Cardionerds: A Cardiology Podcast

It’s another session of CardioNerds Rounds! In these rounds, Co-Chairs, Dr. Karan Desai and Dr. Natalie Stokes and Dr. Tiffany Dong (FIT at Cleveland Clinic) joins Dr. Randall Starling (Professor of Medicine and Director of Heart Transplant and Mechanical Circulatory Support at Cleveland Clinic) to discuss the nuances of guideline directed medical therapy (GDMT) through real cases. As a past president of the Heart Failure Society of America (HFSA) and author on several guidelines, Dr. Starling gives us man pearls on GDMT. Come round with us today by listening to the episodes and joining future sessions of #CardsRounds! This episode is supported with unrestricted funding from Zoll LifeVest. A special thank you to Mitzy Applegate and Ivan Chevere for their production skills that help make CardioNerds Rounds such an amazing success. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. Case details are altered to protect patient health information. CardioNerds Rounds is co-chaired by Dr. Karan Desai and Dr. Natalie Stokes.  Speaker disclosures: None Cases discussed and Show Notes • References • Production Team CardioNerds Rounds PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes – CardioNerds Rounds: Challenging Cases – Modern Guideline Directed Therapy in Heart Failure with Dr. Randall Starling Case #1 Synopsis: A man in his 60s with known genetic MYPBC3 cardiomyopathy and heart failure with a reduced ejection fraction of 30% presents with worsening dyspnea on exertion over the past 6 months. His past medical history also included atrial fibrillation with prior ablation and sick sinus syndrome with pacemaker implantation. Medications are listed below. He underwent an elective right heart catheterization prior to defibrillator upgrade for primary prevention. At the time of right heart catheterization, his blood pressure was 153/99 with a heart rate of 60. His RHC demonstrated a RA pressure of 15mmHg, RV 52/16, PA 59/32 (mean 41), and PCWP 28 with Fick CO/CI of 2.8 L/min and index of 1.2 L/min/m2. His SVR  was 1900 dynes/s/cm-5. He was admitted to the cardiac ICU and started on nitroprusside that was transitioned to a regimen of Sacubitril-Valsartan and Eplerenone. His final RHC numbers were RA 7, PA 46/18/29, PCWP 16 and Fick CO/CI 6.1/2.6. His discharge medications are shown below. Takeaways from Case #1 Unless there are contraindications (cardiogenic shock or AV block), continue a patient’s home beta blocker to maintain the neurohormonal blockade benefits. A low cardiac index should be interpreted in the full context of the patient, including their symptoms, other markers of perfusion (e.g., urine output, mentation, serum lactate), and mean arterial pressure before holding or stopping beta blockade. Carvedilol, metoprolol succinate and bisoprolol are all evidence-based options for beta blockers in heart failure with reduced ejection fraction. If there is concern of lowering blood pressure too much with Sacubitril/Valsartan, one method is to trial low dose of valsartan first and then transition to Sac/Val. Note, in the PARADIGM-HF trial, the initial exclusion criteria for starting Sac/Val included no symptomatic hypotension and SBP ≥ 100. At subsequent up-titration visits, the blood pressure criteria was decreased to SBP ≥ 95. In multiple studies, protocol-driven titration of GDMT has shown to improve clinical outcomes, yet titration remains poor. The following image from Greene et al. in JACC shows that in contemporary US outpatient practices that GDMT titration is poor with few patients reaching target dosing. Case #2 Synopsis: A 43 year-old male with a past medical history of familial dilated cardiomyopathy requiring HVAD placement two years prior now comes in with low flow alarms. He is feeling well otherwise with chronic dyspnea on exertion. A CT chest and abdomen with contrast for showed outflow graft occlusion. Given a TTE showed LV recovery that correlated with invasive hemodynamics, his LVAD was decommissioned. He was tried on a low dose Sacubitril/Valsartan but was unable to tolerate it due to hypotension. He was discharged on carvedilol 3.125mg BID and lisinopril 5mg daily. Over the next 10 months in clinic, his GDMT was titrated to carvedilol 25mg BID, spironolactone 25mg daily and Sacubitril/Valsartan 49-51mg BID.  Takeaways Case #2 In patients with ventricular assist devices, the differential for low flow alarms includes hypovolemia, arrhythmias, RV failure, cardiac tamponade and inflow cannula obstruction. A careful history, exam (with particular attention to the JVD), and bedside echocardiogram can help differentiate the cause. EF recovery occurs in about 5% of patients in large LVAD registries. Favorable prognostic factors for EF recovery include female sex and nonischemic cardiomyopathy of short duration. In the TRED-HF trial, patients were randomly assigned to phased withdrawal or continuation of GDMT over 6 months. The primary endpoint was relapse defined as a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP and to more than 400 ng/L or clinical evidence of heart failure. While a small trial (51 patients were enrolled), over the first 6 months, 44% of patients assigned to treatment withdrawal met the primary endpoint of relapse compared with none assigned to continue treatment (estimated of event rate 45.7% [95% CI 28.5-67.2]; p=0.0001). We still do not have great predictors of relapse, and thus for most patients with HFrecEF, GDMT should continue indefinitely. References – CardioNerds Rounds: Challenging Cases – Modern Guideline Directed Therapy in Heart Failure with Dr. Randall Starling Halliday BP, Wassall R, Lota AS, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet. 2019 Jan 5;393(10166):61-73. doi: 10.1016/S0140-6736(18)32484-X. Epub 2018 Nov 11. PMID: 30429050; PMCID: PMC6319251. Greene SJ, Fonarow GC, DeVore AD, et al. Titration of Medical Therapy for Heart Failure With Reduced Ejection Fraction. J Am Coll Cardiol. 2019 May 21;73(19):2365-2383. doi: 10.1016/j.jacc.2019.02.015. Epub 2019 Mar 4. PMID: 30844480; PMCID: PMC7197490. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30. PMID: 25176015. Production Team Karan Desai, MD Natalie Stokes, MD Amit Goyal, MD Daniel Ambinder, MD

