HRS guidelines for atrial fibrillation that give catheter ablation a 2B recommendation in patients who have heart failure, to potentially lower mortality and reduce hospitalization. And it has a 2A indication in the 2020 ESC guidelines. And we're currently undergoing some revisions of the guidelines for atrial fibrillation, and there'll be new guidelines around atrial fibrillation coming out from AHA/ACC/HRS in the coming years. And so that will also be helpful, I think, to incorporate some of this additional data. Sean Pokorney: When you really look at the guidelines and see what's driving the guidelines, there are several trials now that are really driving the guidelines. And so I think, looking back on the data, we have the AATAC trial, which was a trial of 203 patients that looked at ablation versus amiodarone. And we have the CASTLE-AF trial, which had 363 patients in it and was looking at atrial fibrillation in patients with heart failure with reduced ejection fraction and defibrillators. Dr. Sean Pokorney: And when you put that data into context, the AATAC trial did find lower rates of death and hospitalization as a secondary outcome, and CASTLE-AF did identify a reduction in heart failure hospitalizations and death. At the three year follow-up, there was a statistically significant reduction, although the event number was lower than the previously sort of calculated target sample size. Dr. Sean Pokorney: And so in aggregate, these trials do show a modest evidence of benefit for clinical outcomes in this population. And that's where adding more data is really critical. Dr. Carolyn Lam: That's so true. And actually, Ratika, is there any plan for some meta-analysis or sort of adding the data? And if you could, also speak to, the trial was interrupted at some point, so how that may have impacted things as well. Dr. Ratika Parkash: Those are important questions. So, first of all, there is a planned longer term follow-up for the study, to look at whether or not following these patients out beyond our meeting follow-up of 37 months, it will actually produce a different result than what we observed in the current findings. Dr. Ratika Parkash: I think a meta-analysis is obviously going to show benefit for ablation-based rhythm control, based on the data that Sean had just described. One of the things that we'd need to keep in mind is that this trial, the RAFT-AF study really enrolled patients who were suitable for either ablation-based rhythm control or rate control. So it wasn't a study that looked at rhythm control only. Dr. Ratika Parkash: So, the CASTLE-AF trial had essentially two rhythm control arms. The medical therapy arm was, was amiodarone in that trial, versus catheter ablation. So patients could get rhythm control in both. And so, the types of patients that would've gotten into CASTLE-AF were different than the patients in our trial, even when you look at the reduced ejection fraction patients. Dr. Ratika Parkash: Having said that, our curves, when you look at the reduced ejection fraction group in our study does mirror what was observed in CASTLE-AF. So, even if a patient is not deteriorating initially with rate control, it appears that over time they begin to deteriorate. And that's what all of these trials have shown, is that patients do better with ablation-based rhythm control, the best form of sinus rhythm maintenance that we have. Dr. Ratika Parkash: And it takes time for them to deteriorate and it takes time to accrue those events. And this is evident in all trials of atrial fibrillation. You either need a very large sample size, like 15,000 patients, to look at heart failure in a short period of time, or you follow them longer, so that you can accrue those events. Dr. Ratika Parkash: In terms of the stopping of the trial, certainly, had we reached the sample size of 600, which was the intended sample size after recalculation during the study from 1000 down to 600, I believe we would have reached a positive outcome. But again, we hope that our longer term follow-up might shed some light on that. The interruption of the study was based on the DSMC decision and certainly could have affected the power of the study. Dr. Ratika Parkash: We have to remember that the other possibilities are that ablation-based rhythm control is not superior to rate control. And as someone who is pro-ablation, it's difficult to say that, but we see hints of benefit and we have to recognize that. Dr. Ratika Parkash: The other issue is that the secondary endpoints in our trial were all significant, as overall, it doesn't matter which group you looked at, NT-proBNP, six-minute walk test, quality of life, both for heart failure and atrial fibrillation, as well as ejection fraction, were all improved. And for many of the studies that have been done previously, those were the primary endpoints of those studies. Dr. Ratika Parkash: The idea of whether ablation-based rhythm control reduces heart failure per se, is from our study, purely from our study, we can't be a hundred percent certain. There's definitely a hint of clinical benefit there. From all the secondary endpoints, which are the current guidelines, is what they indicate ablation should be done for, is to improve quality of life. Our study was certainly supportive of that. Dr. Carolyn Lam: You know, Sean, I especially appreciated your discussion of these issues, the early stopping of the trial, the secondary endpoints. Could you know, share some of those thoughts? Dr. Sean Pokorney: I think it's really an important topic. I think that, again, as Ratika said, part of why this trial is so important is that many of the previous trials that have been published and many of the data sets have really looked at rhythm control versus rhythm control in this population, even including the analysis from CABANA, which included almost 780 patients from CABANA that had heart failure. And in that population, they did show a reduction in the composite primary endpoint of death, disabling stroke, serious bleeding, or cardiac arrest. And again, CABANA was, as well, a study of rhythm control with ablation versus medical therapy, most patients getting rhythm control in that medical therapy arm. Dr. Sean Pokorney: And so this data really is additive. I think that one of the challenges is always, how do we make sure to get the most information out of a clinical trial once we commit patients to that scientific process? And I think here, at least in retrospect, it's obviously unfortunate that the trial was stopped early. I think that more data would certainly be helpful. Dr. Sean Pokorney: I appreciate the fact that longer term data may help solve that gap and close that gap a little bit. I think that, I guess, it'd be interesting to hear from Ratika a little bit more about the process that was involved with interaction with the DSMC and stopping the trial. Dr. Ratika Parkash: Yeah. Thanks, Sean. That also is a very good question. The DSMC really evaluated the data, evaluated the progress of the trial, back in 2017. It had been six years since we'd started the study. The data they had, in fact, did not show any benefit to ablation-based rhythm control over rate control at the time. So the follow-up period at the time was around two years. Dr. Ratika Parkash: And again, if you look at our Kaplan-Meier curves, you can understand why they would have made that decision at the time, based on 363 patients for the data that was available to them. They had a futility index that they looked at. it was calculated. The cutoff for stopping of the study was 0.8, and it was 0.81. So, there was a 19% chance that the study was going to show any benefit. And based on that, plus the progress of the trial, they made a decision to stop the study. Dr. Sean Pokorney: Yeah. I think it's really important when we look at these decisions, that there was example when we talk about this in the editorial as well with the ISIS-2 trial, where early on in the data, ISIS-2 was a trial looking at aspirin versus placebo. And basically in that trial, when you looked early on at the events that were accumulating, there was really roughly no difference between aspirin and placebo. And ultimately, that trial became positive and was a really critical trial. And if it had been stopped at that point for futility, we wouldn't have had some really critical data. Dr. Sean Pokorney: So, it's always a challenging decision. And obviously, the decisions are trying to be made in the best interest of the patients. Here, it just shows how important this additional follow-up data is for this trial, for RAFT in particular. And ultimately, it'll be interesting to see, as you mentioned, as we add additional long-term follow-up, how that will affect the results. Dr. Ratika Parkash: Absolutely. So, we hope that our additional follow-up is of benefit to clarifying our results. The unfortunate issue, I agree, was the stopping of the study, but we do trust our DSMCs. We have them for a reason and they perform an important function. So, we have to pay attention of course, to how they see things and evaluate the... at the time. Dr. Ratika Parkash: The other thing we should keep in context is that ablation for those, that time period, is not the same as it is today. Our safety has improved. You may have noticed that there were some adverse events in the study with ablation, and we would expect it to actually be lower, but in this day and age, but at the time, contact force wasn't available. Dr. Ratika Parkash: There were some tools and techniques that we now have at our disposal, improved mapping systems and so on, that allow us to do a safer and more efficacious job. But even in the context of that, our sinus rhythm maintenance was almost 80 to 90% for patients that you wouldn't normally expect to have that much sinus rhythm. Dr. Sean Pokorney: Yeah. I think that's a really critical point. You made a lot of really important points there, actually. Obviously, the vision of the field of electrophysiology is shifting, as you mentioned. And with data from EAST-AFNET 4, we're really shifting towards earlier rhythm control, as well as additional ablation trials attest, stop AFib or stop AF. Dr. Sean Pokorney: So again, there have been several studies that have shown the benefits of earlier rhythm control, EAST-AFNET 4, I think, being obviously one of the most relevant, looking at addressing atrial fibrillation of population of patients who've been diagnosed within the last year, and showing that there was a benefit to rhythm control, although the majority of rhythm control in that study was antiarrhythmic medications. Dr. Sean Pokorney: I think in the heart failure population, the challenge with rhythm control is that we're a lot more limited in terms of the medical therapies that are available for these patients. And I think that's where ablation really plays in a more important role, because not only have you shown that it seems to be efficacious in this patient population, with a really high rate of rhythm control, but in a lot of these patients, it's often a safer alternative than antiarrhythmic therapy. Dr. Ratika Parkash: Absolutely. And we've already shown that amiodarone is ineffective in this population, in AF-CHF. So, using that drug does not seem to be, in a population that could go for an ablation, the appropriate approach. Dr. Sean Pokorney: Yeah. And as well, I think that's important. And when you look back at data from SCD-HeFT as well, there were some concerns with safety signals of amiodarone in patients with heart failure as well, from that study, again, likely related to the side effects of the medication itself. Dr. Sean Pokorney: So again, it is a complex patient population in terms of decision-making and management. And I do think, again, we talked a lot about the trial being stopped earlier than we would've ideally liked. I still think that the data that you guys produced is really important and critical and additive. Again, we're consistently seeing these modest treatment effects across multiple studies. And the fact that all the studies are pointing in the same direction is very reassuring. Dr. Ratika Parkash: Yeah. I was just going to comment on some of the points that Sean had raised, with respect to early rhythm control and the concept of atrial substrate, and how advanced atrial substrate with a negative remodeling effect in patients with heart failure or prolonged atrial fibrillation may not necessarily be in our patient's benefits to then try to intervene, and trying to get these patients early would be useful. Dr. Ratika Parkash: So in RAFT-AF, patients did not have to fail an antiarrhythmic drug in order to get into the study. So that, again, critical, very much along the lines of EAST-AFNET and EARLY-AF, which was also published, demonstrating benefit for early intervention. Dr. Carolyn Lam: Wow. Just, thank you so much, both of you. That was such a rich discussion, really, really unpacking very, very important elements of the trial, not just the trial results, but also the implications of what happens with trial conduct and execution and so on. Dr. Carolyn Lam: Again, thank you so much Ratika, for publishing this very important paper in circulation, Sean, for your beautiful editorial that put it all in context, the audience for listening today. From Greg and I, you've been listening to circulation on the run. Thank you for joining us today, and don't forget to tune in again next week. 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.  

