Cardionerds: A Cardiology Podcast

It’s another session of CardioNerds Rounds! In these rounds, Dr. Loie Farina (Advanced Heart Failure and Transplant Fellow at Northwestern University) joins Dr. Jane Wilcox (Chief of the Section of Heart Failure Treatment and Recovery at Northwestern University) to discuss the nuances of HFpEF diagnosis and management. Dr. Wilcox is also the Associate Director of the T1 Center for Cardiovascular Therapeutics in the Bluhm Cardiovascular Institute and Director of the Myocardial Recovery Clinic at Northwestern University. Dr. Wilcox is a prolific researcher, clinician, and thought leader in Heart Failure and we are honored to have her on CardioNerds Rounds! Notes were drafted by Dr. Karan Desai. Audio editing by CardioNerds Academy Intern, student doctor Akiva Rosenzveig. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. This episode is supported with unrestricted funding from Zoll LifeVest. A special thank you to Mitzy Applegate and Ivan Chevere for their production skills that help make CardioNerds Rounds such an amazing success. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. Case details are altered to protect patient health information. CardioNerds Rounds is co-chaired by Dr. Karan Desai and Dr. Natalie Stokes.  Speaker disclosures: None Challenging Cases – Atrial Fibrillation with Dr. Hugh Calkins CardioNerds Rounds PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes – HFpEF Diagnosis and Management Case #1 Synopsis: A woman in her 80s with a history of HFpEF presented with worsening dyspnea on exertion over the course of a year but significantly worsening over the past two months. Her other history includes prior breast cancer with chemotherapy and radiation therapy, permanent atrial fibrillation with AV node ablation and CRT-P, and CKD Stage III. She presented for an outpatient RHC with exercise to further characterize her HFpEF. Her echo showed normal LV size, no LVH, LVEF of 50%, decreased RV systolic function, severe left atrial enlargement, significantly elevated E/e’ and mild MR. Right heart catheterization showed moderately elevated bi-ventricular filling pressures at rest but with passive leg raise and Stage 1 exercise the wedge pressure rose significantly. We were asked to comment on management. Case #1 Takeaways Amongst the things that were discussed were the role of specific therapies in symptomatic patients with HFpEF. In patients with HFpEF and documented congestion, they will require diuretic therapy for symptomatic relief. But in addition to diuretic therapy, we discussed starting HFpEF-specific therapies. Amongst, those specific therapies mineralocorticoid receptor antagonist (MRA) and sodium-glucose co-transporter 2 (SGLT2) inhibitor. In multiple trials that have included patients with HFPEF, SGLT2i have reduced the risk of hospitalization. This includes the EMPEROR-PRESERVED Trial (see the CardioNerds Journal Club discussion on the trial) in which nearly 6000 patients with NYHA Class II-IV symptoms, EF > 40% and elevated NT-proBNP with a prior HF hospitalization within the past 12 months were randomized to Empagliflozin or placebo. The primary outcome – death from CV causes or hospitalization for Heart Failure – was significantly lower in the SGLT2i arm (13.8% vs 17.1%, 95% CI 0.69-0.90, P <0.001). In regards to MRA, an important trial was the TOPCAT trial which randomized patients with symptomatic HF and LVEF > 45% to receive either spironolactone or placebo. The primary endpoint (death from CV cause, aborted cardiac arrest, or hospitalization for HF) was not statistically different between treatment arms. Of note, however, there were concerns for regional differences which is outlined well in this NEJM Evidence piece. Case #2 Synopsis: A woman in her 70s with history of hypertension, obesity, and COPD presented to the office for an evaluation of dyspnea. She had noted two years of dyspnea with moderate exercise and had developed lower extremity swelling. She had an echocardiogram that showed normal LV size and function, no LVH, global longitudinal strain at -21% (normal), grade 1 diastolic dysfunction and mild left atrial enlargement. Amongst the initial questions we were asked was how would we approach the diagnostic evaluation of her dyspnea? Case #2 Takeaways There were several things we covered with Dr. Wilcox regarding this patient. One of the things we discussed was whether the patient has HFpEF and then concomitantly, if we suspect and confirm HFpEF, attempting to elucidate an etiology for the patient’s HFpEF. There are diagnostic scores, such as the H2FPEF score that can estimate the probability of HFpEF versus a non-cardiac cause of a patient’s symptoms. There are limitations to the scoring systems – including echocardiographic parameters that may not be available at point of care or prone to error – but it can refine a clinician’s pre-test probability for HFpEF. Amongst other testing, an important note is that coronary artery disease is common in patients with HFpEF and may be a potentially treatable and reversible cause of HFpEF. Thus, evaluation for ischemia is recommended and given a Class IIa recommendation in the 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure. References – HFpEF Diagnosis and Management Anker SD, Butler J, Filippatos G et al; EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021 Oct 14;385(16):1451-1461. doi: 10.1056/NEJMoa2107038. Epub 2021 Aug 27. PMID: 34449189. Heidenreich P, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2022 May, 79 (17) e263–e421. Pfeffer MA, Claggett B, Assmann SF et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Circulation2015; 131:34-42.25406305 Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med2014; 370:1383-1392. 10.1056/NEJMoa1313731 24716680. Reddy YNV, Carter RE, Obokata M et al. A Simple, Evidence-Based Approach to Help Guide Diagnosis of Heart Failure With Preserved Ejection Fraction. Circulation. 2018 Aug 28;138(9):861-870. doi: 10.1161/CIRCULATIONAHA.118.034646. PMID: 29792299; PMCID: PMC6202181. Production Team Karan Desai, MD Natalie Stokes, MD Amit Goyal, MD Daniel Ambinder, MD

As the burden of cardiovascular disease increases in the United States, the importance of enhanced screening tools, early risk prediction, and prevention strategies grows. Novel risk scoring methods, including polygenic risk scores (PRS), may help identify patients that benefit from early intervention and risk modification. In this episode, we discuss how a PRS is calculated, how to incorporate a PRS into clinical practice, and current barriers to the equitable implementation of risk scores. In terms of frontiers in clinical genetics we also discuss the burgeoning field of pharmacogenetics and how pharmacogenetics may be used to identify responders and non-responders to certain therapies. Join CardioNerds Dr. Jessie Holtzman (CardioNerds Academy Chief and Chief Resident and soon FIT at UCSF), Dr. Alaa Diab (CardioNerds Academy Fellow and Medicine Resident at GBMC), and student doctor Hirsh Elhence (CardioNerds Academy Intern and medical student at USC Keck School of Medicine) as they discuss frontiers in clinical genetics with Dr. Pradeep Natarajan (Director of Preventive Cardiology, Massachusetts General Hospital). Audio editing by CardioNerds Academy Intern, student doctor Akiva Rosenzveig. This episode was developed in collaboration with the American Society of Preventive Cardiology and is supported with unrestricted educational funds from Illumina, Inc. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. This CardioNerds Cardiovascular Genomics series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Pearls • Notes • References CardioNerds Cardiovascular Genomics PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls – Frontiers in Clinical Genetics in Cardiovascular Prevention For common diseases like coronary artery disease, rare mutations may confer a several-fold increased risk of disease – for instance, in familial hypercholesterolemia, a single rare mutation may confer as much as a three-fold increase in risk of coronary artery disease. However, for most common diseases, the overall cumulative impact of several common genetic variants may be greater than that of a monogenetic trait. Family history is a particularly coarse predictor of CV risk, highlighting the need for polygenic risk scores. In particular, younger patients with borderline cardiovascular risk may benefit from the use of a polygenic risk score in the determination of their overall cardiovascular risk profile. A polygenic risk score (PRS) is a weighted sum of several risk-conferring alleles. The weight assigned to an allele is determined by the strength of the association between the allele and CV disease, as determined by genome-wide association studies (GWAS). The data used for genome-wide associated studies in cardiovascular disease have historically included populations primarily of European ancestry. However, more data is being collected from diverse patient cohorts to increase the external validity and broader applicability of such studies. Pharmacogenetic polygenic risk scores may be used to predict drug efficacy and toxicity, as well as to identify biologically plausible drug targets for clinical trial design. Show notes – Frontiers in Clinical Genetics in Cardiovascular Prevention What is a polygenic risk score (PRS)? Monogenic conditions are those in which a variant in a single gene causes a pathological phenotype. For example, familial hypercholesterolemia is often the result of a mutated allele in the LDL receptor gene. In contrast, polygenic risk suggests that there are variants in multiple genes that all confer risk independently, each with a small individual effect size. By aggregating many variants, a risk score may be able to provide an estimate as to the degree of one’s risk of cardiovascular disease. By comparing the allele frequencies of genes between patients with and without cardiovascular disease, risk-conferring alleles may be identified. These studies are called genome-wide association studies (GWAS). From GWAS, PRS can then be calculated by aggregating several risk-conferring alleles. What is the clinical utility of PRS? Current uses of PRS Family history is a coarse predictor of CV disease. The addition of a PRS to a risk assessment may improve the clinician’s ability to risk stratify patients. Calculating PRS can help identify patients who need early intervention, even in the absence of traditional risk factors (such as hypercholesterolemia or diabetes mellitus). For example, imagine a patient in the top 20th percentile for polygenic risk with a relatively normal LDL. Despite the lack of hyperlipidemia, some evidence may suggest that a statin or aggressive lifestyle modification would lower CV risk in this patient. In particular, for younger patients with borderline CV risk (as measured by traditional risk factors such as blood pressure, age, etc.), a high PRS might promote aggressive lifestyle modification or pharmacotherapy. Potential future uses Pharmacogenomics – Understanding a patient’s genotype may help identify responders and non-responders to certain medications. For example, CYP2C19 is an enzyme that aids in the activation of Clopidogrel. Therefore, patients with a mutation in CYP2C19 may not respond as robustly to Clopidogrel and therefore alternate pharmacotherapy would be recommended. What are the barriers to equity? Historically, GWAS studies largely enrolled patients of European ancestry. As such, the external validity of PRS outside of populations of European descent has been questioned. The NIH has prioritized capturing data from more diverse cohorts, associated with an increase in databases including patients of more varied ancestry. The availability of direct-to-consumer genome sequencing kits may make calculating PRS more feasible for the broader population. However, such tests remain limited in their utility without interpretation by genetic counselors or cardiovascular geneticists. References – Frontiers in Clinical Genetics in Cardiovascular Prevention Khera AV, Chaffin M, Aragam KG, Haas ME, Roselli C, Choi SH, Natarajan P, Lander ES, Lubitz SA, Ellinor PT, Kathiresan S. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018 Sep;50(9):1219-1224. doi: 10.1038/s41588-018-0183-z. Epub 2018 Aug 13. PMID: 30104762; PMCID: PMC6128408. O’Sullivan JW, Raghavan S, Marquez-Luna C, Luzum JA, Damrauer SM, Ashley EA, O’Donnell CJ, Willer CJ, Natarajan P; American Heart Association Council on Genomic and Precision Medicine; Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease. Polygenic Risk Scores for Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2022 Aug 23;146(8):e93-e118. doi: 10.1161/CIR.0000000000001077. Epub 2022 Jul 18. PMID: 35862132.

