Cardionerds: A Cardiology Podcast

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

CardioNerd (Daniel Ambinder) and series co-chairs Mark Belkin (AHFT Fellow, University of Chicago) and Karan Desai (Cardiologist, Johns Hopkins), join fellow lead, Dr. Pablo Sanchez (FIT, Stanford) for a discussion with Dr. Ryan Tedford (Professor of Medicine at the Medical University of South Carolina) about Right Ventricular (RV) predominant cardiogenic shock. In this episode we explore risk factors, pathophysiology, hemodynamics, and treatment strategies in this common and complex problem. We dissect three cases that epitomize the range of diagnostic dilemmas and management decisions in RV predominant shock, as Dr. Tedford expertly weaves us through the pathophysiology and decision-making involved in managing the “people’s ventricle.” Audio editing by Dr. Gurleen Kaur (Director of the CardioNerds internship program, CardioNerds academy fellow, and IM resident at Brigham and Women’s Hospital). 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 – RV Predominant Cardiogenic Shock The degree of RV dysfunction and failure are modulated by stretching its capacity to tolerate insults from deranged afterload, preload, and contractility. Afterload insults are MUCH LESS tolerated than other insults and broadly comprise the most common pathophysiologic cause of both acute and chronic RV failure. RV and left ventricular (LV) function are anatomically and physiologically connected.  Progressive derangements in RV function can lead to the deadly “RV spiral,” in which poor RV function causes lower LV preload, leading to hypotension, and thus worsening RV perfusion and function. In RV failure/shock, some basic tenets including treating reversible causes, optimizing preload and afterload, and using inotropes and/or temporary MCS for as limited time as possible. Many acute RV failure patients can recover, but multiorgan injury plays an important role. Therefore, thoughtful and expeditious use of mechanical circulatory support is important. Show notes – RV Predominant Cardiogenic Shock Notes drafted by Dr. Pablo Sanchez. What is the basic difference between RV dysfunction and failure? Dysfunction: Abnormalities in systolic/diastolic function of the RV, but not necessarily to the point of leading to end-organ perfusion defects. RV dysfunction leads to poor outcomes regardless of mechanism.1 Failure: Clinical syndrome of inability of RV to maintain adequate output despite adequate preload. 1 How is the RV different from the LV and what impact does it have on pathophysiology and hemodynamics? The LV and RV originate from different embryologic “heart fields.”1,2 The RV wall is thinner and more compliant and has only two layers (instead of 3 like the LV).3 Furthermore, unlike the LV which has a significant proportion of endocardial and epicardial transverse myocardial fibers, the RV myocardial fibers are aligned in a longitudinal plane for the most part. Thus, a more significant proportion of RV systolic contraction is longitudinal – base of the ventricle moving towards the apex. The RV is crescent-shaped and has a large surface-to-volume ratio meaning smaller inward motion ejects the same stroke volume. 1 Hemodynamically, the RV takes blood from a low-pressure venous system and gives it to a distensible system with low impedance (the normal pulmonary circuit at baseline typically has a resistance one-tenth of the systemic resistance). Therefore, volume loads (preload) are much better handled than pressure (afterload).1 What is RV-PA coupling? As Dr. Tedford noted, RV-PA coupling describes “the interaction of RV contractility and afterload (resistive and pulsatile components). It is the most comprehensive description of RV function and therefore the Gold Standard.” Whether we are referring to the LV or RV, the basic concept of coupling describes the energy transfer between ventricular contractility and arterial afterload. RV-PA coupling has typically been assessed by pressure-volume loops, with ventricular contractility assessed by end-systolic elastance (a load-independent measure of systolic function) and arterial afterload by effective arterial elastance. MODUS OPERANDI: RV dysfunction and eventual failure is modulated by stretching its capacity to tolerate insults from afterload, preload, and contractility. What leads to ACUTE right heart failure? Most commonly results from:1 Abrupt increases in afterload (e.g., think PE, hypoxia, and acidemia). Decreased contractility (e.g., think ischemia such as RV infarction, myocarditis, and post-cardiotomy). Volume overload can sometimes lead to acute right heart failure, particularly in the setting of another categorical insult such as septic cardiomyopathy or LVAD support. What leads to CHRONIC right heart failure? This is different than acute right heart failure. Most commonly chronic right heart failure results from:1 Gradual increases in afterload (e.g., think pulmonary arterial hypertension). Chronic volume overload (e.g., longstanding tricuspid regurgitation, atrial septal defect, and other congenital lesions like double outlet RV). Contractility (e.g., including the isolated RV cardiomyopathies like arrhythmogenic right ventricular cardiomyopathy or ischemic cardiomyopathy). Other pathologies certainly affect multiple categories (e.g., Ebstein’s anomaly which is a function of contractility and volume overload or single ventricle physiology like post-Fontan patients – for more on these and other ACHD lesions, enjoy the CardioNerds ACHD Series!) MODUS OPERANDI: The cardiovascular system is wholly connected, and acute decompensation leads to progressive derangements in the above levers (including LV function). This phenomenon is called the RV spiral. How do we manage RV failure? The most important and first step is the treatment of reversible causes. For instance, acute coronary syndrome involving the RV requires percutaneous intervention (PCI) or pulmonary embolism requires anticoagulation and/or thrombolytic/device/surgical therapy. PRELOAD OPTIMIZATION Ensuring that there is adequate preload is a key tenet of diagnosing and treating RV failure. This may require diuresis or judicious volume resuscitation to maintain cardiac output. While guiding fluid management in the setting of RV failure, one should STRONGLY consider invasive hemodynamic monitoring (e.g., over-resuscitation can lead to decreased LV output through septal shift and ventricular interdependence from pericardial constraint).1 General target: We could consider a CVP 10-15 mmHg; however, this will be individualized. Another general rule would also be if that a bolus of 500 cc of crystalloid does not result in hemodynamic improvement, further loading should not be continued, especially without invasive hemodynamic guidance. AFTERLOAD OPTIMIZATION  The goal should be to correct reversible causes of elevated pulmonary vascular resistance (e.g., acidosis, hypercapnia, hypoxia, and generally in ventilated patients avoid elevated inspiratory pressures > 30mmHg).1 With specialized expert guidance, we can consider selective pulmonary vasodilators (acutely and short-term): One example includes inhaled NO, and in observational studies, short-term use lowered PVR and increased RV ejection.4 We also have to remember the consequences of reducing RV afterload. Acutely increasing LV preload in a baseline abnormal LV may lead to distention, lowered cardiac output, and pulmonary edema.1 Pulmonary vasodilators can act on specific pathways (e.g., nitric oxide, prostacyclin, endothelin-1, and soluble guanylate cyclase stimulators) and come in various forms (oral, inhaled, and intravenous). CONTRACTILITY AUGMENTATION (INOTROPES) We typically utilize inotropes in concert with the prior two but optimize loading so the time we need inotropes is minimal.1 Short-term use can improve hemodynamics. Longer-term use will typically increase myocardial O2 consumption and is associated with increased mortality.  The RV has coronary perfusion in systole and diastole, so peripheral vasopressors are helpful to maintain perfusion, especially if systolic blood pressure is less than RV systolic pressure.1 GOAL: Increase contractility without increasing RV afterload. For those failing to respond to these above measures to optimize preload, afterload, and contractility, there may be a role for temporary mechanical circulatory support (see #10 below). How do we decide between dobutamine and milrinone? BOTH inotropes can lead to hypotension, have similar clinical outcomes, hemodynamic efficacy and arrhythmogenic potential1 (despite the adage that attributes more arrhythmias to dobutamine, studies show the risk is typically the same in both5). Milrinone is a more potent vasodilator (systemic and pulmonary) typically leading to greater decreases in end-diastolic pressures in the ventricles.1 It is renally cleared, has a longer half-life, and acts through a separate mechanism pathway compared to beta-blockade, thus patients can be on