Atrial fibrillation may reach pandemic proportions in the next 2-3 decades. Factors that drive this phenomenon have been studied in predominantly White populations, leading to a significant underrepresentation of certain racial/ethnic groups in atrial fibrillation epidemiological studies. Most atrial fibrillation epidemiology studies suggest that the non-Hispanic Black population has a lower incidence/prevalence of atrial fibrillation, despite a higher risk factor burden (“Afib paradox”). At the same time, non-Hispanic Blacks have worse outcomes compared to the White population and underrepresented populations and women are less likely than White men to receive optimal guideline-based therapies for atrial fibrillation. In this episode, CardioNerds Dr. Kelly Arps (Co-Chair Atrial Fibrillation series, Cardiology fellow at Duke University), Dr. Colin Blumenthal (Co-Chair Atrial Fibrillation series, CardioNerds Academy House Faculty Leader for House Jones, Cardiology fellow at the University of Pennsylvania), and Dr. Dinu-Valentin Balanescu (CardioNerds Academy Faculty for House Jones, rising internal medicine chief resident at Beaumont Hospital), discuss with Dr. Larry Jackson (cardiac electrophysiologist and Vice Chief of Diversity, Equity, and Inclusion in the Division of Cardiology at Duke University) about atrial fibrillation epidemiology and health equity, challenges and possible solutions to improving diversity in clinical trials, and race/ethnicity/sex/gender differences in the detection, management, and outcomes of atrial fibrillation. Audio editing by CardioNerds Academy Intern, student doctor Akiva Rosenzveig. This CardioNerds Atrial Fibrillation series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Kelly Arps and Dr. Colin Blumenthal. This series is supported by an educational grant from the Bristol Myers Squibb and Pfizer Alliance. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. We have collaborated with VCU Health to provide CME. Claim free CME here! Disclosure: Larry R. Jackson II, MD, MHs, has the following relevant financial relationships:Advisor or consultant for: Biosense Webster Inc.Speaker or a member of a speakers bureau for: Biotronik Inc.; Medtronic Inc. Pearls • Notes • References • Guest Profiles • Production Team CardioNerds Atrial Fibrillation PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes – Atrial Fibrillation: Epidemiology, Health Equity, & The Double Paradox Atrial fibrillation confers an enormous public health burden. It is estimated that it will reach pandemic proportions over the next 30 years, with potentially 100-180 million people worldwide suffering from this condition. Large epidemiological atrial fibrillation registries have very small populations of underrepresented groups. More diverse enrollment in clinical trials is essential and may be obtained by increasing diversity among research staff, principal investigators, and steering committees, and use of mobile/telehealth technologies to remove bias related to differences in presentation. The CardioNerds Clinical Trials Network specifically aims pair equitable trial enrollment with trainee personal and professional development. Most atrial fibrillation epidemiology studies suggest that the non-Hispanic Black population has lower incidence/prevalence of atrial fibrillation, despite higher risk factor burden. This “paradox” is likely due to a multifactorial process, with clinical differences, socioeconomic factors, and genetic factors contributing. Underrepresented populations are less likely than White patients to receive optimal guideline-based management of atrial fibrillation. Though there is a higher incidence of intracranial bleeding on vitamin K antagonists in this population, they are less likely to receive optimal anticoagulation for stroke prevention with direct oral anticoagulants. Also, despite overall worse outcomes, they are less likely to be prescribed rhythm control strategies or offered catheter-based ablation despite known data with improved outcomes with early rhythm control. Gender-based differences in atrial fibrillation epidemiology, management, and outcomes also exist. Compared to men, women have a lower incidence/prevalence of atrial fibrillation but are more likely to be symptomatic. They are also more likely to receive rate instead of rhythm control strategies and suboptimal stroke reduction therapies Overall, women have worse outcomes than men.  “I want to differentiate [equitable care] from equal care. I think this idea of equity means that we have to take into account the myriad of differences that we see between people of different races, ethnicities, genders, sexes, regions, whether they’re citizens or not, whether they’re disabled or not […] and make sure that we’re thinking about those in terms of prescriptions and discussion and communication, and offering our patients therapy, […] it’s not [enough] to offer different people the same therapy because they may have different barriers that may prevent them from uptaking that therapy or utilizing that.” Dr. Larry Jackson Notes – Atrial Fibrillation: Epidemiology, Health Equity, & The Double Paradox Drafted by Dr. Dinu-Valentin Balanescu and reviewed by Dr. Colin Blumenthal. 