Interview with Amil M. Shah, MD, MPH, and Peder L. Myhre, MD, PhD, authors of Sex and Race Differences in N-Terminal Pro–B-type Natriuretic Peptide Concentration and Absolute Risk of Heart Failure in the Community. Hosted by Clyde Yancy, MD.

Interview with Amil M. Shah, MD, MPH, and Peder L. Myhre, MD, PhD, authors of Sex and Race Differences in N-Terminal Pro–B-type Natriuretic Peptide Concentration and Absolute Risk of Heart Failure in the Community. Hosted by Clyde Yancy, MD.

Heart Failure (HF) is a common disease that affects an estimated global population of over 40 million. It is the most frequent cause of hospitalizations in patients over the age of 65, placing a considerable financial and social burden on patients, healthcare providers, and care providers. Accurate clinical assessment of HF and cost-effective management strategies are critical in improving patient outcomes and reducing the socioeconomic burden of this disease. In this podcast episode, we will have a conversation between Dr. Christopher deFilippi, a cardiologist at the Inova Heart and Vascular Institute, and Dr. Ivan Salgo to learn more about heart failure, how it is diagnosed, and the value of using the in-vitro diagnostic test NT-proBNP.   About our Speaker: Dr. Christopher deFilippi is a distinguished cardiologist who currently works at the Inova Heart and Vascular Institute (IHVI) in Fairfax, Virginia as the Vice-Chair of Academic Affairs. In his oversight of clinical research, he has built IHVI to be a national leader in site-based research. He serves on the Editorial boards of Circulation, JACC, and JACC: Heart Failure. He is an Associate Editor for the Journal of Applied Laboratory Medicine. His research is focused on evaluating in-vitro diagnostics and proteomics discovery for diagnosis, prognosis, and therapy guidance across the spectrum of health from detection of preclinical cardiovascular disease to diagnosis and treatment in the critically ill.

FDA 批准颈动脉窦压力反射刺激疗法治疗心衰Lancet 血ACE2水平与心血管疾病及死亡的关系Science子刊 一种具有几何适应性的人工心脏瓣膜BAROSTIM NEO系统BAROSTIM NEO系统包括一个植入式脉冲发生器（IPG）、一个颈动脉窦含铅套件和一个程序。医生将BAROSTIM NEO脉冲发生器植入晚期心力衰竭患者的左或右锁骨下方，并在患者的左或右颈动脉窦处放置颈动脉窦导线，然后将脉冲发生器连接到颈动脉窦导线上。医生根据病人的个人需求制定脉冲发生器程序，然后向颈动脉的压力感受器传递电脉冲。压力反射激活（BAT）疗法的目的是激活颈动脉壁的压力感受器，刺激自主神经系统的传入和传出神经，大脑接收到神经信号作出相应反应：松弛血管、降低心率、并通过改善肾功能来减少液体储留。2019年8月，FDA批准BAROSTIM NEO系统用于药物治疗无效的、不符合心脏再同步化治疗适应症的、难治性心力衰竭患者。《BeAT-HF研究：这项研究证明了压力反射刺激疗法（BAT）对射血分数降低的心力衰竭患者的安全性和有效性》Journal of American College of Cardiology，2020年7月 (1) BeAT-HF研究是一项多中心、前瞻性、随机对照研究，纳入408名射血分数降低的心力衰竭（HFrEF）患者中，入组要求：纽约心功能分级II-III级、射血分数≤35%、药物治疗方案稳定≥4周、不符合心脏再同步化治疗的I类指征。这篇报告重点汇报了D队列中、NT-proBNP

This week on The Rounds Table Kieran Quinn and Katie Wiskar are back with two important studies; the first on visiting hours in the ICU and the second on NT-proBNP guided therapy in heart failure. Katie takes listeners through a systematic review and meta-analysis which showed that flexible ICU visiting policies were associated with reduced ... The post Take a Closer Look: Flexible ICU Visiting Policies & BNP-Guided Inpatient Heart Failure Management appeared first on Healthy Debate.

This week on The Rounds Table Kieran Quinn and Katie Wiskar are back with two important studies; the first on visiting hours in the ICU and the second on NT-proBNP guided therapy in heart failure. Katie takes listeners through a systematic review and meta-analysis which showed that flexible ICU visiting policies were associated with reduced ...The post Take a Closer Look: Flexible ICU Visiting Policies & BNP-Guided Inpatient Heart Failure Management appeared first on Healthy Debate.

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. Does NT-proBNP-guided therapy improve outcomes in acute decompensated heart failure? Well the Prima II trial results are coming right up after these summaries.                                 Is hospital volume a good structural metric assessing the quality of care in heart failure? Well, in the first original paper this week from Dr. Kumbhani and colleagues at UT Southwestern Medical Center, authors determined the relationship between admission volume, process of care metrics, and short and long-term outcomes admitted with acute heart failure in the Get With the Guidelines-Heart Failure registry, which has linked Medicare in patient data at 342 hospitals.                                 They found that lower volume hospitals had worse adherence to important heart failure process measures, than higher volume hospitals. There was no association between risk adjusted in-hospital mortality and hospital heart failure admission volume among older adults.                                 After adjusting for adherence with process measures at discharge, annual heart failure admission volume had a minimal association with mortality, and readmissions up to six months post-discharge. Thus, rather than focusing solely on hospital volume, hospital profiling efforts should perhaps focus more on participation in quality improvement initiatives, adherence to process metrics, and risk standardized outcomes.                                 The next study describes the association between air pollution and heart disease mortality in the United States, with a focus on whether the association differs by race and ethnicity. First and corresponding author Dr. Jennifer Parker from the National Center of Health Statistics Centers of Disease Control and Prevention and her colleagues use data from the 1997 to 2009 National Health Interview Survey linked to mortality records through December 2011 and the Annual Estimates of Fine Particulate Matter or PM2.5 as an index of air pollution.                                 They found that the association between air pollution and heart disease mortality in this national sample was elevated and similar to estimates found in prior studies. After controlling for social demographic and geographic factors, the associations between air pollution and heart disease mortality for non-Hispanic black and Hispanic adults were not statistically significantly different from that of non-Hispanic white adults.                                 Thus, this study supports the application of findings from prior studies of air pollution and mortality, albeit largely from non-Hispanic white adults, but to other races and ethnicities in the United States.                                 The next study suggests that large cardiac muscle patches engineered from human induced pluripotent stem cells may be a reality. First author Dr. Gao, corresponding author Dr. Zhang from University of Alabama at Birmingham generated human cardiac muscle patches of clinically relevant dimensions of 4 x 2 centimeters and they did that by suspending cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human-induced pluripotent stem cells in a fibrin matrix and culturing this construct on a dynamic platform.                                 The results from in vitro assessments of calcium transience, action potential propagation, and forced generation, as well as the presence of intercalated disc-like structures, suggested that cardiomyocytes matured in these human cardiac muscle patches. During the 7-day dynamic culture period. When transplanted onto infarcted swine heart, measurements of cardiac function, infarct size, wall stress all improved with no increase in arrhythmias.                                 Changes in the expression profile of myocardial proteins indicated that the human cardiac muscle patch transplantation partially reversed abnormalities in sarcomeric protein phosphorylation. Collectively, these observations indicate that human cardiac muscle patches can be successfully generated and may improve recovery from ischemic myocardial injury.                                 Does a second arterial conduit improve outcomes after multivessel coronary artery bypass grafting? Well, in the next study from first author Dr. Goldstone, corresponding author Dr. Woo, from Stanford University and their colleagues used a clinical registry including all 126 non-federal hospitals in California to compare all-cause mortality, and rates of stroke, myocardial infarction, repeat revascularization, and sternal wound infection between propensity score matched cohorts, who underwent primary isolated multivessel coronary artery bypass grafting with the left internal thoracic artery, and who received a second arterial conduit or a venous conduit between 2006 and 2011.                                 The authors found that receipt of a second arterial conduit was associated with lower mortality, and at first cardiovascular events, compared with receipt of a venous conduit. The survival benefit associated with the use of a second arterial conduit extended to patients up to 78 years old. As a second arterial conduit, the right internal thoracic artery offered no benefit, compared with the radial artery, but it was associated with an increased risk of sternal wound infection.                                 These findings therefore suggest that surgeons should perhaps consider lowering their threshold for using arterial grafts and that the radial artery may be the preferred second conduit.                                 That wraps it up for our summaries. Now for our future discussion.                                 NT-proBNP and natriuretic peptides in general, have really become mainstay in management of heart failure, in the diagnosis, in the prognostication, but questions still remain regarding NT-proBNP-guided therapy. We heard about the guided trial in chronic heart failure just reported last year, and this year, in fact this week, in this week's journal, we're about to hear about PRIMA II trial in acute heart failure.                                 And how NT-proBNP was tested as a potentially guiding strategy for the management of acute heart failure. I'm so pleased to have the corresponding author with us, Dr. Wouter Kok, from University of Amsterdam, as well as our Senior Editor Dr. Biykem Bozkurt from Baylor College of Medicine. So welcome both of you, and Wouter may I just jump straight in it?                                 PRIMA II means that there was a PRIMA I trial, so could you just briefly tell us a bit about PRIMA I and the rationale for PRIMA II? Dr Wouter Kok: Well the PRIMA II was an in-hospital guiding therapy that was preceded by the PRIMA II, it was a chronic heart failure patient population and one of things that we noticed in PRIMA I was the lack of effect of trying to reach a percentage drop in chronic heart failure patients. Why is that? Is that because there is a long time before you can achieve a therapy adjustment? Or is it something else? And shouldn't we start before patients are discharged from hospitals?                                 So the idea was born to do an in-hospital guiding study instead of chronic heart failure patients study. Dr Carolyn Lam:                Interesting. And could you tell us briefly, the design of PRIMA II and your findings? Dr Wouter Kok: So the PRIMA II was designed based on the previous publication of several authors indicating that a 30% reduction in NT-proBNP would be a good target for heart failure therapy. Now, we first asked ourselves the questions, whether we should put this target in front of the hospital admission, so in the first 2 days or perhaps at the end of the hospital admission? And the 30% reduction was validated only for discharge purposes, so but we also tried to establish whether we could precede this date a little bit before discharge, but it appears that you cannot precede it too much.                                 So you cannot do it at day 3 or day 4, when patients are not stable. Because then you may expect a rise in proBNP again before discharge, and then you already ran the rise patients to discharge. So we decided to do it at discharge. At least 1 or 2 days before discharge, when patients would be clinically stable. And this definition of clinical stability was important because there should be one guideline for doctors to say, OK this patient has been treated well, or not. Dr Carolyn Lam:                Interesting. And so patients were randomized only after clinical stabilization, though in hospital after an acute decompensation, right? And then maybe the randomization arms, and the results please? Dr Wouter Kok: Yeah, so the patients were randomized about day 7 or 8 after clinical stabilization, and day 3, but also patients at day 9, but when they were stable, they were randomized. And then the proBNP was measured, and when it was not reduced more than 30% they were guided. And when they were reduced more than 30% they were not guided but they were made ready for discharge.                                 