In this episode, we discuss the utility of veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) for the temporary management of biventricular failure and cardiogenic shock requiring full cardiopulmonary support. Here, we define the types of ECMO and describe the unique physiology of this mechanical circulatory support platform, as well as review the potential complications and management strategies. Most notably, we highlight indications for and contraindications to the use of VA-ECMO and review the importance of patient selection.  Lastly, we discuss de-escalation and de-cannulation strategies for patients on VA-ECMO as a bridge to recovery. Join Dr. Amit Goyal (CardioNerds Cofounder and FIT at Cleveland Clinic), Dr. Yoav Karpenshif (Series Co-chair and FIT at University of Pennsylvania), and Dr. Megan Burke (Episode FIT Lead and FIT at University of Pennsylvania) as they learn about how to care for some of our sickest patients from Dr. Ann Gage, interventional and critical care cardiologist at Centennial Heart. At the beginning of the episode, enjoy a message from the very first CardioNerds Scholar, Dr. Katie Vaughan (Chief Resident and soon Cardiology Fellow at BIDMC). Episode notes were developed by Dr. Megan Burke. Audio editing by CardioNerds Academy Intern, Hirsh Elhence. The CardioNerds Cardiac Critical Care 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. Mark Belkin, Dr. Eunice Dugan, Dr. Karan Desai, and Dr. Yoav Karpenshif. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Pearls • Notes • References • Production Team CardioNerds Cardiac Critical Care 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 – Biventricular Failure and the Use of VA-ECMO Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a form of temporary mechanical circulatory support that can do the work of both the heart and lungs. The ECMO circuit is a narcissist, i.e. cannulas are named in reference to the circuit and not the patient (“inflow” vs “outflow”). The decision to utilize ECMO should be made by a multidisciplinary shock team and patient selection is KEY! ECMO physiology rule #1: VA-ECMO increases LV afterload Patients on VA-ECMO should be monitored with a PA catheter and an arterial line in the right arm Show notes – Biventricular Failure and the Use of VA-ECMO Notes drafted by Dr. Megan Burke. 1. What is ECMO and what are the different types? Extracorporeal membrane oxygenation (ECMO) is a temporary form of mechanical life support that comes in two flavors: veno-arterial, or “VA” and veno-venous, or “VV.”  VV-ECMO supports extracorporeal gas exchange in the setting of acute respiratory failure VA-ECMO provides full circulatory support in addition to gas exchange, doing the work of both the heart and lungs.  2. What are the components and “anatomy” of the VA-ECMO circuit? The circuit is made up of the following major components: Venous (inflow) cannula Centrifugal Pump Oxygenator (also responsible for CO2 removal) Arterial (outflow) cannula The cannulas are named in reference to the ECMO circuit, not the patient. Dr. Gage suggests that we think of the ECMO circuit (and mechanical circulatory support in general) as narcissistic, i.e. flow is always in reference to the device. Gas exchange happens in the oxygenator. In the oxygenator blood flows through thin filaments that allow for diffusion of oxygen and carbon dioxide. Gas flows in the opposite direction of blood flow to maximize diffusion through the countercurrent effect. Oxygenation is determined by rate of blood flow through the oxygenator and FiO2 delivered. Carbon dioxide removal is determined by rate of countercurrent gas flow, referred to as the sweep speed. 3. What are the indications for VA-ECMO? VA-ECMO is utilized in the setting of severe refractory cardiogenic shock (in the setting of left, right, or biventricular failure) and cardiac arrest. It is a temporary mechanical circulatory support platform, and should be used as a bridge to recovery or a more durable therapy (i.e. durable mechanical support or transplant). Due to lack of randomized data, there are no consensus guidelines for the use of VA-ECMO, and the decision to implement it should be made as part of a multidisciplinary cardiogenic shock team. Common indications include cardiogenic shock, refractory ventricular arrhythmias, massive pulmonary embolism, cardiac arrest, and failure to wean from cardiopulmonary bypass during surgery. The absolute and relative contra-indications to ECMO vary by institution. Given the high mortality rates for patients on VA-ECMO (hospital mortality is approximately 50%, and 6-month survival is as low as 30%), patient selection is key. There are multiple pre VA-ECMO risk factors independently associated with poor outcomes. These include older age, female sex, higher body mass index, and markers of increased severity of illness including laboratory evidence of end-organ dysfunction and longer duration of mechanical ventilation. 4. What are the pathophysiological consequences of VA-ECMO and how do we monitor and treat them? The goal of VA-ECMO is to provide perfusion, however unlike other forms of mechanical circulatory support, it is NOT supporting the heart’s ability to pump blood. In fact, VA-ECMO increases left ventricular afterload, because blood enters the aorta from the outflow cannula somewhere between the aortic root and the diaphragm (depending on cannulation strategy). This creates increased aortic pressure and increased left ventricular volume and afterload, which can lead to pulmonary edema and worsened myocardial demand. In the most extreme cases, the aortic pressure can exceed the left ventricular systolic pressure, thereby preventing blood from ejecting from the LV. This can lead to stasis, thrombus formation, and strokes. For this reason, echocardiography is used frequently to monitor LV ejection. One key marker is the opening of the aortic valve with every beat. Furthermore, hemodynamic monitoring with a pulmonary artery catheter and a RIGHT radial arterial line is essential for management of patient’s on ECMO. The PA catheter allows for an estimation of the filling pressures. Of note, the mixed venous O2 cannot be used to estimate cardiac output when a patient is on VA-ECMO, but low levels still do correlate with poor tissue perfusion and worse outcomes. In general, it is essential to have an arterial catheter in a patient on VA-ECMO to monitor for arterial pulsatility, which is a surrogate for the contribution of the patient’s heart to perfusion. Specifically, a RIGHT radial arterial line is key in these patients because blood from it originates the brachiocephalic artery, which is the closest branch in the aortic arch to the coronary arteries and great vessels of the aortic arch and therefore best estimates the oxygen content in the coronaries and brain. This is key because when a patient is on peripheral VA-ECMO, oxygenated blood arrives to the heart retrograde from the femoral artery. If the left ventricle retains or regains contractility, the poorly oxygenated blood from the lungs (in patients with concurrent significant respiratory failure) is ejected into the proximal aorta. This can lead to the so called “North-south” or “Harlequin” syndrome, where the head and right upper extremity are relatively hypoxic compared to the rest of the body. Arterial blood gases from a right radial arterial line can forewarn of possible coronary and cerebral hypoxia during LV recovery as this syndrome develops and the “mixing” cloud develops. For patients with poor ejection, there are various strategies to decompress, or “vent,” the left ventricle. Strategies include use of medicines to reduce afterload and/or improve inotropy, creation of an atrial septal defect to offload the left heart, and use of temporary mechanical circulatory support devices (IABP or percutaneous LVAD) to allow blood to more easily leave the LV. Treatment of the North-South Syndrome focuses on increasing the oxygenation of blood ejecting from the left ventricle through vent management or adding another venous catheter to pre-oxygenate blood before entering the lungs (VAV-ECMO). Increasing VA-ECMO flow can also shift the mixing zone towards the aortic arch and improve oxygenation, but this will also increase the LV afterload. Other complications of the ECMO circuit include infection, bleeding, and limb ischemia (due to the large bore vascular access), as well as stroke, hemolysis, and thrombus formation (due to the extracorporeal circuitry). 5. How is VA-ECMO weaned? If a patient is on VA-ECMO support as a bridge to recovery, the ability to wean a patient off the circuit relies on invasive hemodynamics, echocardiography, and an assessment of improving end-organ function. The flow of blood out of the circuit can be gradually weaned down to allow for the patient’s native heart to do more of the work of perfusion. Once the patient is thought to be ready for decannulation it is common to perform a turndown study under echocardiographic guidance, where serial evaluations of biventricular function are done at different flow speeds. VA-ECMO is usually decannulated in the operating room to allow for surgical repair of the vasculature in the setting of large bore access. References – Biventricular Failure and the Use of VA-ECMO Papolos AI, Kenigsberg BB, Berg DD, Alviar CL, Bohula E, Burke JA, Carnicelli AP, Chaudhry SP, Drakos S, Gerber DA, Guo J, Horowitz JM, Katz JN, Keeley EC, Metkus TS, Nativi-Nicolau J, Snell JR, Sinha SS, Tymchak WJ, Van Diepen S, Morrow DA, Barnett CF; Critical Care Cardiology Trials Network Investigators. Management and Outcomes of Cardiogenic Shock in Cardiac ICUs With Versus Without Shock Teams. J Am Coll Cardiol. 2021 Sep 28;78(13):1309-1317. doi: 10.1016/j.jacc.2021.07.044. PMID: 34556316. Burkhoff D, Sayer G, Doshi D, Uriel N. Hemodynamics of Mechanical Circulatory Support. J Am Coll Cardiol. 2015;66(23):2663-2674. doi:10.1016/j.jacc.2015.10.017 Guglin M, Zucker MJ, Bazan VM, et al. Venoarterial ECMO for Adults: JACC Scientific Expert Panel. J Am Coll Cardiol. 2019;73(6):698-716. doi:10.1016/j.jacc.2018.11.038 Keebler ME, Haddad EV, Choi CW, et al. Venoarterial Extracorporeal Membrane Oxygenation in Cardiogenic Shock. JACC Heart Fail. 2018;6(6):503-516. doi:10.1016/j.jchf.2017.11.017 Rao P, Khalpey Z, Smith R, Burkhoff D, Kociol RD. Venoarterial Extracorporeal Membrane Oxygenation for Cardiogenic Shock and Cardiac Arrest. Circ Heart Fail. 2018;11(9):e004905. doi:10.1161/CIRCHEARTFAILURE.118.004905 Tehrani BN, Truesdell AG, Psotka MA, et al. A Standardized and Comprehensive Approach to the Management of Cardiogenic Shock. JACC Hear Fail. 2020;8(11):879-891. doi:10.1016/j.jchf.2020.09.005 Grant C, Richards JB, Frakes M, Cohen J, Wilcox SR. ECMO and Right Ventricular Failure: Review of the Literature. J Intensive Care Med. 2021;36(3):352-360. doi:10.1177/0885066619900503  Debaty G, Babaz V, Durand M, et al. Prognostic factors for extracorporeal cardiopulmonary resuscitation recipients following out-of-hospital refractory cardiac arrest. A systematic review and meta-analysis. Resuscitation. 2017;112:1-10. doi:10.1016/j.resuscitation.2016.12.011 Russo JJ, Aleksova N, Pitcher I, et al. Left Ventricular Unloading During Extracorporeal Membrane Oxygenation in Patients With Cardiogenic Shock. J Am Coll Cardiol. 2019;73(6):654-662. doi:10.1016/j.jacc.2018.10.085 ELSO General Guidelines Extracorporeal Life Support Organization (ELSO) General Guidelines for All ECLS Cases.; 2017. www.elso.org. Accessed April 10, 2021. Su Y, Liu K, Zheng JL, Li X, Zhu DM, Zhang Y, Zhang YJ, Wang CS, Shi TT, Luo Z, Tu GW. Hemodynamic monitoring in patients with venoarterial extracorporeal membrane oxygenation. Ann Transl Med. 2020 Jun;8(12):792. doi: 10.21037/atm.2020.03.186. PMID: 32647717; PMCID: PMC7333156. CardioNerds Cardiac Critical Care Production Team