milrinone and beta blockers at the same time on a case-by-case basis.1 Dobutamine has a shorter half-life, with rapid onset/offset and so may be more ideal in unstable/hypotensive patients.1 What if the patient is hypotensive? In this circumstance, we would need an ino-constrictor or peripheral vasoconstrictor. Vasopressin has almost no impact on PVR, so unlike catecholamines, it does not directly worsen RV afterload.1 What are some important invasive hemodynamic parameters to be aware of? RAP/PCWP ratio: Disproportionate RV dysfunction can be portrayed by an RAP/PCWP ratio > 0.5-0.8 (depending on the clinical situation). In other words, the closer that RAP and PCWP are, the more likely you have disproportionate RV dysfunction. The predictive power of this ratio is different depending on the situation. Pre-operatively, a ratio > 0.63 is associated with RHF post-LVAD.6 In acute inferior MI, a ratio of > 0.86 is associated with RHF.7 PAPi: The PA pulse pressure gives us an idea of the ability of the RV to generate SV. Dividing this by the RAP, gives us an index that takes into account right-sided filling pressures. As above, the context is important. In acute inferior MI a PAPi of < 1.0 is predictive of mortality or MCS need,8 while a pre-operative PAPi < 1.8 was predictive of RHF after LVAD.9 Caveats: As Dr. Tedford mentioned, the PAPi is related to RV function, but not a direct measure of it. Manipulation of each component (e.g., pulse pressure or RA pressure) can ultimately lead to a similar absolute value of PAPi under very different loading conditions. PA pulse pressure is a function not only of SV but also of PA capacitance. In other words, a narrow pulse pressure can be due to a failing RV or a low pulmonary capacitance (from fluid overload for example). This isn’t clearly gleaned from the PAPi alone and requires us to keep in mind the context of the equation. Note: The gold standard assessments of RV contractility are derived from Pressure-Volume loops which require both simultaneous assessment of pressure and volume as well as alteration of preload over multiple beats. This limits applicability because it is technically challenging to do.10  What are important concepts to remember for Mechanical Support of the RV? One of the first things to consider is the end-game: are we using MCS as a bridge to recovery, bridge to decision, bridge to transplant, or bridge to durable MCS? Many acute RHF patients can recover with adequate support and a significant prognostic factor is preventing multiorgan failure.11,12 If MCS is needed, early use is better than later. Another important question is if we need oxygenation? Many of the MCS options, except the Impella RP, can have an oxygenator spliced into the system.11 A key question will be if we need RV-only support or biventricular support?11 RV-targeted support will increase LV preload, and the LV has to be able to accommodate the increased volume. If the LV is unable to tolerate the increased return, systemic cardiac output can become inadequate, LV filling pressures will rise, which can lead to pulmonary edema and increase mean PA pressures further (which can also lead to acute lung injury and worse outcomes). In these circumstances, biventricular support with either VA-ECMO or permutations of isolated RV + LV support may be needed. We also have to ask ourselves, if pulmonary arterial HTN primarily responsible for RV shock?11 If so, then VA-ECMO may be the most appropriate option. Increased flow from an RVAD, combined with a pre-existing elevated PVR can lead to elevated pulmonary artery pressures, which can precipitate pulmonary hemorrhage.1 References – RV Predominant Cardiogenic Shock Konstam MA, Kiernan MS, Bernstein D, et al. Evaluation and Management of Right-Sided Heart Failure: A Scientific Statement From the American Heart Association. Circulation. 2018;137(20). doi:10.1161/CIR.0000000000000560 Haddad F, Hunt SA, Rosenthal DN, Murphy DJ. Right ventricular function in cardiovascular disease, part I: Anatomy, physiology, aging, and functional assessment of the right ventricle. Circulation. 2008;117(11). doi:10.1161/CIRCULATIONAHA.107.653576 Sheehan F, Redington A. The right ventricle: Anatomy, physiology and clinical imaging. Heart. 2008;94(11). doi:10.1136/hrt.2007.132779 Wasson S, Govindarajan G, Reddy HK, Flaker G. The Role of Nitric Oxide and Vasopressin in Refractory Right Heart Failure. J Cardiovasc Pharmacol Ther. 2004;9(1). doi:10.1177/107424840400900i102 Mathew R, Di Santo P, Jung RG, et al. Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock. N Engl J Med. 2021;385(6). doi:10.1056/nejmoa2026845 Kormos RL, Teuteberg JJ, Pagani FD, et al. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: Incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg. 2010;139(5). doi:10.1016/j.jt Lopez-Sendon J, Coma-Canella I, Gamallo C. Sensitivity and specificity of hemodynamic criteria in the diagnosis of acute right ventricular infarction. Circulation. 1981;64(3 I). doi:10.1161/01.CIR.64.3.515 Korabathina R, Heffernan KS, Paruchuri V, et al. The pulmonary artery pulsatility index identifies severe right ventricular dysfunction in acute inferior myocardial infarction. Catheter Cardiovasc Interv. 2012;80(4). doi:10.1002/ccd.23309 Morine KJ, Kiernan MS, Pham DT, Paruchuri V, Denofrio D, Kapur NK. Pulmonary Artery Pulsatility Index is Associated with Right Ventricular Failure after Left Ventricular Assist Device Surgery. J Card Fail. 2016;22(2). doi:10.1016/j.cardfail.2015.10.019 El Hajj MC, Viray MC, Tedford RJ. Right Heart Failure: A Hemodynamic Review. Cardiol Clin. 2020;38(2). doi:10.1016/j.ccl.2020.01.001 Esposito ML, Bader Y, Morine KJ, Kiernan MS, Pham DT, Burkhoff D. Navin K. Kapur, MD Mechanical Circulatory Support Devices for Acute Right Ventricular Failure. Circulation. 2017;136. Cheung AW, White CW, Davis MK, Freed DH. Short-term mechanical circulatory support for recovery from acute right ventricular failure: Clinical outcomes. J Hear Lung Transplant. 2014;33(8). doi:10.1016/j.healun.2014.02.028 CardioNerds Cardiac Critical Care Production Team Karan Desai, MD Dr. Mark Belkin Dr. Yoav Karpenshif Amit Goyal, MD Daniel Ambinder, MD

CardioNerds (Dr. Patrick Azcarate, Dr. Teodora Donisan, and Amit Goyal) discuss Radiation-Associated Cardiovascular Disease (RACD) with Dr. Eric Yang, cardio-oncologist, assistant professor of medicine, and associate fellowship program director at UCLA. RACD is a consequence of radiation treatment for various mediastinal tumors (breast, lung, lymphoma). It is the second most common cause of morbidity and mortality in patients treated with mediastinal radiation for cancer. While novel techniques decrease radiation exposure during cancer treatment, the incidence is expected to increase because of historical practices and delayed onset of symptoms. The prevalence of RACD is difficult to estimate given under-recognition. Additionally, most of the data comes from patients treated with radiation techniques from decades ago. In this discussion we review every nook and cranny of RACD to help guide you the next time you see a patient with a history of chest radiation. Review this CardioNerds Case Report of radiation associated cardiovascular disease for more: Episode #169. Chest pain in a Young Man – “A Gray (Gy) Area” – UC San Diego. Audio editing by CardioNerds Academy Intern, student doctor Yousif Arif. This episode is supported by a grant from Pfizer Inc. This CardioNerds Cardio-Oncology 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. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.  Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Pearls • Notes • References • Production Team CardioNerds Cardio-Oncology 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 – Radiation-Associated cardiovascular disease Due to the legacy effect, the incidence of RACD will continue to increase in the next few years. When treating patients with a history of mediastinal radiation, we should remember to ask: How much radiation was given? Could the heart have been exposed? Radiation can affect every part of the heart by causing coronary artery disease (CAD), valvulopathy, myocardial disease, conduction disease, and pericardial disease. Exposure to ~25-30 Gy or more significantly increases the risk but RACD can occur at lower doses. Try to delay surgery as much as possible and do all you can in one operation to avoid re-operation in the future. For revascularization, percutaneous coronary intervention (PCI) is typically preferred over coronary artery bypass grafting (CABG) but the choice should be individualized in consultation with a multidisciplinary heart team experienced in the management of RACD. In general, for aortic valve disease, transcatheter replacement is recommended over surgical aortic valve replacement. For mitral valve disease, surgical replacement is recommended over repair. Every decision should be made with a heart team approach and made unique to that specific patient. Show notes – Radiation-Associated cardiovascular disease Notes were drafted by Dr. Patrick Azkarate. 