So this was the randomization group. And the conventional group, the NT-proBNPs were measured at the randomization, and also at discharge, but nothing was revealed to the doctors. So it was only as a comparison for example, in the number of days necessary to wait before discharge, if this would influence the results.                                 The main finding is that the end point was negative for total mortality after 6 months, in combination with heart failure readmissions. So there were about 36% end point in both groups. Dr Carolyn Lam:                Yeah Wouter, you know, we've just come from the guided trial that was so soon neutral and infect, ended early and that was in the chronic heart failure setting so very different from what you tested in PRIMA II. Congratulations first of all for a beautifully done study.                                 But may I just ask, because in guided it was mentioned repeatedly that perhaps even the control arm was treated so well because these were such specialized centers. So what kind of centers took part in PRIMA II? Dr Wouter Kok: We started at centers in Amsterdam, they were all very well educated in heart failure treatments, and all were using proBNP before the study started, so they were experienced in interpreting proBNPs. Because we had too little centers, and the inclusion rate was not so fast, then we asked other centers to participate, and we asked 2 for instance in Barcelona and Porto in Portugal, which helped us to complete the trial. Dr Carolyn Lam:                Oh that's really nice. And the design is really quite special, and I'm so appreciative that you took the time to explain that they were randomized only when stabilized.                                 Biykem, what do you think of that? Dr Biykem Bozkurt:         It's a fascinating trial, I have to congratulate Wouter and his colleagues. The number one very important finding I think is, about two-thirds of the patients before randomization are able to achieve reduction of NT-proBNP more than 30%. So subsequent to that in the guided therapy we're able to achieve maybe an incremental additional 15% adding to about, I think 80% of the patients initially randomized to the NT-proBNP arm. Achieving a reduction more than 30%. So overall, if the patient's naturally before randomization, achieve a reduction NT-proBNP, two-thirds of the time, pushing it further, trying to achieve a further dry state, by randomization does not appear to make any changes in readmission rates, or mortality at six months.                                 So this very important finding is the majority of the patients on conventional strategies are able to be decongested and achieve clinical stability. Now the other important finding is, I think about 17-20% of the patients regardless of what we do, do not demonstrate this significant drop in their NT-proBNP levels. Which I call as a non-responder team, which is a fascinating group of individuals. So we have the yin-yang, individuals may actually demonstrate that they're responsive. And when they're responsive, then the majority of the patients do demonstrate a reduction by more than 30%, and even if we push it further by targeted therapies, don't make a difference in outcomes.                                 About 17-20% regardless of what we do, do not respond, and from former studies we know that those patients are associated with worse outcomes. The other important finding I think, is what changed in the study? What medications, what therapies were changed? It was fascinating from Wouter's group to recognize that there was a little, significant, but a little increase in the ACE admission prescription. But there was also an interesting finding in the guided therapy, that the beta blocker used was slightly lower.                                 That raises a question of if we were to just chase the numbers, meaning try to just target therapies according to the NT-proBNP levels, whether we would see some unintended consequences such as reduction in medications, just because the numbers may be going in one way or the other. This is acknowledged in Lynne Warner Stevenson's editorial that will be accompanying the paper. And the editorial is very nicely titled "Getting to Dry". So I found that fascinating to recognize that the therapies, when especially the conventional arm is treated well, did not differ.                                 As was the case in the guided trials. When you treat the patients very well, as was seen in this trial, there was not much of a difference. But again trying to treat a number by targeted therapies may not result in all the optimization that as we envisioned to see. And the third concept is the length of stay, of course in the U.S. is a major issue, and I do realize when we're trying to treat a number, sometimes the length of stay may end up being longer. And I do realize that perhaps in the targeted therapy group, the length of stay was a little bit longer, maybe Wouter can comment on that.                                 But overall it didn't result in any change in outcomes, or was not associated with any of the outcomes. So that was also an interesting finding. Because we tend to focus a lot on length of stay, but interestingly I guess by secondary analysis, there was no association with the clinical outcome. Dr Carolyn Lam:                Wouter, would you want to comment the length of stay concept? Dr Wouter Kok: Well it's indeed in the guided group, and the randomized group who were trying to attain the 30% NT-proBNP reduction, the length of stay was longer. Something about 11 days, compared to those who did not need guiding was about 8 days. Still long compared to U.S. standards, but it was the same in the conventional group, so about 9 days is respective of whether they reached a 30% reduction or not.                                 So here is the clinical experience. So the patient cannot tell whether he is reduced more than 30%, and the doctor isn't able to tell either. Because then the admission would have been longer probably. But trying to lower the 30% more, has some effect. There's little effect, but it has some effect. And then they have to do a sort of economic analysis, is 3 days longer in hospital, is it worthwhile to do that compared to for example reduction in admissions that you receive? This is a small population, only one-third of the patients who need guiding, and more than half of them you will reach somewhat more reduction than if you don't try at all.                                 So for us, that is the main result of the trial, if there is a signal, then it is still possible to do something, and the other remark about whether you increase or decrease medication, that's something that was discussed in the guided study too. So what is the best for the patient, is that the maximum medication or not, and we see for example, that if we reduce beta blockers, in some patients then some will improve in their functioning and also in the BNP.                                 So it's not always necessary to increase and increase medication. So that was also some signal that we tried to do some more research in. What is the target? Is the target a guideline, saying that more medication is better? Or is the target itself for proBNP a possibly better target than that? Dr Biykem Bozkurt:         And the other interesting finding for that, there were no differences in chemo concentration levels in the guided versus non-guided groups. And last point that I wanted to make is the larger BNP reduction was amongst the individuals who did not require any guidance in successfully guided versus unsuccessfully guided, compared to those who did not need the guidance.                                 Those who were able to achieve the more than 30%, when you look at the magnitude, meaning amongst the individuals who are going to naturally respond to therapy, the natural responders, the decrement, or the decrease in the BNP levels are larger, than those ones we're trying to push. So that was another interesting, fascinating ... I was almost thinking whether that in the future we should look at responsiveness of patients, if we see they're responders then try to target their therapy or not.                                 So in a sense the non-responders, they now respond regardless of what we do. Responders may be gaugeable or titratable, or maybe with the precision respond to targeted therapies that almost have a dichotomous approach. What do you think about that Wouter? Dr Wouter Kok: I say yeah we made a big mistake in thinking that more than 30% for patients who still needed guiding would be the same as rating the more than 30% without guiding. But the difficulty you have in reaching the 30% is already indicative somewhat less increase in prognosis than you will reach it spontaneously.                                 So we have to adapt our numbers for the trial, so it is recalculation that how many patients we would need to be successful in our trial, and that would be 600 patients in every arm, and then even then, you have to recalculate some of the effects that you will have to reach them. Perhaps the mid-range risk group is a better risk group to target than the highest risk group. That's something that we have to think about too. Dr Biykem Bozkurt:         I think we will probably need to focus on individualization, I almost feel as though we will need to learn from the cancer trials, and see whether we could try to target rather than you know the population based clinical trials, trying to do the targeted therapies. Maybe fine tune the ability to precisely target, and of course that requires a little bit more layering of the markers and or a signal that we're going to be profiling in the individual.                                 So I don't think it's the end of targeted therapies, perhaps requiring a little bit of a more precision, and maybe individualization. But I am fascinated by first realizing it's a responder, and then maybe trying to accelerate and or optimize therapy, perhaps especially when we are forced or driven by administrative concepts such as length of stay or others. So making sure that maybe these variables, these biomarkers may help us recognize that maybe we haven't achieved that appropriately dry state yet.                                 But those all need to be determined, of course, by future trials, so far targeted therapies both in the acute and in the chronic does not seem to result in implementing outcomes. Dr Wouter Kok: Well and the next step for us is to try and think how can reduce proBNP in all patients, we tried it with medication, but didn't do that much of catheterizations for those who were ... there were 50% of patients who were ischemic so why don't we do much of these catheterizations now days. So that's something we're thinking about how can we improve these patients? What are we missing? Dr Carolyn Lam:                Yeah, if I could add my two cents. So Wouter mentioned finding the right therapies that can effectively reduce NT-proBNP safely, and well you mentioned choosing the right patients to use this in. And if I may, you know, just adding perhaps the right settings as well. Because it's well known that not all of us take care of heart failure patients the same way. And maybe there are settings where having a number to guide us may be more useful than others. But what do you do? You know, we wait for more data, but in the meantime, just congratulations. Heartfelt, heartfelt congratulations Wouter for a beautiful study, thank you so much for the privilege of publishing it in Circulation.                                 Thank you for being on this podcast, and listeners don't forget to tune in again next week.

