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There is increasing evidence regarding the prevalence of genetic cardiomyopathies, for which arrhythmias may be the first presentation. Ventricular and atrial arrhythmias presenting in the absence of known myocardial disease are often labelled as idiopathic, or lone. While ventricular arrhythmias are well-recognized as presentation for arrhythmogenic cardiomyopathy in the right ventricle, the scope of arrhythmogenic cardiomyopathy has broadened to include those with dominant left ventricular involvement, usually with a phenotype of dilated cardiomyopathy. In addition, careful evaluation for genetic cardiomyopathy is also warranted for patients presenting with frequent premature ventricular contractions, conduction system disease, and early onset atrial fibrillation, in which most detected genes are in the cardiomyopathy panels. Sudden death can occur early in the course of these genetic cardiomyopathies, for which risk is not adequately tracked by left ventricular ejection fraction. Only a few of the cardiomyopathy genotypes implicated in early sudden death are recognized in current indications for implantable cardioverter defibrillators which otherwise rely upon a left ventricular ejection fraction ≤0.35 in dilated cardiomyopathy. The genetic diagnoses impact other aspects of clinical management such as exercise prescription and pharmacological therapy of arrhythmias, and new therapies are coming into clinical investigation for specific genetic cardiomyopathies. The expansion of available genetic information and implications raises new challenges for genetic counseling, particularly with the family member who has no evidence of a cardiomyopathy phenotype and may face a potentially negative impact of a genetic diagnosis. Discussions of risk for both probands and relatives need to be tailored to their numeric literacy during shared decision-making. For patients presenting with arrhythmias or cardiomyopathy, extension of genetic testing and its implications will enable cascade screening, intervention to change the trajectory for specific genotype-phenotype profiles, and enable further development and evaluation of emerging targeted therapies.

Cardiomyopathies are a heterogeneous group of cardiac muscle disorders that result in dilated, hypertrophic, or restrictive pathophysiological entities. Dilated cardiomyopathy (DCM) is the most common form in sub-Saharan Africa (SSA). However, population-specific research studies reporting the actual burden of DCM in this region are still lacking. Also, little is known about the genetic basis of DCM in this population, and genetic testing is still not readily accessible. This review describes the common pathogenic genes implicated in DCM globally and discusses the evidence-based management of patients with DCM. We also present a summary of studies describing genes implicated or associated with DCM in patients residing in SSA.

Background: Spontaneously depolarizing nodal cells comprise the pacemaker of the heart. Intracellular calcium (Ca 2+ ) plays a critical role in mediating nodal cell automaticity and understanding this so-called Ca 2+ clock is critical to understanding nodal arrhythmias. We previously demonstrated a role for Jph2 (junctophilin 2) in regulating Ca 2+ -signaling through inhibition of RyR2 (ryanodine receptor 2) Ca 2+ leak in cardiac myocytes; however, its role in pacemaker function and nodal arrhythmias remains unknown. We sought to determine whether nodal Jph2 expression silencing causes increased sinoatrial and atrioventricular nodal cell automaticity due to aberrant RyR2 Ca 2+ leak. Methods: A tamoxifen-inducible, nodal tissue-specific, knockdown mouse of Jph2 was achieved using a Cre-recombinase-triggered short RNA hairpin directed against Jph2 (Hcn4:shJph2). In vivo cardiac rhythm was monitored by surface ECG, implantable cardiac telemetry, and intracardiac electrophysiology studies. Intracellular Ca 2+ imaging was performed using confocal-based line scans of isolated nodal cells loaded with fluorescent Ca 2+ reporter Cal-520. Whole cell patch clamp was conducted on isolated nodal cells to determine action potential kinetics and sodium-calcium exchanger function. Results: Hcn4:shJph2 mice demonstrated a 40% reduction in nodal Jph2 expression, resting sinus tachycardia, and impaired heart rate response to pharmacologic stress. In vivo intracardiac electrophysiology studies and ex vivo optical mapping demonstrated accelerated junctional rhythm originating from the atrioventricular node. Hcn4:shJph2 nodal cells demonstrated increased and irregular Ca 2+ transient generation with increased Ca 2+ spark frequency and Ca 2+ leak from the sarcoplasmic reticulum. This was associated with increased nodal cell AP firing rate, faster diastolic repolarization rate, and reduced sodium-calcium exchanger activity during repolarized states compared to control. Phenome-wide association studies of the JPH2 locus identified an association with sinoatrial nodal disease and atrioventricular nodal block. Conclusions: Nodal-specific Jph2 knockdown causes increased nodal automaticity through increased Ca 2+ leak from intracellular stores. Dysregulated intracellular Ca 2+ underlies nodal arrhythmogenesis in this mouse model.

Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores (PRS), monogenic risks, family history, and clinical risk assessments via a Genome Informed Risk Assessment (GIRA) report and will assess uptake of care recommendations after return of results.GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022.Return of a novel report for communicating monogenic, polygenic, and family history based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

Background: One in three Americans will have atrial fibrillation (AF) during their lifetime. Obesity and metabolic derangements are key risk factors for AF. It is unclear, however, which subset of patients would benefit most from targeted interventions aimed at weight loss and control of metabolic derangements to prevent incident AF. Methods: A landmark analysis to compare time-to-AF after a three-year run-in period was performed among 95,160 subjects from COMMODORE, a cohort with rich longitudinal data obtained from a de-identified copy of the Vanderbilt University Medical Center Electronic Health Record. Included subjects were required to have four height and weight measures collected during a prespecified three-year qualification (i.e., “landmark”) period, with approximately one year (8 to 16 months) between each measure (t 0 -t 3 ), and did not have AF prior to t 3 . We determined the subject weight during the run-in period and metabolic status according to absence, development, or presence at the start of the landmark period, t 0 , of: hypertension (HTN), diabetes mellitus, low high-density lipoprotein, and elevated triglycerides. Results: From the study population of 95,160 adults, incident AF occurred in 9,094 participants (9.6%), over a median follow-up of 6.35 (IQR: 4.40-9.16) years. Participants who developed AF were more likely to be older, heavier, White, males, and have the four metabolic derangements studied. A cox-proportional hazards model was fit using median population values and varying t3 weight to estimate the 10-year AF risk based on weight alone. We observed a U-shaped pattern of risk where participants with a BMI in the range of 18.5 kg/m 2 to 25 kg/m 2 have the lowest 10-year AF risk. Presence of any of the derangements, either chronic or developed, was associated with a decrease in AF-free probability during the outcome period (p0 resulted in a significant decrease in AF-free probability compared to those who developed the condition (p Conclusions and Relevance: In this analysis of a large real-world clinical cohort, both overweight (BMI > 25 kg/m 2 ) and underweight (BMI < 15 kg/m 2 ) participants are at an increased risk for AF development. The presence of metabolic derangements, regardless of diagnostic time, significantly increases AF risk and metabolic burden corresponds to increments in risk. Our findings suggest that prevention of metabolic derangements is critical to AF risk mitigation and that weight loss for AF management should be targeted to overweight patients regardless of metabolic status.

Elevated fibroblast growth factor-23 (FGF23) has been consistently associated with heart failure, particularly heart failure with preserved ejection fraction, among patients with CKD and in the general population. FGF23 may directly induce cardiac remodeling and heart failure. However, biases affecting observational studies impede robust causal inferences. Mendelian randomization leverages genetic determinants of a risk factor to examine causality. We performed a two-sample Mendelian randomization to assess causal associations between FGF23 and heart failure.Genetic instruments were genome-wide significant genetic variants associated with FGF23, including variants nearGenetically determined FGF23 was not associated with overall heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium (odds ratio, 1.13; 95% confidence interval, 0.89 to 1.42 per unit higher genetically predicted log FGF23) and the full BioVU sample (odds ratio, 1.32; 95% confidence interval, 0.95 to 1.84). In stratified analyses in BioVU, higher FGF23 was associated with overall heart failure (odds ratio, 3.09; 95% confidence interval, 1.38 to 6.91) among individuals with low eGFR-polygenic risk score (1 SD below the mean), but not those with high eGFR-polygenic risk score (We found no association between genetically predicted FGF23 and heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium. In BioVU, genetically elevated FGF23 was associated with higher heart failure risk, specifically heart failure with preserved ejection fraction, particularly among individuals with low genetically predicted eGFR.This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_07_28_CJN00960122.mp3.

Introduction: Animal models of human diseases are used extensively to interrogate molecular mechanisms in a reductionist fashion. We tested whether aggregation and integration of preclinical data can identify new causative pathways that faithfully model human disease mechanisms. We have termed this novel technique, the Preclinical Science Integration and Translation (PRESCIANT) method. Methods and Results: Data were extracted from 716 manuscripts in the journal Arteriosclerosis, Thrombosis, and Vascular Biology from 1995-2019 using the apolipoprotein E knockout mouse (ApoE-KO) to study atherosclerosis. We identified 360 unique studies in which genes were experimentally perturbed in ApoE-KO mice to impact atherosclerotic plaque size and/or composition. Impacts of the interventions on plaque size, inflammation, and lipid content were analyzed using Ingenuity Pathway Analysis. The top upstream regulatory network (sc-58125, a COX2 inhibitor) linked 37.2% (134) of the genes implicated in atherosclerosis into a single network. Further, Ingenuity Pathway Analysis identified TREM1 signaling, LXR/RXR activation, and renin-angiotensin signaling as the top 3 pathways associated with changes in atherosclerosis parameters. Specifically, early atherogenesis genes were enriched with pathways associated with inflammatory cell migration and infiltration (including TREM1) whereas late atherosclerosis genes were associated with cell metabolism and survival (including LXR/RXR activation). These two pathways were interrogated in a clinical cohort of 88,660 patients by testing for association between genetically predicted expression of the human homologs of mouse pathway genes and a composite phenotype composed of 27 human atherosclerosis diagnoses. There was a significant enrichment (p Conclusion: PRESCIANT can successfully leverage decades of animal investigations to translate results from large-volume singular preclinical studies to make novel causal inferences into human disease.