The CardioNerds Cardiovascular Genomics Series continues! In this episode Dr. Dan Ambinder (CardioNerds Cofounder and Interventional Cardiologist), Dr. Anjali Wagle (FIT Ambassador at Johns Hopkins) and Dr. James Sampognaro (medicine resident at Johns Hopkins Osler Medicine Residency) learn from Dr. Allison Hays (Associate Professor of Medicine, Division of Cardiology, Johns Hopkins CMR researcher and Medical Director of Echocardiography) and Dr. Cindy James (Associate Professor of Medicine and certified genetic counselor at Johns Hopkins with research focusing on cardiovascular genetic counseling and arrhythmogenic cardiomyopathies). They discuss arrhythmogenic RV cardiomyopathy as the context to learn about genetic counseling and family screening.  Episode script and notes were developed by Dr. Anjali Wagle. Audio editing by CardioNerds Academy Intern, student doctor Chelsea Amo Tweneboah. This episode was developed in collaboration with the American Society of Preventive Cardiology and is supported with unrestricted educational funds from Illumina, Inc. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. This CardioNerds Cardiovascular Genomics series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs. Check out this REVIEW describing the “Multimodality Imaging in Arrhythmogenic Right Ventricular Cardiomyopathy” by Nitin Malik, Allison Hays, and colleagues.   For related episodes, please enjoy these case-based discussions:  Ep 56. Case Report: Arrhythmogenic Desmoplakin Cardiomyopathy – Northwestern University  Ep 74. Case Report: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) – Summa Health  Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Pearls • Notes • References CardioNerds Cardiovascular Genomics PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes – Genetic Counseling & Family Screening in Arrhythmogenic Cardiomyopathies Notes (developed by Dr. Anjali Wagle)   What is the underlying pathophysiology of arrhythmogenic RV cardiomyopathy (ARVC)?  Fibrofatty replacement cardiac myocytes  Associated with genetically mediated disruption of desmosomal proteins   This leads to thinning and weakness of the heart that can lead to aneurysms and progressive dilatation and failure of the right ventricle (RV)  How is ARVC diagnosed?  2010 taskforce criteria (Marcus et al, 2010):    RV structural abnormalities including findings seen on echocardiogram, MRI, and RV angiography  Pathological criteria  Repolarization abnormalities   Depolarization/conduction abnormalities   Ventricular arrhythmias   Genetics and/or family history   How does ARVC present?   Young, healthy individual will have symptoms of arrhythmias (syncope, pre-syncope, SCD) or heart failure  Family screening   What are the inheritance and genetic factors of ARVC?  Autosomal dominant pattern  Low penetrance and variable expressivity   Half of patients who are index cases will be found to have a mutation in the desmosomal gene.   What are the most common mutations associated with ARVC?  Most commonly the genes involved are plakophilin-2 (PKP-2) and desmoplakin.   For PKP-2 the most common mutations are truncating mutations.   In patients who have inherited two truncating mutations, this will result in neonatal lethality.   Is there a difference in the genetic factors of left and right arrhythmogenic cardiomyopathy?   ACM is disproportionally a right dominated cardiomyopathy. Left dominated cardiomyopathy has a different genetic profile.   Pathogenic variants in desmoplakin disproportionally cause biventricular forms of ACM or left dominated forms.   What are the echocardiographic findings in ACM?  Wall thinning and aneurysmal dilation in the sub-tricuspid region, RV outflow tract, or base also known as the “triangle of dysplasia.”  Progression of disease tends to be from the base to the apex.  Why is cardiac MRI the preferred imaging modality in ACM?  Higher spatial resolution and improved visualization of the right ventricle  Can imaging help define prognosis in ACM?  Top two strongest measures of prognostic value in ACM are:  RV fractional change area < 33%  Tricuspid annular plane systolic exertion < 1.7cm   References – Genetic Counseling & Family Screening in Arrhythmogenic Cardiomyopathies Malik, N., Mukherjee, M., Wu, K. C., Zimmerman, S. L., Zhan, J., Calkins, H., James, C. A., Gilotra, N. A., Sheikh, F. H., Tandri, H., Kutty, S., & Hays, A. G. (2022). Multimodality Imaging in Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation. Cardiovascular Imaging, 15(2), e013725. https://doi.org/10.1161/CIRCIMAGING.121.013725  Marcus FI, McKenna WJ, Duane S, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MGPJ, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DMY, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia. Circulation. 2010;121:1533–1541.  

Congenital heart disease is the most common birth defect, affecting 1 in 100 babies. Amongst these ventricular septal defects are very common with the majority of patients living into adulthood. In this episode we will be reviewing key features of VSDs including embryologic origin, anatomy, physiology, hemodynamic consequences, clinical presentation and management of VSDs. Dr. Tommy Das (CardioNerds Academy Program Director and FIT at Cleveland Clinic), Dr. Agnes Koczo (CardioNerds ACHD Series Co-Chair and FIT at UPMC), and Dr. Anu Dodeja (Associate Director for ACHD at Connecticut Children’s) discuss VSDs with expert faculty Dr. Keri Shafer. Dr. Shafer is an adult congenital heart disease specialist at Boston Children’s Hospital, and an assistant professor of pediatrics within Harvard Medical School. She is a medical educator and was an invited speaker for the inaugural CardioNerds Sanjay V Desai Lecture, on the topic of growth mindset. Script and notes were developed by Dr. Anu Dodeja. Audio editing by CardioNerds Academy Intern, Shivani Reddy. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. The CardioNerds Adult Congenital Heart Disease (ACHD) series provides a comprehensive curriculum to dive deep into the labyrinthine world of congenital heart disease with the aim of empowering every CardioNerd to help improve the lives of people living with congenital heart disease. This series is multi-institutional collaborative project made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Josh Saef, Dr. Agnes Koczo, and Dr. Dan Clark. The CardioNerds Adult Congenital Heart Disease Series is developed in collaboration with the Adult Congenital Heart Association, The CHiP Network, and Heart University. See more Disclosures: None Pearls • Notes • References • Guest Profiles • Production Team CardioNerds Adult Congenital Heart Disease PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls – Ventricular Septal Defects Most common VSDs: Perimembranous VSD The shunt volume in a VSD is determined largely by the size of the defect and the pulmonary vascular resistance. VSDs cause left to right shunt. The long-term effects are left sided chamber dilation, as is the case with PDAs (post-tricuspid shunts) VSDs can be associated with acquired RVOTO, double chamber right ventricle, LVOTO/sub aortic membrane formation, and aortic regurgitation from aortic valve prolapse. Eisenmenger syndrome results from long-term left-to-right shunt, usually at higher shunt volumes. The resulting elevated pulmonary artery pressure is irreversible and leads to a reversal in the ventricular level shunt, desaturation, cyanosis, and secondary erythrocytosis. Endocarditis prophylaxis is not indicated for simple VSD. It is required for 6 months post VSD closure, in patients post VSD closure with a residual shunt and in Eisenmenger patients with R—>L shunt and cyanosis. Show notes – Ventricular Septal Defects Notes (developed by Dr. Anu Dodeja): What are types OF VSD? (Please note that there are several nomenclatures) Perimembranous VSD Most common type of VSD – 80% of VSDs Occurs in the membranous septum and can be associated with inlet or outlet extension Located near the tricuspid and aortic valves, often time can be closed off by tissue from the septal leaflet of the tricuspid valve and associated with abnormalities in the septal leaflet of the tricuspid valve secondary to damage from the left to right shunt Can be associated with acquired RVOTO, double chamber right ventricle, LVOTO/sub aortic membrane formation On TTE, the parasternal short axis view at the base demonstrates this type of VSD at the 10-12 o’clock position. Muscular VSD Second most common VSD – 15-20% of VSDs Completely surrounded by muscle, usually restrictive, can be multiple defects These usually close spontaneously by direct apposition of the muscular borders. Supracristal (also known as sub-arterial/sub-pulmonary/conal/juxta-arterial) Represent 5% of VSDs Located beneath the semilunar valves in the conal or outlet septum Do not usually close spontaneously May be associated with progressive aortic regurgitation due to prolapse of the right aortic cusp and aneurysm of the sinus of Valsalva. Aortic valve prolapse: Prolapsing of the right or non-coronary aortic valve cusp may initially reduce the degree of left-to-right shunt but results in development of aortic regurgitation Aortic valve prolapse usually involves the right coronary cusp and less frequently the non-coronary cusp  In its early stage: prolapse occurs only in the systolic phase because of the venturi effect resulting from the rapid shunt flow through the defect In later stages the prolapse also present last with the valve cusps cannot withstand intra-aortic pressure.  Eventually the prolapsing aortic valve becomes incompetent because of the significant damage to the valve cusps and annulus As a prolapsing aortic valve may completely close the ventricular septal defect, shunt physiology may disappear with progressive development of aortic regurgitation Some case reports of aneurysms of sinus of Valsalva indicate that the original defect might be ventricular septal defect complicated by aortic valve prolapse with complete obliteration of the defect Rarely the prolapsed valve cusp may perforate with resultant aortic regurgitation into the right ventricle On TTE, the parasternal short axis view at the base demonstrates these VSDs at the 12 to 2 o’clock position Inlet/AV canal type Occur in the inlet portion of the ventricular septum immediately inferior to the AV valve apparatus Can be associated with a common AV valve May be associated with AV septal malalignment and straddling Due to endocardial cushion defect AVSD are the most common CHD in patients with Down syndrome. Malalignment type of VSDs Occur in the output or infundibular septum Malalignment of the outlet septum may occur either anteriorly towards the right ventricle or posteriorly towards the left ventricle The anterior malalignment of the outlet septum is the most common type of malalignment. In this situation the outlet septum is pulled anteriorly towards the right ventricular outflow tract resulting in a large ventricular septal defect with overriding aortic valve and pulmonary stenosis as seen in Tetralogy of Fallot. Posterior malalignment results in sub-aortic obstruction and can be associated with Coarctation of aorta and IAA. Rarely patients can have a LV-RA shunt known as a Gerbode defect Absence of the atrioventricular septal tissue resulting in an isolated LV to RA