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 about statins, and it's the first population-based study to show a dose-dependent benefit on amputation and survival in peripheral artery disease. Very important data and a very important discussion coming right up after these summaries.                                                 The first original paper this week indicates for the first time that the natural history of coronary stenosis is better predicted by physiologic information by FFR, or fractional flow reserve, than by anatomic information from angiography. First author, Dr. Ciccarelli, corresponding author, Dr. DeBruyne, from OLV Hospital in Belgium compared the values of angiographic diameter stenosis and of fractional flow reserve in predicting the natural history among 607 patients from the FAME 2 trial who had documented stable coronary disease and in whom no revascularization was performed. The primary end point was defined as vessel oriented clinical end point at two years, and this was a composite of prospectively adjudicated cardiac death, vessel-related myocardial infarction, vessel-related urgent and non-urgent revascularization.                                                 The overall results showed that FFR predicted the natural history better than diameter stenosis. In addition, among the stenosis with mismatch between diameter stenosis and FFR, more than half had a low FFR in the presence of an angiographically mild stenosis and the rate of primary outcome was higher in those with reduced FFR regardless of whether diameter stenosis was significant or not. The take-home message is, therefore, that measurements of FFR should be considered not only an angiographically intermediate stenosis but also perhaps a mild or severe stenosis by visual evaluation.                                                 The next study provides population-based data on cardiovascular outcomes and risks after initiation of a sodium glucose cotransporter-2 inhibitor, or SGLT2 inhibitor. First and corresponding author, Dr. Udell, from University of Toronto, and his colleagues, performed population-based cohort study among type 2 diabetes patient with established cardiovascular disease and newly initiated on antihyperglycemic agents within the US Department of Defense Military Health System between 2013 and 2016. After propensity matching, more than 25,250 patients were followed for a median of 1.6 years. Initiation of SGLT2 inhibitors was associated with a lower all-cause mortality, lower hospitalization for heart failure events, lower major adverse cardiovascular events, but higher below-knee amputation risk. Findings underscore the potential benefits and risks to be aware of when initiating SGLT2 inhibitors. Importantly, it remains unclear whether the risk of below-knee amputation extends across a class of medications as the study was not powered to make comparisons among individual treatments.                                                 The next paper reports results of the redefined trial, which is the first trial to study the effects of renin-angiotensin-aldosterone system inhibitors in adults with tetrology of Fallot and mild right ventricular dysfunction in the absence of severe valvular lesions. First author, Dr. Bokma, and corresponding author, Dr. Bouma from Academic Medical Center Amsterdam, and their colleagues, studied 95 patients in the redefined trial and found that 150 mg of losartan daily did not significantly improve the primary outcome of right ventricular ejection fraction change compared to placebo. There were no significant treatment effects on secondary outcomes of left ventricular ejection fraction, peak aerobic exercise capacity or NT-proBNP. However, in a post hoc analysis, losartan was associated with improved right ventricular ejection fraction in a subgroup of 30 patients with nonrestrictive right ventricles and incomplete remodeling. The conclusion is, therefore, that losartan had no significant effect on right ventricular dysfunction or secondary outcome parameters in repaired tetralogy of Fallot. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups.                                                 The final study reinforces that vesicle trafficking plays an essential role in the signal regulation of pathologic hypertrophy and identifies a novel potential target in this process. This novel target is the transmembrane BAX inhibitor motif containing 1, or TMBIM1. First author, Dr. Deng, corresponding author, Dr. Li, from Wuhan University in China, and their colleagues, found that TMBIM1 expression levels were substantially decreased in both clinical and experimental hypertrophic hearts. Mechanistically, TMBIM1 interacted directly with tumor susceptibility gene 101 and accelerated the formation of multivesicular bodies to degrade activated toll-like receptor 4. Toll-like receptor 4 degradation in turn was essentially for the progression of cardiac hypertrophy. Importantly, expressing TMBIM1 in monkeys via lentivirus protected their hearts from aortic banding induced cardiac hypertrophy. In summary, these findings shed light on the role of vesicle trafficking in signal regulation during cardiac hypertrophy and provide a novel therapeutic target for treating hypertrophy.                                                 That wraps it up for our summaries. Now for our feature discussion.                                                 Peripheral artery disease, a disease that affects more than 200 million individuals worldwide and associated with a high risk of cardiovascular events and death and, of course, the much feared amputations. Yes, statin guidelines for peripheral artery disease are largely based on coronary artery disease or stroke data. Well, today's feature paper really addresses an important knowledge gap between statins, doses, amputation survival in peripheral artery disease. I'm delighted to have the first and corresponding author, Dr. Shipra Arya from Stanford University School of Medicine and, of course, our favorite, Dr. Josh Beckman, Associated Editor from Vanderbilt University.                                                 Now, Josh. I understand there's a bit of a back story of how this paper came to circulation. Want to share? Dr Josh Beckman:            Oh, absolutely. First of all, I have to say that one of the jobs of an associated editor is someone who kind of goes antiquing in every single store. Every place I am where people are presenting really good science, I'm kind of scoping it out. I'm interested. I want to see what's going on. I like to talk to the people who are doing the work to see how they're thinking about it, and I was lucky enough to see Dr. Arya's presentation. I think it was at an ATVB meeting, wasn't it? Dr Shipra Arya:                  That's right. Dr Josh Beckman:            I thought that this is an incredibly cool piece of work, and I basically hoped, I prayed, I asked. I said, "You know, maybe you should send this to us because we would really like to see the full manuscript," because inside I hoped that it would be just as impressive when it was written out as a full manuscript as it was when she was discussing it at the meeting. And, lo and behold, we were lucky enough that she submitted it to us and you can see the results online right now. Dr Carolyn Lam:                Indeed! Well put. Shipra, with that kind of lineup, please, tell us about your study and what you found. Dr Shipra Arya:                  Thank you for that invitation to submit to Circulation because initially I wasn't sure if Circulation would be interested in my work, so it was really great to hear when Josh said that this is something that it would certainly consider. The basic premise was to try and find out whether high-intensity statins as defined by the 2013 lipid guidelines, they would also have limb protective effects for PAD along with reduction mortality. As you said in the introduction, most of the data comes from either coronary data or comes from small groups of PAD patients, but never from such a large population.                                                 We identified about 150,000 veterans in the National VA database from 2003 to 2014 and excluded people who didn't have a diagnosis of PAD before 2003, and why this was such a labor of love was also to figure out how to identify the certainty that people had PAD and then getting into their pharmacy files and trying to parse out whether they were on high-intensity, low, moderate, or no statin. Initially, I had done the analysis of no statin, but then after review and discussion, it became clear that we needed a control group, which was people who were also on some guideline-directed therapy and not just no statin because they could be patients who were the noncompliant patients and who don't show up to the doctor's visits, and that's why they do poorly.                                                 That's why we chose a control group which were on antiplatelet therapy, at least aspirin or Plavix, any other antiplatelet agent. Even in that comparison, we find that after risk adjustment, patients who are on high-intensity statin had a more than 30% risk reduction of amputation as well as about a 24, 25% risk reduction of mortality compared to people who did not take a statin but at least took an aspirin. Low to moderate intensity statins were also effective, about 20%. Risk reduction in both amputation and mortality, but high-intensity statins when directly compared to the low to moderate intensity statins outperformed them.                                                 