Over 1,500 gene mutations are known to cause hypertrophic cardiomyopathy (HCM). Previous studies suggest that cardiac β-myosin heavy chain (MYH7) gene mutations are commonly associated with a more severe phenotype, compared to cardiac myosin binding protein-C (MYBPC3) gene mutations with milder phenotype, incomplete penetrance and later age of onset. Compound mutations can worsen the phenotype. This study aimed to validate these comparative differences in a large cohort of individuals and families with HCM. We performed genome-phenome correlation among 80 symptomatic HCM patients, 35 asymptomatic carriers and 35 non-carriers, using an 18-gene clinical diagnostic HCM panel. A total of 125 mutations were identified in 14 genes. MYBPC3 and MYH7 mutations contributed to 50.0% and 24.4% of the HCM patients, respectively, suggesting that MYBPC3 mutations were the most frequent cause of HCM in our cohort. Double mutations were found in only nine HCM patients (7.8%) who were phenotypically indistinguishable from single-mutation carriers. Comparisons of clinical parameters of MYBPC3 and MYH7 mutants were not statistically significant, but asymptomatic carriers had high left ventricular ejection fraction and diastolic dysfunction when compared to non-carriers. The presence of double mutations increases the risk for symptomatic HCM with no change in severity, as determined in this study subset. The pathologic effects of MYBPC3 and MYH7 were found to be independent of gene mutation location. Furthermore, HCM pathology is independent of protein domain disruption in both MYBPC3 and MYH7. These data provide evidence that MYBPC3 mutations constitute the preeminent cause of HCM and that they are phenotypically indistinguishable from HCM caused by MYH7 mutations.

MYBPC3Δ25bp/D389V is associated with hyperdynamic features, which are an early finding in hypertrophic cardiomyopathy and thought to reflect an unfavorable energetic state. These findings support that a subset of MYBPC3Δ25bp carriers, those with D389V, account for the increased risk attributed to MYBPC3Δ25bp.

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The specialized cardiac conduction system (CCS) consists of the sinoatrial node (SAN) and the atrioventricular (AV) conduction system (AVCS), which includes proximal (AV node, bundle of His and bundle branches) and distal (Purkinje fibers) components. In four CCS marker mice [two transgenic (cGATA6|lacZ, CCS|lacZ) and two targeted gene knock-in (minK|lacZ, Hop|lacZ)] the expression of the lacZ gene (β-gal) has been reported to mark portions of the proximal and distal AVCS; the expression of this marker in the adult SAN is unknown. The primary objective of this study was to analyze the utility of these marker mice in the identification of the SAN. Intercaval and interventricular septal regions, containing all the components of the CCS, were freshly dissected from adult mice based on the anatomical landmarks and sectioned. Immunohistochemical characterization was performed with SAN markers (Cx45, HCN4), compared to the reporter expression (β-gal) and markers of the working myocardium (Cx40 and Cx43). In all four of the CCS marker mice, we found that β-gal expression is consistently observed in the proximal and distal AVCS. However, the presence of lacZ gene expression in the working myocardium outside the CCS and/or the absence of this reporter expression in the SAN prevent the effective use of these mice to identify the SAN, leading us to conclude that none of the four CCS marker mice we studied specifically mark the SAN.

The South Asian population, numbered at 1.8 billion, is estimated to comprise around 20% of the global population and 1% of the American population, and has one of the highest rates of cardiovascular disease. While South Asians show increased classical risk factors for developing heart failure, the role of population-specific genetic risk factors has not yet been examined for this group. Hypertrophic cardiomyopathy (HCM) is one of the major cardiac genetic disorders among South Asians, leading to contractile dysfunction, heart failure, and sudden cardiac death. This disease displays autosomal dominant inheritance, and it is associated with a large number of variants in both sarcomeric and non-sarcomeric proteins. The South Asians, a population with large ethnic diversity, potentially carries region-specific polymorphisms. There is high variability in disease penetrance and phenotypic expression of variants associated with HCM. Thus, extensive studies are required to decipher pathogenicity and the physiological mechanisms of these variants, as well as the contribution of modifier genes and environmental factors to disease phenotypes. Conducting genotype-phenotype correlation studies will lead to improved understanding of HCM and, consequently, improved treatment options for this high-risk population. The objective of this review is to report the history of cardiovascular disease and HCM in South Asians, present previously published pathogenic variants, and introduce current efforts to study HCM using induced pluripotent stem cell-derived cardiomyocytes, next-generation sequencing, and gene editing technologies. The authors ultimately hope that this review will stimulate further research, drive novel discoveries, and contribute to the development of personalized medicine with the aim of expanding therapeutic strategies for HCM.