shunt Can occur when the VSDs located slightly more superior to the tricuspid valve apparatus Can also be due to deficient tricuspid valve septal leaflet Can occur as a post-operative complication The effective impact of such a shunt is to produce right ventricular volume overload and elevated right atrial pressure and are at increased risk for endocarditis. If VSDs are left to right shunts, why do they cause left sided chamber dilation? The timing of the left to right shunt in ventricular septal defects is predominantly in ventricular systole so the blood goes left to right but is pumped directed out the PA resulting in increased pulmonary venous return to the LA and LV. As such, the RV does not directly see the increased blood volume. There are a few cases in which there maybe RA dilation including: Gerbode defect, Eisenmenger syndrome, and DCRV. What are the indications for VSD repair? Evidence of left ventricular volume overload and hemodynamically significant shunt (Qp: Qs> 1.5:1), if PA pressures are less than 50% systemic and pulmonary vascular resistance is less than 1/3 systemic (2018 ACHD Guidelines) What is the relevance of the conduction system in the approach to VSDs? The nature of the VSD will also allow for understanding the course of the conduction system. Perimembranous defects – the bundle of His runs along the posterior and inferior rim of the VSD. Post-operatively, patients may have a right bundle branch block pattern on ECG. Patients are at risk for surgical CHB which can occur even years post-VSD closure. Inlet type VSD – the bundle of His runs anterior and superior to the defect which can be seen as a northwest axis deviation on EKG (-90 to 180°). Patients are at risk for surgical CHB, which can occur even years post-VSD closure. Surgically induced AV block is less likely with a muscular or supracristal/outlet type of defects because they are distant from the AV nose and bundle of His.  What are clinical exam features of VSDs? VSDs cause a holosystolic murmur if pressure in the right ventricle is lower than the left ventricle throughout systole, resulting in a holosystolic left-to-right shunt Small restrictive VSD will have a loud, harsh, holosystolic murmur usually with a thrill in the third or fourth ICS along the LSB Muscular VSDs can have shorter systolic murmurs Absence of VSD murmur, with a loud P2, RV heave is indicative of elevated RV pressures with equalization in ventricular pressures indicating Eisenmenger syndrome. These patents will also have cyanosis, clubbing, over time can have a holosystolic murmur due to functional TR Systolic ejection murmur at the LUSB may be indicative of RVOTO Presence of a diastolic murmur in the RUSB, wide pulse pressure, and prominent carotid pulses indicate AR What are imaging characteristics of VSDs? First and foremost will be location and size of the VSD Parasternal long axis view: Distinct visualization of muscular, membranous, and supracristal/infundibular VSDs Perimembranous and supracristal defects are seen below the aortic valve Can also show aortic cusp prolapse and associated aortic regurgitation Perimembranous VSDs are usually seen while sweeping in the PSL towards the tricuspid valve Parasternal short axis view: If you consider the aortic valve as a clock perimembranous defects would be in the 10 to 12o’clock position whereas an infundibular defect is adjacent to the pulmonary valve corresponding to the 12-2 o’clock position This view may show associated sinus of Valsalva aneurysm, AR, and DCRV Dr. Nadas proposed size of VSD based on comparison to the aortic valve Small <1/3 aortic size Medium 33-50% Large > 50% Apical view Inlet, muscular, and Gerbode defects Inlet VSDs are adjacent to the mitral and tricuspid valves extend into the chordal attachments of the tricuspid valve Muscular VSDs are located in the trabecular septum away from the cardiac valves Gerbode defects are best visualized within the cardiac crux on apical four-chamber view in which color flow Doppler demonstrates an LV-to-RA shunt Qp:Qs is generally not calculated by echocardiography due to technical limitations. However, the presence of LA and LV dilation represents a hemodynamically significant shunt with a QP: Qs >1.5:1. The presence of normal LA and LV size in an adult is suggestive of a small restrictive uncomplicated VSD with a small left-to-right shunt Additional features to assess: Is there tricuspid valve tissue partially closing the defect, direction and velocity of shunt, restrictive defect will be high velocity shunts, TR to estimate RVSP, septal configuration signs of PH, presence of DCRV, LVOTO, sub-aortic membrane CMR: If there is concern for LV dilation by ECHO, Cardiac MRI can give accurate measurement of ventricular volume and function Such data are helpful in determining timing of intervention or repair in adults with VSDs CMR phase contrast cine techniques enable quantification of Qp:Qs which correlates strongly with results obtained by cardiac catheterization. May be helpful for assessment of coexisting lesions in the pulmonary artery, pulmonary veins, or aorta. What is Double Chamber RV? RVOT Obstruction from Muscle Bundles/Hypertrophy in context of VSD Can develop over time Most common with perimembranous defects; 3 -10% percent of patients with perimembranous VSDs Caused by hypertrophy of an aberrant muscle bundle that develops in the RV in the region of the membranous VSD jet flow RV is divided into two chambers: a proximal high-pressure chamber close to the tricuspid valve and a distal low-pressure chamber proximal to the pulmonary valve separated by the obstructive muscle bundle Protects against the development of PH There are reports of DCRV developing even after surgical repair of the VSD in the absence of a residual ventricular septal defect Other causes for acquired right ventricular outflow tract obstruction in patient with VSDs include hypertrophy and progressive obstruction of the malaligned infundibular septum which usually presents with a pre-existing pressure gradient between the right ventricle and pulmonary artery that progresses over time which changes in the infundibular septum A prolapsing aortic valve leaflet may also obstructed right ventricular outflow tract. Acquired right ventricular outflow tract obstruction may result in apparent reduction in the magnitude of the left-to-right shunting. What is Eisenmenger Syndrome? Patients with systemic-to-pulmonary communication, such as a nonrestrictive ventricular septal defect develop pulmonary vascular remodeling resulting elevated PVR and pulmonary hypertension and subsequent net right to left shunting and cyanosis Large left to right shunt causes increase in pulmonary blood flow which eventually leads to development of pulmonary vascular remodeling, pulmonary arteriolar intimal and medial hypertrophy, pulmonary vascular disease which results in increased PVR The increase in PVR causes an increase in pulmonary artery pressure PAH causes reversal of the shunt and net right-to-left shunting The elevated pulmonary artery pressure is irreversible and leads to a reversal in the ventricular level shunt, desaturation, cyanosis, and secondary erythrocytosis The risk of developing Eisenmenger syndrome appears to be determined by the size of the initial left-to-right shunt and the volume of pulmonary blood flow, with larger shunts having increased risk Diagnosis should be confirmed by cardiac catheterization and complete work up for other causes of PAH should also be performed. What are indications for infective endocarditis prophylaxis? Post VSD closure for the first 6 months S/p VSD closure with a residual shunt Eisenmenger Syndrome (R L shunt with cyanosis) Small restrictive VSD does NOT meet criteria for SBE prophylaxis References – Ventricular Septal Defects 1. Stout K, Daniels C, Aboulhosn J, et al. 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: Executive Summary. J Am Coll Cardiol. 2019 Apr, 73 (12) 1494–1563.https://doi.org/10.1016/j.jacc.2018.08.1028 2. Allen Hugh D, Driscoll D, Shady R, Feltes T. ed. Moss & Adams’ Heart Disease in Infants, Children, and Adolescents: Including the Fetus and Young Adult. Lippincott Williams & Wilkins; 8th edition, October 15, 2012 Meet Our Collaborators! Adult Congenital Heart AssociationFounded in 1998, the Adult Congenital Heart Association is an organization begun by and dedicated to supporting individuals and families living with congenital heart disease and advancing the care and treatment available to our community. Our mission is to empower the congenital heart disease community by advancing access to resources and specialized care that improve patient-centered outcomes. Visit their website (https://www.achaheart.org/) for information on their patient advocacy efforts, educational material, and membership for patients and providers CHiP Network The CHiP network is a non-profit organization aiming to connect congenital heart professionals around the world. Visit their website (thechipnetwork.org) and become a member to access free high-quality educational material, upcoming news and events, and the fantastic monthly Journal Watch, keeping you up to date with congenital scientific releases. Visit their website (https://thechipnetwork.org/) for more information. Heart UniversityHeart University aims to be “the go-to online resource” for e-learning in CHD and paediatric-acquired heart disease. It is a carefully curated open access library of educational material for all providers of care to children and adults with CHD or children with acquired heart disease, whether a trainee or a practicing provider. The site provides free content to a global audience in two broad domains: 1. A comprehensive curriculum of training modules and associated testing for trainees. 2. A curated library of conference and grand rounds recordings for continuing medical education. Learn more at www.heartuniversity.org/ CardioNerds Adult Congenital Heart Disease Production Team Amit Goyal, MD Daniel Ambinder, MD