1. What factors contribute to the atrial fibrillation epidemic and where do we expect to be over the next 20-30 years? The current global prevalence of atrial fibrillation is unclear. It is estimated that over the next 30 years, the prevalence of atrial fibrillation may reach pandemic proportions, with potentially 100-180 million people worldwide suffering from this condition.1 Factors that drive this increase: Classic: heart failure, coronary artery disease, hypertension, diabetes, tobacco use, obesity. Novel risk factors: obstructive sleep apnea, metabolic syndrome, left ventricular hypertrophy, left atrial enlargement. Novel markers (inflammatory, biochemical): B-type natriuretic peptide, CRP. Many of the above factors have been determined by studying predominantly White populations. 2. There is conflicting data regarding the incidence of atrial fibrillation across race and ethnicity, with most studies suggesting a higher incidence in the non-Hispanic White population compared to non-Hispanic Black or Hispanic individuals, while some suggest a similar prevalence. How is this discrepancy explained? The discrepancy may stem from various rates of clinical detection, rather than incidence or prevalence, of atrial fibrillation between different race/ethnicity groups (“ascertainment bias”). Conflicting data persists even when detection is adjusted for. A cohort of the MESA study showed that the prevalence among race and ethnicity was similar when the diagnosis was made using Holter monitor data.2 Data from the ASSERT trial suggest that when using implantable loop recorders, the incidence of atrial fibrillation among the non-Hispanic Black population was lower than a European White population.3 There is a substantial need for further study on the epidemiology of atrial fibrillation across race/ethnicity. 3. Non-Hispanic Black populations have a higher risk factor burden for atrial fibrillation than White patients, but as described above most studies demonstrate a lower incidence – how is this “paradox” explained? The “atrial fibrillation paradox” is a double paradox, as Dr. Jackson explains: despite a higher risk factor burden, non-Hispanic Blacks have a lower incidence/prevalence of atrial fibrillation. At the same time, non-Hispanic blacks have worse outcomes compared to the white population.4 This is likely due to a multifactorial process, with clinical differences, socioeconomic factors, and genetic factors contributing.5 Specifically: Ascertainment bias. Certain racial/ethnic groups may have access issues preventing them from seeking medical attention for rhythm assessment and/or may be less likely to be prescribed rhythm monitors for objective assessment. Additionally, it has been shown that the non-Hispanic Black population has more paroxysmal symptoms, which could lead to difficulties in diagnosis. Survival bias. Non-Hispanic Whites have a longer life expectancy compared to underrepresented racial/ethnic groups, which may lead to a greater risk of developing atrial fibrillation over time. Genetic/epigenetic differences. Stronger European ancestry within non-Hispanic Blacks is associated with a higher risk of atrial fibrillation. Genome-wide association studies suggest that non-Hispanic Blacks may have protective genes compared to whites. 4. What are barriers to the diagnosis of atrial fibrillation in understudied populations and how can inclusion in research studies be improved? Large epidemiological registries have traditionally included very small proportions of underrepresented groups. A more diverse enrollment in clinical trials is essential. Clinical trial participation of marginalized populations may be achieved by: Using mobile/telehealth technologies to recruit and follow patients. Increasing diversity and heterogeneity among research staff, principal investigators, steering committees, which has been shown to improve study diversity. From a clinical standpoint, barriers may be removed by: Educating patients on atrial fibrillation, its complications, its treatments, and its outcomes. Involving family and other social communities as part of decision-making support. The CardioNerds Clinical Trials Network specifically aims pair equitable trial enrollment with trainee personal and professional development 5. How are race and ethnicity associated with the workup for atrial fibrillation and the use of specialized diagnostic equipment? Clinicians should have a high index of suspicion for atrial fibrillation while understanding the racial/ethnic/gender differences in presentation and management. Patients from various racial/ethnic/gender groups may present with different symptoms of atrial fibrillation. For example, non-Hispanic Blacks are more likely to be more symptomatic, but also more paroxysmal. They are also more likely to have a have lower quality of life.6 If clinical index of suspicion is high, ambulatory monitoring should be pursued. 6. What are the differences in management between White and black patients when it comes to rate versus rhythm control, anticoagulation, and procedures? With regards to anticoagulation: Black patients are less likely than white patients to be prescribed anticoagulation or, if prescribed, are significantly less likely to be prescribed a direct oral anticoagulant (DOAC).7 Underrepresented populations have a higher risk of intracranial hemorrhage while on a vitamin K antagonists (VKA) compared to whites. DOACs overall have a lower risk of intracranial hemorrhage and should preferentially be prescribed over VKAs.8 Pivotal trials comparing DOACs to VKAs have had a very low enrollment of Hispanic and non-Hispanic black populations, so it is possible the benefit is even greater in this population. With regards to rhythm control strategies: Black patients are less likely to receive rhythm control therapies (whether cardioversion, medical, or invasive) and more likely to receive rate control therapy.8 Black patients have a better response to catheter ablation of atrial fibrillation compared to white patients. This treatment may be preferred in underrepresented populations to improve outcomes compared to medical