Just to be sure of our findings, we did it so many different ways. We did the Cox modeling. Then we did propensity matching that which person is more likely to receive the statin versus the other. Then we did subgroup analyses where we put people in different subgroups that people who had coronary artery disease as an indication, maybe that's why they were on these statins. But, people without coronary artery disease also same association [stack 00:11:12]. We were pretty confident in our findings, and that's why we sent it to Circulation. Dr Carolyn Lam:                Wow. You know, Josh, you are the best at putting papers like this into context and really expounding on the significant. Tell us, why did this catch your attention so much? Dr Josh Beckman:            Every time I think that statins have become just a standard part of therapy for patients with atherosclerosis, the first thing I noticed in this paper was that there were so many people who were still not on any statins or people who were on homeopathic doses of statins, and I can't understand how that happens. I think the mortality data was nice and consistent, but the amputation data is what really made a big difference. I'll ask Dr. Arya, but in my impression, the literature has been sort of back and forth as to whether or not statins really reduced limb outcomes. Your paper, I think, was clearly the largest sample that had taken a look at that question. Can you sort of separate out your papers from some of the previous work in that area? Dr Shipra Arya:                  Sure. I would add that a lot of work about amputations has been coming out from vascular surgery data, and a lot of that work just focuses on short term outcome for limb loss. They look at 30 days. Maybe they'll go look up to six months to a year, but actually patency of bypasses, patency of vessels is a long-term phenomenon. Much like mortality that can happen years later, your amputation risk can happen years later, too. I think what separates us is the lifetime followup for these patients, and we are looking in a cohort of patients who are in this veterans' healthcare system so the data is automatically getting captured even if they get their care outside. Records do make it back and diagnoses do make it back. It's the VA [inaudible 00:13:03], and we did some sensitivity analysis to show that, yes, most of the veterans we have in [inaudible 00:13:09] actually get their care and have data being added continuously into the corporate data warehouse.                                                 That was something I think that lent to the power of making the [sure 00:13:20] conclusion and that's where previous studies have not been able to show a significant association with amputation. The studies, if they are single center or they are focused from electronic medical records or perspective followup, either the patients get lost to followup or go see other doctors or other healthcare systems, and that information doesn't get back to the researchers, while mortality data you can get from Social Security Death Index or other sources. I think that's what makes the study different than other studies in this similar field in terms of followup. Dr Josh Beckman:            I don't think you're giving yourself enough credit. There's a whole bunch of things that make the study unique. One of the things that I was most taken with right upfront was the way that you defined peripheral artery disease for this population. There has been, as far as I know, at least seven or eight different definitions that people have used with administrative data to try and ferret out who has PAD, and in contrast to coronary disease and stroke, it's a much more complicated endeavor to do that. So, when I saw the way that you did it ... I'm going to say this in a way that I know is going to sound funny, but you made the complicated look really simple. Your definition is not something that required 3,000 lines of ICD-9 codes within inclusion and exclusion criteria and speaks, in my opinion, to the power of the large sample because, basically, they needed one ICD-9 code and either two ABIs, a visit to a vascular surgeon or procedural code. Now, I know that this definition comes from some of your work, so can you tell us how you derive this and then let's talk about what that means. Dr Shipra Arya:                  Absolutely. We looked at practice patterns for patients with vascular disease across the VA, and most patients who undergo procedures for PAD, we can confidently say that they do have PAD. When we look at the specificity of just that occurrence, it's pretty high, like [90% 00:15:23]. Then what we did was we did some random sampling in the VA data, about 300 patients, and used different codes to see if patients came back to the vascular surgeon within ... We used 14 months because it's usually one year followup that most people prescribe, so whether they went two months before or after because the appointment hours. We found that that was again a high specificity of about 80%. Then, when you look at patients who come back with ABI followup. So, we looked at CPT codes for ABI. We found out it's like a 99% specificity. If you have ABI followup within a year, and we relaxed it to 14 months, you could be 99% confident that this patient does have PAD.                                                 We just combined all those three together, and this is ... If Circulation is interested, I can send you this, too. We are working on this manuscript where we are giving researchers different algorithms that they could use to identify PAD because I wanted a more specific sample because I was looking at PAD outcomes. I wanted the PAD definition to be tight. Our specificity is greater than 80% combining all these three together, about 84%. We are fairly confident in this that, yes, these patients truly have PAD, so when we follow them up for outcomes, we can be confident in our results. If researchers wanted a more relaxed definition of PAD, they could use other algorithms that we are putting in that paper where they could say, "We will only use one ABI measurement, or we would use a combination of these." Dr Josh Beckman:            That brings up two points. You talk about this brings up the power of large data and the ability to tone down on people who really, truly, absolutely have PAD without any question. So, number one, are you worried that you're missing people that probably do have PAD and would benefit from therapy, and number two, do you worry that you're basically concentrating on the sickest right end of the curve of the group of PAD patients? Dr Shipra Arya:                  Right. That's a great point, and I discussed that with my coauthors and mentors and we wanted to be sure about our outcomes and not want to include people who did not have PAD, and then we are kind of including the effect size of what we may find, but yes, these are truly what we are calling a symptomatic PAD, and I think I mentioned that in the manuscript somewhere, that we probably would be missing people who are asymptomatic and not really being followed up. If we extended this analysis to people who are not regularly being followed or being under surveillance for their PAD, the results could be different. So, yes, it does not generalize the whole of that population. If we had gone that route and relaxed our inclusion, my worry was that we would get ... Because of large data setting up, as you say, if we include a bunch of people who are truly not PAD, we would be a [threading 00:18:17] risk in non-PAD patients. Dr Carolyn Lam:                Josh and Shipra, I loved the paper, but after this discussion I'm even more in love with the paper and impressed, so I think I just have a question for both of you. Is there any excuse not to give statins now? Do we actually think a trial is going to come on this topic? Is this the best data that we have? Is it going to enter guidelines? What do you think? Dr Josh Beckman:            I can give you my opinion first, if you want, because you're the person who actually has control of all the data. I would say this. I think it's been well known that statins should be used in all the patients with PAD for their cardiac outcome. My guess is that there are two things that are going to happen that are going to make people consider statins for limb outcomes.                                                 One, data like this and there's never going to be a trial, a prospective randomized trial at this point, I mean unless you disagree, but there's no way people will randomize to not statin. I think the second reason is the recent data on the PCSK9 inhibitor, evolocumab, which showed that on top of statins in PAD patients, there was a further reduction in limb events. I think we're heading towards getting the LDL to zero. It may take a couple more steps, but that's basically what's going to happen. Dr Shipra Arya:                  I agree. I think there has been time and time again data that shows, especially those already data supporting the mortality benefit for larger cohorts of patients with cardiovascular disease including PAD. I think this study really nails down the limb protector effects of statins, and doing a trial of this magnitude would be very difficult to do because to get that would be effect size that you have. You would need a huge cohort of patients, and you probably won't find statin-naïve patients because you have already half the patients with PAD have coronary artery disease, as well. So, not every study needs a trial. Not every question needs a trial, in my opinion. I think that's the power of large data sets. I think the evidence is overwhelming, and I would agree with Josh. Dr Josh Beckman:            I have always had a hard time explaining to people who came to see me for legs problems that they have to take a drug for their heart. It's sort of a weird two-step that people have a hard time accommodating. Do you think by telling them that this drug will also save their leg that they're going to be more likely to take the medicine by the end of the year? Dr Shipra Arya:                  Yes, absolutely. That's what I tell my patients who come and see me, that this medication works on arterial plaques, and it stabilizes them. It's not just the same plaque that you have in your heart is the one you have in your leg. Maybe a little different, but to oversimplify, yes. This is not just a heart medication, and this is not just a cholesterol medication. This is a medication for your plaques, for your blockages. That's how I explain it to them, and I think the uptake would be more if we explain to them that, yes, this will help you keep your leg, stay ambulatory and stay at home and not end up in assisted living or nursing home. Dr Josh Beckman:            Carolyn, this is so much fun, especially when we get to talk to the people that do so much hard work to put stuff in circulation, so I just want to say thanks again to Shipra and her coauthors. Dr Shipra Arya:                  Thank you so much, and thank you for giving us the opportunity. I think the comments from Circulation really made our paper better, so thank you for doing that. Dr Carolyn Lam:                I wish that we could just keep going on and on because I just know that Josh has even more great questions up his sleeve. See, Shipra, I told you, he's amazing. But, there you go. You're amazing, too. Your paper is amazing. Thank you so much for joining us today.