The field of Cardiovascular Genomics has advanced tremendously over the past two decades, having a significant clinical impact and changing the perception of the role and scope of genetic testing in several cardiovascular domains.  To kickstart the Cardiovascular Genomics series, CardioNerds Dr. Sara Coles (FIT at Duke University), Dr. Colin Blumenthal (CardioNerds Academy faculty and FIT at UPenn), and Dr. Karla Asturias (CardioNerds Academy fellow and medicine resident at Pennsylvania Hospital) have a great discussion with Dr. James Daubert, a clinical electrophysiologist at Duke University, with a particular interest in inherited arrhythmia syndromes and sports cardiology. In this episode, we review basic concepts of cardiovascular genomics and genetics in electrophysiology while discussing when to (and when not to!) test our patients and their families and how to approach those results. Audio editing by CardioNerds academy intern, Pace Wetstein. This episode was developed in collaboration with the American Society of Preventive Cardiology and is supported with unrestricted educational funds from Illumina, Inc. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. This CardioNerds Cardiovascular Genomics series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Pearls • Notes • References CardioNerds Cardiovascular Genomics 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 – Genetics in Electrophysiology The first step is identifying the right phenotype! Getting the right phenotype is crucial, as genetic testing done in a patient without a clear phenotype (or an incorrect one) would lead to significant anxiety, unnecessary tests and interventions, and potentially misleading and dangerous conclusions for patients and their families. Genetic testing typically should be reserved for patients with a confirmed or suspected diagnosis of an inherited disease or for individuals with a previously diagnosed pathogenic variant in a first-degree relative.1 Discuss with your patient! Genetic counseling is essential and recommended for all patients before and after genetic testing. It should include a thorough discussion of risks, benefits, and possible outcomes, including variants of uncertain significance.2 Cardiovascular genetics is a dynamic and rapidly evolving field. New information can cause a variant of uncertain significance to be reclassified as a pathogenic or likely pathogenic variant or to be downgraded to benign or likely benign as variant databases expand. Another possibility is that new research might identify novel genes for a particular disease, which could warrant retesting, particularly for phenotype-positive and genotype-negative patients.1 Brugada syndrome is an inherited arrhythmogenic disorder characterized by ST-segment elevation in the right precordial leads and malignant ventricular arrhythmias, with occasional conduction disease and atrial arrhythmias. It is diagnosed in patients with ST-segment elevation ≥ 2 mm in ≥ 1 lead among the right precordial leads, with a type I morphology (J-point elevation with slowly descending or concave ST segment elevation merging into a negative T wave), shown in the image below. This pattern can be observed spontaneously or after provocative drug testing (e.g., procainamide). Pathogenic genetic variants in SCN5A that result in loss of function of the cardiac sodium channel are identified in approximately 20% of cases.3,4 Image adapted from Batchvarov VN. The Brugada Syndrome – Diagnosis, Clinical Implications and Risk Stratification. Eur Cardiol Rev. 2014;9(2):82. doi:10.15420/ECR.2014.9.2.82 Measure the QT interval yourself! A correct determination of the QT interval is essential. Although automatic measurements are widely available, the interval can be underestimated or overestimated, particularly in atrial arrhythmias or complex T-wave morphologies. Determining the end of the T-wave can be challenging in this setting, and can be assessed through the tangent method, which determines the end of the T-wave by the intersection between the baseline (U-P segment) and the “tangent” drawn to the steepest last limb of the presumed T-wave.5,6 Image adapted from Postema PG, De Jong JSSG, Van der Bilt IAC, Wilde AAM. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Hear Rhythm. 2008;5(7):1015-1018. doi:10.1016/J.HRTHM.2008.03.037 When encountering a patient with prolonged QT, it is essential to exclude secondary causes like QT-prolonging drugs and electrolyte imbalances. As the acute cause is removed and the acute illness resolves, “see what happens while the dust is settling” and reassess the QT. Show notes – Genetics in Electrophysiology Notes were developed by Dr. Karla Asturias: What are some key basic concepts in clinical genetics? A mutation is defined as a permanent change in the nucleotide sequence, while a polymorphism is a mutation that occurs in more than 1% of a particular population. While both terms are often used, it can lead to confusion due to incorrect assumptions of pathogenicity. Therefore, both terms have been replaced by the term genetic variant, which we now encounter in the literature and guidelines. Proband is the first presenting person in a family that serves as a starting point for a genetic study. The phenotype refers to the clinical syndrome observed in our patients, while the genotype relates to the genetic composition, including the presence or absence of any genetic variants. In the case of Brugada syndrome, the phenotype includes the type I Brugada pattern on ECG and the presence of ventricular arrhythmias. In many cases, the genotype consists of genetic variants in SCN5A that result in the loss of function of the cardiac sodium channel. While particular genotypes can cause disease, the expression of the clinical phenotype can vary, leading to incomplete penetrance, where only a proportion of individuals carrying a specific genetic variant manifest the phenotype. In patients with Brugada syndrome, there is variability in the frequency of ECG abnormalities, even with the same pathogenic variants. Among individuals with an SCN5A pathogenic variant, only 20-30% have an ECG diagnostic of Brugada syndrome, and approximately 80% manifest the characteristic ECG changes when challenged with a sodium channel blocker.4 Additionally, the Brugada phenotype has been reported to be 8 to 10 times more common in men than in women.7 Most cardiovascular diseases exhibit genetic heterogeneity, with mutations in multiple genes causing the same condition, meaning multiple genotypes can cause a similar phenotype. In the cases of congenital long QT syndrome and hypertrophic cardiomyopathy, multiple genes have been implicated in these conditions. How do we classify genetic testing results according to the American College of Medical Genetics and Genomics (ACMG) guidelines? The American College of Medical Genetics and Genomics (ACMG) guidelines are internationally accepted and describe standard terminology and methods in clinical genetic testing.8 They classify genetic variants into five different tiers: Pathogenic Likely pathogenic Variant of uncertain significance (VUS) Likely benign Benign It should be noted that, at present, we have no data to support a quantitative assignment of variant certainty to any of the five categories given the heterogenous nature of most diseases. A variant of uncertain significance does not provide a definitive genetic etiology of disease and should not be used for clinical decision-making nor to determine risk for disease in unaffected relatives. 9 Variant interpretation is a dynamic process, and classification may change over time as additional evidence about the variants becomes available. A negative result does not exclude the possibility of genetic disease but indicates that a causative variant could not be identified with the currently available technology and knowledge. What types of genetic testing are available, and when do we use them?3 Sanger sequencing Method of DNA sequencing for a single geneHigh accuracy and low cost, compared to broader genetic testingUsed during cascade family evaluation Panel sequencing Tests for a pre-specified “set” of genes related to a particular phenotype or clinical condition First-line diagnostic test for the proband Usually, tests for exons only Larger panels may be warranted for overlap or ambiguous phenotypes, with the recognition that larger panels may lead to the identification of more variants of uncertain significance For unequivocal phenotypes, targeted panels are preferred, as larger panels are unlikely to increase clinical yield and may introduce ambiguous results Whole-exome and whole-genome sequencing Comprehensive genetic characterization of coding regions only (exome) or entire genome Typically reserved for research settings, but can be considered in the evaluation in proband in very heterogenous conditions Non-sequencing testing is also available through PCR for pre-specified variants What is the role of genetic testing in the management of inherited cardiovascular diseases? 9 Genetic testing is used to identify the underlying genetic etiology in a patient with a known or suspected inherited cardiovascular disease.  Genetic testing is beneficial when the result alters the treatment, informs about the prognosis, and leads to testing in immediate family members. Common inherited cardiovascular diseases include Brugada syndrome, long QT syndrome, arrhythmogenic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia, Marfan syndrome, and familial hypercholesterolemia, among others. How do we approach patients with a confirmed or suspected diagnosis of an inherited cardiovascular disease? 1,3 A thorough and detailed disease-appropriate phenotyping and a comprehensive family history with at least three generations should be performed. Genetic testing should be considered if these elements strongly suggest an inherited cardiovascular disease. The patient should undergo pretesting genetic counseling, after which the patient and provider can make a shared decision as to whether to proceed with testing. As with any medical procedure, the patient should understand potential benefits, risks, and limitations before consenting, including the potential uncertainty related to the results. If the decision is made to proceed with genetic testing, the next step is to decide the scope of genetic testing. The choice of testing ranges from single genes to large gene panels, knowing that the broader the test, the bigger the risk of finding more variants of unknown significance. For the proband, a panel of genes is usually the first approach.The discussion of any genetic testing results should be accompanied by post-testing genetic counseling to help the patients understand the implication of the results for themselves and their family members.If a pathogenic or likely-pathogenic variant is found, cascade testing should be offered to first-degree relatives to assess their genetic predisposition for a known variant. Cascade testing is usually done by testing for the particular variant that was found in the proband. If variants of uncertain significance were found, a periodic review of the results should be performed to manage patients appropriately in light of new evidence and developments. References – Genetics in Electrophysiology Musunuru K, Hershberger RE, Day SM, et al. Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association. Circ Genomic Precis Med. 2020;13(4):E000067. doi:10.1161/HCG.0000000000000067 Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Hear Rhythm. 2011;8(8):1308-1339. doi:10.1016/J.HRTHM.2011.05.020 Wilde AAM, Semsarian C, Márquez MF, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases. Hear Rhythm. 2022;19(7):e1-e60. doi:10.1016/J.HRTHM.2022.03.1225 Batchvarov VN. The Brugada Syndrome – Diagnosis, Clinical Implications and Risk Stratification. Eur Cardiol Rev. 2014;9(2):82. doi:10.15420/ECR.2014.9.2.82 Postema PG, De Jong JSSG, Van der Bilt IAC, Wilde AAM. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Hear Rhythm. 2008;5(7):1015-1018. doi:10.1016/J.HRTHM.2008.03.037 Postema PG, Wilde AA. The Measurement of the QT Interval. Curr Cardiol Rev. 2014;10(3):287. doi:10.2174/1573403X10666140514103612 Benito B, Sarkozy A, Mont L, et al. Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol. 2008;52(19):1567-1573. doi:10.1016/J.JACC.2008.07.052 Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/GIM.2015.30 Cirino AL, Harris S, Lakdawala NK, et al. Role of Genetic Testing in Inherited Cardiovascular Disease: A Review. JAMA Cardiol. 2017;2(10):1153-1160. doi:10.1001/JAMACARDIO.2017.2352 Supplementary bibliography: Eifling M, Razavi M, Massumi A. The Evaluation and Management of Electrical Storm. Texas Hear Inst J. 2011;38(2):111. Accessed April 16, 2022. /pmc/articles/PMC3066819/ Lahrouchi N, Raju H, Lodder EM, et al. Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome. J Am Coll Cardiol. 2017;69(17):2134-2145. doi:10.1016/J.JACC.2017.02.046 Honarbakhsh S, Providencia R, Garcia-Hernandez J, et al. A Primary Prevention Clinical Risk Score Model for Patients With Brugada Syndrome (BRUGADA-RISK). JACC Clin Electrophysiol. 2021;7(2):210-222. doi:10.1016/J.JACEP.2020.08.032 Towbin JA, McKenna WJ, Abrams DJ, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Hear Rhythm. 2019;16(11):e301-e372. doi:10.1016/J.HRTHM.2019.05.007 Seidelmann SB, Smith E, Subrahmanyan L, et al. Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults. Circ Cardiovasc Genet. 2017;10(1). doi:10.1161/CIRCGENETICS.116.001573 Nafissi NA, Abdulrahim JW, Kwee LC, et al. Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics. Circ Genomic Precis Med. Published online September 22, 2022. doi:10.1161/CIRCGEN.121.003675 Grondin S, Davies B, Cadrin-Tourigny J, et al. Importance of genetic testing in unexplained cardiac arrest. Eur Heart J. 2022;43(32):3071-3081. doi:10.1093/EURHEARTJ/EHAC145 Monasky MM, Micaglio E, Locati ET, Pappone C. Evaluating the Use of Genetics in Brugada Syndrome Risk Stratification. Front Cardiovasc Med. 2021;8. doi:10.3389/FCVM.2021.652027 Tadros R, Tan HL, El Mathari S, et al. Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores. Eur Heart J. 2019;40(37):3097-3107. doi:10.1093/EURHEARTJ/EHZ435