1. Understand the pathophysiology of RACD Ionizing radiation has the potential to damage DNA. Both normal cells and cancer cells get damaged, but cancer has less effective DNA repair mechanisms and therefore malignant cells are more vulnerable to radiation therapy. After radiation causes acute damage, this sets off an inflammatory cascade leading to myofibroblast activation, fibrosis and collagen deposition, and subsequent stiffening of the myocardium and vessels. 2. What may increase one’s risk of developing RACD? Young age (<50 years-old) at the time of radiation High cumulative dose (>30 Gy) or high dose of radiation fractions (>2 Gy/day) Anterior or left chest radiation (breast cancer, lung cancer, lymphoma) Pre-existing cardiovascular disease Tumor in or next to the heart Concomitant chemotherapy (e.g. anthracyclines) 3. What are some techniques being used to reduce radiation exposure? Shielding Respiratory gating techniques (e.g. deep inspiratory breath-hold, activated breathing control) Smaller repeated fractions Narrow tangential beams Proton therapy 4. What are prevention and screening strategies for RACD? Annual history and physical examinationTreat pre-existing conditionsScreen for RACD (myocardial, valvular, pericardial, CAD, or conduction system disease)5 years post-exposure, screen for CAD and consider stress test every 2 years10 years post-exposure, screen for valvular heart disease with an echocardiogram every 2 years1 5. Discuss diagnosis and management of specific complications of RACD CAD The risk of radiation induced CAD (RICAD) is 7.5% per Grey Unit (Gy). The risk is roughly constant, begins several years after exposure, and persists for at least 2-3 decades (>50% of excess ischemic events occurring >10 years after RT).2 Radiation causes inflammatory plaque with high collagen and fibrin content, similar to accelerated atherosclerosis. Angiographic characteristics: Ostial or proximal Anterior and central (predominantly affecting the left anterior descending and the right coronary arteries) Severe, diffuse Long, smooth, concentric, and tubular Treatment: CABG vs PCI While there are no head-to-head trials comparing CABG vs PCI in patients with RICAD, it is known that compared to the general population, following CABG they have worse outcomes (increased risk of wound dehiscence, infection, graft failure, and death).3 The data for PCI is mixed but most recently have shown that patients with RICAD undergoing PCI have similar outcomes compared to patients without radiation exposure.4 Unless there is an additional indication for surgery, PCI for chronic CAD usually preferred. If multi-vessel CAD or higher Syntax score (≥ 22) consider CABG. Other considerations might guide percutaneous vs surgical revascularization Porcelain aorta Fibrotic bypass grafts (internal mammary artery) in the radiation field Multi-valvular disease Valvular disease Radiation causes progressive valve thickening and calcification leading to valve leaflet retraction, followed by regurgitation and then stenosis. Patients usually become symptomatic 1-2 decades after radiation exposure (later than CAD). Prevalence of aortic regurgitation (AR) at 10 years is 4% and at 20 years is 60%. The prevalence of aortic stenosis (AS) at 10 years 0% but at 20 years: 16% Mitral regurgitation (MR) and AR are the most common and occur due to leaflet retraction. These ultimately progress to stenosis. MR is the most common reason for surgery. Echocardiogram is done to evaluate the valves. Surrounding structures may show calcification, such as the annulus, subvalvular apparatus, or aorta-mitral curtain (a hallmark of previous heart irradiation which is associated with mortality in patients undergoing cardiac surgery). Management decisions are complex, depends on the valvular lesion(s) involved, and should be guided by a heart team approach. For aortic valve disease, TAVR is preferred over SAVR (unless there is another indication for surgery or there is excess risk for coronary obstruction or annular rupture). If SAVR is pursued, usually try to replace all valves (even if one is just mild to moderate) to avoid re-operation. For the mitral valve, data is mixed between surgical vs transcatheter approaches. In general, if surgery is indicated then the valve is replaced and not repaired (irradiated valve tissue is fibrotic and calcified) Given increased risk of reoperation, mechanical