therapy alone.9 7. What are gender-based differences in AF epidemiology and management and are there underlying differences in the electrical conduction system between men and women that affect management decisions? Compared to men, women: Have a lower incidence and prevalence of atrial fibrillation. Are more likely to be symptomatic. Are more likely to receive rate control strategies as opposed to rhythm control strategies. Are less likely to receive stroke reduction therapies (e.g., anticoagulation or left atrial appendage closure). Have worse outcomes: higher risk of stroke, QTc prolongation and torsades de pointes, heart failure, and mortality.10,11 These differences may be due to: Autonomic differences (especially in the 2nd-5th decades of life). Differences in the effects of sex hormones. Estrogen can affect the differential expression of ion channel subunits, ion channel function, inhibits the hERG K channel. Certain sex hormones may also impact action potential duration and alter calcium metabolism. 8. Are the differences in the diagnosis, work-up, and treatment of atrial fibrillation among racial/ethnic/gender groups associated with differences in outcomes? Underrepresented groups have worse outcomes compared to the White population: higher risk of stroke, heart failure, and mortality.12 Differences in the management of atrial fibrillation among racial/ethnic/gender groups contribute to these worse outcomes, e.g., lower rates of stroke prevention therapies and rhythm control strategies (patients in sinus rhythm had a 50% reduction in mortality in the AFFIRM trial).9 The field needs to progress in a way that teaches clinicians to understand barriers in optimal care faced by certain racial/ethnic/gender groups. 9. Dr. Larry Jackson – what makes your heart flutter about electrophysiology and studying health inequity? The chance to provide equitable care. Equitable care is different from equal care. Equity implies acknowledging the differences between people of different races, ethnicity, genders, regions. These factors should be taken into account when offering therapies to our patients. It is not practical to offer different patients the same therapy, as they may have different barriers preventing them from utilizing that therapy. Optimal communication and assessment of patient goals with a focus on race/ethnicity/gender leads to better more personalized care. References – Atrial Fibrillation: Epidemiology, Health Equity, & The Double Paradox 1. Martinez C, Katholing A, Wallenhorst C, Granziera S, Cohen AT, Freedman SB. Increasing incidence of non-valvular atrial fibrillation in the UK from 2001 to 2013. Heart. Nov 2015;101(21):1748-54. doi:10.1136/heartjnl-2015-307808 2. Rodriguez CJ, Soliman EZ, Alonso A, et al. Atrial fibrillation incidence and risk factors in relation to race-ethnicity and the population attributable fraction of atrial fibrillation risk factors: the Multi-Ethnic Study of Atherosclerosis. Ann Epidemiol. Feb 2015;25(2):71-6, 76.e1. doi:10.1016/j.annepidem.2014.11.024 3. Lau CP, Gbadebo TD, Connolly SJ, et al. Ethnic differences in atrial fibrillation identified using implanted cardiac devices. J Cardiovasc Electrophysiol. Apr 2013;24(4):381-7. doi:10.1111/jce.12066 4. Mendys P, Jackson LR, 2nd, Solimon EZ, Howard G, Ferdinand K. The atrial fibrillation paradox -connecting hypertension to atrial disease and stroke. Am J Prev Cardiol. Dec 2021;8:100284. doi:10.1016/j.ajpc.2021.100284 5. Essien UR, Kornej J, Johnson AE, Schulson LB, Benjamin EJ, Magnani JW. Social determinants of atrial fibrillation. Nat Rev Cardiol. Nov 2021;18(11):763-773. doi:10.1038/s41569-021-00561-0 6. Norby FL, Benjamin EJ, Alonso A, Chugh SS. Racial and Ethnic Considerations in Patients With Atrial Fibrillation: JACC Focus Seminar 5/9. J Am Coll Cardiol. Dec 21 2021;78(25):2563-2572. doi:10.1016/j.jacc.2021.04.110 7. Ugowe FE, Jackson LR, 2nd, Thomas KL. Racial and ethnic differences in the prevalence, management, and outcomes in patients with atrial fibrillation: A systematic review. Heart Rhythm. Sep 2018;15(9):1337-1345. doi:10.1016/j.hrthm.2018.05.019 8. Golwala H, Jackson LR, 2nd, Simon DN, et al. Racial/ethnic differences in atrial fibrillation symptoms, treatment patterns, and outcomes: Insights from Outcomes Registry for Better Informed Treatment for Atrial Fibrillation Registry. Am Heart J. Apr 2016;174:29-36. doi:10.1016/j.ahj.2015.10.028 9. Meschia JF, Merrill P, Soliman EZ, et al. Racial disparities in awareness and treatment of atrial fibrillation: the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Stroke. Apr 2010;41(4):581-7. doi:10.1161/strokeaha.109.573907 10.     Schnabel RB, Pecen L, Ojeda FM, et al. Gender differences in clinical presentation and 1-year outcomes in atrial fibrillation. Heart. Jul 2017;103(13):1024-1030. doi:10.1136/heartjnl-2016-310406 11.     Westerman S, Wenger N. Gender Differences in Atrial Fibrillation: A Review of Epidemiology, Management, and Outcomes. Curr Cardiol Rev. 2019;15(2):136-144. doi:10.2174/1573403×15666181205110624 12.     Magnani JW, Norby FL, Agarwal SK, et al. Racial Differences in Atrial Fibrillation-Related Cardiovascular Disease and Mortality: The Atherosclerosis Risk in Communities (ARIC) Study. JAMA Cardiol. Jul 1 2016;1(4):433-41. doi:10.1001/jamacardio.2016.1025 Guest Profiles Dr. Larry Jackson Dr. Larry Jackson is a cardiac electrophysiologist and assistant professor of medicine in the Division of Cardiology at Duke University Medical Center. Dr. Jackson is also an expert researcher, focusing on analyzing racial and ethnic disparities and the impact of social determinants of health on arrhythmia care. Dr. Dinu Balanescu Dr. Dinu Balanescu. Dinu is an internal medicine resident and upcoming chief resident at Beaumont Hospital in Royal Oak, Michigan. He also serves as House Faculty for House Jones in the CardioNerds Academy.