CardioNerds Cofounder Dr. Amit Goyal is joined by Dr. Douglas Salguero (Internal medicine resident), Dr. Francisco Ujueta (Cardiology fellow), and Dr. Priscilla Wessly (Chief cardiology fellow) from the Columbia University Division of Cardiology at Mount Sinai Medical Center in Miami to discuss a rare case of isolated non-compaction cardiomyopathy. Expert commentary is provided by Dr. Christos Mihos (Director, Echocardiography Laboratory, Columbia University Division of Cardiology, Mount Sinai Medical Center). Audio editing by CardioNerds Academy Intern, Shivani Reddy.   Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. 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 – Non-Compaction Cardiomyopathy Episode Schematics & Teaching The etiology has been a constant debate since 1980. It has been debated among researchers and clinicians whether LVNC is a physiologic or a pathologic manifestation. Waning et al., classified 327 unrelated patients into 3 categories: 1) genetic, 2) probably genetic, or 3) sporadic, identifying the most common mutations: MYH7, MYBPC3 and TTN in the genetic LVNC patients, which mostly encode for sarcomere, Z-disc and nuclear-envelope proteins. This supports the hypothesis that the inherited phenotype can arise from a gene mutation possibly during embryogenesis, disrupting the physiologic compaction of normally developing myocardium, which progresses from the base to the apex of the cardiac tissue. It is estimated that genetic LVNC accounts approximately 18-44% of cases, with autosomal dominant transmission being the most common form of inheritance. Physiologic remodeling with prominent trabeculations may be noted in athletes and pregnant women, in comparison to pathologic remodeling which may be encountered in patients with cardiomyopathy (e.g. pressure or volume load).  (1) There is no pathognomonic signs or symptoms in LVNC. LVNC patients may encounter various potential clinical characteristics. Presentations are myriad and include heart failure symptoms (HFrEF or HFpEF), ventricular tachycardia (VT/VF), atrial fibrillation, thromboembolism including cerebrovascular accident (CVA), and syncope. In a cohort of 95 probands with LVNC investigated in Europe, as many as 32.3% had an ICD/CRT-D implantation, with 11.8% experiencing a cardiovascular death and 18.2% having an appropriate ICD shock. (2) Imaging plays a key role in diagnosis for LVNC. The identification and diagnosis of LVNC is evaluated using 2D echocardiography. The initial proposed method by Chin et al., evaluated the size of the trabeculation in the center. (3) The most commonly used criteria, Jenni et al. (4), entail the following four finding: Two-layer structure, with a thin compacted layer and a thick non-compacted layer measure at end-systole at the parasternal short-axis view. LVNC is defined by a ratio of N/C > 2 Absence of co-existing cardiac structural abnormalities Prominent, excessive trabeculations and deep intra-trabecular recesses Recesses supplied by intraventricular blood on color doppler Cardiac MRI has increased the diagnostic accuracy in the diagnosis of LVNC. It has been suggested that a NC/C ratio of > 2.3 in diastole distinguished pathological non-compaction, with sensitivity of 86% and a specificity of 99%, respectively. Although studies have shown an increase specificity with cardiac MRI, caution is needed as it may overestimate the presence of LVNC. Late gadolinium enhancement which suggests myocardial fibrosis or scar has been shown to have some prognostic value in LVNC patients. (5) Management for LVNC is multifaceted. As above,LVNC has a variety of presentations and prevailing manifestations will differ among patients. Therefore, the diagnostic and management approach much be personalized for a given patient. Heart failure with reduced ejection fraction is the most common presentation, thus treatment follows guided directed medical therapy, including ACEi/ARB/ARNi, beta-blockers, MRA, SGLT2i, etc. The risk for thromboembolism in patients with LVNC has not been well-established although case-series have noted an increase in clot formation due to the increase in intertrabecular recesses. Although no definitive criteria for anticoagulation have been suggestive in patients with LVNC and atrial fibrillation who meet current recommendations. There is a weak recommendation for anticoagulation in patients with LVNC and LVEF < 40% with or without atrial fibrillation. (6) Arrhythmias in LVNC is frequent. Ambulatory rhythm monitoring may be used to detect atrial fibrillation and ventricular arrhythmias. As with our patient, individuals with LVNC who survive an episode of sustained ventricular tachycardiac or sudden cardiac death, an ICD is indicative as secondary prevention.  Otherwise, LVNC in patients with LVEF ≤ 35 percent and NYHA class II to III heart failure, ICD implantation is suggested. (6) Patients should be referred for genetic counseling with testing and subsequent cascade family screening as appropriate. Genetic testing has an important role in the management of LVNC. The identification of genetic LVNC is more predictive of major adverse cardiovascular events in the pediatric population than in adults, based on the finding from Waning et al. It has also been noted that patients with left ventricular dysfunction predicted a higher risk of MACE in carriers of the mutation compared to nongenetic cases.  The 2018 Heart Failure Society of America (HFSA) guideline recommends a careful family history for at least three generation and screening of first-degree relatives of all patients with LVNC. Clinical screening should include physical history, echocardiogram, physical examination, electrocardiogram, and creatinine kinase. The HFSA recommends genetic testing for the individual displaying the most affect phenotype of disease. If the individual displays an abnormal disease-causing gene-variant then first degree relatives are recommended to undergo clinical screening for the disease followed by genetic counseling. (7) References – Non-Compaction Cardiomyopathy 1. van Waning JI, Caliskan K, Hoedemaekers YM, et al. Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy. J Am Coll Cardiol. 2018;71(7):711-722. doi:10.1016/j.jacc.2017.12.019 https://www.jacc.org/doi/epdf/10.1016/j.jacc.2017.12.019 2. Sedaghat-Hamedani F, Haas J, Zhu F, et al. Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy. Eur Heart J. 2017;38(46):3449-3460. doi:10.1093/eurheartj/ehx545https://academic.oup.com/eurheartj/article/38/46/3449/4364851?login=true#104113970 3. Chin TK, Perloff JK, Williams RG, Jue K, Mohrmann R. Isolated noncompaction of left ventricular myocardium. A study of eight cases. Circulation. 1990;82(2):507-513. doi:10.1161/01.cir.82.2.507https://www.ahajournals.org/doi/10.1161/01.cir.82.2.507 4. Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart. 2001;86(6):666-671. doi:10.1136/heart.86.6.666https://heart.bmj.com/content/heartjnl/86/6/666.full.pdf 5. Dodd JD, Holmvang G, Hoffmann U, et al. Quantification of left ventricular noncompaction and trabecular delayed hyperenhancement with cardiac MRI: correlation with clinical severity. AJR Am J Roentgenol. 2007;189(4):974-980. doi:10.2214/AJR.07.2364https://www.ajronline.org/doi/10.2214/AJR.07.2364 6. Towbin JA, McKenna WJ, Abrams DJ, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019;16(11):e301-e372. doi:10.1016/j.hrthm.2019.05.007. https://www.heartrhythmjournal.com/article/S1547-5271(19)30438-2/fulltext 7. Hershberger RE, Givertz MM, Ho CY, et al. Genetic Evaluation of Cardiomyopathy-A Heart Failure Society of America Practice Guideline. J Card Fail. 2018;24(5):281-302. doi:10.1016/j.cardfail.2018.03.004. https://www.onlinejcf.com/article/S1071-9164(18)30101-5/fulltext

CardioNerds (Dan Ambinder), episode lead Dr. Sarah Fahnhorst (ACHD Cardiologist at Spectrum Health in Grand Rapids, Michigan), and series co-chair Dr. Agnes Koczo (fellow at UPMC) learn about ASD from Dr. Richard Krasuski (ACHD Cardiologist and Director of ACHD at Duke University). Audio editing by CardioNerds Academy Intern, student doctor Adriana Mares An atrial septal defect (ASD) is a common congenital heart disease most often diagnosed in childhood, but initial presentation can be in adulthood. ASDs are abnormal communications between the left and the right atrium.  There are four types of ASDs with different embryologic origins. If the defects are large, they will require percutaneous or surgical closure. Unrepaired defects can lead to symptoms of shortness of breath, exercise intolerance, recurrent chest infections, or pulmonary hypertension. This episode of CardioNerds will review the natural history, embryologic origin, diagnostic modalities/findings, indication for closure and long term complications of repaired and unrepaired atrial septal defects.  Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. The CardioNerds Adult Congenital Heart Disease (ACHD) series provides a comprehensive curriculum to dive deep into the labyrinthine world of congenital heart disease with the aim of empowering every CardioNerd to help improve the lives of people living with congenital heart disease. This series is multi-institutional collaborative project made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Josh Saef, Dr. Agnes Koczo, and Dr. Dan Clark. The CardioNerds Adult Congenital Heart Disease Series is developed in collaboration with the Adult Congenital Heart Association, The CHiP Network, and Heart University. See more Disclosures: None Pearls • Notes • References • Guest Profiles • Production Team CardioNerds Adult Congenital Heart Disease PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls – Atrial Septal Defects It’s a CLASSIC! – On physical exam a wide fixed split S2 along with a systolic ejection murmur due to increased blood flow across the pulmonary valve and potentially a diastolic rumble across the tricuspid valve are CLASSIC findings with atrial septal defects.  Atrial septal defects are not all the same. There are four types of atrial septal defects: secundum ASD, primum ASD, sinus venosus and coronary sinus defects (NOTE – the latter are atrial level defects which actually do not involve the interatrial septum). The different types warrant a different approach to closure.  