Podcasts about probnp

Kritisk gennemgang af litteratur med fokus på klinisk anvendelighed og hvilke faldgruber vi skal passe på når vi overfører resultaterne til vores egne patienter Læs blogversionen her I denne tredje udgave af "Men hvad betyder det?" er vores nye medvært, Morten Weyhe, med i studiet og vi gennemgår i fællesskab fire studier der dækker bredt over flere emner: Risikoen for recidiv af lungeemboli uden behandling ved tilfældigt fundne lungeembolier DOAC vs. Vitamin K antagonist for AFLI hos patienter med rheumatisk hjertesygdom Klinisk anvendelighed af FLUS vs. RU thorax og proBNP i diagnosticeringen af akut hjertesvigt hos patienter indlagt med dyspnø Forskelle i tilstrækkelig smertedækning imellem etniske grupper i amerikanske akutmodtagelser Får du ikke stillet din evidens-sult her på siden, så læs vores andre "Men hvad betyder det?" episoder her. Som altid er I meget velkomne til at komme med feedback i kommentarfeltet her på siden eller direkte til akutmedicineren@gmail.com

CardioNerds (Amit and Dan) join join Dr. Andrew Dicks (Vascular medicine physician at Prisma Health, former fellow at Mass General Vascular) and Dr. Prateek Sharma (Vascular interventional & medicine fellow at MGH) for an ice-cold drinks at the Esplanade in Boston, MA to discuss a case about a patient who developed a pulmonary embolism and masterfully discuss the diagnosis and management of of pulmonary emboli. Dr. Ido Weinberg (Director, Vascular Medicine Fellowship at MGH) provides the ECPR for this episode. Case Abstract: A 59-year-old Spanish-speaking man with no significant past medical history presents after falling 15-20 feet from a ladder and landing on his back. He was found to have an L1 fracture and left radial fracture and underwent T12-L2 fusion with neurosurgery on hospital day 1 and ORIF of left radial fracture with orthopedic surgery on hospital day 2. On hospital day 5, he develops acute onset tachycardia with HR in the 130s bpm with new O2 requirement associated with mild shortness of breath at rest without any chest discomfort. His labs were notable for an elevated troponin and proBNP. He underwent CTPA which demonstrated acute bilateral occlusive pulmonary emboli (PE) extending in the right and left main pulmonary arteries. TTE demonstrated right ventricle dilation. The patient was started on a heparin infusion and a PE response team (PERT) meeting was held to discuss treatment options. Given recent surgery, use of thrombolytic therapy was felt to be too risky and thus he was taken for percutaneous thrombectomy in the cath lab. PA pressure prior to intervention was 51/21 mmHg. The patient underwent suction thromboembelectomy with the Flow Triever device with extraction of thrombus and improvement in PA pressure to 19/11 mmHg. He was treated with anticoagulation thereafter and discharged home two days after the procedure. Jump to: Case media - Case teaching - References CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Case Media Acute bilateral occlusive and nonocclusive pulmonary emboli extending from the right and left main pulmonary arteries to the lobar and segmental arteries of all the lobes.  Moderate right heart strain including the right atrium and the right ventricle. RV/LV ratio > 1.0. Right ventricular cavity is dilated (RV size at the base measures to 45mm). Right ventricular systolic function is moderately decreased. Right ventricular free wall is hypokinetic with sparing of the right ventricular apex consistent with acute right ventricular strain Pulmonary angiography demonstrated extensive proximal bilateral PEs Caption: Post-procedure TTE demonstrated resolution of RV strain with normalization of RV size and function. Episode Schematics & Teaching Pearls While there are markers to suggest PE, such as ECG findings or evidence of RV dilatation, a PE cannot be confirmed without imaging.Elevation of cardiac biomarkers and evidence of RV dysfunction are used to risk stratify PE, not the degree of thrombus burden or locale of thrombus.Enoxaparin is the preferred anticoagulant to initiate at time of PE diagnosis if comorbidities allow.Optimal treatment of intermediate risk PE remains uncertain as there is little data about long-term outcomes. Aggressive treatment should be used judiciously and chosen on a case-by-case basis.PE response teams (PERT) allow for multidisciplinary expert opinion in the face of scarce evidence to determine what is felt to be the best management strategy. Notes 1. What is a PERT team and why is it helpful? We have several tools and approaches for the management of PE. There are also many subspecialities involved in the care of patients with PE, including vascular medicine,

Please join author Maria Nunes and Associate Editor Ntobeko Ntusi as they discuss the article “Incidence and Predictors of Progression to Chaga Cardiomyopathy: Long-Term Follow-Up of Trypanosoma cruzi-Seropositive Individuals.” 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. Well Carolyn, this feature this week, we're going to talk about Chagas disease and we have some really important long-term, really for the first time, observational data and a cohort that's been followed in Brazil. And it's just a wonderful discussion from a team that's been working very hard in this area over an extended period of time. But before we get to that, how about we grab a cup of coffee and get started on some of the other articles in this issue? Would you like to go first? Dr. Carolyn Lam:             I would. And with your coffee, I would like to tell you about non-combustible nicotine or tobacco products. Fancy a smoke with your coffee? Well, you know that those are novel forms of nicotine consumption composed of things like nicotine vaping products that vaporize the nicotine-containing fluids and heated tobacco products that really heat the tobacco products without combustion. Now, these have recently gained popularity because they're portrayed as being safer modes of smoking compared with the traditional combustible cigarettes. However, their associations with subsequent cardiovascular disease risks are still unclear. So Greg, here's today's quiz. Gosh, I miss our quizzes. What do you think? Are they safer or are they not? Dr. Greg Hundley:           Oh, Carolyn, you're catching me on this and I never know which way to go, but I'm going to guess not. How about you tell us? Dr. Carolyn Lam:             Well, the paper will tell us, and this is from co-corresponding authors Dr. Lee from Seoul National University Bundang Hospital and Dr. Park from Seoul National University College of Medicine and their colleagues. And they basically studied more than 5,000,000 adult men who underwent health screening examinations during both a first and second phase of health screening periods from the Korean National Health Insurance Service Database spanning 2014 to 2018. Initial combustible cigarette smokers who subsequently quit that cigarette smoking and converted to a non-combustible nicotine or tobacco product use was associated with a lower incident cardiovascular disease risk compared to those who continue the combustible cigarette use. However, compared with combustible cigarette quitting without using these non-combustible substitutes, those who ceased smoking but continued with the non-combustible products was associated with a higher cardiovascular disease risk. So the take home message is although the non-combustible nicotine or tobacco products may be associated with a lower cardiovascular disease risk compared with continued combustible cigarette smoking, those who quit without using these substitutes may benefit the most in reducing the risk of developing future cardiovascular disease events. And this is discussed in a wonderful editorial by Dr. Auer, Diethelm and Berthet. Dr. Greg Hundley:           Very nice, Carolyn. Great presentation and really new information in this space. Well, my paper comes from the world of preclinical science and it involves long noncoding RNAs. And Carolyn, they are important regulators of biological processes involved in vascular tissue homeostasis and cardiovascular disease development. And so, the current study, led by Professor Lars Maegdefessel from Karolinska Institute, assessed the functional contribution of the long noncoding RNAs myocardial infarction associated transcripts and their relationship to atherosclerosis and carotid artery disease. Dr. Carolyn Lam:             Hmm, interesting. They are the rage, these lncRNAs. So what did they find, Greg? Dr. Greg Hundley:           Right, Carolyn. So long noncoding RNAs possess key regulatory functions directly interacting and mediating expression and functionality of proteins, other RNAs, as well as DNA. Next, the long noncoding RNA myocardial infarction associated transcript plays a key role during atherosclerotic plaque development and lesion destabilization. Its expression becomes highly increased in high risk patients with vulnerable plaques. And so, Carolyn, the take home therapeutic targeting of the long noncoding RNA myocardial infarction associated transcript, using antisense oligonucleotides, well that offers novel treatment options for patients with advanced atherosclerosis in the carotid arteries that are at risk of stroke. Dr. Carolyn Lam:             Oh, very interesting. So from the preclinical world back to the clinical world with an important clinical trial. Now, we know that percutaneous closure of the left atrial appendage is an alternative to chronic oral anticoagulation to reduce stroke risk in patients with nonvalvular atrial fibrillation. The Amplatzer Amulet Left Atrial Appendage Occluder IDE trial, called the Amulet IDE trial, was designed to evaluate the safety and effectiveness of the dual seal mechanism of the Amulet left atrial appendage occluder compared with the WATCHMAN device. And here, 1,878 patients with nonvalvular atrial fibrillation at increased risk of stroke were randomly assigned to undergo percutaneous implantation of a left atrial appendage occluder with the Amulet occluder or a WATCHMAN device. And the primary end points included safety, which was a composite of procedure-related complications all cause death or major bleeding at 12 months, and effectiveness, which was a composite of ischemic stroke or systemic embolism at 18 months. They also looked at the rate of left atrial appendage occlusion at 45 days. And this paper is from Dr. Lakkireddy and colleagues from Kansas City Heart Rhythm Institute. Dr. Greg Hundley:           Well Carolyn, these devices, they are really being heavily tested in patients with atrial fibrillation. So what did they find? Dr. Carolyn Lam:             The Amulet occluder was non-inferior with respect to safety and effectiveness compared to the WATCHMAN device, and superior with respect to left atrial appendage occlusion; however, procedure-related complications were higher with the Amulet occluder, largely related, perhaps, to more frequent pericardial effusion and device embolization. And the authors noted that the procedure-related complications decreased with operator experience; however, I think all of this still needs to be further investigated. Well, those were really nice original papers, but let's also discuss what else there is in today's issue. There is an exchange of letters between Drs. Mueller and Allen regarding the article “Diagnostic Performance of High Sensitivity Cardiac Troponin T Strategies and Clinical Variables in a Multisite U.S. Cohort.” There's a perspective piece by Dr. Olson, “Toward CRISPR Therapies for Cardiomyopathies.” Dr. Greg Hundley:           And Carolyn, I've got a research letter from Professor Layland entitled “Colchicine in Patients with Acute Coronary Syndromes: Two Year Follow Up of the Australian COPS Randomized Clinical Trial.” Well, what a great set of papers that we've discussed. Now, let's get on to that feature discussion and learn a little bit more about the longitudinal history and progression of cardiovascular disease and patients with Chagas disease. Dr. Carolyn Lam:             Yay. Let's go, Greg. Dr. Greg Hundley:           Well, listeners, we are here for our feature discussion today and a very exciting one we have, pertaining to Chagas disease. And we have with us today Dr. Maria Nunes from Belo Horizonte, Brazil, and also one of our Associate Editors, Dr. Ntobeko Ntusi from Cape Town, South Africa. Welcome to you both. And Maria, we'll start with you. Could you describe for us some of the background information pertaining to your study and what was the hypothesis that you wanted to address? Dr. Maria Nunes:             Yes, thank you for these opportunities. My main hypothesis is that Chagas disease is the major cause of dilated cardiomyopathy in endemic areas. So we selected patients without cardiomyopathy at baseline to see if the Trypanosoma cruzi seropositivity is a predictor of further developing of cardiomyopathy. Dr. Greg Hundley:           Very nice. And so tell us, how did you construct this study? What was your design? And then also, maybe describe for us how you selected the participants for this study. Dr. Maria Nunes:             We selected the participants from two blood donor centers. One in Sao Paulo and one in Montes Claros, which is north of Minas Gerais State. We select blood donors because it's the way that we have Chagas disease's screening tests. And in asymptomatic patients, usually at the hospital, patients comes to us with heart failure or a kind of symptoms related to Chagas disease. Our main goals in this study is to select healthy participants based on the screen test of Trypanosoma cruzi. So the population was blood donors selected from two centers. Dr. Greg Hundley:           Very good. And then again, your study design. So did you follow these two groups of individuals longitudinally over time, and for how long? Dr. Maria Nunes:             Yes, we have different visits of this study with the patients initially was selected at first in 1996 and 2002. At this time, they don't have cardiovascular exams. And our study actually is starting 2008 to 2010, and we select all these patients with all comprehensive cardiovascular evaluation with the clinical examination, echocardiogram and electrocardiogram, and then just the baseline for our patient population. And we follow them 10 years on average until 2018, 2019. Dr. Greg Hundley:           Very nice. So it sounded like from individuals in two regions of Brazil, identified those through screening of the blood, and I guess these were blood donors, and then performed a series of cardiovascular exams 2008 to 2010 and followed them for the next 10 years. And you're going to tell us about the results that occurred 2018 to 2019. And so what were those results? Dr. Maria Nunes:             We found that Trypanosoma cruzi seropositive is a risk factor for developing cardiomyopathy. Nowadays, this is still a risk factor, seropositive without cardiomyopathy at baseline has two times higher risk of developing cardiomyopathy compared to the seronegative controls. And we have also detected that the parasite load or the level of parasite in the blood expressed by antibodies against Trypanosoma cruzi is an important risk factor for disease progression. That means some patients have Chagas disease, but the level of antibodies is not too high. These patients go well. And other hand, the patients with high level antibodies means the parasite load may be higher too. This is the high risk of disease progression to cardiomyopathy or of dying too. Dr. Greg Hundley:           Very nice. And were there any subgroups of patients where you found these relationships to be particularly more striking? So for example, the elderly, or was there a discrepancy based on sex, men versus women? Dr. Maria Nunes:             Yes, other studies has already shown that the male gender is a risk factors in Chagas disease. Usually they progress more, they have more severe clinical presentation, usually die at the age between 30 and 50 years old, the most productive years of the life. That's why Chagas is so important here in Brazil and Argentina, in Latin America countries because people die at early ages. Dr. Greg Hundley:           And your results confirmed what was previously known in that regard. Dr. Maria Nunez:             Yes, patients with developing cardiomyopathy with heart failure has a high mortality rate. And then even patients with cardiomyopathy detected by exams like based on ECG or echo, they asymptomatic, but they progress more for dying or to develop cardiomyopathy compared to seronegative with similar risk effects for cardiovascular disease, such as hypertension, diabetes, smoking. Dr. Greg Hundley:           Very good. Well Ntobeko, you see many papers come across your desk as an Associate Editor for Circulation, and what attracted you to this paper and the results that Maria has described? Dr. Ntobeko Ntusi:          Thank you, Greg. I was attracted to this paper because it's an important natural history study of Chagas disease. But secondly, it's also one of the largest contemporaneous cohorts of Chagas disease which provides important insights and advances in our knowledge with regard to this clinical entity. And for me, there were three things that stood out. The first one was an important description of the outcomes of Chagas cardiomyopathy. The second was the contemporaneous description of the epidemiology in a well-characterized cohort. And the third and novel contribution was the description of the determinants of disease progression. So I thought overall, the really important contribution to the field. Dr. Greg Hundley:           Very good. And for those that might not live in the endemic area, but might occasionally encounter someone with Chagas disease, what results from this paper can we use to help manage patients in this situation? Dr. Ntobeko Ntusi:          Thanks, Greg. So this was a study which had a number of really positives. Firstly, it's a large study, it was non acute [inaudible 00:16:42] design and it used PCR for diagnosis. And unlike many other studies, also ascertained antibody levels and had very good clinical characterization, which included electrocardiographic, echocardiographic assessment, including serum assessment of proBNP and CK-MB. And all really important take home messages are for me. The first one is understanding that the relationship of your antibody levels and baseline LV function to mortality. In other words, are finding that in those with existing LV structural abnormalities, or higher levels of antibody titers, mortality was higher. The second important contribution is a description of the incidence of Trypanosoma cruzi, and this was highest as one would expect in the seropositive donors and much lower in seronegative donors. The third important contribution relates to our improved understanding of the determinants of disease progression, which were related to the Trypanosoma cruzi antibody levels. In other words, the higher your antibody titers, the quicker you progressed to manifest the cardiomyopathic phenotype. And then lastly, the predictors of mortality, which were related to your PCR being positive, as well as your antibody titers. Important is this contribution is there are a number of important caveats. The first is that the study is limited by the huge amount of loss to follow up, which as you can imagine, adds a number of biases to our conclusions. The second is that the observations may of course be confounded by comorbidity in particular because these patients are older and had higher comorbidity. The third is that we assume that the PCR positivity and antibody titers actually correlate with parasite pattern, but in fact, we know that is not always the case. And then lastly, for people who read this paper from non-endemic parts of the world, the result may not be clearly generalizable to those parts of the world. Dr. Greg Hundley:           Very nice. Well, we've had a great discussion, listeners. From Maria and Ntobeko sort of presenting the paper and then what are some of the take home messages. So now I'd like to go back to both of them and Maria, first you and then Ntobeko. Maria, what do you think is the next study to really be performed in this sphere of research? Dr. Maria Nunes:             We may should stratify patients with Chagas disease. Those who have high antibodies titers should refer to a kind of treatment or benznidazole treatment. We should intervene in this subgroup. Dr. Greg Hundley:           Very good. And Ntobeko, anything to add? Dr. Ntobeko Ntusi:          Yes, Greg, I think that there are two important next steps. The first one is that I think we need other large designed prospective studies that will validate the observations by Dr. Nunes and colleagues. And then the second key step for me would be the design of randomized controlled trials to test therapeutic agents with antitrypanosomal activity to demonstrate their ability to retard or completely block disease progression, which would be a nice way to complete the story. Dr. Greg Hundley:           Very nice. Well listeners, we've had a great discussion today and we want to thank Maria Nunes from Brazil and Ntobeko Ntusi from South Africa for bringing these really informative results pertaining to Chagas disease, and highlighting the natural history and showing an association between these high titer values and poor cardiovascular outcomes. 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, 2021. 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, visit ahajournals.org.