CardioNerds Tommy Das (Program Director of the CardioNerds Academy and cardiology fellow at Cleveland Clinic), Rick Ferraro (cardiology fellow at the Johns Hopkins Hospital), and Dr. Aliza Hussain (cardiology fellow at Baylor College Medicine) take a deep dive on the REDUCE-IT trial with Dr. Peter Toth, director of preventive cardiology at the CGH medical center in Sterling, Illinois, clinical professor in family and community medicine at the University of Illinois School of Medicine, and past president of the National Lipid Association and the American Board of Clinical Lipidology.  Special introduction to CardioNerds Clinical Trialist Dr. Jeff Wang (Emory University). Audio editing by CardioNerds academy intern, Shivani Reddy. This episode is part of the CardioNerds Lipids Series which is a comprehensive series lead by co-chairs Dr. Rick Ferraro and Dr. Tommy Das and is developed in collaboration with the American Society For Preventive Cardiology (ASPC). Relevant disclosures: None Pearls • Notes • References • Guest Profiles • Production Team CardioNerds Cardiovascular Prevention PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls – REDUCE-IT The Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT) trial was a large randomized controlled trial that showed a significant reduction in atherosclerotic cardiovascular disease (ASCVD) events with use of icosapent ethyl ester in secondary prevention patients and high risk primary prevention patients with diabetes and residual elevated triglycerides between 135 to 499 mg/dL on top of maximally tolerated statin therapy1. Despite the use of high intensity statin therapy, considerable residual risk for future atherosclerotic cardiovascular disease exists in patients with ASCVD. Elevated triglycerides (TGs) are an important marker of increased residual ASCVD risk2. There are two primary types of Omega-3 fish oils: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omege-3 fish oils have been shown to lower triglyceride levels. Low-dose combination EPA and DHA has not exhibited incremental cardiovascular benefit in either primary prevention and secondary prevention patients on top of statin therapy3-5. REDUCE-IT showed the use of high dose EPA in patients with either ASCVD or DM and one additional risk factor, and relatively well-controlled LDL-C levels on maximally tolerated statin therapy and residual hypertriglyceridemia (TG 135-499 mg/dL) results in significant reductions in cardiovascular events over a median follow-up period of 4.9 years1. Show notes – REDUCE-IT Multiple epidemiologic and Mendelian randomization studies have established elevated triglyceride (TG) levels as an important risk factor for atherosclerotic cardiovascular events6-8. However previous clinical trials using TG-lowering medication such as niacin, fibrates and low dose omega-3 fish oil have not shown to reduce cardiovascular events when added to statin therapy in patients with or without ASCVD,9,10. The JELIS trial first demonstrated a significant reduction in cardiovascular events when 1.8g daily of eicosapentaenoic acid (EPA) was added to low-intensity statin therapy in patients with ASCVD and hypercholesterolemia, However, the trial was limited due to open label design without placebo, use of low doses of background statin therapy, and geographic/demographic limitations to participants in Japan11. In a large international multicenter randomized controlled trial, the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) randomized 8,179 patients with established atherosclerotic heart disease or diabetes and an additional risk factor, on maximally tolerated statin therapy, to 4 gm/day of icosapent ethyl (a highly purified and stable EPA ethyl ester) or mineral oil1.  Over a median follow up of 4.9 years, the use of icosapent ethyl ester was associated with significant reductions in major cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina) compared to placebo, with an absolute risk reduction of 4.8% and NNT of 21. There were similar reductions in the key components of the primary endpoint, including a 20% relative risk reduction in cardiovascular death with icosapent ethyl. Median TG levels were reduced by 18% in the icosapent ethyl group and rose by 2.2% in the placebo group. LDL levels increased in both groups, although to a lesser degree in the icosapent ethyl group. There was a trend towards increased bleeding (2.7% with icosapent ethyl versus 2.1% with placebo, p=0.06) and a modest but significant increase in hospitalizations for atrial fibrillation or flutter with icosapent ethyl (3.1% versus 2.1%). Since the publication of REDUCE-IT, several clinical practice guidelines, including those of the American Diabetes Association (ADA), National Lipid Association (NLA) and the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS), have endorsed the use of icosapent ethyl in their recommendations to further reduce ASCVD risk in select patients. References – REDUCE-IT Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi: 10.1056/NEJMoa1812792. https://www.nejm.org/doi/full/10.1056/nejmoa1812792 Libby P. Triglycerides on the rise: Should we swap seats on the seesaw? Eur Heart J. 2015;36(13):774-776. doi: 10.1093/eurheartj/ehu500.  https://academic.oup.com/eurheartj/article/36/13/774/475534 Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-prevenzione trial. gruppo italiano per lo studio della sopravvivenza nell’infarto miocardico. Lancet. 1999;354(9177):447-455. doi: S0140673699070725. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)07072-5/fulltext Risk and Prevention Study Collaborative Group, Roncaglioni MC, Tombesi M, et al. N-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013;368(19):1800-1808. doi: 10.1056/NEJMoa1205409. https://www.nejm.org/doi/10.1056/NEJMoa1205409?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018;379(16):1540-1550. doi: 10.1056/NEJMoa1804989. https://www.nejm.org/doi/10.1056/NEJMoa1804989?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration, Sarwar N, Sandhu MS, et al. Triglyceride-mediated pathways and coronary disease: Collaborative analysis of 101 studies. Lancet. 2010;375(9726):1634-1639. doi: 10.1016/S0140-6736(10)60545-4. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60545-4/fulltext Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45(11):1345-1352. doi: 10.1038/ng.2795. https://www.nature.com/articles/ng.2795 Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 western prospective studies. Circulation. 2007;115(4):450-458. doi: CIRCULATIONAHA.106.637793. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.106.637793?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet. 2005;366(9500):1849-1861. doi: S0140-6736(05)67667-2. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67667-2/fulltext ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563-1574. doi: 10.1056/NEJMoa1001282. https://www.nejm.org/doi/full/10.1056/nejmoa1001282 Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090-1098. doi: S0140-6736(07)60527-3. https://www.thelancet.com/article/S0140-6736(07)60527-3/fulltext Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: The STRENGTH randomized clinical trial. JAMA. 2020;324(22):2268-2280. doi: 10.1001/jama.2020.22258. https://doi.org/10.1001/jama.2020.22258. . Guest Profiles Dr. Peter Toth Dr. Peter Toth is the Director of Preventive Cardiology at CGH Medical Center in Sterling, IL, and Professor of Clinical Family and Community Medicine at the University of Illinois College of Medicine in Peoria, and adjunct associate professor of medicine, Johns Hopkins University School of Medicine. He received his medical degree from Wayne State University School of Medicine in Detroit, MI, and PhD in Biochemistry from Michigan State University in East Lansing. He has written extensively on the topic of lipids and is Co-Editor of twenty textbooks in preventive cardiology, diabetes, hypertension, and lipidology. Additionally, Dr. Toth is the President of the American Society of Preventive Cardiology, past President of the National Lipid Association, as well as incoming chair of the American Heart Association’s Council on Lipoproteins, Lipid Metabolism, and Thrombosis. Dr. Aliza Hussain Dr. Aliza Hussain is a cardiology fellow at Baylor College of Medicine. She completed a fellowship in prevention at Baylor College of Medicine Cardiovascular Research Institute, and internal medicine residency at UPCM. CardioNerds Lipids Production Team Tommy Das, MD Dr. Rick Ferraro Amit Goyal, MD Daniel Ambinder, MD

Dr. Laurence Sperling discusses the inconsistent placement of referrals and enrollment in cardiac rehabilitation programs. They highlight the European Society of Cardiology's chosen threshold of effectiveness and strategies to enhance participation. The speakers emphasize the benefits of cardiac rehabilitation as a comprehensive risk reduction program and advocate for improved access through new care models.