prostheses may be appealing, especially for younger patients. If there are contraindications to anticoagulation, then a bioprosthesis should be used. General cardiothoracic surgery principles in patients with RACD Worse long-term outcomes compared to age and sex-matched controls undergoing similar procedures Reoperation portends significantly higher risk compared to non-RACD patients Delay surgical intervention as long as possible Address all issues with a complete operation the first time Surgical planning may involve cardiac magnetic resonance imaging (CMR) to look for fibrosis, computer tomography (CT) to identify calcified structures (intra- and extra-cardiac), transthoracic echocardiogram (TTE), right and left heart catheterization to evaluate for restriction vs constriction, coronary angiogram. Myocardial disease In terms of pathophysiology, radiation causes an acute inflammatory cascade, then a pro-fibrotic milieu which leads to myocardial fibrosis and reduced microvascular proliferation and density. RACD-related myocardial dysfunction is defined as >10% decrease in LVEF to a value <50% confirmed by repeated imaging 2-3 weeks after the first diagnostic study or heart failure with preserved ejection fraction (HFpEF) HFpEF is more common than heart failure with reduced ejection fraction (HFrEF). Risk of myocardial disease increases with total radiation dose, fraction size, and volume of heart in the radiotherapy field. Benefit of heart failure pharmacotherapy in subclinical myocardial dysfunction remains unknown, however guideline directed medical therapy is recommended. While transplant is not broadly recommended due to poor outcomes and high risk of recurrent malignancy, this remains a consideration.  Conduction system disease The conduction system can sustain direct damage from radiation or can be affected by ischemia or fibrosis. 75% of long-term survivors who received mediastinal radiation have conduction defects on electrocardiogram (ECG). Acutely, we can see transient, nonspecific repolarization abnormalities. Long-term, patients may develop right bundle branch block (anteriorly located). High risk for ectopy, supraventricular ventricular tachycardia, ventricular tachycardia, and non-specific T-wave and ST-segment ECG changes. Inappropriate sinus tachycardia is a sign of extensive RACD. There are no specific treatments in RACD patients and providers should treat according to guidelines. Radiation and Devices Radiation can impair healing after device implantation Devices can malfunction Manufacturers advise that the lifetime dose a device can take is 5 Gray (this is when circuit board can start to malfunction) It is recommended to interrogate device before and after radiation therapy Pericardial disease Radiation causes pericardial thickening, calcification, and fibrosis with subsequent constriction and effusion. It can be hard to diagnose constriction since many patients may have concomitant restrictive physiology. Patients may present with pericarditis, pericardial effusion, chronic pericardial disease, or cardiac tamponade. TTE, CT, and CMR are helpful to identify pericardial thickening, enhancement and septal shift. When in doubt, simultaneous right and left heart catheterization can help with the diagnosis. To treat constriction, we can try anti-inflammatory therapy first (in case of reversibility), then standard of care. References – Radiation-Associated cardiovascular disease Desai MY, Windecker S, Lancellotti P, et al. Prevention, Diagnosis, and Management of Radiation-Associated Cardiac Disease: JACC Scientific Expert Panel. J Am Coll Cardiol. 2019;74(7):905-927. doi:10.1016/j.jacc.2019.07.006 Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987-998. doi:10.1056/NEJMoa1209825 Wu W, Masri A, Popovic ZB, et al. Long-term survival of patients with radiation heart disease undergoing cardiac surgery: a cohort study. Circulation 2013;127:1476–85. Liang JJ, Sio TT, Slusser JP, et al. Outcomes after percutaneous coronary intervention with stents in patients treated with thoracic external beam radiation for cancer. J Am Coll Cardiol Intv 2014;7:1412–20. Heidenreich PA, Hancock SL, Lee BK, et al. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol 2003;42:743–9. Meet Our Collaborators International Cardio-Oncology Society ( IC-OS). IC-OS exits to advance cardiovascular care of cancer patients and survivors by promoting collaboration among researchers, educators and clinicians around the world. Learn more at https://ic-os.org/.