This week's episode features author Kieran Docherty and Associate Editor Torbjørn Omland as they discuss the article "The Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients with Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction." 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. Well, Carolyn, we've got an exciting feature this week involving Neprilysin license inhibition and left ventricular remodeling in patients with asymptomatic left ventricular systolic function after they've sustained myocardial infarction. But before we get to that feature discussion, how about we grab a cup of coffee and jump in on some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I'd love to, and I want to talk about transcatheter aortic valve replacement, or TAVR, that we all know is really transforming our management of aortic stenosis. Despite rapid improvements, however, serious complications remain relatively common and are not well-described by single outcome measures. So the purpose of this paper was to determine if there was site-level variation in TAVR outcomes in the United States using a novel 30-day composite measure. And this is from Dr. Desai and colleagues from Hospital of University of Pennsylvania. So they performed a retrospective cohort study using data from the STS/ACC TVT registry to develop a novel-ranked competent performance measure that incorporates mortality and serious complications. Based on the associations with one-year risk adjusted mortality and health status, they identified for peri-procedural complications to include in the composite risk model, in addition to mortality. And ranked empirically, according to severity, these were: stroke, major life-threatening or disabling bleeding, stage three acute kidney injury, and moderate or severe perivalvular regurgitation. Dr. Carolyn Lam: Now, based on these ranked outcomes, they found that there was significant site-level variation in quality of care in TAVR in the United States. Overall, better-than-expected site performance was observed in 8% of sites, whereas performance as-expected was observed in 80%, and worse-than-expected performance was observed in 11% of sites. Dr. Greg Hundley: Carolyn, really interesting comprehensive data. So how do we put this all together? And what's the take-home message for us, clinically? Dr. Carolyn Lam: Well, there are substantial variations in the quality of TAVR care received in the United States, and 11% of sites were identified as providing care below the average level of performance. Further study is necessary to determine the structural, process-related, and technical factors associated with high- and low-performing sites. And all this is discussed in a beautifully, beautiful accompanying editorial by Drs. Dharam Kumbhani and Eric Peterson.   Dr. Greg Hundley: Oh, fantastic. You know, Carolyn, those editorials are so helpful in helping us put these new data in perspective. Well, my next paper comes to us from the world of preclinical science, and it's from Professor Vincent Christoffels from Amsterdam in UMC. So genetic variants of SCN10A, encoding the neural voltage-gated sodium channel NaV1.8 are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities, and heart rate. And these investigators studied the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A, and coding the major essential cardiac sodium channel NaV1.5. Dr. Carolyn Lam: Wow, great. So what did they find, Greg? Sounds like a first-of-its-kind study. Dr. Greg Hundley: Right, Carolyn. So genetic variants in and around SCN10A modulate enhancer function and expression of the cardiac-specific NCN10A short transcript, and the authors propose that non-encoding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV .8 and cardiomyocytes that impacts NaV1.5 function, cardiac conduction velocities, and arrhythmia susceptibility. Dr. Carolyn Lam: Wow, that was a lot. So what are the implications, Greg? Could you simplify it for us? Dr. Greg Hundley: Yes. Right, Carolyn. So three things. First, the authors uncovered a novel alternative mechanism for how the SCN10A locus regulates cardiac conduction. Second, their data implicate that genetic variation-sensitive regulation of expression of NCN10A short modulates conductivity of the heart, and can predispose to arrhythmia in the human population. And then finally, Carolyn, in deciphering the underlying mechanism of the increased NaV1.5 mediated current density by NaV1.8 short, the authors believe their findings could ultimately lead to the development of novel therapeutic strategies for particular conduction disorder. Dr. Carolyn Lam: Thanks, Greg. Well, this next paper is really interesting. It's the first validation of the enhanced potency of human-induced pluripotent stem cells-derived cardiomyocytes over-expressing Cyclin D2, or CCND2, under the control of myosin heavy chain promoter, and differentiated into cardiomyocytes. Now, that was a mouthful, but so interesting, because Dr. Zhang and colleagues from University of Alabama in Birmingham used infarcted pig hearts, and transplanted these amazing cardiomyocytes, and found that they were associated with proliferation of recipient heart cardiomyocytes, epithelial cells, and smooth muscle cells, all, at least partly, by paracrine activity. Dr. Greg Hundley: Well, Carolyn. Really an involved clinical design. So, what are the clinical implications of all this research?   Dr. Carolyn Lam: Well, first, I think the paper validated a novel therapeutic strategy aimed at upregulating proliferation of recipient cardiac cells using human-induced pluripotent stem cells-derived cell or cell products. Furthermore, targeting the myocyte cell cycle regulators, such as Cyclin D2, holds a strategic potential for re-muscularization of an infarcted region. Dr. Greg Hundley: Very good, Carolyn. Well, how about we see what else is in this issue? So I'll start first. There's a Research Letter by Professor Marston, entitled 'Combining High-Sensitivity Troponin with the American Heart Association/American College of Cardiology Cholesterol Guidelines to Guide of Avelumab Therapy'. Next, there's an ECG challenge from Dr. Feliciano, entitled 'An Ominous EKG'. And then finally, there's a very nice exchange of letters from Drs. Lang and Sattar regarding a prior publication: volume status is the key in heart failure. Dr. Carolyn Lam: And finally, a very important perspective piece by Dr. Catapano on omega-3 for cardiovascular disease: where do we stand after reduce it in strength? Wow, that was great, Greg. But let's move on now to our feature discussion. Dr. Greg Hundley: You bet. Dr. Greg Hundley: Well, listeners, we are on to our feature discussion today, on this July 20 issue. And we're very excited to have with us Dr. Kieran Docherty from University of Glasgow in Glasgow, Scotland, and our own associate editor, Dr. Torbjørn Omland from University of Oslo in Oslo, Norway. Welcome, gentlemen. And Kieran, let's start with you. Could you describe some of the background related to your study, and what was the hypothesis that you wanted to address? Dr. Kieran Docherty: Well, firstly, thank you very much for the invitation to discuss our trial today on the podcast. The background of our trial was that we are all aware that the development of left ventricular systolic dysfunction following acute myocardial infarction places patients at a subsequent increased risk of the development of heart failure, and the process of progressive dilatation of the left ventricle and a reduction in stroke volume, known as adverse left ventricular remodeling, is the process which underlies this elevated risk of heart failure. And many of the treatments that have been shown to be beneficial following myocardial infarction, such as [inaudible 00:09:24] , and angiotensin receptor blockers and beta blockers, the benefit of these medications, in part, is due to their ability to attenuate this process of adverse remodeling. Now, our hypothesis was that it would be possible to further attenuate, prevent, or delay the process of adverse remodeling in patients at risk of heart failure following myocardial infarction, by the addition of a Neprilysin inhibitor to current standard of care. Dr. Kieran Docherty: Now, as we all know, a Neprilysin inhibitor in the form of sacubitril valsartan when combined with an angiotensin receptor blocker, has been shown to improve outcomes in patients with symptomatic heart failure, with reduced ejection fraction in the PARADIGM-HF trial, and Neprilysin inhibitors increase endogenous levels of natriuretic peptides, amongst a range of other substrates for Neprilysin, including adrenomedullan, GLP-1, and bradykinin. And our hypothesis was that adding in a Neprilysin inhibitor, thereby increasing endogenous levels of these peptides with potentially beneficial effects, such as reducing fibrosis, reducing hypertrophy, [inaudible 00:10:34] and diuresis, may have an additive beneficial effect on left ventricular remodeling in these high-risk patients with left ventricular systolic dysfunction following myocardial infarction. Dr. Greg Hundley: Very nice hypothesis. So, how did you set up, Kieran, your study design, and what study population, how many patients and whatnot, did you include in your study? Dr. Kieran Docherty: Well, the first consideration when designing the study was broadly, what group of patients should we involve? And the main limitation was the indication for the use of sacubitril valsartan in patients with symptomatic heart failure, so we did not feel that we could include these patients. Therefore, our study population included patients who had asymptomatic left ventricular systolic dysfunction following previous myocardial infarction. And specifically, we wanted patients who were at least three months following my cardiac infarction. And the reason for that was to try and exclude patients who had transient systolic dysfunction or left ventricular stunning. And we performed a screening transthoracic echo at this time point. And if patients had an ejection fraction of 40% or less on echo, and if they were tolerant of a minimum dose of an ACE inhibitor, 2.5 milligrams of ramipril BD or equivalent, and they were taking a beta blocker, unless contraindicated or not tolerated, then they were suitable for randomization. Dr. Greg Hundley: Very good. And what did you find? Dr. Kieran Docherty: So we find that in comparison with the ARB Valsartan, sacubitril valsartan did not have any beneficial effects on cardiac MRI-based measures of left ventricular remodeling. And the primary end point of our study was left ventricular end systolic volume index. There was also no improvements in biomarkers of myocardial stress, i.e. NT-proBNP, or my cardio injury, i.e. high sensitivity to Troponin I. Dr. Greg Hundley: Very nice. And any pertinent issues relevant to, perhaps, some subgroups, regardless of age or perhaps gender? Dr. Kieran Docherty: So in a post-hoc analysis, we performed an analysis of the primary endpoint in patients who were below or at or above the median NT-proBNP level, which is 238 p-grams per mil. And we found, very interestingly, the suggestion of a benefit, in terms of left ventricular remodeling with a reduction and systolic volume index in patients who had higher levels of NT-proBNP compared to those who had lower levels. Dr. Greg Hundley: Very good. Well, listeners, let's turn now to our associate editor, Dr. Torbjørn Omland, who... Torbjørn, you see many papers come across your desk. What attracted you to this manuscript? And then how do you put the results of this study in the context with other studies that have been published, particularly recently, in patients with heart failure that have received sacubitril valsartan? Dr. Torbjørn Omland: So, Greg, there were many aspects of this trial that made it very attractive for circulation. I think the hypothesis was very interesting, and also it is a very well-conducted study using the reference methods for assessing left ventricular function, using that for assessing the primary endpoint. And they also have a broad array of secondary end points that also sort of provide insight in potential pathways or mechanisms that can explain the effect sacubitril Valsartan. So, that's also a very sort of hot topic within the cardiology research currently, and we know that the ACC, actually a much larger study, PARADISE-MI, was presented. And we knew that this study was also very interesting, because we knew when we received this manuscript, that another, bigger trial that's sort of related would be presented at the ACC at the late-breaking clinical trial sessions there the PARADISE-MI study. But this sort of provided insight that nicely complimented the results of that study. Dr. Torbjørn Omland: And I think as Kieran alluded to, we already have the very impressive results from PARADIGM-HF is showing a very substantial benefit in patients with chronic heart failure and reduced ejection fraction. And then we have sort of the borderline results from the Paragon trial, in those with preserved ejection fraction, where it actually was a gradient from those with mildly elevated, where there seemed to be a beneficial effect to those with more normal EF, where there was no effect. So, this study sort of provided new information, very relevant to the whole field, I think. Dr. Greg Hundley: Very nice. Well, gentlemen, I want to turn back to you and ask each of you, first Kieran, and then Torbjørn. Kieran, what do you think is the next study that needs to be performed in, really, this sphere of research? Dr. Kieran Docherty: As Torbjørn has already alluded to, PARADISE-MI kind of... It fills the gap across the spectrum of heart failure. So in patients who are at high risk of heart failure immediately following myocardial infarction, that that group of patients were studied in PARADISE-MI. And there is an echocardiographic sub-study of PARADISE-MI, which we await the results for. And I think that will be very interesting, because our patient population was distinct from the group studied in PARADISE-MI, namely the fact that the median time from MI was 3.6 years. So, these patients were not in the throes of the neural humoral activation at the time of acute myocardial infarction and prior to the development of established my cardio scar and fibrosis. And so, it may be that the addition of a Neprilysin inhibitor to patients immediately following myocardial infarction may have some benefits, in terms of attenuating or preventing ventricular dilatation reduction and injection fraction that is observed. So I think we await the echocardiographic results of PARADISE-MI with great interest. Dr. Greg Hundley: Very good. And Torbjørn , do you have anything to add? Dr. Kieran Docherty: Yes. I found observations that actually, in terminal proBNP measurements, could potentially identify a higher-risk group that actually could benefit from the intervention. It was very interesting. So I think we always speak about precision medicine and cardiology, and I think this is sort of one avenue that we should pursue and see whether we use biomarkers like NT-proBNP to identify those patients who will benefit most from interventions like sacubitril Valsartan Dr. Greg Hundley: Excellent. Well, listeners, we've heard a really interesting discussion today. Another study investigating Neprilysin inhibition in combination with angiotensin receptor blockers, and basically highlighting that in patients with asymptomatic left ventricular dysfunction following several years after myocardial infarction, that treatment with sacubitril Valsartan did not have a significant reverse remodeling effect just compared with valsartan alone. Well, on behalf of Carolyn and myself, we want to thank Dr. Kieran Docherty and his submission here to circulation, and also our own associate editor, Dr. Torbjørn Omland. Dr. Greg Hundley: And for all of you, we wish you a great week, and we hope to catch you next week on The Run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. 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 visit ahajournals.org.  