Background Multi-system inflammatory syndrome in children (MIS-C) is a rare consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MIS-C shares features with common infectious and inflammatory syndromes and differentiation early in the course is difficult. Identification of early features specific to MIS-C may lead to faster diagnosis and treatment. We aimed to determine clinical, laboratory, and cardiac features distinguishing MIS-C patients within the first 24 hours of admission to the hospital from those who present with similar features but ultimately diagnosed with an alternative etiology. Methods We performed retrospective chart reviews of children (0-20 years) who were admitted to Vanderbilt Children’s Hospital and evaluated under our institutional MIS-C algorithm between June 10, 2020-April 8, 2021. Subjects were identified by review of infectious disease (ID) consults during the study period as all children with possible MIS-C require an ID consult per our institutional algorithm. Clinical, lab, and cardiac characteristics were compared between children with and without MIS-C. The diagnosis of MIS-C was determined by the treating team and available consultants. P-values were calculated using two-sample t-tests allowing unequal variances for continuous and Pearson’s chi-squared test for categorical variables, alpha set at < 0.05. Results There were 128 children admitted with concern for MIS-C. Of these, 45 (35.2%) were diagnosed with MIS-C and 83 (64.8%) were not. Patients with MIS-C had significantly higher rates of SARS-CoV-2 exposure, hypotension, conjunctival injection, abdominal pain, and abnormal cardiac exam (Table 1). Laboratory evaluation showed that patients with MIS-C had lower platelet count, lymphocyte count and sodium level, with higher c-reactive protein, fibrinogen, B-type natriuretic peptide, and neutrophil percentage (Table 2). Patients with MIS-C also had lower ejection fraction and were more likely to have abnormal electrocardiogram. Conclusion We identified early features that differed between patients with MIS-C from those without. Development of a diagnostic prediction model based on these early distinguishing features is currently in progress. Disclosures Natasha B. Halasa, MD, MPH, Genentech (Other Financial or Material Support, I receive an honorarium for lectures - it’s a education grant, supported by genetech)Quidel (Grant/Research Support, Other Financial or Material Support, Donation of supplies/kits)Sanofi (Grant/Research Support, Other Financial or Material Support, HAI/NAI testing) Natasha B. Halasa, MD, MPH, Genentech (Individual(s) Involved: Self): I receive an honorarium for lectures - it’s a education grant, supported by genetech, Other Financial or Material Support, Other Financial or Material Support; Sanofi (Individual(s) Involved: Self): Grant/Research Support, Research Grant or Support James A. Connelly, MD, Horizon Therapeutics (Advisor or Review Panel member)X4 Pharmaceuticals (Advisor or Review Panel member)

PARADIGM-HF showed that sacubitril/valsartan (sac/val) improved quality of life (QOL) vs enalapril in heart failure with reduced ejection fraction (HFrEF), yet limited data are available regarding QOL changes after sac/val initiation in routine practice. PROVIDE-HF was a prospective study of HFrEF

Introduction: Radiotherapy for thoracic cancer causes incidental cardiac exposure and increases risk of ischemic heart disease. Less clear is whether radiotherapy similarly increases risk of arrhythmias. Radiotherapy induces cardiac inflammation and fibrosis, which are risk factors for atrial fibrillation (AF). Hypothesis: In patients with thoracic tumors, radiotherapy is associated with incident AF. Methods: We conducted a retrospective study of electronic medical records (EMR) of patients who had a primary tumor of the breast, lung, mediastinum, or esophagus diagnosed between 1994 and 2014, did not have AF at time of diagnosis, and did not have previous thoracic radiotherapy. Patients were followed for incident AF until the end of the EMR or death. Incident AF was determined using a validated algorithm with a positive predictive value of 95.6%. After multiple imputation of missing variables, the association between radiotherapy and incident AF was assessed using Cox proportional hazards models. Results: 4163 patients were included in the analysis. Mean (SD) age was 61.2 (13.3) years and 71% were women; 600 underwent radiotherapy. After a median (25 th -75 th percentile) 796 (255-2032) days of follow-up, the incidence of AF was 6.8% with and 6.2% without radiotherapy (P=0.538). After adjustment for potential confounders, radiotherapy was not associated with incident AF [hazard ratio (HR): 1.02, 95% confidence interval: 0.72-1.44]. Age [HR (per year): 1.05 (1.04-1.06), P=6.0*10 -15 ], male sex [HR: 2.44 (1.80-3.30), P=9.5*10 -9 ], coronary artery disease [HR: 1.42 (1.06-1.92), P=0.02], hypertension [HR: 6.44 (2.04-20.3), P=0.001], and heart failure [HR: 3.20 (2.31-4.44), P=3.4*10 -12 ] were associated with incident AF. Among 3908 patients with unilateral breast or lung tumors, radiotherapy was not associated with incident AF [HR: 1.23 (0.79-1.92)] and tumor laterality did not modify the effect (P for interaction: 0.201). Conclusions: In this large retrospective cohort study, radiotherapy for thoracic tumors was not associated with incident AF. Rather, previously described AF risk factors were the most important drivers of AF risk. Larger studies with extended follow-up may further elucidate whether thoracic radiotherapy is a risk factor for AF.