Cardiogenic shock (CS) remains a complex, multifactorial syndrome associated with significant morbidity and mortality. The CardioNerds Critical Care Cardiology Series tackles this important syndrome in a series of several episodes including: LV-predominant Shock, RV-predominant Shock, and Bi-ventricular Shock. In this episode, we review the definitions, pathophysiology, evaluation, and contemporary management, including use of inotropes and mechanical circulatory support, of left ventricular (LV) predominant CS. Series co-chairs Dr. Eunice Dugan and Dr. Karan Desai along with CardioNerds Co-founders Dr. Amit Goyal and Dr. Daniel Ambinder were joined by FIT lead, Dr. Vanessa Blumer, the recipient of the AHA 2021 Laennec Fellow in Training Clinician Award and currently pursuing Advanced Heart Failure and Transplant fellowship at the Cleveland Clinic. Our episode expert is Dr. Shashank Sinha, an Advanced Heart Failure, Mechanical Circulatory Support, and Cardiac Transplant cardiologist, Medical Director of the Cardiac Intensive Care Unit, and Director of the Cardiovascular Critical Care Research Program at INOVA Fairfax Hospital. His illustrious career accomplishments include being a Steering Committee member and site Principal Investigator for the multicenter Cardiogenic Shock Working Group and Critical Care Cardiology Trials Network. Audio editing by CardioNerds academy intern, Anusha Gandhi. 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 – LV Predominant Cardiogenic Shock LV-CS is complex! It is important to recognize that the pathophysiology of heart failure-related cardiogenic shock (HF-CS) is distinct from that of acute myocardial infarction (AMI-CS), and also crucial to differentiate between LV-dominant, right ventricular (RV)-dominant and biventricular (BiV)-shock. The SCAI SHOCK Stage Classification provides a unified and standardized vocabulary when assessing severity of CS, and facilitates communication about the diagnosis, presentation, and evolving nature of CS. Norepinephrine is considered the initial vasopressor of choice in most CS patients; the initial inotrope choice is a bit more nuanced! When considering mechanical circulatory support (MCS) for LV shock, high-quality data to guide therapy is lacking but one must always consider “the right patient, for the right device, at the right time” and remember that “pumps pump blood, decisions save lives”. Multidisciplinary, team-based care is paramount to improving survival of the critically ill patient with CS. Show notes – LV Predominant Cardiogenic Shock Notes drafted by Dr. Vanessa Blumer. 1. What tools do you use to define LV CS? CS is a hemodynamically complex and multifactorial syndrome, one of the most common indications for admission to a cardiac intensive care unit, with short-term mortality ranging from 35-50%. It is defined by systemic hypoperfusion and tissue hypoxia due to a primary cardiac insult or dysfunction. Clinical criteria used to define CS typically include evidence of hypotension (classically defined as SBP < 90 mmHg for 30 minutes and/or use of vasopressors, inotropes, or MCS to maintain systolic blood pressure > 90 mmHg) AND evidence of end-organ hypoperfusion (for example, serum lactic acid > 2 mmol/L, acute kidney injury, acute liver injury, altered mental status) in the setting of acute coronary syndrome or acute decompensated heart failure. Laboratory markers, including serum lactic acid, liver function tests, kidney function, and biomarkers including troponin and natriuretic peptides may be helpful. An echocardiogram is an excellent point of care tool to help demonstrate and confirm evidence of LV systolic dysfunction and/or valvular abnormalities.  Finally, a right heart catheterization (demonstrating an abnormally low cardiac output and index with elevated filling pressures) may be useful in facilitating the diagnosis and subsequent management. 