贊助我們做更好的內容https://pay.firstory.me/user/ck4fgb04n698h0804wzdkaycj ▪貓咪最常見的心臟問題是什麼？ ▪肥厚性心肌病有好發品種嗎？ ▪貓咪的心臟病該如何去篩檢呢？ ▪proBNP跟心臟超音波該如何選擇？ ▪可怕的貓血栓是怎麼形成的？ ▪貓血栓目前治療上的共識。 貓咪很多疾病的初期症狀，都不太顯性，希望藉由這集能夠幫大家認識一下，貓咪心臟疾病這個無聲的殺手。 歡迎大家一起關心並表達自己的想法給我們！ Powered by Firstory Hosting

myths get busted - Jana Husemann ging der Frage nach, ob Zucker Kinder tatsächlich hyperaktiv macht. Ilja Karl quälte sich durch Statistik-Literatur und versucht, die Begriffe Sensitivität, Spezifität, negativer Vorhersagewert und positiver Vorhersagewert sowie Prävalenz zu klären und entzaubert dabei das nt-proBNP als wenig hilfreich. Thomas Kötter beleuchtet Sinn und Unsinn einer Früherkennungsuntersuchung auf das Prostata-Karzinom. Wir freuen uns auf die urologischen Stellungnahmen!

Vitals & Useful Links: Learn about one important cause of lower extremity edema (see spoilers below if you want to know which one) Podcast: BNP for Diagnosis of Acute CHF - EM Cases Podcast, a great discussion of BNP in the diagnosis of CHF Clinical Reference: ACC Guidelines for Management of Heart Failure Time to learn about some puffy legs! This week Kyle (MS4) leads Arman (MS4) and Abby (MS4) through a case he had of a 56-year old male with a swollen legs. How would approach this case? As always, we learn a couple very important points about one etiology of lower extremity edema. You can check out a great discussion about the use of BNP in diagnosing CHF on the EM Cases Podcast, and here's a great reference for headaches from ACC's guidelines on CHF management. If you have any questions, concerns, or comments, please email us at emjccast@gmail.com *EPISODE SPOILERS BELOW* Here's the article we presented today Daniels, L. B., Clopton, P., Bhalla, V., Krishnaswamy, P., Nowak, R. M., McCord, J., ... & Abraham, W. T. (2006). How obesity affects the cut-points for B-type natriuretic peptide in the diagnosis of acute heart failure: results from the Breathing Not Properly Multinational Study. American heart journal, 151(5), 999-1005. Here's the ACC's Guideline on CHF Management Yancy, C. W., Jessup, M., Bozkurt, B., Butler, J., Casey, D. E., Colvin, M. M., ... & Hollenberg, S. M. (2017). 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Journal of the American College of Cardiology, 70(6), 776-803. How Salt Affects BNP Levels Morten Damgaard, Jens Peter Goetze, Peter Norsk, Niels Gadsbøll, Altered sodium intake affects plasma concentrations of BNP but not proBNP in healthy individuals and patients with compensated heart failure, European Heart Journal, Volume 28, Issue 22, November 2007, Pages 2726–2731. We briefly mentioned Lasix dosing in CKD, here's an article describing various dosage considerations Oh, S. W., & Han, S. Y. (2015). Loop Diuretics in Clinical Practice. Electrolyte & blood pressure : E & BP, 13(1), 17–21. DISCLAIMER: The views/opinions expressed in this podcast are that of the hosts/guests and do not reflect their respective institutions. This is NOT a medical advice podcast, if you are having a medical emergency you should call 911 and get help. This is an educational podcast, and as such, sometimes we get things wrong - if you notice this, please email us at emjccast@gmail.com.

In Folge 11 präsentieren wir euch ein Interview mit Martin Fandler von den Nerdfallmedizinern zum Thema NIV. Dazu gibt es in unserer Laborreihe noch eine Zusammenfassung zum ProBNP von Marius.