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.                                                 Our feature discussion this week centers on the temporal changes in natriuretic peptides preceding heart failure hospitalizations and patients at high risk. Data that are really novel and have implications for the way we perhaps monitor and categorize these high risk patients. Well, more soon right after these summaries.                                                 The first original paper this week provides the first epigenome-wide association study in patients with heart failure. Now, epigenetics refers to biochemical DNA modification such as methylation of gene bodies, and post-translational modification of histones, which is increasingly recognized to play a crucial, regulatory interface between genes, environment, and the transcriptome.                                                 The lack of availability of myocardial specimens from patients has been a major roadblock for elucidating the impact of such epigenetic changes on complex cardiovascular traits. However, in today's paper from first author, Dr. Meder, corresponding author, Dr. Katiz and colleagues from University of Heidelberg, Germany. The authors performed the first multi-omic study in myocardial tissue and blood of patients with dilated cardiomyopathy compared to controls.                                                 They detected 59 epigenetic loci that are significantly associated with dilated cardiomyopathy, with three of them reaching epigenome-wide significance. 29 of these loci could be replicated in independent cohorts and authors further linked a subset of 517 epigenetic loci with dilated cardiomyopathy and cardiac gene expression.                                                 Finally, they identified distinct epigenetic methylation patterns that are conserved across tissues. Thus representing novel, epigenetic biomarkers for heart failure.                                                 The next study is the first to assess a diagnostic and prognostic value of cardiac myosin binding protein-C in patients presented with possible acute myocardial infarction or AMI. Cardiac myosin binding protein-C is a cardiac restricted protein that is more abundant than the cardiac troponins and is released more rapidly following AMI.                                                 In today's paper, first author, Dr. Kaya, corresponding author, Dr. Marber and colleagues from the Rayne Institute In St. Thomas's hospital in London evaluated cardiac myosin binding protein-C as an adjunct or alternative to cardiac troponins in the early diagnosis of AMI in 1,954 unselected patients presenting to the emergency department with symptoms suggestive of AMI.                                                 The final diagnosis of AMI was independently adjudicated in 340 patients. The authors found that concentrations of cardiac myosin binding protein-C at presentation were significantly higher in those with versus without an AMI. The discriminatory power for AMI quantified by the area under receiver operating curve was comparable for cardiac myosin binding protein-C to high sensitivity cardiac troponins T and I, and even superior to standard sensitivity cardiac troponin I. The use of cardiac myosin binding protein-C more accurately classified patients with a single blood test and to rule out or rule in categories in early presenters, meaning those with chest pain of less than three hours.                                                 The improvement in rule in or rule out classification with cardiac myosin binding protein-C was larger compared with higher sensitivity cardiac troponins T and I. Finally, cardiac myosin binding protein-C was superior to high sensitivity and standard troponin I and similar to high sensitivity cardiac troponin T at predicting death at three years. Thus in summary, this paper shows that cardiac myosin binding protein-C at presentation provides discriminatory power comparable to high sensitivity troponins T and I in the diagnosis of AMI and may perform favorably in patients presenting early after symptom onset.                                                 The next paper describes the discovery of a novel candidate cardiomyopathy or arrhythmia gene. First author, Dr. Barryfield, corresponding author Dr. McNally from Center of Genetic Medicine in Chicago and colleagues studied a family with dilated cardiomyopathy and associated conducted system disease in whom prior clinical cardiac gene panel testing was unrevealing. Whole genome sequencing however, identified a premature stop codon in the gene encoding a novel myo filament component, the myosin binding protein-H-like.                                                 Having identified this gene, they turned to experimental approaches. The myosin binding protein-H-like gene was found to have high atrial expression with low ventricular expression. The truncated protein failed to incorporate into the myo filament. Human cell modeling demonstrated reduced expression of the mutant allele. Heterozygotes and nullumites exhibited a reduction in fractional shortening and increased diastolic ventricular chamber size, aberrant atrio-ventricular conduction and an increased rate of arrhythmia associated with the expression of the myosin binding protein-H-like in the atria, as well as in discrete puncta throughout the right ventricular wall and septum.                                                 These findings therefore support that myosin binding protein-H-like truncations may increase the risk for human arrhythmias and cardiomyopathy.                                                 Transplantation of cells into the infarctant heart has significant potential to improve myocardial recovery. However, low efficacy of cell engraftments still limits the therapeutic benefit. In today's paper, authors describe a method for the unbiased, in-vivo selection of cytokines that may improve Mesenchymal stromal cell engraftment into the heart. In this paper from first author, Dr. Bortolotti, corresponding author Dr. Giacca, and colleagues from University of Trieste in Italy, an arrayed library of 80 secreted factors were individually cloned into adeno-associated viral vectors.                                                 Pools from this library were then used for the batch transduction of bone marrow derived Mesenchymal stromal cells ex-vivo, followed by intra myocardial cell administration in normal and infarctant mice. Three weeks after injection, the vector genomes were recovered from the few persisting cells, and identified by sequencing DNA barcodes that were uniquely labeled for each of the tested cytokines.                                                 Using this novel, competitive, engraftment screening methodology, the authors identified that the most effective molecule was cardiotrophin-1 a member of the IL-6 family. Intra cardiac injection of Mesenchymal stromal cells preconditioned with cardiotrophin-1 preserved cardiac function and reduced infarct size parallel to the persistence of the transplanted cells in the healing hearts for at least two months after injection. Thus, preconditioning with cardiotrophin-1 might represent an efficient manner to improve the currently poor cell retention in patients treated with Mesenchymal stromal cell therapy.                                                 The final paper presents results of the early myo trial, a non-inferiority trial comparing a pharmacoinvasive strategy with half-dose alteplase versus primary PCI in patients with STEMI, presenting six hours or less after symptom onset but with an unexpected PCI related delay.                                                 First author, Dr. Poole, corresponding author, Dr. Hua and colleagues from Shanghai Jiao Tong University in China randomized a total of 344 patients from seven centers to a pharmacoinvasive arm or a primary PCI arm. They found that pharmacoinvasive strategy was non-inferior to primary PCI for the primary endpoint of complete epicardial and myocardial reperfusion after PCI defined as TIMI flow grade 3, TIMI myocardial profusion grade 3, and ST-segment resolution of more than 70%.                                                 There was no significant differences in the frequency of the individual components of the combined endpoint. Infarct size and left ventricular ejection fraction were similar in both groups and there was no significant differences in 30-day rates of total death, re-infarction, heart failure, major bleeding events, or intracranial hemorrhage. However, minor bleeding was observed more often in the pharmacoinvasive group.                                                 Thus the authors concluded that a pharmacoinvasive approach with reduced dose alteplase seems to offer effective and safe reperfusion in low-risk patients with STEMI with an unexpected PCI related delay. Further large, randomized control trials powered for clinical endpoints are needed.                                                 Well, that wraps it up for your summaries. Now for our feature discussion.                                                 The measurement of natriuretic peptides BNP, NT-proNP have certainly become the cornerstone of heart failure management. We measure these levels by guidelines in patients who are presenting with symptoms and suspected heart failure, in patients who are hospitalized. We measure them for prognostication purposes at discharge. However, what we don't really know is how the preceding changes in natriuretic peptides may precede heart failure hospitalization in patients who are at high risk of developing heart failure.                                                 For example, patients with a recent coronary event or type-2 diabetes. And this is the very subject of our feature paper today, and I am so pleased to have the corresponding author of today's paper which is really a research letter. Dr. Brian Claggett from Brigham and Women's Hospital as well as Dr. Biykem Bozkurt who's our senior editor from Baylor College of Medicine.                                                 Welcome both, and maybe I could start, Biykem could you let us know, what are the unanswered questions in heart failure relating to natriuretic peptides and how do you see this paper falling in, clinically? Dr. Biykem Bozkurt:        Carolyn, this is a wonderful I think prelude to perhaps preventing heart failure events. And as you are aware, we in the recent year changed our guidelines at the ACC, AHA, and the HFSA incorporating screening high risk patients for development of incident heart failure. And the study that resulted in this consideration was a STOP-HF trial which was utilizing natriuretic peptides in high risk patients to determine whether their closer follow up in a multidisciplinary fashion would result in earlier detection and prevention of heart failure, and which it did.                                                 And this study I think is straddling the concept of high risk or stage A or B patients because they are individuals who have had heart attacks, coronary events, and they have type-2 diabetes so they are definitely high risk. And doing natriuretic peptides as an outpatient, whether that would predict the heart failure hospitalizations.                                                 And in essence I think it's a good concept. Perhaps the challenging concepts are how often should we screen our patients, and what will be the threshold of the rise that would potentially make us act in either earlier diagnostic strategies, or management strategies. I think those are the two unanswered questions that remains.                                                 How are we gonna screen our patients? Our high risk patients to determine when they are developing heart failure before they become symptomatic? So, what threshold are we going to use? Dr. Carolyn Lam:               That is a perfect set up. I just wanted to add as well in addition to STOP-HF there was the PONTIAC study in diabetics which is very relevant to today's paper that also sort of used NT-proBNP to risk stratify patients for prevention of heart failure. But neither of these studies talked about the temporal changes in natriuretic peptides. And I think a lot of the reason for that is, is that the methods, I mean the statistical methods to do that sort of thing are mind-blowing.                                                 And so Brian, could you now please share with us what you did, the methodology and basically what you found before we discuss the two questions that Biykem brought up? Dr. Brian Claggett:           What was really interesting is the method that we came up with to look at these questions. It's something that we like to believe will be generalizable and can be used in other scenarios and for other biomarkers. But the idea that we have is that we are always used to thinking about the design of a clinical trial as being very regimented. So, you see a patient once at baseline, and then maybe six months later, and then maybe six months after that, and so on. And so it's hard to know what's going on, on a day to day or week to week basis.                                                 