The Genetic Basis of Sudden Cardiac Death: From Diagnosis to Emerging Genetic Therapies.

Sudden cardiac death (SCD) is an abrupt, tragic manifestation of a number of cardiovascular diseases, primarily ion channelopathies and heritable cardiomyopathies. Because these diseases are heritable, genetics play a key role in the diagnosis and management of SCD-predisposing diseases. Historically, genetics have been used to confirm a diagnosis and identify at-risk family members, but a deeper understanding of the genetic causes of SCD could pave the way for individualized therapy, early risk detection, and a transformative shift toward genetically informed therapies.

Promise and Peril of a Genotype-First Approach to Mendelian Cardiovascular Disease.

Precision medicine, which among other aspects includes an individual's genomic data in diagnosis and management, has become the standard-of-care for Mendelian cardiovascular disease (CVD). However, early identification and management of asymptomatic patients with potentially lethal and manageable Mendelian CVD through screening, which is the promise of precision health, remains an unsolved challenge. The reduced costs of genomic sequencing have enabled the creation of biobanks containing in-depth genetic and health information, which have facilitated the understanding of genetic variation, penetrance, and expressivity, moving us closer to the genotype-first screening of asymptomatic individuals for Mendelian CVD.

ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ~1 in 500 and exhibits marked genetic heterogeneity. Previously published in 2019, 57 HCM-associated genes were curated providing the first systematic evaluation of gene-disease validity. Here we report work by the ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel (HCVD-GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes.

Cardiovascular disease risk factors in congenital heart disease survivors are associated with heart failure.

Background: Despite advances in treatment and survival, individuals with congenital heart defects (CHD) have a higher risk of heart failure (HF) compared to the general population.

Objective: To evaluate comorbidities associated with HF in patients with CHD with a goal of identifying potentially modifiable risk factors that may reduce HF-associated morbidity and mortality.

Methods: Five surveillance sites in the United States linked population-based healthcare data and vital records.

Risk Factors and Outcomes Associated with Gaps in Care in Children with Congenital Heart Disease.

Adults with congenital heart disease (CHD) benefit from cardiology follow-up at recommended intervals of ≤ 2 years. However, benefit for children is less clear given limited studies and unclear current guidelines. We hypothesize there are identifiable risks for gaps in cardiology follow-up in children with CHD and that gaps in follow-up are associated with differences in healthcare utilization.

Underrepresentation of Diverse Ancestries Drives Uncertainty in Genetic Variants Found in Cardiomyopathy-Associated Genes.

Background: Thousands of genetic variants have been identified in cardiomyopathy-associated genes. Diagnostic genetic testing is key for evaluation of individuals with suspected cardiomyopathy. While accurate variant pathogenicity assignment is important for diagnosis, the frequency of and factors associated with clinically relevant assessment changes are unclear.

Obesity Predisposes Anthracycline-Treated Survivors of Childhood and Adolescent Cancers to Subclinical Cardiac Dysfunction.

Anthracyclines are effective chemotherapeutics used in approximately 60% of pediatric cancer cases but have a well-documented risk of cardiotoxicity. Existing cardiotoxicity risk calculators do not include cardiovascular risk factors present at the time of diagnosis. The goal of this study is to leverage the advanced sensitivity of strain echocardiography to identify pre-existing risk factors for early subclinical cardiac dysfunction among anthracycline-exposed pediatric patients.

Cardiovascular Disease in Childhood, Adolescent, and Young Adult Cancer Survivors: The Impact of Family History of Premature Heart Disease.

Childhood, adolescent, and young adult (CAYA) cancer survivors (age 0-39 years at diagnosis) are at increased risk of cardiovascular disease (CVD). Family history of early heart disease increases the risk of CVD in the general population; however, it is unknown whether this association is seen in CAYA cancer survivors. Self-report data from the National Health and Nutrition Examination Survey (2005-2018) were used to identify CAYA survivors (>5 years post-diagnosis).

Junctional Ectopic Tachycardia Caused by Junctophilin-2 Expression Silencing Is Selectively Sensitive to Ryanodine Receptor Blockade.

Junctional ectopic tachycardia (JET) is a potentially fatal cardiac arrhythmia. Hcn4:shJph2 mice serve as a model of nodal arrhythmias driven by ryanodine type 2 receptor (RyR2)-mediated Ca leak. EL20 is a small molecule that blocks RyR2 Ca leak.

Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.

Background: PRDM16 plays a role in myocardial development through TGF-β (transforming growth factor-beta) signaling. Recent evidence suggests that loss of PRDM16 expression is associated with cardiomyopathy development in mice, although its role in human cardiomyopathy development is unclear. This study aims to determine the impact of PRDM16 loss-of-function variants on cardiomyopathy in humans.

Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in the UK Biobank.

Background: Inherited cardiomyopathies present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the general population.

Objectives: The authors aimed to determine the risk of mortality and composite cardiomyopathy-related outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the UK Biobank.

Cardiovascular Risk Factor Disparities in Adult Survivors of Childhood Cancer Compared With the General Population.

Background: It is unknown whether a history of childhood cancer modifies the established disparities in cardiovascular risk factors (CVRFs) observed in the general population.

Objectives: We sought to determine if disparities in CVRFs by race/ethnicity are similar among childhood cancer survivors compared with the general population.

Methods: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort with a longitudinal follow-up of 24,084 5-year survivors diagnosed between 1970 and 1999.

: A Web-Based Precision Medicine Tool for Predicting Variant Pathogenicity in Cardiomyopathy- and Channelopathy-Associated Genes.

Background: With genetic testing advancements, the burden of incidentally identified cardiac disease-associated gene variants is rising. These variants may carry a risk of sudden cardiac death, highlighting the need for accurate diagnostic interpretation. We sought to identify pathogenic hotspots in sudden cardiac death-associated genes using amino acid-level signal-to-noise (S:N) analysis and develop a web-based precision medicine tool, , to improve variant evaluation.

Deletion Is Associated With Sex-dependent Cardiomyopathy and Cardiac Mortality: A Translational, Multi-Institutional Cohort Study.

Background: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor . Early studies suggest that deletion of may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of loss is unknown.

Interpreting Incidentally Identified Variants in Genes Associated With Heritable Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Rapid advances in genetic technologies have led to expanding use of diagnostic, research, and direct-to-consumer exome and genome sequencing. Incidentally identified variants from this sequencing represent a significant and growing challenge to interpret and translate into clinical care and include variants in genes associated with heritable cardiovascular disease such as cardiac ion channelopathies, cardiomyopathies, thoracic aortic disease, dyslipidemias, and congenital/structural heart disease. These variants need to be properly reported, the risk of associated disease accurately assessed, and clinical management implemented to prevent or lessen the disease so that cardiovascular genomic medicine can become both predictive and preventive.