Heart failure is a leading cause of morbidity and mortality worldwide with prevalence expected to increase over the next 20 years.  Early diagnosis and optimal management of heart failure are key to reducing its impact. Because B-type natriuretic peptide, or BNP, and amino terminal proBNP, or NT-proBNP, as well as their precursor proBNP, are secreted by the heart in direct proportion to the degree of cardiac dysfunction and clinical severity, measurement of these peptides is now mandated by authoritative international guidelines for the diagnosis and risk stratification of the disease.  However, circulating concentrations of both BNP and NT-proBNP are reduced by obesity, and this phenomenon is one of the key weaknesses of the diagnostic performance of the natriuretic peptides in heart failure. A paper appearing in the September 2019 issue of Clinical Chemistry shows that obesity is associated with decreased concentrations of proBNP that is not glycosylated at threonine at position 71 of the peptide.  Decreased proBNP substrate amenable to processing could partially explain the lower NT-proBNP and BNP concentrations measured in obese individuals, including those presenting with heart failure.  

Sacubitril/Valsartan, known as Entresto, is a new dual drug therapy that includes an angiotensin receptor inhibitor and is indicated to reduce the risk of cardiovascular death and hospitalization in patients with chronic heart failure.  Since its approval for the treatment of chronic heart failure with reduced injection fraction, a commonly raised question is whether treatment with this drug challenges the use of B-type natriuretic peptide, or BNP, testing compared to the N terminal proBNP assay because Sacubitril may interfere with BNP clearance. The clinical and analytical studies addressing this issue are limited, along with the fact the diversity of both BNP and NT-proBNP assays used in clinical laboratory practice have not been adequately evaluated in clinical trials or studies to provide an evidenced-based on final decision as to what assay or assays should be used or eliminated from use when a patient is on Entresto. In the September 2019 issue of Clinical Chemistry, a Q&A feature titled, “Role of BNP vs NT-proBNP Testing in the Age of New Drug Therapies” asked five experts with different roles in this field to discuss this issue. 

B-type natriuretic peptides, or BNP, and N-terminal proBNP, or NT-proBNP, are peptides produced in the heart in response to increased wall stretch and volume overload.  Their production and secretion increases in the heart with the progression of heart failure and they have emerged as useful heart failure biomarkers.  Since the discovery of BNPs in the 1980s, much effort has been made to precisely determine the BNP and NT-proBNP levels via immunoassays for reliable heart failure diagnostics. Entresto™ is a new heart failure therapy that includes sacubitril as one of its components.  Sacubitril is a specific inhibitor of neprilysin. This is a zinc-dependent metalloproteinase that cleaves various peptides including BNP.  In fact, augmentation of circulating BNP due to neprilysin inhibition is considered as a possible mechanism of Entresto’s positive effects.  A paper appearing in the October 2019 issue of Clinical Chemistry examines the circulating products of BNP proteolysis by neprilysin and how they might reflect impact on the metabolism of active BNP. 

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Gregory Hundley:       And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.                                                 Well, Carolyn, this week's feature is from Professor Carl Lindstrom from Helsinki University Hospital and the University of Helsinki and evaluates whether administration of simvastatin via nasogastric tube in brain-dead individuals prior to cardiac transplant donation improves transplant recipient cardiac-related outcomes. It is a randomized trial using an inexpensive therapy, and I look forward to that discussion with Professor Lindstrom. How about we grab a cup of coffee and start off our discussion today. Dr Carolyn Lam:                All right, so here goes. The first paper that I want to discuss really looks at the question, is DNA methylation related to incident coronary heart disease? Well, Dr Agha from Columbia University in New York and colleagues looked at this and profiled epigenome-wide blood leukocyte DNA methylation in 11,461 individuals from nine population-based cohorts in the United States and Europe using the Illumina Infinium 450K microarray and prospectively ascertained coronary heart disease events. Dr Gregory Hundley:       So Carolyn, what did they find? Dr Carolyn Lam:                Well, they found that differences in blood leukocyte DNA methylation at 52 cytosine phosphate guanine sites were associated with incident coronary heart disease or myocardial infarction with a false discovery rate of less than 0.05. Several of the differentially methylated loci mapped to genes related to calcium regulation and kidney function. Exploratory analyses with Mendelian randomization supported a causal effect of DNA methylation on incident coronary heart disease at loci in active regulatory regions with links to noncoding, RNAs and genes involved in cellular and tissue structural components.                                                 Very nice Caroline. So what's the summary for us clinically? Dr Gregory Hundley:       So, these findings really provide the first evidence that genomic regulation via epigenetic modifications in kidney function and calcium homeostasis related pathways may be involved in the development of coronary heart disease. The findings of epigenetic, loci related non-coding RNAs highlight pathways that have not immersed in genome-wide studies of coronary heart disease and therefore represent novel therapeutic targets, which thus far have not been explored. Dr Carolyn Lam:                Very good, Caroline. Well, I've got a basic paper that I want to present and it's from professor Xander Wehrens from the Baylor College of Medicine. And this study addresses factors that promote atrial fibrillation. The investigators found that reduced levels of protein phosphatase-1 regulatory subunit R3A in human atria are causally linked to abnormal calcium handling and atrial fibrillation pathogenesis.                                                 In the absence of protein phosphatase-1 regulatory subunit R3A reducing binding of PP1 catalytic subunit increases phosphorylation levels of the ryanodine receptor, R2 calcium release channel, and phospholamban. Complex zone, profiling, a technique that combines native gel electrophoresis with mass spectrometry to obtain the composition of multi protein assemblies revealed that PP1 R3A is part of a macro molecular protein complex containing the ryanodine calcium release channel and the circuit 2APLN calcium uptake transporter. Dr Gregory Hundley:       Wow. Complex zone profiling. That's so cool, but what does it all mean for us clinically, Greg? Dr Carolyn Lam:                Well reduced levels of PP1 regulatory subunit contribute to abnormal calcium release and re-uptake and atrial monocytes, thereby promoting atrial fibrillation pathogenesis. And thus normalizing levels of PP1R3A phosphatase sub unit may represent a novel therapeutic approach to manage atrial fibrillation. Dr Gregory Hundley:       That's so cool. I next have a preclinical paper which contributes really to the understanding of molecular basis of pathological myocardial remodeling in heart failure. And this is from co-corresponding authors, doctors, Jung, Liu, and Lin-Jung from Shanghai East Hospital Tongji University School of Medicine in China. And the paper really focused on Forkhead box transcription factor P1 or Foxp1 in endothelial cells. Dr Carolyn Lam:                So Foxp1 Carolyn, tell me a little bit more about that. Dr Gregory Hundley:       Is it good that you asked before I asked you. Forkhead box proteins P or Foxp are large modular transcription repressors that bind to DNA via their highly conserved Forkhead DNA binding domains. Fox p1 is highly expressed in vascular endothelial cells and it's essential for normal cardiac development.                                                 So, these authors found significantly down regulated Fox P1 expression in cardiac endothelial cells during cardiac remodeling induced by to angiotensin 2. Endothelial cell Fox P1 loss of function resulted in cardiac dysfunction following angiotensin 2 infusion and in the transverse aortic constriction model with severe cardiac fibrosis and mild adaptive cardiac hypertrophy.                                                 Whereas endothelial cell Foxp1 gain of function protected against pathological cardiac remodeling and improved cardiac dysfunction transforming growth factor beta 1 signals were identified as Foxp1 direct target genes in endothelial cells which mediated the pathological cardiac fibrosis through cardiac fibroblasts proliferation and myofibroblast formation and maladaptive cardiac hypertrophy through TGF beta 1 promoted endothelial one expression during pathological cardiac remodeling. Dr Carolyn Lam:                Wow. Carolyn, this was very sophisticated work. What do we take away from it clinically? Dr Gregory Hundley:       These data really identified endothelial Foxp1 mediated TGF beta 1 signal pathway involvement in the promotion of cardiac fibrosis and cardiac hypertrophy via TGF beta 1 induction of the endothelin one pathway. So targeted delivery of TGF beta 1 silencing RNA or small interfering RNA to inhibit endothelial cell specific TGF beta 1 for the improvement of pathological cardiac remodeling may actually represent a future novel therapeutic strategy in managing this maladaptive cardiac fibrosis and hypertrophy during progression of heart failure. Dr Carolyn Lam:                That was an excellent summary of a very technical but informative basic science paper. I'm going to shift gears a little bit and talk a little bit about a study relating to clopidogrel and aspirin from the point study.                                                 This study comes from Claiborne Johnston at the Dell Medical School and University of Texas. And in patients with acute minor ischemic stroke or high risk transient ischemic attack enrolled in the point trial. The combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage compared to aspirin alone. This current paper is a secondary analysis of Point and involves 4,881 subjects in which the investigators assess the time course for benefit and risk from the combination of clopidogrel and aspirin.                                                 The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction or ischemic vascular death, and the primary safety outcome was major hemorrhage. Risks and benefits were estimated for delayed times of treatment initiation using left truncated models. Dr Gregory Hundley:       So, what did the study show Greg? Dr Carolyn Lam:                Well through 90 days, the rate of major ischemic events was initially high, then decreased markedly while the rate of major hemorrhage remained low but stayed constant throughout the study. Using a model based approach the optimal change point for major ischemic events was 21 days with a hazard ratio of 0.65 for clopidogrel aspirin versus aspirin at a P value of 0.0015 compared to later at 22 to 90 days. Where that hazard ratio was 1.38 and the P value only 0.24.                                                 And the models showed benefits of clopidogrel aspirin for treatment delayed as long as three days after symptom onset. So Carolyn, the authors conclude that the benefit of clopidogrel aspirin occurs predominantly within the first 21 days and outweighs the low but ongoing risk of major hemorrhage. When considered with the results of the CHANCE study, a similar trial treating with clopidogrel aspirin for 21 days and showing no increase in major hemorrhage. The combined results suggest limiting clopidogrel aspirin use to 21 days may maximize benefit and reduce risk after TIA or minor ischemic stroke. Very practical paper. Dr Gregory Hundley:       Indeed. Thanks Greg. That was nice. Dr Carolyn Lam:                You bet. Dr Gregory Hundley:       Welcome everyone to our podcast and we're very pleased today to have Dr Antti Nykänen from Helsinki University in Finland as well as an associate editor, Justin Ezekowitz from Edmonton, Canada to discuss a very interesting randomized clinical trial related to the administration of simvastatin in those that are donors for heart transplantation and looking at subsequent outcomes in the patients that received the transplants. Antti, we're very excited for you to bring this to circulation. This particular paper and I wonder if you might outline for us what were your hypotheses that you are trying to test and what was your overall study design. Dr Antti Nykänen:            These things are routinely admitted to heart transplant recipients starting one to two days after transplantation. As previous clinical studies show that recipient that treatment has beneficial long-term effects on mortality and cardiac allograft vasculopathy. So in this clinical study, we basically tried to answer the question whether having the statin effect on the board even earlier before the transplant procurement by giving statins to the organ donor, if that would protect the transplanted hearts.                                                 And this question was based potential rapid vascular and cardioprotective effects of statin and when our previous experimental study showing that treating the organ donor with statins will decreases vascular profusion injury in a heart transplant model. So basically we went on the test donor simvastatin clinically and randomize brain dead heart transplant donors either to a control group or to receive a signal 80 milligram dose of simvastatin before organ procurement. Dr Gregory Hundley:       I'm imagining that you would administer the simvastatin through either an intravenous mechanism or perhaps an NG tube, something like that. Maybe tell us a little bit about how you accomplish this and then what were your study results? Dr Antti Nykänen:            So, the simvastatin was administered to the donor via a nasogastric tube so there is no intravenous simvastatin formulation available. It needs to be absorbed and then activated through the liver so that can form. So, what we did in our previous experimental study was that we included a few clinical human brain-dead donors and basically investigated whether by giving simvastatin through the nasogastric tube would be metabolized and if you could detect that in in the donor plasma.                                                 And that was actually the case. So in a few hours we saw up-regulated levels of simvastatin and also the active form in the donor or so basically showing off that treatment in a clinical brain dead donor of situation would be feasible. So we went on to use that method, clinical study and basically our primary outcome was plasma levels of cardiac injury biomarkers after transplantation.                                                 And interestingly by treating the donor with simvastatin decreased and recipients for troponin INT levels six hours after transplant's profusion. Therefore, it seems that organ donor’s statin treatment reduces biomarkers of myocardial injury after transplantation in a clinical setting. Dr Gregory Hundley:       And did you examine any other functional measures of these patients? For example, ejection fraction by echo or anything, or was it primarily a biomarker study? That's the first question. Second question. Do you have any other information on other organs that also may have been donated? Would the statin have impacted, for example, liver transplantation? Dr Antti Nykänen:            That's a good question. So we did follow up cardiac function and the routine and serial measurements with the echocardiographic and we did not find any changes in the left ventricle. It took some traction after transplantation.                                                 We did however find the decrease in proBNP levels into recipients. And that was maybe then at one week after transplantation and then it's leveled out after that.                                                 And then regarding the next question about other transplanted organs. So once he was in a multi organ donor situation, so the same donor could have donated kidneys or livers, lungs, pancreas. So we did a follow up of the close recipients also. And I can say that there was no adverse effects, no decline in the survival or primary function of the transplanted organs. And interestingly we did find in the liver recipient that if the recipient received the liver from a donor simvastatin treated the liver function tests were better at day seven post-transplant. Dr Gregory Hundley:       Very interesting. And then lastly, just another outcome related question. Sometimes I know these patients undergo assessments for rejection by biopsy. Any information that you can share with us on outcomes related to biopsies. Dr Antti Nykänen:            We took routine biopsies, myocardial biopsies from the recipients and we did not find any significant differences in the biopsy program rejections either at 30 days or one year after transplantation. We did also monitor, we checked some treatments, so during the first 30 days there was significant decrease in the amount of rejection treatments for hemodynamically rejects it about not for the first year. Dr Carolyn Lam:                Wow. Just fabulous results. Thank you so much Antti. So Justin, I wanted to turn the conversation over toward you. Tell us about post-transplant management of these patients and then how do you see these study results integrating into our current standards of care. Dr Justin Ezekowitz:        Thanks Greg and Dr Nykänen and thanks for also letting us look at your work, which is terrific and extremely hard to do from the translation of your original 2011 circulation publication in animals and moving forward into the current publication years later. And thinking forward into the next few years of how we translate this into practice so that the current management after transplantation obviously involve multiple anti-rejection medications and many activities around detecting rejection is one of the key ways in which patients are managed other than their hemodynamics and other things that happen early.                                                 What I was interested in is the generation of the idea where the simvastatin will really affect the clinical outcomes on the recipient and thinking that into the practice environment is, it's a very simple intervention to think about that would be easily applicable in, I think, most hospitals that do transplantation as either the recipient or the donor.                                                 And Dr Nykänen, when you think about translating this into practice over either Europe or in Finland, I don't sense that this is going to be very difficult. Statins are well tolerated. The cardiology and other communities are very familiar with using a statin. But do you anticipate any barriers to translating this into practice as I think the guidelines may pick this up as something of interest. Dr Antti Nykänen:            Yes, I think we can show that it's feasible and we did a result on the biomarkers, so indicating that the damage the heart undergoes during the transplantation was smaller after donor statin treatment, so it is feasible, it's very cheap and it generally has a good safety profile. The timeframe for the treatment also feeds into the window of creating a brain dead organ donor. So in that sense it would be applicable in a donor treatment situation. Dr Justin Ezekowitz:        Right. And so I think this is the key point is even though it's a smaller trial in terms of the cardiology thinks about its trials. This is an area that doesn't have a lot of clinical trials were randomized clinical trials and so any evidence of benefit with a known, generally considered safe medication such as a statin, you would think that we should be able to broadly apply pretty quickly even on what are often not hard outcomes that are softer outcomes.                                                 Because the benefit to risk ratio is generally favorable here. Dr Nykänen, my only other question to you is to think about the team getting this done must have been incredibly hard, but do you think there is a need for a larger trial to test this hypothesis on clinical outcomes or do you think this is really as far as you can go in the transplant world for an RCT. Dr Antti Nykänen:            So, it's been a long road from artery to single center clinical trial, which took time, so the patient numbers are fairly small in our study. We had 42 in the control group on 42 in the treatment group. I agree the risk benefit ratio is probably beneficial. But for sure it would be very nice to see larger studies that would look at the biomarker effects, but also would look at the other clinical end points. Dr Justin Ezekowitz:        Right, and that's a great point. It's only 84 patients, but a continued study of the area's important while perhaps implementation studies could go on to take what you found in both an animal translation into humans in a single center RCT and now translation into a larger population of recipients and their donors. I think that's probably the key next step in the transplantation world which has a tougher time getting larger number of patients into clinical trials for a variety of reasons.                                                 So, congratulations to you and your team in getting this one to the point where we could probably apply this in a reasonable way with reasonable safety and an expected benefit to a broader group of patients. Dr Gregory Hundley:       Well this has been a fascinating discussion, Antti as well as Justin and what a relatively simple, clever idea that could have profound outcomes for this transplant population. We certainly want to thank you Antti for bringing this to circulation and sharing it with our readership. Are there any few last words you'd like to share with us before we close today? Dr Antti Nykänen:            Very nice to see how things evolve after this. We will for sure try to look more closely at the mechanisms and follow up the patient population for a long term follow up. And I hope this will stimulate some other experiments in the field. Dr Gregory Hundley:       Justin, any parting comments from the editorial team? Dr Justin Ezekowitz:        This is a great example of a full clinical trial that is mechanistic, but also has MR outcomes, and I just want to congratulate the authors on providing a very full picture of all the pieces that it takes to do in a clinical trial environment. Plus also collecting genetic and other biomarker material and imaging material. So, my compliments to the authors both to yourself, Dr Nykänen, but also the team that you assembled over the last six or eight years of doing this project, which we know was a huge task and my congratulations to you and your team. Dr Gregory Hundley:       We want to thank Dr Nykänen and his team from Finland and Justin Ezekowitz. We look forward to chatting with you next week. Dr Carolyn Lam:                This program is copyright American Heart Association, 2019