But if you think backwards, and you think backwards from the time of any sort of event, because those events whether they're hospitalizations or MIs or death, they happen not on that same schedule. And so odds are at the end of a trial, you had a patient who came to a scheduled visit and then had an event the next day. And you probably had a patient who came in for a visit two days before an event, and another patient who came in a week before an event. So if you start thinking on that time scale, you can piece together all these different time frames when you do have data collected and try to reconstruct something that looks like an actual continuous natural history of what that biomarker would have looked like over say a two year period, if it had been measured continuously. Dr. Carolyn Lam:               So, tell us what you found. First of all, let's just make sure that everyone knows you were looking at the ELIXA cohort, right? Dr. Brian Claggett:           Yes, the data that we had available for this analysis comes from the ELIXA trials, it was 6,068 patients all with type-2 diabetes and a recent ACS event. Recent meaning within the last 180 days. And they were randomized placebo versus a diabetes drug, lixisenatide. And they were followed up for cardiac outcomes.                                                 Beyond that, the natriuretic peptides were measure systematically at baseline, month 6, month 18, and month 24 in all patients who were participating in the trial. So this was the richest collection of a large number of patients being measured multiple times, systematically and not in just a sub-sample of the population. So, we felt like this was a great opportunity to learn something about what happens. What can you learn when you measure these natriuretic peptides over and over again.                                                 And even more interesting than that, the fact that this wasn't a heart failure trial meant that some of the patients already had heart failure at baseline. Other patients didn't have heart failure, but as the trial went on, they developed or were hospitalized for heart failure for the first time. And so we were able to also look at differences between patients experiencing their first heart failure, versus those with more long standing disease. Dr. Carolyn Lam:               And that was very, very unique methodology that you spoke about. And I fully agree that it's going to be used more. I am staring at your beautiful figure one right now. That really, really says it all. Could you walk us through the results? Dr. Brian Claggett:           Sure, I think our key finding is that, I guess no matter when you measure patients. Patients with a higher level of NT-proBNP, or a higher level of BNP at any given time are going to be at higher risk of developing heart failure in the future.                                                 But as we start looking at this as a temporal process, what we see is that there seem to be a noticeable acceleration in these increases, specifically in the last six months before development of heart failure. Or, before a hospitalization for heart failure. And that increase in the final six months seems to occur both in patients who had no prior history of heart failure and also in patients with a history of heart failure. So that six month window I think is something that we learned that we didn't necessarily know before. Dr. Carolyn Lam:               But, going back to Biykem's questions, do you think we have answers to how often we need to survey natriuretic peptides in these high risk patients and what threshold we need to act on? Dr. Brian Claggett:           I think both are very important. I think maybe the timing and the thresholds are somewhat separate questions. I think we're better able to answer the timing question. At the very least we can say that if dramatic changes are happening over a six month window that measuring patients only once every six months probably isn't enough. Whether that means it needs to be every three months, or two months, or one month, or something more than that, I think it's hard to know exactly what the right answer is. But I think we are confident in saying that things happen relatively quickly and we need to be measuring these things more frequently.                                                 As far as the question of thresholds, I think that's maybe even a more difficult question. Or even the idea of a threshold means that we think that there's some magic number and I am not sure that we know for sure what's more important, the absolute number or is it the ... if someone starts relatively low and that relatively low number doubles over the course of six months. That might still be prognostically just as important as someone who's been consistently edging just below or just about that threshold level.                                                 I'm not sure that we're confident enough to say that the changes, the speed of the changes, or the relative changes, or some absolute threshold is the most important thing to be paying attention to. But, I think where these two are related is the more ... that we can start to collect this data more frequently and be able to analyze it. I think that gives us a lot better chance of being able to successfully answer that question about thresholds. Dr. Carolyn Lam:               Indeed. Stuff for future work, huh? Biykem, what do you think? Dr. Biykem Bozkurt:        I wanted to point out two things from Brian's study which was quite interesting. One is the trajectory of the rise, or the delta changes in the natriuretic peptides was quite different in the patients with no history of heart failure compared to those with a history of heart failure. The trajectory, or the linear rise, or the delta changes were more prominent in the individuals with no history of heart failure. Probably intuitively expected so because their baseline levels are not as high as the individuals with history of heart failure.                                                 So, it almost gives the impression that maybe in low low risk, the screening or the frequency may need to be lower, and if low, then probably the likelihood of the rise may be less. But those individuals who, as you said, are edging upward, then maybe the frequency may need to be higher and there may be perhaps a linear rise or a more prominent rise about six months before the incident event.                                                 So, it's an interesting concept just to look at people's trajectories. But, as you said, probably individualization and monitoring or targeting may need to be individualized according to personal risk and other features. And one then wonders futuristically if this would be a concept that would be point of care testing maybe done by the patients similar to glucose monitoring. And in the event that we were to be able to carry the platform to self-test. Dr. Brian Claggett:           You're talking to a statistician, so I am always going to be in favor of collecting more data all the time. So I agree with that. Dr. Carolyn Lam:               Wow, what an insightful discussion. Thank you both for joining us on this podcast today.                                                 Ladies and gentlemen out there, you heard it right here in Circulation on the Run. Tune in again next week.

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. What is the association between fetal congenital heart defects and maternal risk of hypertensive disorders of pregnancy? We will be discussing new data in this area in just a moment, following these summaries.                                                 The first paper describes the effect of long-term metformin and lifestyle measures on coronary artery calcium. This is a paper from Dr. Goldberg of George Washington University Biostatistics Center and colleagues of the Diabetes Prevention Program Research Group. The Diabetes Prevention Program and its outcome study is a long-term intervention study in subjects with prediabetes, which showed reduced diabetes risk with lifestyle and metformin compared to placebo.                                                 In the current study, the authors looked at subclinical atherosclerosis, which was assessed in 2,029 participants using coronary artery calcium measurements after 14 years of average follow-up. They found that men but not women with prediabetes treated with metformin for an average duration of 14 years had lower coronary calcium scores than their placebo counterparts. No difference in coronary calcium scores was observed in the group receiving a lifestyle intervention as compared to the placebo group.                                                 These findings provide the first evidence that metformin may protect against coronary atherosclerosis in men with prediabetes, although demonstration that metformin reduces cardiovascular disease events in these subjects is still needed before firm therapeutic implications of these findings can be made. The reason for an absence of an effect in women is unclear and deserves further study.                                                 The next study provides insights on the physiology of angina from invasive catheter laboratory measurements during exercise. Dr. Asrress of Royal North Shore Hospital in Sydney, Australia, and colleagues, studied 40 patients with exertional angina and coronary artery disease who underwent cardiac catheterization via radial axis and performed incremental exercise using a supine cycle ergometer. As they developed limiting angina, sublingual GTN was administered to half the patients and all patients continued to exercise for two minutes at the same workload. Throughout exercise, distal coronary pressure and flow velocity, and central aortic pressure were recorded using sensor wires.                                                 Using this novel invasive approach, the authors showed that administration of GTN ameliorated angina by reducing myocardial oxygen demand as well as increasing supply with a key component being the reversal of exercise-induced coronary lesion vasoconstriction. This was evidenced by the fact that there was a relationship between the diastolic velocity pressure gradient with significant increase in relative stenosis severity. In keeping with exercise-induced vasoconstriction of stenosed epicardial segments and dilation of normal segments, with trends towards reversal with GTN.                                                 Thus, this study describes the development of a paradigm where patients with coronary artery disease can exercise while simultaneously having coronary and central aortic hemodynamics measured invasively, and has shown that this provides a unique opportunity to study mechanisms underlying the physiology of angina. In treating patients with exercise-induced angina, the results highlight the importance of after-load reduction and the use of agents that reduce arterial wave reflection and promote coronary artery vasodilation.                                                 The next study provides mechanistic insights into reverse cholesterol transport, where excess cholesterol is removed from macrophage-derived foam cells in atherosclerotic plaques. It suggests that melanocortin receptor-1, or MC1-R, may play a role. As background, the melanocortin system, consisting of melanocyte-stimulating hormones and their receptors, regulate a variety of physiological functions, ranging from skin pigmentation to centrally-mediated energy balance control. At the cellular level, the biological actions are mediated by G protein-coupled melanocortin receptors, such as MC1-R. MC1-R not only affects melanogenesis in the skin but also has immunomodulatory effects through its wide expression in the cells of the immune system.                                                 In the current study from Dr. Rinne of University of Turku in Finland, and colleagues, human and mouse atherosclerotic samples and primary mouse macrophages were used to study the regulatory functions of MC1-R. The impact of pharmacological MC1-R activation on atherosclerosis was further assessed in apolipoprotein E deficient mice. Their findings identified a novel role for MC1-R in macrophage cholesterol transport. Activation of MC1-R conferred protection against macrophage foam cell formation through a dual mechanism. It prevented cholesterol uptake while it concomitantly promoted reverse cholesterol transport by increasing the expression of ATP-binding cassette transporters, ABCA1 and ABCG1.                                                 Thus, the identification of MC1-R in lesional macrophages, demonstration of its role in regulating reverse cholesterol transport, combined with its established anti-inflammatory effects, suggests that MC1-R could be a novel new therapeutic target for preventing atherosclerosis.                                                 