Dr. Eugenia Gianos, director of the Women’s Heart Program at Lenox Hill Hospital, discusses the management of a 70-year-old man with multiple comorbidities and a prior NSTEMI. Topics include appropriate duration of dual antiplatelet therapy, the use of low dose river oxaben in clinical practice, and individualized decision-making based on patient risk factors.

Dr. Eileen Handberg discusses the ESC guidelines for LDL-C levels in a patient with coronary artery disease. The recommended goal LDLC level is <55mg/dL. They explore the importance of lower LDL cholesterol levels and high potency statin prescriptions for improved cardiovascular outcomes.

The following question refers to Section 4.3 of the 2021 ESC CV Prevention Guidelines. The question is asked by Dr. Maryam Barkhordarian, answered first by pharmacy resident Dr. Anushka Tandon, and then by expert faculty Dr. Noreen Nazir. Dr. Noreen Nazir is Assistant Professor of Clinical Medicine at the University of Illinois at Chicago, where she is the director of cardiac MRI and the preventive cardiology program. The CardioNerds Decipher The Guidelines Series for the 2021 ESC CV Prevention Guidelines represents a collaboration with the ACC Prevention of CVD Section, the National Lipid Association, and Preventive Cardiovascular Nurses Association. Question #9 Mr. A is a 28-year-old man who works as an accountant in what he describes as a “desk job” setting. He shares that life got “a little off-track” for him in 2020 between the COVID-19 pandemic and a knee injury. His 2022 New Years’ resolution is to improve his overall cardiovascular and physical health. He has hypertension and a family history of premature ASCVD in his father, who died of a heart attack at age 50. Prior to his knee injury, he went to the gym 3 days a week for 1 hour at a time, split between running on the treadmill and weightlifting. He has not returned to the gym since his injury and has been largely sedentary, although he is trying to incorporate a 20-minute daily walk into his routine. Which of the following exercise-related recommendations is most appropriate? A. A target of 75-150 minutes of vigorous-intensity or 150-300 minutes of moderate-intensity aerobic physical exercise weekly is recommended to reduce all-cause mortality, CV mortality, and morbidity. B. Bouts of exercise less than 30 minutes are not associated with favorable health outcomes. C. Exercise efforts should be focused on aerobic activity, since only this type of activity is associated with mortality and morbidity benefits. D. Light-intensity aerobic activity like walking is expected to have limited health benefits for persons with predominantly sedentary behavior at baseline. Answer #9 The correct answer is A. There is an inverse relationship between moderate-to-vigorous physical activity and CV morbidity/mortality, all-cause mortality, and incidence of type 2 diabetes, with additional benefits accrued for exercise beyond the minimum suggested levels. The recommendation to “strive for at least 150-300 min/week of moderate-intensity, or 75-150 min/week of vigorous-intensity aerobic physical activity, or an equivalent combination thereof” is a Class 1 recommendation per the 2021 ESC guidelines, and a very similar recommendation (at least 75 minutes of vigorous-intensity or 150 minutes of moderate-intensity activity) is also Class 1 recommendation per 2019 ACC/AHA primary prevention guidelines. Both the ESC and ACC/AHA provide examples of activities grouped by absolute intensity (the amount of energy expended per minute of activity), but the ESC guidelines also offer suggestions for measuring the relative intensity of an activity (maximum/peak associated effort) in Table 7, which allows for a more individualized, customizable approach to setting activity goals. Importantly, individuals who are unable to meet minimum weekly activity recommendations should still be encouraged to stay as active as their abilities and health conditions allow to optimize cardiovascular and overall health. Choice B is incorrect, as data suggests physical activity episodes of any duration, including <10 min, are associated with favorable outcomes like all-cause mortality benefit. The duration of a single exercise bout is less correlated with health benefits than the total physical activity time accumulated per week. Choice C is incorrect. Per the ESC guidelines, it is a class 1 recommendation to perform resistance exercise, in addition to aerobic activity, on 2 or more days per week to reduce all-cause mortality. Data indicate that the addition of resistance exercise to aerobic activity is associated with lower risks of total CV events and all-cause mortality, so it’s expected that a combination of weightlifting and aerobic activity may be more beneficial for than either type of activity alone. The 2019 ACC/AHA prevention guidelines do not make a formal recommendation regarding resistance exercise; they do note that it has multiple health benefits (e.g., BP-lowering, improved glycemic control) though state its association with ASCVD risk reduction is unclear.  Choice D is incorrect: sedentary time is independently associated with greater risk for several major chronic diseases and mortality. Reducing sedentary time for inactive adults and adding in light-intensity physical activity (as little as 15 minutes daily) is a class 1 recommendation to reduce all-cause and CV mortality and morbidity. The 2019 ACC/AHA guidelines suggest that reduced sedentary behavior may be “reasonable for ASCVD risk reduction” (Class 2b). Assuming our patient has had predominantly sedentary behavior, starting with a 20-minute daily walk can provide initial health benefits while working up to more and higher-intensity activity. Main Takeaway Physical activity should be individually assessed and prescribed in terms of frequency, intensity, time (duration), type, and progression. Guideline Location Section 4.3.1, Pages 3268-3269, Table 7 CardioNerds Decipher the Guidelines – 2021 ESC Prevention Series CardioNerds Episode Page CardioNerds Academy Cardionerds Healy Honor Roll CardioNerds Journal Club Subscribe to The Heartbeat Newsletter! Check out CardioNerds SWAG! Become a CardioNerds Patron!