2-Minute Tip — Remove Filler Words   Filler or crutch words are the bane of many a speaker’s existence. The ums, ahs, likes, verys, you knows, and more clutter up our talks and conversation so much we don’t even notice them. They waste time, annoy the audience and distract from your message. So get rid of them.   Easier said than done.   One technique is to have a friend or colleague listen to you practice your talk and ring a bell every time they hear a filler word. Once you actually know you are using them in real time, it becomes easier to eliminate them and relish the power of silence   Post Tip Discussion — Meet John Rohe   One of the terms you hear in the training field (and likely other education related fields as well) is the “sage on the stage.”   In describes the lecture format in many education contexts. The wise experts stands on the stage at the front of the room and imparts knowledge on to the lucky audience members. It’s one way communication, and it has its place, but can have a certain amount of arrogance associated with it.   Bio   John Rohe is a speaker who eschews the lectern and the stage. He a speaker and trainer in both the commercial and ecclesiastical fields, and one of themes that comes through in the episode is the importance of humility with your audience.   John’s experience ranges from start-ups to established multi-billion dollar enterprises. John launched the cardiac marker proBNP for Roche Diagnostics and the first personalized health (test and drug) for osteoarthritis for Roche Pharma, Roche Diagnostics and GSK.   ​ He also internationalized sales for RPS, revived sales of Procalcitonin for Thermo Fisher, grew Alere’s PT/INR home testing from $9 million to $25 million in 1 year and boosted equipment service contracts for BD.   ​ John has taken products from R&D through FDA clearance and achieved CMS and other third-party reimbursement. He has implemented user friendly CRMs and automated quoting systems, and he integrated marketing collateral with sales force access. He has also been responsible for developing and implementing automated quoting and contracting systems.     John’ Speaker Evaluation Checklist   Are they using filler words? Do they appear to be knowledgeable about the material? Are they speaking to the audience? Are they looking down at their notes? Are they reading slides to me? Are they moving around? Are they actively engaged with the audience?   Kirkpatrick Levels of Training Evaluation   How do the learners feel about their training experience? How effectively did the learners acquire new skills or knowledge? How effectively did the learners apply what they learned in training? How effectively did the training ultimately meet its goals for the organization?   You can read more about the Kirkpatrick framework here. It’s a fascinating mental exercise.   Links   Hycap Consulting http://hycapconsulting.org John’s Email John.rohe@hycap.org John on LinkedIn https://www.linkedin.com/in/johnrohe1/ John on Twitter https://twitter.com/johnrohe Kirkpatrick Model https://www.kirkpatrickpartners.com/Our-Philosophy/The-Kirkpatrick-Model Servant  Leadership with Lyle Tard http://2MinuteTalkTips.com/ServantLeader Caring and Connection with Richard Kauffman http://2MinuteTalkTips.com/Richard   Call To Action Check out the work John is doing at Hycap.org Share this episode with another speaker or trainer by giving the link http://2MinuteTalkTips.com/JohnRohe Don’t get best…get better   2-Minute Talk Tips is the public speaking podcast that help you become a more effective speaker in as little as 2 minutes a 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. Dr Greg Hundley:             And I'm Greg Hundley, Associate Editor of Circulation and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article is going to focus on trastuzumab-induced cardiac dysfunction in breast cancer patients. We will discuss with Stanford investigators their use of pluripotent stem cells that are differentiated to cardiomyocytes and subsequently exposed to toxins to determine an individual's susceptibility to cardio-toxicity from cancer treatment. But before we get to that, Carolyn, do you have a paper that you'd like to discuss? Dr Carolyn Lam:                Well, the first paper deals with cardiac biomarkers and asks the questions, can these biomarkers be useful for the diagnosis and risk stratification of syncope?" Now, this paper is from Dr Mueller and colleagues from University of Hospital Basel in Switzerland. They evaluated the diagnostic and prognostic accuracy of BNP, NT-proBNP, high-sensitivity cardiac troponin T, and high-sensitivity cardiac troponin I concentrations, alone and against the ones of clinical assessments in more than 1,500 patients presented with syncope to the emergency department in a prospective, diagnostic multi-center study. Now, cardiac syncope was adjudicated in 234 or 15% of patients. What they found was that the diagnostic accuracy from cardiac syncope, as quantified by the area under curve, was 0.77 to 0.78 for all four biomarkers. That was superior to that of the syncope-specific diagnostic score, EGSYS.                                                 Now, combining the four biomarkers further improved diagnostic accuracy to an area under curve of 0.81. Furthermore, using the four biomarkers at cutoffs achieved predefined thresholds for sensitivity and specificity and allowed rule-in or rule-out of 30% of all patients. Finally, the biomarkers predicted adverse cardiac outcomes with moderate to good prognostic accuracy and better than some of the existing syncope risk-prediction scores. Dr Greg Hundley:             Very interesting, Carolyn. Do you think we can now use this clinically? Should we be drawing these biomarkers on patients with syncope? Dr Carolyn Lam:                These results really do imply that these biomarkers look like useful tools for the early rule-out and/or rule-in of cardiac syncope in the emergency department. After all, these biomarkers are readily available, inexpensive, and results of this study suggest that they have potential to simplify diagnosis and to risk stratify in challenging presentations. However, before embracing the concept of ordering cardiac biomarkers routinely for syncope presentation, we really need to read the editorial by Dr Sandhu and Sheldon, in which important perspectives are presented, such as considerations of the certainty of the diagnosis of syncope, the usefulness of the comparative scores, the timing of testing, the potential unintended adverse consequences of testing. These editorialists concluded that, although promising, further work is needed to determine how the use of cardiac biomarkers should be incorporated into a risk-stratification algorithm. Dr Greg Hundley:             Wow, Carolyn. It sounds like we'd get a lot out of that particular editorial. I'm going to switch over and talk about NT-proBNP in patients with pulmonary hypertension. This is a paper from Dr Kelly Chin from UT Southwestern, and the study evaluated the utility of end terminal pro BNP level thresholds and assessing prognosis in pulmonary hypotension using the GRIPHON study. So GRIPHON is a global double blind, randomized placebo control event driven phase 3 study which assesses the safety and efficacy or a Prostacyclin agonist that promotes pulmonary arterial vasodilation.                                                 They performed the study in patients that were 18 to 75 years old with a diagnosis of idiopathic pulmonary hypertension, heritable hypertension or pulmonary hypertension associated with connective tissue disease, repaired congenital systemic pulmonary shunts, HIV infection, drug use or toxin exposure; and the diagnosis of pulmonary hypertension was confirmed by right heart catheterization and by a reduced 6-minute walk distance of 50 to 450 meters.                                                 Eligible patients were permitted to take their other therapies including Endothelin receptor agonists and phosphodiesterase type-5 inhibitors. The patients were categorized into low, medium and high in terminal BNP level subgroups according to two thresholds. First, by just the tertiles within the study overall and the secondly by the ESC guideline cutoff ranges. Dr Carolyn Lam:                Nice, so what did they find Greg? Dr Greg Hundley:             Well first of all both thresholds either the tertile one of the ESC in follow-up NT-proBNP categories were highly prognostic for future morbidity and mortality. And their time dependent analysis the risk of experience a morbidity or mortality even was 92% and 83% lower in the treated patients with a low and medium NT Pro BNP level. And 90% and 56% lower in placebo treated patients with low and medium NT-proBNP levels. So both, whether you're taking that drug of not, the NT-proBNP levels were prognostically valuable. More pronounced treatment benefit of selexipag was seen in the medium and low proBNP groups. There was a positive value for the interaction term. Dr Carolyn Lam:                Wow, sounds like two really important findings. Dr Greg Hundley:             Yes, exactly Carolyn. So first, NT-proBNP levels are highly prognostic for pulmonary arterial hypertension progression. And having NT-proBNP in the low range, by improving to or maintaining low NT-proBNP levels is a clinically relevant treatment goal for those with pulmonary artery hypertension. And of course as we described this was a very diverse well represented group of many different types of patients with pulmonary hypertension. Then second, while selexipag the study drug was beneficial in all NT-proBNP categories, the treatment effect was greater in those with low and medium categories versus the very high. Suggesting that earlier selexipag treatment may be of greater benefit. But very interesting biomarker study that follows up on yours Carolyn. Dr Carolyn Lam:                Indeed! Dr Greg Hundley:             Carolyn what about your next paper? Dr Carolyn Lam:                Well I want to switch tracks now and talk about iron. And the question is, how does intravenous iron repletion augment exercise capacity in chronic heart failure? Even if hemoglobin doesn't change. So, first some background right, now, besides hemoglobin it's important to recognize that iron is an obligate component of the mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine. So dynamic phosphorous magnetic resonance spectroscopy is a noninvasive tool that can really quantify the in vivo muscle energetics by measuring the kinetics of phosphocreatine recovery after exertion. These authors use this technique, and these are Dr Okonko from King's College, London British Heart Foundation sender of excellence, school of cardiovascular medicine and sciences. The James Black Center in London and colleagues. And what they did was they tested the hypothesis that intravenous iron repletion in chronic heart failure would enhance skeletal muscle energetics as reflected by a shorter phosphocreatine recovery halftime on phosphorous magnetic resonance spectroscopy imagining of the skeletal muscles. And they looked at 40 patients with chronic heart failure with reduced deduction and iron deficiency in a randomized double blind placebo controlled ferric iron and heart failure trial. Dr Greg Hundley:             So, what did they find? Dr Carolyn Lam:                They found that a single total dose infusion of intravenous iron repleted iron stores and augmented skeletal muscle energetics at 2 weeks post infusion. Enhancements in the skeletal muscle energetics which implied better mitochondrial function were accompanies by improved symptoms despite no change in hemoglobin at 2 weeks. So, this trial really provides mechanistic support for iron repletion in patients with chronic heart failure and its very importantly discussed in an editorial by Peter van der Meer, Haye van der Wal, and Vojtech Melenovsky. And I really suggest that everybody read that. Dr Greg Hundley:             Well, I'm going to talk a little bit about dietary omega-6 fatty acids and the incidence of cardiovascular disease and mortality. And this paper is from Matti Marklund from the Georgia Institute for Global Health and the University of New South Wales in Sydney, Australia. The study focuses on linoleic acid which is an omega-6 polyunsaturated fatty acid that we get from pumpkin seeds, flax seeds, walnuts, soybean oil, canola oil and grapeseed. It's been associated with a decrease in cardiovascular risk, but others have worried about an effect of consumption mainly the downstream production of arachidonic acid which can give rise to eicosanoids that are both pro inflammatory and pro thrombotic.                                                 