The next study suggests that obesity-related heart failure with preserved ejection fraction, or HFpEF, is a genuine form of cardiac failure and a clinically relevant phenotype that may require specific treatments. First author, Dr. Obokata, corresponding author, Dr. Borlaug, and colleagues from Mayo Clinic Rochester and Minnesota studied 99 patients with obese HFpEF with a BMI above 35, with 96 non-obese HFpEF with a BMI less than 30, and 71 non-obese controls without heart failure. All subjects underwent detailed clinical assessment, echocardiography, and invasive hemodynamic exercise testing.                                                 The authors found that, compared to non-obese HFpEF, obese HFpEF patients displayed greater volume overload, more biventricular remodeling, greater right ventricular dysfunction, worse exercise capacity, more impaired pulmonary vasodilation, and more profound hemodynamic arrangements, despite a lower NT-proBNP level. Obese HFpEF patients displayed other important contributors to high left ventricular filling pressures, including greater dependence on plasma volume expansion, increased pericardial restraint, and enhanced ventricular interaction, which was exaggerated as pulmonary pressure load increased.                                                 These data provide compelling evidence that patients with the obese HFpEF phenotype have real heart failure and display several pathophysiological mechanisms that differ from non-obese patients with HFpEF. These and other issues are discussed in an accompanying editorial by Dr. Dalane Kitzman and myself. We hope you enjoy it.                                                 The final study identifies a novel long noncoding RNA that regulates angiogenesis. As background, although we know that the mammalian genome is pervasively transcribed, a large proportion of the transcripts do not encode a protein, and are thus regarded as noncoding RNAs. Based on their length, they can be divided into small or long noncoding RNAs, long being described as more than 200 nucleotides. Although their function is not fully understood, long noncoding RNAs have been increasingly reported to mediate the expression of other genes, affect the organization of the nucleus, and modify other RNAs.                                                 In the current study by first author, Dr. Leisegang, corresponding author, Dr. Brandes, and colleagues of Goethe University in Frankfurt, Germany, epigenetically controlled long noncoding RNAs in human umbilical vein endothelial cells were searched by axon array analysis following knockdown of the histone demethylase JARID1B. The authors discovered a novel noncoding RNA named MANTIS to be strongly upregulated. MANTIS is located in the antisense strand of an intronic region of the gene for annexin A4, calcium- and phospholipid-binding protein. MANTIS is a nuclear long noncoding RNA that is enriched in endothelial cells but also expressed in other cell types. Reducing MANTIS levels led to impaired endothelial sprouting, tube formation, attenuated endothelial migration, and inhibition of the alignment of endothelial cells in response to shear stress.                                                 Brahma-like gene 1, or BRG-1, was identified as a direct interaction partner of MANTIS, implying a role of MANTIS in the formation of the switch/sucrose non-fermentable chromatin remodeling complex. MANTIS binding to BRG-1 was shown to stabilize the BRG-1 interaction, hence by inducing an open chromatin conformation, MANTIS was proposed to maintain the endothelial angiogenic potential. The implications of these findings are discussed in an accompanying editorial by Dr. Zampetaki and Mayr from Kings College London.                                                 That brings us to the end of our summaries. Now for our feature discussion.                                                 Today, we are going to be discussing the association between fetal congenital heart defects and maternal risk of hypertensive disorders of pregnancy. To discuss this, I have the first and corresponding author of our feature paper, Dr. Heather Boyd, from Statens Serum Institut in Copenhagen, and our familiar Dr. Sharon Reimold, content editor for special populations from UT Southwestern. Welcome, Heather and Sharon. Dr. Heather Boyd:            Thank you. Dr. Sharon Reimold:        Thank you. Dr. Carolyn Lam:               Heather, it's a topic that I can't say I'm very familiar with, association between fetal congenital heart defects and maternal risk of hypertensive disorders of pregnancy. Could you start by sharing why would we think there would be a link? What was the hypothesis you were testing? Dr. Heather Boyd:            A couple years ago, there was a paper published in the European Heart Journal that reported evidence of angiogenic imbalance in women with fetuses with major congenital heart defects, so women who were pregnant with babies that had heart defects, and then in fetuses that were terminated because of this kind of defect. My research group focuses a lot of attention on preeclampsia. In the last decade or so, angiogenic imbalance in preeclampsia has been a really hot topic. Women with preeclampsia, particularly women with early-onset preeclampsia, have big angiogenic imbalances. When we saw the European Heart Journal paper, we immediately thought, "What's the connection between preeclampsia and heart defects in the offspring?" Dr. Carolyn Lam:               Oh! Dr. Heather Boyd:            Exactly. That was our entry point to it, was the term "angiogenic imbalance" in that paper sort of was a flag for us. It wasn't a completely new idea, but we in Denmark have one big advantage when considering research questions that involve either rare exposures and/or rare outcomes, and that's our National Health Registry. We have the ability to assemble these huge cohorts and study conditions like heart defects with good power, so we decided just to go for it. Dr. Carolyn Lam:               That makes a lot of sense now. Please, tell us what you did and what you found. Dr. Heather Boyd:            The first thing we did was look at the association between carrying a baby with a heart defect and then whether the mom had preeclampsia later in the same pregnancy. We had information on almost 2 million pregnancies for this part of the study. We found that women carrying a baby with a heart defect were seven times as likely as women with structurally normal babies to develop early preterm preeclampsia. We defined that as preeclampsia where the baby has to be delivered before 34 weeks, so the really severe form of preeclampsia. Then, women carrying a baby with a heart defect were almost three times as likely to develop late preterm preeclampsia as well. That's where they managed to carry it until 34 weeks but it has to be delivered some time before 37 weeks.                                                 These findings were similar to those of other studies, but we were able to go a step further and look at individual heart defect subtypes. What we found there waws that these strong associations were similar across defect categories. Then we decided to see if we could shed any light on the origin of the problem, whether it was coming from the mom's side or the baby's side. To do this, we looked at women with at least two pregnancies in our study period to see whether preeclampsia in one pregnancy had any bearing on the chance of having a baby with a heart defect in another pregnancy or vice versa.                                                 This part of the study included 700,000 women. We found very similar findings. We found that women with early preterm preeclampsia in one pregnancy had eight times the risk of having a baby with a heart defect in a subsequent pregnancy. Late-term preeclampsia in one pregnancy was associated with almost three times the risk of offspring heart defects in later pregnancies. Then, we found that it worked the other way around too. Women who had a baby with a heart defect were twice as likely to have preterm preeclampsia in subsequent pregnancies.                                                 Those results were really, really exciting, because whatever mechanisms underlie the associations between preterm preeclampsia in moms and heart defects in the babies, they operate across pregnancies. Therefore, that pointed towards something maternal in origin. Dr. Carolyn Lam:               That is so fascinating. Sharon, please, share some of the thoughts, your own as well as those of the editors when we saw this paper. Dr. Sharon Reimold:        I think that there's a growing data about the links between hypertensive disorders of pregnancy and preeclampsia with subsequent abnormal maternal outcome. But this paper, I think, has implications for how we look at moms who are going to have offspring with congenital heart defects as well as those with preeclampsia. For instance, I would look at a patient now that has preeclampsia, especially in more than one pregnancy, to identify that they may be at risk to have offspring with congenital defects in the future if they have additional children. But the mom is also at risk based on other data for developing other cardiovascular risk factors and disease as she gets older. It was really the link going back and forth with the hypertensive disorders and the congenital defects that we found the most interesting. Dr. Carolyn Lam:               That struck me too, especially when you can look at multiple pregnancies and outcomes. That's amazing. You know what, Heather, could you share a little bit about what it's like working with these huge Danish databases? I think there must be a lot more than meets the eye. Dr. Heather Boyd:            It's an interesting question, because I'm a Canadian and I was trained in the US. I did my PhD in epidemiology at Emery, and then I moved to Copenhagen. When I first got here, I was absolutely floored at the possibility of doing studies with millions of women in them. It opens some amazing possibilities, like I said earlier, for certain outcomes and certain exposures. You just need to have a question where the information you want is registered. Dr. Carolyn Lam:               Yeah. But I think what I also want to put across is, having worked with big databases, and certainly not as big as that one, it's actually a lot of work. People might think, "Oh, it's just all sitting there." But, for example, how long did it take you to come to these observations and conclusions? Dr. Heather Boyd:            I have a fabulous statistician. I think she's the second author there, Saima Basit. She spends a lot of her time pulling together data from different registers. But yes, you're right. The data don't always just mesh nicely. The statisticians we have working with us are real pros at this sort of data slinging. Dr. Carolyn Lam:               Could I just pose one last question to both of you. What do you think are the remaining gaps? Dr. Sharon Reimold:        I think that this is a clinical link. Then, going back to figure more about what's going on biologically to set up this difference? Because right now there's really no intervention that's going to make a difference, it's just a risk going forward. This is sort of like medicine done backwards, that there's this association and now we need to figure out exactly why. Dr. Heather Boyd:            I can piggyback on what Sharon said a little bit, because I think one of the things we need to remember is that not all women with preeclampsia have babies with heart defects. Not by a long shot. What we need to do now is to figure out what distinguishes the women who do get this double whammy from the vast majority who don't.                                                 One of the things that Denmark does really nicely is that there are large bio banks. One of the things we want to do is go back to bank first trimester maternal blood samples and see if we can identify biomarkers that are unique to the women with both preterm preeclampsia and babies with heart defects. That's one of the things we're thinking about to address this gap. Because, as Sharon says, we've got to figure out what the mechanism is.                                                 The other thing we want to do is to see whether the association between preeclampsia and heart defects extends, for example, to other things, to cardiac functional deficits, for example, because it's probably not just severe structural defects. If there's an association, it's probably on a continuum. Are babies born to preeclamptic moms, do their cardiac outputs differ? Do their electrical parameters differ? Do they just have different hearts?                                                 We're really lucky because right now the Copenhagen Baby Heart Study is offering to scan the hearts of all infants born at one of the three major university hospitals in the Copenhagen area. We're about to have echocardiography data on 30,000 newborn hearts to help us look at this. I'm really excited about that possibility. Dr. Carolyn Lam:               I've learnt so much from this conversation. I'm sure the listeners will agree with me. Thank you both very, very much.