This question refers to Sections 3.1 of the 2021 ESC CV Prevention Guidelines. The question is asked by CardioNerds Academy Intern, student Dr. Hirsh Elhence, answered first by internal medicine resident at Beaumont Hospital and soon to be Mayo Clinic cardiology fellow and Dr. Teodora Donisan and then by expert faculty Dr. Eugene Yang. Dr. Yang is professor of medicine of the University of Washington where he is medical director of the Eastside Specialty Center and the co-Director of the Cardiovascular Wellness and Prevention Program. Dr. Yang is former Governor of the ACC Washington Chapter and current chair of the ACC Prevention of CVD Section. The CardioNerds Decipher The Guidelines Series for the 2021 ESC CV Prevention Guidelines represents a collaboration with the ACC Prevention of CVD Section, the National Lipid Association, and Preventive Cardiovascular Nurses Association. Question #8 Please read the following patient vignettes and choose the FALSE statement. A. A 39-year-old man who comes for a regular physical, has normal vitals and weight, denies any significant past medical or family history – does not need systematic cardiovascular disease (CVD) assessment.B. A 39-year-old woman who comes for a regular physical, has normal vitals and weight, and has a history of radical hysterectomy (no other significant past medical or family history) – could benefit from systematic or opportunistic CVD assessment.C. A 39-year-old woman who comes for a regular physical, has normal vitals except for a BMI of 27 kg/m2 and a family history of hypertension – requires a systematic global CVD assessment.D. A 39-year-old man who comes for a regular physical, has normal vitals and weight, and has a personal history of type I diabetes – requires a systematic global CVD assessment. Answer #8 The correct answer is C. Option A is an accurate statement, as systematic CVD risk assessment is not recommended in men < 40 years-old and women < 50 years-old, if they have no known cardiovascular (CV) risk factors. (Class III, level C) Option B is an accurate statement, as this patient had a radical hysterectomy, which means the ovaries have been removed as well and she is considered postmenopausal. Systematic or opportunistic CV risk assessment can be considered in men > 40 years-old and women > 50 years-old or postmenopausal, even in the absence of known ASCVD risk factors. (Class IIb, level C) Option C is a false statement and thus the correct answer, as the recommendations for global screening in this patient are not as strong and would require shared decision making. Opportunistic screening of blood pressure can be considered in her, as she is at risk for developing hypertension. Blood pressure screening should be considered in adults at risk for the development of hypertension, such as those who are overweight or with a known family history of hypertension. (Class IIa, level B) Option D is an accurate statement, as systematic global CVD risk assessment is recommended in individuals with any major vascular risk factor (i.e., family history of premature CVD, familial hyperlipidemia, CVD risk factors such as smoking, arterial hypertension, DM, raised lipid level, obesity, or comorbidities increasing CVD risk). (Class I, level C) Additional learning points: Do you know the difference between opportunistic and systematic CVD screening? Opportunistic screening refers to screening without a predefined strategy when the patient presents for different reasons. This is an effective and recommended way to screen for ASCVD risk factors, although it is unclear if it leads to benefits in clinical outcomes. Systematic screening can be done following a clear strategy formally evaluating either the general population or targeted subpopulations (i.e., type 2 diabetics or patients with significant family history of CVD). Systematic screening results in improvements in risk factors but has no proven effect on CVD outcomes. Main Takeaway Systematic CVD risk assessment in the general population without CV risk factors does not seem to be cost effective and has unclear benefits on outcomes, although it does lead to increased detection of potentially actionable CV risk factors. Risk assessment is not a one-time event and should be repeated (e.g., every 5 years), but there is no clear data to guide intervals. Guideline Location Section 3.1, page 3236; Table on page 3242. CardioNerds Decipher the Guidelines – 2021 ESC Prevention SeriesCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron!