And it's interesting Carolyn, several organizations suggest replacing saturated fat and carbohydrates with linoleic acid. So this study was really performed to address whether consumption of linoleic acid is associated with future cardiovascular events. In the study, investigators measured linoleic acid as well as arachidonic acid levels and from a global consortium across 30 perspective observational studies from 13 countries they performed multi variable adjusted associations of circulating an adipose tissue linoleic and arachidonic acid biomarkers with incident total cardiovascular disease and subtypes of cardiovascular disease including, coronary heart disease, ischemic stroke and cardiovascular mortality and this was all done as pre-specified analytic plan. Dr Carolyn Lam:                Wow, so what did they find? Dr Greg Hundley:             Well did I put you to sleep discussing all of that? Dr Carolyn Lam:                No! You have to tell me what they found. I'm seriously so interested in this topic because being vegetarian I actually get my source of omega fatty acids exactly from these sources. Dr Greg Hundley:             Okay, so Carolyn, higher levels of linoleic acid were associated with lower risk of total cardiovascular disease, ischemic stroke, cardiovascular mortality. While arachidonic acid was not associated with cardiovascular risks. And so, the clinical implications of the results support the potential benefits of main dietary omega- 6 fatty acid. That is linoleic acid for cardiovascular disease prevention. Now, while the trial is not randomized so we don't have definitive answers, the results do not support any theorized cardiovascular harms of consuming omega-6 fatty acids. And there is an excellent review on polyunsaturated versus saturated fat intake by Thomas Sanders from King's College, London as an editorial to this piece. So Carolyn I think we're safe right now in consuming linoleic acid. So how about a transition to our featured article and learn a little bit more about trastuzumab-induced cardiac dysfunction. Dr Carolyn Lam:                Absolutely! Dr Greg Hundley:             Great.                                                 Welcome everybody, we have a fantastic paper to discuss. We're going to review human induced pluripotent stem cell derived cardiomyocytes and how they can be used to identify individuals at risk of trastuzumab-induced cardiac dysfunction after treatment for breast cancer. We have today Nazish Sayed and also Dr Joseph Wu, both from Stanford University in California.                                                 Welcome gentlemen. Dr Joseph Wu:                   Thank you for inviting us. Dr Nazish Sayed:              Thank you. Dr Greg Hundley:             Nazish tell us a little bit about what are these human induced pluripotent stem cells and then also describe your experiment and what were your results? Dr Nazish Sayed:              So, induced pluripotent stem cells is about 10 years ago I knew technology where you can actually turn back the clock by you taking human fiber blast or blood cells and then you can test full reprogramming factors and turn back differentiated cells to pluripotent stem cells will mimic like catalytic stem cells. The catalytics include self-renewal, pluripotency and the most important that they can be differentiated to any cell type in the body. For example, cardiomyocytes or endothelial cells the neuron and kind of mimic these differentiated cells from the same individual from where the IPSCs were derived from.                                                 So, what we did in our study is we used this platform to derive these pluripotent stem cells from patients and then differentiated them into a cardiomyocyte to understand what would these human cardiomyocytes behave in a dish when treated with a Herceptin or trastuzumab and then kind of determine the underlying mechanism for this cardiac dysfunction. It seemed really difficult to model trastuzumab and use cardiac dysfunction as a heart which is the receptor for the trastuzumab is expressed only in humans.                                                 People have usually relied on animal model and for the first time what we did is we used these ideas of cardiomyocytes to model this dysfunction in a dish. Our results were pretty straightforward. We found that the IPSCs cardiomyocytes when treated with the chemotherapy agent showed cardiac dysfunction in the case of decrease contractility. The contraction velocity of these each individual cardiomyocytes is significantly reduced. More with this was also confirmed by having impaired calcium cycling which is very important for the contractility of these cardiomyocytes.                                                 But I think the most important thing which we determined from the study is that individuals who are treated with trastuzumab have a metabolic impairment in these cardiomyocytes which is convenient but however have a severe impact on this contractility and calcium handling in these cardiomyocytes. And that was one of the gist of these papers to figure out the metabolic impairment could be a target where we can improve this cardiac dysfunction in these patients. Dr Greg Hundley:             And so, after you discovered this, I noticed you also did some work with AMPK activators and perhaps would reverse some of the dysfunction. Could you describe a little bit what are AMPK activators and then how did they reverse the dysfunction that you observed? Dr Nazish Sayed:              In our study we characterized these IPS cardiomyocytes from these individuals and then we ran a whole sequencing of them after treatment where trastuzumab to see which of the pathways which could be down regulated or dysfunction when compared to the control patients which are not treated with trastuzumab. And one of the most significant pathways which we found was in PK pathways which was down regulated in the trastuzumab treated IPSC cardiomyocytes. So knowing that the AMPK activators are used for metabolic diseases, for example being diabetes and metabolic dysfunction, we thought that this same thing could be used in a dish where we can take these AMPK activators and simultaneously cotreat cardiomyocytes with Herceptin or trastuzumab to see if we can rescue the phenotype and indeed you can see in our paper we used 4 different AMPK activators with metformin which is a commonly used diabetic drug. Showing the best rescue for that trastuzumab induced cardiac dysfunction. Dr Greg Hundley:             Very intriguing because it looks like you've been able to harvest cells from individuals and then pre-treat them, understand the mechanism of dysfunction, understand who's at risk of dysfunction and then offer therapeutic interventions to perhaps prevent that dysfunction in this patient population. Joe, turning to you now, this is really revolutionary technology it seems to me. Can you describe how long does this process take? Is this something that we see might come into clinical medicine soon? Dr Joseph Wu:                   We're really excited about this technology that Nazish has described. I think as you know we've been working on this platform for the past 10+ years. In terms of the timeline, right now it takes us about a month to generate the induced pluripotent stem cells. It takes us another month to expand, propagate the IP itself. It takes us another month to generate the IPS cardiomyocytes. And it will take us probably another month to do all the phenotypic characterization in terms of using these IPS cardiomyocytes to expose them to various chemotherapy drugs and see how the chemotherapy drugs have an effect on these cardiomyocytes.                                                 So, I would say the total timeline is 12 months at this moment. Is it possible that the timeline could be crunched, could be shrunk over time? Yes that's possible, I think the technology is improving month by month, week by week because there are many different labs trying to work on this platform trying to improve the whole process. But right now one of the limitations that as you pointed out is this 4 month time period. And also the cost that's associated with this. But we're hopeful that over time that both the time, the costs can go down so that we can offer this type of platform to help patients diagnosed with cancer, find out what kind of chemotherapy is safe to use, what kind of chemotherapy is not safe to use. Dr Greg Hundley:             So, we're working towards clinical applications but at this point in time it looks like a fantastic platform for understanding, diagnoses and understanding pathways that for patients particularly as they are treated for cancer will experience cardiovascular dysfunction. So, switching a little bit and asking a related question. Patients that receive trastuzumab often also receive doxorubicin. Especially the breast cancer patients. If you looked at this technology trying to understand, and certainly those more at risk for trastuzumab associated left ventricular dysfunction, are the patients that previously received doxorubicin. Have you and your group looked at patients that have also received doxorubicin and then went on to receive trastuzumab relative to those that received trastuzumab alone? Dr Joseph Wu:                   I think for these two populations for this particular study, we tried to keep them clean. Meaning that we're looking mostly for trastuzumab treated patients, otherwise it's hard for us to piece out whether the toxicity was due to one medication or the other medication. But what you are asking is very important because as you pointed out many of these patients received both and I think for future studies we should be able to model both medications, meaning that take some IPS cardiomyocytes treated with doxorubicin, treated with Herceptin by itself and treated with both the medications.                                                 In previous studies we have studied using IPS cardiomyocytes the effects of doxorubicin induced cardiac toxicity. In just the assessment, doxorubicin is a very common effective chemotherapy for breast cancer medications and just like Herceptin, the clinicians struggled with the issue, as we cannot predict which patient will develop toxicity. And then granted the doxorubicin induced toxicity has a slight different mechanism compared to perception induced mild cardiac dysfunction that this Nazish had mentioned about. But these are kind of the studies that we're very excited because now for the first time we have a way to model this. Otherwise they alternative would be not possible, for example it would not be possible for us to biopsy breast cancer patients woman's heart to study the cells.                                                 Especially in the case of perception. The receptor that's being studied is not present in animal model cells. For example not present in mouse cardiomyocytes and therefore it would be very difficult to understand the mechanism and this is the reason why the patient specific and disease specific IPS cardiomyocytes become so useful. Dr Greg Hundley:             Do you find another emerging therapy in this entire realm is the immunotherapies? Do you think this technology will be applied to determine susceptibility to immune mediated toxicity? Dr Joseph Wu:                   This is a very good question as well Greg. We've been thinking about studying that and as you know, it's a more complicated system because it involves patients’ immune response, the myocardial, to inflammatory infiltrates that happens. So we have a couple projects going on. One is to study direct effect of the immunotherapy on the cardiomyocytes and then the second angle is to take patients who are in full myocarditis and collect their patients urine samples, blood samples and to see if we could expose these IPS cardiomyocytes to the patients urine samples to see what is the effect. For these IPS cardiomyocytes for future studies we're also trying to make it more complicated by generating not just the cardiomyocytes by itself, but generating what we call engineered heart tissues. In which it's a chunk of human heart muscles that would have the patients cardiomyocytes, patients fibroblast, patients endothelial cells and expose them to the patients serum.                                                 But that kind of study would take much longer period of time because the number of people who have these types of immunotherapy induced myocarditis it's relatively low compared to patients who have Herceptin or doxorubicin induced cardio toxicity. This is also part of the reason why we're very much interested in collaborating with big centers throughout the country like York Center to see if we could understand this process better as a team. Dr Greg Hundley:             Excellent. I want to thank both of you for this really elegant discussion and perfect work moving forward. In summary, you've illustrated an ability to withdraw human pluripotent stem cells, differentiate them to cardiomyocytes and then perform tests on them to forecast susceptibility to various treatments used commonly for women with breast cancer. And in this study identifying mechanisms for trastuzumab toxicity. And then perhaps therapeutic interventions using again human cells which has a marked leap as you've identified over doing mouse studies, particularly for studying trastuzumab when the receptors the HER2 receptors in mirroring models differ substantially to those in human subjects. Dr Joseph Wu:                   Thank you Greg. And we want to also express our thanks to our collaborators, our colleagues who contributed to the study and most importantly to the patients who helped us with these studies. Dr Greg Hundley:             I want to thank both Nazish and Dr Wu from Stanford and Carolyn and I wish you the best for the coming week and we look forward to speaking with you again next week. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