Use your tools and if your suspicion is high for an atrial septal defect, keep looking. Sinus venosus defects can easily be missed since the superior vena cava is difficult to image in adults. Diagnostic tools include: history and physical exam (USE the stethoscope), ECG, echocardiogram, cardiac MRI, cardiac CT, and cardiac catheterization. Not all defects NEED to be closed immediately. Moderate-large defects with a shunt greater than 1.5:1 should be closed due to increased risk of pulmonary hypertension and arrhythmias, barring contraindications.  Surgery was previously the gold standard for closure of ASDs, but many defects especially secundum atrial septal defects are closed in the cath lab.    Show notes – Atrial Septal Defects Notes (developed by Dr. Sarah Fahnhorst What are the four different types of atrial level defects? Secundum atrial septal defect Most common type of atrial septal defect (75%) Located in the center of the atrial septum (fossa ovalis) Hole in the primum septum due to deficiency of the septum secundum Primum atrial septal defect Accounts for 15-20% of ASD Located at the inferior portion of the atrial septum In the spectrum of atrioventricular septal defects/endocardial cushion defects Defect in the development of the septum primum Associated with cleft left AV valve, ventricular septal defects, and subaortic stenosis Sinus venosus defect Accounts for 5-10% of atrial level defect Not a “septal” defect! Located near the superior vena cava-right atrial junction or very rarely at the mouth of the inferior vena cava 80-90% of sinus venosus defects are associated with partial anomalous pulmonary venous return Coronary sinus defect Least common <1% of all ASD Not a “septal” defect! Communication between the coronary sinus and left atrium (“unroofed” coronary sinus)  Not often seen in isolation but are associated with complex congenital heart disease such as heterotaxy syndrome What are the presenting signs, symptoms and diagnostic findings associated with atrial level defects? If small, then asymptomatic Moderate to large defects: shortness of breath, exercise intolerance, or recurrent pulmonary infections. Physical exam Wide fixed split S2, with a systolic ejection murmur due to increased blood flow across the pulmonary valve.  Diastolic flow rumble may be heard across the tricuspid valve If there is pulmonary hypertension the S2 may be particularly loud.  Chest X-Ray Right heart enlargement, prominent pulmonary artery and increased pulmonary vascularity ECG: Primum defect – left axis deviation, rSR’, and right atrial enlargement Secundum defect – incomplete right bundle branch block and possible right axis deviation (could also be normal) Sinus venosus defect – inverted P waves in the inferior leads suggesting an absent or deficient sinus node (particularly with prior surgical repair) Severe pulmonary hypertension – rSR’ replaced by Q waves and tall monophasic R waves with deep inverted T waves Diagnostic modalities: Echocardiogram Cardiac CT or cardiac MRI Cardiac catheterization What are the indications for closing an atrial septal defect? Some defects close spontaneously. Nearly 100% of defects <3mm will close by 3-5 years of age vs ~90% of defects between 3-5m vs ~80% of defects between 5-8mm will close in that time frame.  Defects greater than 8mm are unlikely to close. Large left to right shunt (Qp:Qs > 1.5:1) and no signs of pulmonary hypertension Symptomatic with a large shunt or signs of right heart enlargement or decreased systolic function Primum, sinus venosus, and coronary sinus defects will not close spontaneously What are treatment options available for each type of atrial septal defect? Surgical: Primum, sinus venosus, and coronary sinus defects are typically closed surgically.  Some centers are closing sinus venosus defects percutaneously if anatomy is suitable particularly when surgery is deemed high risk. If there are additional structural heart defect such as a VSD or cleft mitral valve, then surgical closure is preferred.  Transcatheter device closure: Secundum defects can be closed in the cath lab if they have sufficient rims, otherwise they will require surgical closure What are complications of repaired and unrepaired atrial septal defects? Repaired: Transcatheter Residual defect Small increased risk for atrial arrhythmias Device embolization Surgical Residual defect Small increased risk for atrial arrhythmias Unrepaired Pulmonary hypertension Eisenmenger syndrome Atrial arrhythmias (atrial fibrillation or atrial flutter) Right heart failure Decreased exercise and functional capacity Increased risk of paradoxical embolism leading to risk of thromboembolic stroke References – Atrial Septal Defects Perloff JK. Surgical Closure of Atrial Septal Defect in Adults. New England Journal of Medicine. 1995;333(8):513-514. doi:10.1056/nejm199508243330809 Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(14):e698-e800. doi:doi:10.1161/CIR.0000000000000603 Baumgartner H, De Backer J, Babu-Narayan SV, et al. 2020 ESC Guidelines for the management of adult congenital heart disease: The Task Force for the management of adult congenital heart disease of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Adult Congenital Heart Disease (ISACHD). Eur Heart J. 2020;42(6):563-645. doi:10.1093/eurheartj/ehaa554 Gatzoulis MA, Webb GD, Daubeney PEF. Diagnosis and management of adult congenital heart disease. 3 ed. Elsevier Health Sciences; 2017. Saremi F. Cardiac CT and MR for Adult Congenital Heart Disease. Springer New York; 2013. Allen HD. Moss & Adams’ heart disease in infants, children, and adolescents, including the fetus and young adult. 9 ed. Lippincott Williams and Wilkins; 2016. Meet Our Collaborators! Adult Congenital Heart AssociationFounded in 1998, the Adult Congenital Heart Association is an organization begun by and dedicated to supporting individuals and families living with congenital heart disease and advancing the care and treatment available to our community. Our mission is to empower the congenital heart disease community by advancing access to resources and specialized care that improve patient-centered outcomes. Visit their website (https://www.achaheart.org/) for information on their patient advocacy efforts, educational material, and membership for patients and providers CHiP Network The CHiP network is a non-profit organization aiming to connect congenital heart professionals around the world. Visit their website (thechipnetwork.org) and become a member to access free high-quality educational material, upcoming news and events, and the fantastic monthly Journal Watch, keeping you up to date with congenital scientific releases. Visit their website (https://thechipnetwork.org/) for more information. Heart UniversityHeart University aims to be “the go-to online resource” for e-learning in CHD and paediatric-acquired heart disease. It is a carefully curated open access library of educational material for all providers of care to children and adults with CHD or children with acquired heart disease, whether a trainee or a practicing provider. The site provides free content to a global audience in two broad domains: 1. A comprehensive curriculum of training modules and associated testing for trainees. 2. A curated library of conference and grand rounds recordings for continuing medical education. Learn more at www.heartuniversity.org/ CardioNerds Adult Congenital Heart Disease Production Team Amit Goyal, MD Daniel Ambinder, MD

CardioNerds Cofounder Dr. Amit Goyal is joined by an esteemed group of UCLA cardiology fellows – Dr. Patrick Zakka (CardioNerds Academy Chief), Dr. Negeen Shehandeh (Chief Fellow), and Dr. Adrian Castillo – to discuss a case of primary cardiac angiosarcoma. An expert commentary is provided by Dr. Eric Yang, beloved educator, associate clinical professor of medicine, assistant fellowship program director, and founder of the Cardio-Oncology program at UCLA.   Case synopsis: A female in her 40s presents to the ED for fatigue that had been ongoing for approximately 1 month. She also developed night sweats and diffuse joint pains, for which she has been taking NSAIDs. She was seen by her PCP and after bloodwork was done, was told she had iron deficiency so was on iron replacement therapy. Vital signs were within normal limits. She was in no acute distress. Her pulmonary and cardiac exams were unremarkable. Her lab studies showed a Hb of 6.6 (MCV 59) and platelet count of 686k. CXR was without significant abnormality, and EKG showed normal sinus rhythm. She was admitted to medicine and received IV iron (had not consented to receiving RBC transfusion). GI was consulted for anemia work-up. Meanwhile, she developed a new-onset atrial fibrillation with rapid ventricular response seen on telemetry, for which Cardiology was consulted. A TTE was ordered in part of her evaluation, and surprisingly noted a moderate pericardial effusion circumferential to the heart. Within the pericardial space, posterior to the heart and abutting the RA/RV was a large mass measuring approximately 5.5×5.9 cm. After further imaging work-up with CMR and PET-CT, the mass was surgically resected, and patient established care with outpatient oncology for chemotherapy.  Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. 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 – primary cardiac angiosarcoma Episode Schematics & Teaching Pearls – primary cardiac angiosarcoma The pericardium is composed of an outer fibrous sac, and an inner serous sac with visceral and parietal layers.   Pericardial masses can be primary (benign or malignant) or metastatic. There are other miscellaneous pericardial masses.  Imaging modalities for the pericardium include echocardiography, cardiac CT and cardiac MRI. There is also role for PET-CT in pericardial imaging for further characterization of pericardial masses.   Cardiac angiosarcomas are extremely rare but are the most common cardiac primary malignant tumors.  Evidence-based management if lacking because of paucity of clinical data given the rarity of cardiac angiosarcomas. Surgery is the mainstay of therapy. Radiotherapy and chemotherapy are often used as well.  Notes – primary cardiac angiosarcoma Pericardial Anatomy  The pericardium is a fibroelastic sac composed of two layers.   Outer layer: fibrous pericardium (<2 mm thick)  Inner layer: serous pericardium, two-layered sac.  Visceral pericardium: adherent to underlying myocardium  Parietal pericardium: lines fibrous sac.  Between the serous layers, there is the pericardial cavity which normally contains up to 50 cc pericardial fluid.  Pericardial Masses  Benign  Lipoma: slow-growing, collection of adipose cells, thought to arise in AV groove  Teratoma: benign germ cell tumors, often right sided. Can cause compressive symptoms of RA, SVC, PA, aortic root.   Fibroma: solid mass of connective tissue  Hemangioma: vascular mass, often arising from visceral pericardium  Malignant  Sarcoma: various types including angiosarcoma and liposarcoma.   Lymphoma: usually non-Hodgkin B-cell lymphoma, often in immunocompromised patients  Mesothelioma: no apparent association with asbestos. Pericardial effusions with nodules/plaques are seen.  