The following question refers to Section 3.4 of the 2021 ESC CV Prevention Guidelines. The question is asked by student Dr. Adriana Mares, answered first by early career preventive cardiologist Dr. Dipika Gopal, and then by expert faculty Dr. Michael Wesley Milks. Dr. Milks is a staff cardiologist and assistant professor of clinical medicine at the Ohio State University Wexner Medical Center where he serves as the Director of Cardiac Rehabilitation and an associate program director of the cardiovascular fellowship. He specializes in preventive cardiology and is a member of the American College of Cardiology’s Cardiovascular Disease Prevention Leadership Council. The CardioNerds Decipher The Guidelines Series for the 2021 ESC CV Prevention Guidelines represents a collaboration with the ACC Prevention of CVD Section, the National Lipid Association, and Preventive Cardiovascular Nurses Association. Question #7 While you are on holiday break visiting your family, your aunt pulls you aside during the family gathering to ask a few questions about your 70-year-old uncle. He has hypertension, hyperlipidemia, type 2 diabetes mellitus, and moderate chronic obstructive pulmonary disease. His medications include Fluticasone/Salmeterol, Tiotropium, Albuterol, Lisinopril, Simvastatin, and Metformin. She is very concerned about his risk for heart disease as he has never had his “heart checked out.” She asks if the presence of COPD increases his chance of having heart disease. Which of the following statements would best answer her question? A. Systemic inflammation and oxidative stress caused by COPD promote vascular remodeling and a paradoxical ‘anticoagulant’ state affecting all vasculature types. B. Although chronic COPD is associated with increased cardiovascular events, individual exacerbations have no impact on risk of cardiovascular events. C. Patients with mild-moderate COPD are 8-10x more likely to die from atherosclerotic cardiovascular disease than respiratory failure. D. Cardiovascular mortality increases proportionally with an increase in forced expiratory volume in 1 second (FEV1) Answer #7 The correct answer is C. Patients with mild-moderate COPD are 8-10x more likely to die from atherosclerotic cardiovascular disease than respiratory failure. Patients with COPD have a 2-3-fold increased risk of CV events compared to age-matched controls even when adjusted for tobacco smoking, a shared risk factor. This can be partly explained by other common risk factors including aging, hypertension, hyperlipidemia, and low physical activity. Interestingly, CVD mortality increases proportionally with a decrease (rather than increase) in FEV1, making answer choice D wrong (28% increase CVD mortality for every 10% decrease in FEV1). Additionally, COPD exacerbations and related infections are associated with a 4x increase in CVD events, making answer choice B incorrect. COPD has several effects on the vasculature which creates a ‘procoagulant’ not ‘anticoagulant’ effect on all vascular beds. This is associated with increased risk of cognitive impairment due to cerebral microvascular damage as well as increased risk of ischemic and hemorrhagic stroke. Main Takeaway The presence of COPD (even mild to moderate) has a significant impact on the incidence of non-fatal coronary events, stroke, and cardiovascular mortality mediated by inherent disease process and progression, risk factors (smoking, aging, hypertension, and hyperlipidemia), and systemic inflammation altering vasculature creating a ‘procoagulant’ effect. The ESC gives a Class I indication (LOE C) to investigate for ASCVD and ASCVD risk factors in patients with COPD. Guideline Location 3.4.5, Page 3264. CardioNerds Decipher the Guidelines – 2021 ESC Prevention Series CardioNerds Episode Page CardioNerds Academy Cardionerds Healy Honor Roll CardioNerds Journal Club Subscribe to The Heartbeat Newsletter! Check out CardioNerds SWAG! Become a CardioNerds Patron!

CardioNerds (Amit Goyal, Daniel Ambinder) and special co-host Dr. Mark Belkin, join the Journal of Cardiac Failure Family to discuss the 2022 AHA/ACC/HFSA Guideline for The Management of Heart Failure. The JCF Editor-In-Chief Dr. Robert Mentz, Deputy Editor Dr. Anu Lala, and FIT editors — Dr. Vanessa Bluemer, Dr. Ashish Corrhea, and Dr. Quinton Youmans — share their hot takes and practical takeaways from the guidelines. At JCF, we’re privileged to share this important document that will support improved care for those living with heart failure,” stated Editor-in Chief Dr. Robert J. Mentz and Deputy Editor Anu Lala. “The 2022 guidelines convey patient-centered updates regarding the language we use to communicate disease considerations (e.g., stages of HF) and practice-changing guidance around the diagnosis and management of HF including newer therapeutics (e.g., SGLT2i). There is an emphasis not only on managing HF but also on how to treat important comorbidities as part of the holistic care for patients living with HF.” 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure Executive Summary A Clinician’s Guide to the 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure by Dr. Michelle Kittleson CardioNerds Heart Success Series PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Guideline Top 10 Take-Home Messages – Guideline for The Management of Heart Failure 1. Guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (HFrEF) now includes 4 medication classes that include sodium-glucose cotransporter-2 inhibitors (SGLT2i). 2. SGLT2i have a Class of Recommendation 2a in HF with mildly reduced ejection fraction (HFmrEF). Weaker recommendations (Class of Recommendation 2b) are made for ARNi, ACEi, ARB, MRA, and beta blockers in this population. 3. New recommendations for HFpEF are made for SGLT2i (Class of Recommendation 2a), MRAs (Class of Recommendation 2b), and ARNi (Class of Recommendation 2b). Several prior recommendations have been renewed including treatment of hypertension (Class of Recommendation 1), treatment of atrial fibrillation (Class of Recommendation 2a), use of ARBs (Class of Recommendation 2b), and avoidance of routine use of nitrates or phosphodiesterase-5 inhibitors (Class of Recommendation 3: No Benefit). 4. Improved LVEF is used to refer to those patients with previous HFrEF who now have an LVEF >40%. These patients should continue their HFrEF treatment. 5.Value statements were created for select recommendations where high-quality, cost-effectiveness studies of the intervention have been published. 6. Amyloid heart disease has new recommendations for treatment including screening for serum and urine monoclonal light chains, bone scintigraphy, genetic sequencing, tetramer stabilizer therapy, and anticoagulation. 7. Evidence supporting increased filling pressures is important for the diagnosis of HF if the LVEF is >40%. Evidence for increased filling pressures can be obtained from noninvasive (e.g., natriuretic peptide, diastolic function on imaging) or invasive testing (e.g., hemodynamic measurement). 8. Patients with advanced HF who wish to prolong survival should be referred to a team specializing in HF. A HF specialty team reviews HF management, assesses suitability for advanced HF therapies, and uses palliative care including palliative inotropes where consistent with the patient’s goals of care. 9. Primary prevention is important for those at risk for HF (stage A) or pre-HF (stage B). Stages of HF were revised to emphasize the new terminologies of “at risk” for HF for stage A and pre-HF for stage B. 10.Recommendations are provided for select patients with HF and iron deficiency, anemia, hypertension, sleep disorders, type 2 diabetes, atrial fibrillation, coronary artery disease, and malignancy.