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. Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.                                                 In today's episode, we are discussing very important new data regarding stroke risk stratification in patients with atrial fibrillation. First though, let me give you the highlights of this week's journal.                                                 The first paper provides mechanistic evidence that endothelial-derived microparticles may play a key role in the development of endothelial dysfunction following acute coronary syndrome. In this paper from first author, Dr. Abbas, co-corresponding authors, Dr. Toti and Morel from the University of Strasbourg in France, authors expose core sign coronary artery endothelial cells to microparticles shed from senescent cells, or circulating microparticles from patients with acute coronary syndrome.                                                 They showed that exposure to these microparticles induced increase senescence-associated beta-galactosidase activity, oxidative stress, and early phosphorylation of MAP kinases and AKT, and upregulation of p53, p21 and p16. Depletion of endothelial-derived microparticles from acute coronary syndrome patients reduced the induction of senescence.                                                 On the other hand, pro-senescent microparticles promoted endothelial cell thrombogenicity. These microparticles exhibited angiotensin-converting enzyme activity and upregulated AT1 receptors and ACE in endothelial cells. Losartan and AT1 receptor antagonist and inhibitors of either MAT kinases or PI3-kinase prevented the microparticle-induced endothelial senescence.                                                  In summary, these findings indicate that endothelial-derived microparticles from acute coronary syndrome patients induce premature endothelial senescence and thrombogenicity suggesting that targeting endothil-derived microparticles and their bioactivity may be a promising therapeutic strategy to limit the development of endothelial dysfunction post-acute coronary syndrome.                                                 The next study is the first large and prospective study showing that NT-proBNP is associated with cardiovascular events in patients with adult congenital heart disease independent of multiple clinical and echocardiographic variables.                                                 This is a study from first author, Dr. Bekan; and corresponding author, Dr. Roos-Hesselink and colleagues from the Erasmus University Medical Center in Rotterdam, the Netherlands. The author studied 595 clinically stable patients with adult congenital heart disease who attended the outpatient clinic between 2011 and 2013.                                                 All patients underwent clinical assessment, electrocardiography, echocardiography and biomarker measurement, including NT-proBNP, high-sensitivity troponin T and growth differentiation factor 15. Patients were prospectively followed over a median of 42 months for the occurrence of cardiovascular events including death, heart failure, hospitalization, arrhythmia, thromboembolic events and reintervention.                                                 They found that of the three evaluated biomarkers, NT-proBNP was most strongly associated with cardiovascular events. Importantly, patients with a low-risk of death and heart failure could be accurately identified with a high negative predictive value.                                                 In patients with elevated NT-proBNP, elevations of high sensitivity troponin T and growth differentiation factor 15 identified those patients at highest risk of cardiovascular events.                                                 In summary, these biomarkers may play an important role in the monitoring and management of patients with adult congenital heart disease.                                                 The next study describes heart failure stages among older adults in the community. Dr. Shah and colleagues from the Brigham and Women's Hospital in Boston Massachusets classified more than 6,000 participants in the atherosclerosis risk and community study into heart failure stages. These were stage A; asymptomatic individuals with heart failure risk factors, but no cardiac structural or functional abnormalities. Stage B; asymptomatic individuals with structural abnormalities such as left ventricle hypertrophy, dilation, dysfunction, or valve disease. Stage C1; clinical heart failure without prior hospitalization. Stage C2; clinical heart failure with prior hospitalization.                                                 They found that only 5% of examined participants were free of heart failure risk factors or structural heart disease. 52% were categorized as stage A, 30% stage B, 7% stage C1, and 6% stage C2. Worst heart failure stage was associated with a greater risk of incident heart failure hospitalization or death at a median follow up of 608 days.                                                 Left ventricular ejection fraction was preserved in 77% of stage C1 and 65% of stage C2 respectively. In corporation of longitudinal strain measurements and diastolic dysfunction into the stage B definition, reclassified 14% of the sample from stage A to B.                                                 Abnormal LV structure, systolic function, whether based on ejection fraction of longitudinal strain, and diastolic dysfunction, were each independently and additively associated with the risk of incident heart failure hospitalization or death in stage A and B participants.                                                 The authors concluded that the majority of older adults in the community are at risk of heart failure, appreciably more compared to previous reports in younger community-based samples. The study also highlighted the burden of heart failure with preserved ejection fraction in the elderly and provided evidence that left ventricular diastolic function and longitudinal strain provide incremental prognostic value beyond conventional measures of LV structure and ejection fraction in identifying patient at risk of heart failure hospitalization or death.                                                 The next study sheds light on the association of the LPA gene, ethnicity and cardiovascular events. First author, Dr. Lee; corresponding author Dr. Tsimikas and colleagues from University of California San Diego studied 1,792 black, 1,030 white, and 597 Hispanic subjects all enrolled in the Dallas Heart Study. They measured LPA snips, apolipoprotein A isoforms, LP(a) and oxidized phospholipids on apolipoprotein B100.                                                 These individuals were also followed for a median of 9.5 years for major adverse cardiovascular events. The authors found that the prevalence of LPA snips and apolipoprotein A isoforms were very different across ethnic groups. LPA snips that were associated with elevated LP(a) in whites were associated with low LP(a) in Hispanics mainly due to differences in apoliproprotein A isoforms size.                                                 After multi-variable adjustment, LP(a) and oxidized phospholipids on apolipoprotein B were both predictors of major adverse cardiovascular events. Conversely, LPA snips and apolipoprotein A isoforms did not add predictive value to models and did not show clinical utility in this study.                                                 These data suggests that much of LP(s) mediated major adverse coronary events is driven by oxidized phospholipids. Importantly, elevated LP(a) and oxidized phospholipids on apolipoprotein B must be recognized as important predictors of major adverse cardiovascular events across racial groups.                                                 The final study addresses the question of the optimal antithrombotic regimen for longterm management of patients with symptomatic peripheral artery disease, or PAD, with a history of limb revascularization. To answer this question, Dr. Jones and colleagues from Duke Clinical Research Institute looked at the EUCLID trial, or examining use of ticagrelor in PAD trial, which randomized patients with PAD to treatment with ticagrelor 90 milligrams twice daily, or clopidogrel 75 milligrams daily.                                                 As a reminder, patients in EUCLID were enrolled based on a normal ankle-brachial index of less .8, or a prior lower extremity revascularization. The current paper really focus on the subset of 7,875 patients who were enrolled based on a prior lower extremity revascularization criterion.                                                 The authors found that after adjustment for baseline characteristics, patients enrolled based on prior revascularization for PAD had higher higher rates of myocardial infarction and acute limb ischemia with similar composite rates of cardiovascular death, myocardial infarction and stroke when compared with patients enrolled based on the ankle brachial index criterion.                                                 Overall, there were no significant differences between ticagrelor and clopidogrel for the reduction of cardiovascular or acute limb events.                                                 Those were your highlights. Now, for our featured discussion.                                                 On today's podcast, we are discussing the very, very important issue of stroke risk in patients with atrial fibrillation. Most of us use the international guidelines for anticoagulation in atrial fibrillation that mostly suggest that we use the CHADS VASc scoring system to determine the stroke risk in a particular patient and then determine whether or not this patient meets the threshold for anticoagulation.                                                 This assumes that the CHADS VASc score corresponds to a fixed stroke rate. Today, in our journal, we have very, very interesting results from a paper with corresponding author, Dr. Daniel Singer who really suggest that we may need to rethink that. Dr. Daniel Singer joins us today from Massachusets General Hospital.                                                 Welcome Daniel. Dr. Daniel Singer:             Thank you for having me. Dr. Carolyn Lam:               Great. Today, we also have Dr. Sana Al-Khatib who's the associate editor from Duke University who managed this paper. Welcome Sana. Dr. Sana Al-Khatib :         Thank you Dr. Carolyn, I'm happy to be here. Dr. Carolyn Lam:               Daniel, could we start by you letting us know what you sought to do in your study and what you found? Dr. Daniel Singer:             We all know that anticoagulants are extraordinarily effective at preventing stroke in patients with atrial fibrillation, but they also raise the risk of bleeding, and sometimes that bleeding could be quite serious and even fatal. As a result, for that past 10, 15 years, we have used a risk-based approach to the decision about whether to start a patient on anticoagulation, and that risk is the stroke risk that a patient faces if they weren't taking anticoagulants. Then we figured that anticoagulants will reduce it by about two-thirds.                                                 There are formal decision analysis and then a more informal sense that a patient has to face an anticoagulated risk of stroke of about 2%, some people might say 1% to 2% before anticoagulation results in an expected net clinical benefit that the effect in reducing ischemic stroke will exceed the risk of increasing bleeding.                                                 While the CHADs VASc score has been widely accepted as the basis for estimating that risk, it became apparent to us as we looked across the studies that were underlying that assumption, that the risk that were associated with various CHADs VASc scores were extremely variable. Many of these risks actually were less than that 1% or 2% threshold for anticoagulation.                                                 What I mean is that the stroke risk associated with CHADs VASc score of one, or two, which is the basis for the guideline threshold for anticoagulation actually corresponded to risk less than 1% in many of these very large studies. We have conducted a systematic review just to be sure that we were capturing the overall evidence base for this, and that's what we report in our paper. Dr. Carolyn Lam:               Perhaps you could start by letting us know exactly how far off are we in our stroke risk estimation. Dr. Daniel Singer:             We looked at 34 studies that were quite large and then we zeroed in on the largest one. If you looked at the rate for stroke overall, they varied enormously in terms of the overall stroke rate. Then when we focused down on CHADs VASc score of 1, or 2, we found that the majority of these studies, actually, for CHADs VASc 1, was less than 1% per year. For CHADs VASc 2 score was in the majority these studies less than 2% per year.                                                 