Background: The use of inconsistent definitions for anaphylaxis outcomes limits our understanding of the natural history and epidemiology of anaphylaxis, hindering clinical practice and research efforts. Objective: Our aim was to develop consensus definitions for clinically relevant anaphylaxis outcomes by utilizing a multidisciplinary group of clinical and research experts in anaphylaxis. Methods: Using Delphi methodology, we developed agenda topics and drafted questions to review during monthly conference calls. Through online surveys, a 19-member panel consisting of experts in allergy and/or immunology and emergency medicine rated their level of agreement with the appropriateness of statements on a scale of 1 to 9. A median value of 1.0 to 3.4 was considered inappropriate, a median value of 3.5 to 6.9 was considered uncertain, and a median value of 7.0 to 9.0 was considered appropriate. A disagreement index was then calculated, with values less than 1.0 categorized as ''consensus reached.'' If consensus was not reached after the initial survey, subsequent surveys incorporating the aggregate deidentified responses from prior surveys were sent to panel members. This process was repeated until consensus was reached or 4 survey rounds had been completed, after which the question was categorized as ''no consensus reached.'' Results: The panel developed outcome definitions for persistent, refractory, and biphasic anaphylaxis, as well as for persistent and biphasic nonanaphylactic reactions. There was also consensus among panel members regarding the need to develop an anaphylaxis severity grading system. Conclusion: Dissemination and application of these definitions in clinical care and research will help standardize the terminology used to describe anaphylaxis outcomes and serve as the foundation for future research, including research From the

IntroductionThere remain significant knowledge gaps about the management and outcomes of children with anaphylaxis. These gaps have led to practice variation regarding decisions to hospitalise children and length of observation periods following treatment with epinephrine. The objectives of this multicentre study are to (1) determine the prevalence of and risk factors for severe, persistent, refractory and biphasic anaphylaxis, as well as persistent and biphasic non-anaphylactic reactions; (2) derive and validate prediction models for emergency department (ED) discharge; and (3) determine data-driven lengths of ED and inpatient observation prior to discharge to home based on initial reaction severity.Methods and analysisThe study is being conducted through the Pediatric Emergency Medicine Collaborative Research Committee (PEMCRC). Children 6 months to less than 18 years of age presenting to 30 participating EDs for anaphylaxis from October 2015 to December 2019 will be eligible. The primary outcomes for each objective are (1) severe, persistent, refractory or biphasic anaphylaxis, as well as persistent or biphasic non-anaphylactic reactions; (2) safe ED discharge, defined as no receipt of acute anaphylaxis medications or hypotension beyond 4 hours from first administered dose of epinephrine; and (3) time from first to last administered dose of epinephrine and vasopressor cessation. Analyses for each objective include (1) descriptive statistics to estimate prevalence and generalised estimating equations that will be used to investigate risk factors for anaphylaxis outcomes, (2) least absolute shrinkage and selection operator regression and binary recursive partitioning to derive and validate prediction models of children who may be candidates for safe ED discharge, and (3) Kaplan-Meier analyses to assess timing from first to last epinephrine doses and vasopressor cessation based on initial reaction severity.Ethics and disseminationAll sites will obtain institutional review board approval; results will be published in peer-reviewed journals and disseminated via traditional and social media, blogs and online education platforms.