2. How do HF-CS and AMI-CS lead to different phenotypes? It is important to recognize that HF-CS is now the predominant cause of CS, accounting for more than half of all CS. AMI-CS is characterized by an abrupt presentation due to a primary myocardial ischemic insult leading to necrosis (occurring in 5-10% of AMI patients) and can occur after STEMI or NSTEMI. The canonical clinical course is hypotension due to primary myocardial dysfunction leading to hypoperfusion with congestion as a later clinical or hemodynamic finding. Conversely, a patient with heart failure related shock commonly presents with acutely decompensated heart failure and congestion, leading to hypoperfusion, and culminating in hypotension. 3. How do you distinguish LV-dominant, RV-dominant and BiV shock? LV predominant CS is characterized by high pulmonary capillary wedge pressure (PCWP) and normal or reduced central venous pressure (CVP) in the setting of reduced cardiac output (CO). RV dominant CS is characterized by elevated CVP, normal to low PCWP, and normal to reduced CO. BiV shock is characterized by hypotension, elevated CVP, normal or elevated PCWP, and reduced CO. 4. What is the current role for inotropes, vasodilators, and vasopressors in the management of LV CS? The Acute Cardiovascular Care Association of the European Society of Cardiology published a position statement for the diagnosis and treatment of patients with AMI complicated by CS in 2020. According to this, vasopressors (norepinephrine preferable over dopamine) in the presence of persistent hypotension received a Level of IIb/B recommendation. Intravenous inotropes to increase cardiac output received a IIb/C recommendation. Based on the available evidence and its accompanying limitations, norepinephrine is considered the initial vasopressor of choice in most CS patients. 5. When should we consider management with temporary mechanical circulatory support (t-MCS) devices and how should one strategize device selection? Initiation or escalation of t-MCS largely depends on matching the right device to the right patient at the right time. Because the risk and number of complications increases with duration and type of MCS, these decisions are complex, nuanced, and must consider operator and institutional expertise. When considering type of device (IABP, Impella, ECMO), SCAI Staging and phenotyping (AMI vs HF CS) are absolutely critical. 6. What are treatment goals when following patients with LV CS? Optimize preload, afterload, and contractility Perform serial reassessment (≤ q 6hr) of hemodynamics & end-organ perfusion Aim for timely and tailored treatment escalation/de-escalation    Assess for LV and RV recovery (wean t-MCS, vasopressors and inotropes as able Early identification of worsening shock:  Rising Lactate  Increasing pressor requirement  Worsening end-organ function  CPO < 0.6 and/or PAPi < 1  RA > 15 and/or PCWP > 15 References – LV Predominant Cardiogenic Shock Abraham J, Blumer V, Burkhoff D, Pahuja M, Sinha SS, Rosner C, Vorovich E, Grafton G, Bagnola A, Hernandez-Montfort JA, Kapur NK. Heart Failure-Related Cardiogenic Shock: Pathophysiology, Evaluation and Management Considerations: Review of Heart Failure-Related Cardiogenic Shock. J Card Fail. 2021 Oct;27(10):1126-1140. doi: 10.1016/j.cardfail.2021.08.010. PMID: 34625131. Kapur NK, Kanwar M, Sinha SS, Thayer KL, Garan AR, Hernandez-Montfort J, Zhang Y, Li B, Baca P, Dieng F, Harwani NM, Abraham J, Hickey G, Nathan S, Wencker D, Hall S, Schwartzman A, Khalife W, Li S, Mahr C, Kim JH, Vorovich E, Whitehead EH, Blumer V, Burkhoff D. Criteria for Defining Stages of Cardiogenic Shock Severity. J Am Coll Cardiol. 2022 Jul 19;80(3):185-198. doi: 10.1016/j.jacc.2022.04.049. PMID: 35835491. CardioNerds Cardiac Critical Care Production Team Karan Desai, MD Dr. Mark Belkin Dr. Yoav Karpenshif Amit Goyal, MD Daniel Ambinder, MD

Dr. Rick Nishimura, a professor of medicine at Mayo Clinic, discusses managing mitral regurgitation in challenging cases. The podcast covers topics such as guidelines, real patient cases, treatment challenges, microclip usage, atrial fibrillation impact, and postoperative complications. The conversation delves into the nuances of mitral regurgitation management and the importance of echocardiograms in therapy decisions.