Both of those stroke risks have raised us the question where are these patients could gain in that clinical benefit from being anti-coagulated, because those stroke risk, if they were reduced by two-thirds, would really be a very small reduction in risk and yet they'd still face the bleeding risk.                                                 Among the most interesting findings actually is that we found that a Swedish national database and the large Danish national database came up with threefold difference in their estimate of stroke rates. The Swedish database produced lower risk, and the Danish database produced substantially higher risk.                                                 If you think about it, there are probably no two countries in the world that are more similar in terms of gene, social environmental, medical care systems, and that raises the specific question of, "Is it underlying rates that vary across different cohorts and different geographies, or is it a different in methodology?"                                                 We think a lot of the differences are due to methodologic difference, and that we need to standardize these differences together, better handle on what the real stroke rate is among patients with these low CHADs VASc scores. Dr. Carolyn Lam:               The variability that you pointed on your paper is really striking, but another possibility, do you think, is that maybe stroke risk isn't static. Dr. Daniel Singer:             Yeah. If that's the case, we face a great difficulty in developing predictions rules of what the stroke risk could be. I think most people feel it's the function of their age, and whether they've had a prior stroke, and whether they have the comorbidity, hypertension, and diabetes, and so on, that are incorporated into the various stroke risk scores, in particular, CHADs VASc.                                                 We tend to think that that's pretty fixed until you get older or until you accumulated another comorbidity. I think the striking difference is that, one, that we actually anticipated in the beginning, was that the stroke rates in people with atrial fibrillation were also coming down. The stroke rates in general have been dramatically decreasing for decades now.                                                 One issue is whether that applies as well to atrial fibrillation associated stroke. There is a suggestion of that, but the variability across the cohorts is so great that you can't pick up a strong signal in terms of calendar time. Although I suspect that there is a strong calendar effect. Exactly why that is, we could speculate. I suspect a lot of it is control of blood pressure, but that's speculation. Dr. Carolyn Lam:               Daniel, congratulations again for that fascinating and really very sobering findings.                                                 Sana, you managed this paper. It's very important paper. In fact, important enough that you invited an editorial. Could you please share some of your thoughts? Dr. Sana Al-Khatib :         Oh, yeah. Absolutely. First, I'd like to start by congratulating Daniel and his team on conducting this really important study. I enjoyed reading it and managing it. Definitely, congratulations.                                                 A couple of thoughts that I have. I completely agree with this really important finding, that there is a lot of variability in the rates of stroke that come from different patient populations and databases. As you pointed out Daniel, I think this is indeed largely due to differences in methodology in terms of how the information was selected, how certain things were defined.                                                 I agree with you there. You called for standardization of this, and I wonder if you have any thoughts about how we can go about doing that. I also want to bring up some of the newer studies now that are showing some significance in terms of biomarkers. Is that really adding significantly to the predictive ability of risk prediction models? I wanted to get your thoughts on that as well. Dr. Daniel Singer:             Let me address your last question, which is simply you state that the CHADs VASc score, the CHAD score and so on, are based on very simple clinical features, and it would be unusual for them to be highly predictive. In fact, they're only mediocrely predictive, and the addition of biomarkers high-sensitivity troponin proBNP, now, people have suggested the imaging biomarkers like magnetic resonance to asses fibrosis in the left atrium. These are all very, very promising in terms of getting better models.                                                 The problem is to do that on a very scale such that we can get precise and well-calibrated predictions. We've found when we're analyzing to pair risk scores, we found that the most important issue is the underlying risk, so that, yes, you can get a great model, but if you have high variability in the underlying rate, you can have a problem specifying an individual with a stroke risk.                                                 We have to standardize and improve the quality of bringing people into these cohorts, and of interrogating the cohorts and databases and making sure that we have the same approach to assessing outcomes.                                                 This could probably be best done in very big scientific prospective registry studies, but it's tough to get all that information. There are some registry studies now ongoing, the ORBIT registries, the GARFIELD registries that may help us a lot with specifying stroke risk, but they don't have the biomarkers embedded in them. I'm hopeful that with better message, and large studies, and incorporating biomarkers, that we'll really get down to very accurate and generalizable stroke risk.                                                 I think the CHADs VASc and similar simple stroke risk scores will be in the rear-view mirror. Dr. Sana Al-Khatib :         That's great. Can I ask one other question, because I completely agree with you looking at your numbers and the data that you presented, is that when you look, especially at the CHADs VASc score 1 patient, the risk seems to be pretty low.                                                 As you very well know, the guideline documents don't really ... At least, for the American AHA/ACC guideline document, they don't really verbalize very definitively the need to anticoagulate patients with a CHADs VASc score of 1.                                                 If you look at the numbers related to a CHADs VASc score of 2, I'm not sure that I completely agree that the risk is very low. Certainly, there was 33% of the studies reported stroke rates of greater than 2% per year. I think maybe different people have different thresholds. While I completely agree with you on the CHADs VASc score of 1 patients, I find that the findings on patients with a CHADs VASc score of 2 a bit more concerning.                                                 In fact, if anything, I would want based even on your data, not on the guidelines to offer anticoagulation to patients with CHADs VASc score of 2. What would you say to that? Dr. Daniel Singer:             I'm looking at our table that has this, and a lot of the CHADs VASc 2 scores are under 2%, but they're in mid 1%. In the North American cohorts in particular, the rates tend to be lower. That said, I think the heart of the problem here is that we have focused on the threshold for anticoagulation. I think there's an argument to be made that you lay out the risks and benefits to the patients and engage them in a decision, particularly with regards to these lower CHADs VASc scores.                                                 At least you make a lot of, perhaps, even more emphasis on being sure that the higher CHADs VASc scores, that anticoagulation is the net benefits of anticoagulation are made very clear to the patient, and that we don't have large fractions of patients who can take anticoagulants not taking them.                                                 We know from the pinnacle registry and other registries, that even at high CHADs VASc scores, we have 40% plus of atrial fibrillation patients who are not getting anticoagulants. I think that's where we have a lot more assurance that the net benefit is positive and that we can make a different both in terms of a patient in front of us, and in terms of the overall public health aspects of atrial fibrillation and stroke. Dr. Sana Al-Khatib :         I do believe that this is really important, but it is also important to keep in mind that with the novel novel oral anticoagulants, I think the whole landscape has changed. Not only do patients have different options to consider, but certainly, the risk of bleeding, which is the other part of this equation, has gone down significantly with the novel agents.                                                 I think as we engage in shared decision making with patients, I think it is really important to highlight these really very remarkable features about the agents that have really changed the care of patients with atrial fibrillation.                                                 One thing to add to this whole topic is, really, all the new advances that we're seeing in this field that has been really life-changing for us and for our patients. Dr. Carolyn Lam:               Indeed Sana. I was about to bring up the bleeding risk part, the flip side of the coin as well. Also, the point that most of my patients with atrial fibrillation, they really strongly value the avoidance of stroke even more than avoidance of bleeding. Someone, that needs to be taken into consideration as well.                                                 Daniel, I'd love to give you the last words. You mentioned that you like to highlight, maybe, some more of the implications of your findings. Dr. Daniel Singer:             I guess I would say there's a scientific implication, which is what we've ben discussing, which is the importance of trying to get these rates down correctly and accurately, and maybe we have to get people together to say how they're doing these studies.                                                 The second is, for the individual patient, that we should engage them in this discussion. Maybe patients who are perfectly willing to a novel anticoagulant and CHADs VASc score of zero. That would come out of a discussion with the patient. That our emphasis at this point since we're a little unsure about the threshold level, our emphasis both at the individual patient level, and then from the public heath perspective should be on the higher CHADs VASc scores where we know that we can expect a net clinical benefit from the vast majority of patients with AF.                                                 I agree with Dr. Al-Khatib, that the novel anticoagulants post an important advantage in the sense not so much in their overall bleeding, but particularly in terms of their intercranial bleeding, which is the lethal bleeding we most want to avoid. Dr. Carolyn Lam:               Thank you both for joining us. Thank you listeners for joining us. Don't forget to tune in next week.  

Protease neprilysin is known to be responsible for the degradation of natriuretic peptides. A recent heart failure (HF) drug, LCZ696 (EntrestoTM), that combines a neprilysin inhibitor and an angiotensin II receptor inhibitor was suggested to augment circulating B-type natriuretic peptide (BNP) concentrations, making the results of BNP measurements diagnostically ambiguous. Because the main form of measured BNP in HF patients is represented by its uncleaved precursor, proBNP, it is important to know the susceptibility of proBNP to cleavage by neprilysin.

Alistair Lindsay talks to Leong Ng about his work into using biomarkers to identify which groups of patients will benefit from ACE inhibition after acute coronary syndrome.See also:Identification of potential outcome benefit from ACE inhibition after acute coronary syndrome: a biomarker approach using N-terminal proBNP http://bit.ly/11hAfKc