Metastatic  Often associated with hemorrhagic pericardial effusions  Breast cancer, lung cancer, melanoma and renal cell carcinoma are most common  Pericardial Imaging  Echocardiography  Advantages:   widely available  low cost   safe  can be performed in multiple settings (e.g., HD unstable)  Disadvantages:   limited view/windows  operator dependent  technical difficulties (lung disease, obesity, surgical bandages)  limited tissue characterization  Cardiac Computed Tomography  Advantages:  Superior tissue characterization compared to echocardiography  Can identify extra-cardiac disease  Identification of calcification  Pre-operative planning  High spatial resolution   Disadvantages:   Use of ionizing radiation and iodinated contrast  Difficult gating in patients with tachycardia/arrhythmias; use of breath hold  HD stable patients only  Cardiac Magnetic Resonance Imaging  Advantages:  Superior tissue characterization compared to echocardiography/computed tomography  Disadvantages:  Time consuming, expensive  Difficulty gating in patients with tachycardia/arrhythmias; use of breath holds for some sequences  Challenges in patients with electronic implants  Use of gadolinium contrast  Extra-cardiac structures not well visualized; calcifications less well-visualized  Positron Emission Tomography/Computed Tomography (PET/CT)  Has been shown to be an effective additional imaging modality in patients in whom cardiac mass is suspected to be malignant, and helps provide further confirmation and screening for metastatic disease.   Angiosarcoma of the Pericardium  Very rare, but most common cardiac primary malignant tumor.  Typically right-sided and secondarily involves the pericardium.  Primary pericardial angiosarcoma usually occurs in middle-aged, more frequently in males.  Often metastatic at time of diagnosis.   Clinical presentation  Variety of symptoms, and often undetected early on.  Symptoms include dyspnea, chest pain, cough, fatigue/malaise, and signs of caval obstruction.   Clinical picture rapidly deteriorates as it can eventually result in intractable heart failure and death due to multi-organ failure.   Lab/Imaging Tests  Tumor marker CA125 elevated.  Pericardiocentesis usually reveals bloody fluid (containing RBCs, WBCs). Cytology often misses malignant cells.   EKG can show non-specific ST-T wave abnormalities and low QRS voltage.  CXR may show an enlarged cardiac silhouette.   Transthoracic echocardiography can show pericardial effusion but may fail to show echogenic mass if no good acoustic windows. Large masses in the pericardium may be seen in some patients.   CT can show location, size, and extent of mass.  CMR can further show tumor necrosis or hemorrhage. Can help characterize and stage tumors.  PET/CT can help detect metastasis from pericardial tumors.   Definitive diagnosis = biopsy (mediastinoscopy, exploratory pericardiotomy or thoracotomy). Extensive excision is usually recommended. Angiosarcomas histologically are characterized by presence of anastomosing vascular channels that are lined by atypical/malignant endothelial cells showing frequent mitoses.   Immunohistochemical staining: endothelial markers (CD31, CD34, vimentin, factor VII).  Management  Because of rarity there is little clinical evidence-based data for management.  Usually responds poorly to chemotherapy and radiation.  Surgery is challenging because these tumors are diagnosed late and there is already metastatic disease.  Orthotopic cardiac transplantation is sometimes done and has prolonged life, though incidence of metastatic disease limits utility. Could be helpful in patients who have unresectable but locally aggressive tumors without metastasis.  Palliative treatment options are usually resorted to because the disease often presents so late. Length of survival after diagnosis ranges between 6-11 months.   Ultimately, surgical resection with negative margins is associated with best outcome; there is some benefit to then adding chemotherapy and radiotherapy.   References – primary cardiac angiosarcoma Burke A, Tavora F. The 2015 classification of tumors of the heart and pericardium. J Thorac Oncol. 2015; 11(4): 441-452. https://www.jto.org/article/S1556-0864(15)00109-4/fulltext41  Yin H, Mao W, Tan H, et al. Role of 18F-FDG PET/CT imaging in cardiac and pericardial masses. J Nucl Cardiol. 2022; 29(3):1293-1303. https://pubmed.ncbi.nlm.nih.gov/33462788/  -452, APRIL 01, 2016  Xie M, Li Y, Wenfang G. Pericardial angiosarcoma: Status quo. Acc.org 2019. https://www.acc.org/latest-in-cardiology/articles/2019/09/04/06/43/pericardial-angiosarcoma 

It’s another session of CardioNerds Rounds! In these rounds, Dr. Priya Kothapalli (Interventional FIT at University of Texas at Auston, Dell Medical School) joins Dr. Deepak Bhatt (Dr. Valentin Fuster Professor of Medicine and Director of Mount Sinai Heart) to discuss the nuances of antithrombotic therapy. As one of the most prolific cardiovascular researchers, clinicians, and educators, CardioNerds is honored to have Dr. Bhatt on Rounds, especially given that Dr. Bhatt has led numerous breakthroughs in antithrombotic therapy. Come round with us today by listening to the episodes of #CardsRounds! Audio editing by CardioNerds Academy Intern, Dr. Christian Faaborg-Andersen. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. This episode is supported with unrestricted funding from Zoll LifeVest. A special thank you to Mitzy Applegate and Ivan Chevere for their production skills that help make CardioNerds Rounds such an amazing success. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. Case details are altered to protect patient health information. CardioNerds Rounds is co-chaired by Dr. Karan Desai and Dr. Natalie Stokes.  Speaker disclosures: None Challenging Cases – Atrial Fibrillation with Dr. Hugh Calkins CardioNerds Rounds PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes – Antithrombotic Management with Dr. Deepak Bhatt Case #1 Synopsis: A woman in her early 70s with a history of hypertension, hyperlipidemia, and paroxysmal atrial fibrillation presented with sudden-onset chest pressure and diaphoresis while at rest and was found to have an acute thrombotic 99% mid-LAD occlusion. The patient received OCT-guided PCI with a single drug-eluting stent. We discussed what the appropriate antithrombotic strategy would be for a patient with recent acute coronary syndrome and atrial fibrillation. Case #1Takeaways According to the recent 2021 revascularization guidelines, in patients with atrial fibrillation undergoing PCI and taking oral anticoagulant therapy, it is recommended to discontinue aspirin after 1 to 4 weeks while maintaining P2Y12 inhibitors in addition to a non-vitamin K oral anticoagulant or warfarin. There are two recent trials – AUGUSTUS and the ENTRUST-AF PCI trial – that evaluated regimens of apixaban and edoxaban, respectively, that support earlier findings reporting lower bleeding rates in patients maintained on oral anticoagulant plus a P2Y12 inhibitor compared to triple therapy. Of note, none of these trials were specifically powered for ischemic endpoints, but when pooling data from these trials, rates of death, MI and stent thrombosis with dual therapy were similar to those seen in patients on triple therapy. Additionally, all of these patients enrolled in these trials were briefly treated with triple therapy after PCI before the aspirin was discontinued. In the 2021 guidelines, it is noted that analyses of stent thrombosis suggest that 80% of events occur within 30 days of PCI. Thus, it is reasonable to consider extending triply therapy to 1 month after PCI in high risk patients to reduce risk of stent thromboses. In AUGUSTUS, 90% of patients received clopidogrel as their P2Y12 inhibitor Case #2 Synopsis: A man in his mid-50s with a history of peripheral vascular disease with prior SFA stent for chronic limb ischemia, hyperlipidemia, tobacco use, diabetes, and chronic kidney disease presented with a two day history of “reflux” that was worse with exertion and that improved with rest and associated with diaphoresis. He was diagnosed with an NSTEMI. His LHC revealed 99% mid-RCA thrombotic occlusion with moderate disease in the LAD. He underwent thrombectomy and PCI with a single drug-eluting stent to the RCA. We discussed his short-term and long-term antithrombotic therapy Case #2 Takeaways There were several things discussed regarding the management of this patient’s “poly-vascular disease.” One of the aspects was what to do with his antithrombotic therapy after one year and specifically how the COMPASS trial may apply to this patient. In the COMPASS trial, more than 27,000 patients with stable CAD or peripheral arterial disease (PAD) were randomly assigned to rivaroxaban plus aspirin, rivaroxaban alone, or aspirin alone with a mean follow-up of about 23 months. Of note, the dose of rivaroxaban in the combination arm was 2.5 mg orally twice per day. The patients on combination therapy compared to aspirin alone had a 23% relative risk reduction in CV mortality (1.7 vs. 2.2%; HR 0.78 [95% CI 0.64-0.96]) and nearly 50% reduction in ischemic stroke. As expected, there was high rates of major bleeding in the combination arm (3.1 vs. 1.9%; HR 1.7 [95% CI 1.4-2.05]). As with most decisions in medicine, each clinician would need to balance reducing ischemic events with bleeding risk for each individual patient. However, the COMPASS trial provides further evidence that low-dose oral anticoagulant with rivaroxaban in addition to aspirin can be effective in reducing ischemic events and CV mortality in patients with established atherosclerotic disease. Case #3 Synopsis A man in his early 60s with a history of hypertension and active tobacco use presented to a local hospital with anteroseptal STEMI c/b cardiac arrest with ventricular tachycardia. After multiple defibrillation attempts and CPR, the patient was able to achieve return of spontaneous circulation with intact mental status. The patient was pre-loaded with aspirin, ticagrelor, cangrelor and heparin and brought to the catheterization lab. There was diffuse moderate to severe stenoses in the RCA and a hazy distal LM lesion, but the culprit was a complete occlusion of the proximal LAD to which the patient received a single DES and another to the mid LAD. The patient was then brought to a tertiary care center where consideration was given for elective CABG given the residual disease. We discussed timing of CABG and when/if to pursue it, as well as antithrombotic management in this circumstance Case #3 Takeaways Amongst the things we discussed was the role of cangrelor pre-left heart catheterization. Cangrelor is a potent, short-acting, and reversible intravenous P2Y12 inhibitor with rapid onset of platelet inhibition. And within 1 hour of discontinuation, platelet function can be restored. In the small CANTIC trial, patients undergoing primary PCI pre-treated with crushed 180-mg loading dose of ticagrelor were randomized to cangrelor versus placebo. Within five minutes, cangrelor led to significant P2y12 inhibition which persisted throughout the drug infusion. Of note, there were no drug interactions with ticagrelor given concomitantly with cangrelor at the start of PCI. Thus, in this trial, cangrelor proved to be an effective strategy in bridging latent platelet inhibition that can be seen with oral drugs. This trial was not powered for clinical outcomes, but serves as evidence that cangrelor can be considered for pre-treatment to bridge the gap in platelet inhibitor effects in select patients in whom oral absorption may be compromised or slowed. References Eikelboom JW, Connolly SJ, Bosch J et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017 Oct 5;377(14):1319-1330. Franchi F, Rollini F, Rivas A et al. Platelet Inhibition With Cangrelor and Crushed Ticagrelor in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. Circulation. 2019 Apr 2;139(14):1661-1670. Lopes RD, Heizer G, Aronson R, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019; 380:1509–1524. Writing Committee Members, Lawton JS, Tamis-Holland JE et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):197-215 Production Team Karan Desai, MD Natalie Stokes, MD Amit Goyal, MD Daniel Ambinder, MD