Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases.

Transmembrane protein 43 ( or ) encodes a highly conserved protein found in the nuclear and endoplasmic reticulum membranes of many cell types and the intercalated discs and adherens junctions of cardiac myocytes. TMEM43 is involved in facilitating intra/extracellular signal transduction to the nucleus via the linker of the nucleoskeleton and cytoskeleton complex. Genetic mutations may result in reduced expression and altered TMEM43 protein cellular localization, resulting in impaired cell polarization, intracellular force transmission, and cell-cell connections.

Unraveling the genetic blueprint of doxorubicin-induced cardiotoxicity through systems genetics approaches.

Background: Anthracycline-induced cardiotoxicity (ACT) is a significant concern for cancer survivors, while genetic basis of ACT remains unclear. This study employs a murine genetic reference population (GRP) of BXD recombinant inbred strains, derived from DBA/2J (D2) and C57BL/6J (B6) crosses, to map quantitative trait loci (QTLs) linked to doxorubicin (DOX)-induced phenotypes through systems genetics approaches.

Methods: To model variability in ACT, 58 BXD strains and parental B6 and D2 mice (n ≥ 4 mice/sex/strain, 3-4-month-old) underwent an intraperitoneal injection of DOX (20 mg/kg).

Genetic mapping of electrocardiographic parameters in BXD strains reveals Chromosome 3 loci to be associated with cardiac repolarization abnormalities.

Risk factors for cardiac arrhythmias that can cause sudden death and heart failure include genetics, age, lifestyle, and other environmental factors. The study assessed electrocardiography (ECG) traits in BXD mice and explored associated quantitative trait loci (QTLs). Five-minute electrocardiograms were recorded in 44 BXD strains at 4-5 mo of age ( ≥ 5 mice/sex/strain).

Unraveling the Genetic Blueprint of Doxorubicin-Induced Cardiotoxicity Through Systems Genetics Approaches.

Background: Anthracycline-induced cardiotoxicity (ACT) is a significant concern for cancer survivors. The genetic basis of ACT remains unclear because of the impact of lifestyle and environmental factors in human studies. This study employs a murine genetic reference population (GRP) of BXD recombinant inbred strains, derived from DBA/2J (D2) and C57BL/6J (B6) crosses, to map quantitative trait loci (QTLs) linked to doxorubicin (DOX)-induced cardiotoxic phenotypes through systems genetics approaches.

Genomics of pediatric cardiomyopathy.

Cardiomyopathy in children is a leading cause of heart failure and cardiac transplantation. Disease-associated genetic variants play a significant role in the development of the different subtypes of disease. Genetic testing is increasingly being recognized as the standard of care for diagnosing this heterogeneous group of disorders, guiding management, providing prognostic information, and facilitating family-based risk stratification.

Animal Models for Mechanical Circulatory Support: A Research Review.

Heart failure is a clinical syndrome that has become a leading public health problem worldwide. Globally, nearly 64 million individuals are currently affected by heart failure, causing considerable medical, financial, and social challenges. One therapeutic option for patients with advanced heart failure is mechanical circulatory support (MCS) which is widely used for short-term or long-term management.

Impact of hematopoietic cell transplantation on myocardial fibrosis in young patients with sickle cell disease.

Serial cardiovascular magnetic resonance evaluation of children and young adults with SCD who underwent hematopoietic cell transplantation showed mean ECV, representing diffuse myocardial fibrosis, decreased 3.4% from baseline to 12 months posttransplantation. This trial was registered at www.

Exploring the Regulation and Function of in the Development of Early-Onset Dilated Cardiomyopathy and Congestive Heart Failure Using Systems Genetics Approach.

Background: Cardiomyopathies, diseases affecting the myocardium, are common causes of congestive heart failure (CHF) and sudden cardiac death. Recently, biallelic variants in ribosomal protein L3-like (RPL3L) have been reported to be associated with severe neonatal dilated cardiomyopathy (DCM) and CHF. This study employs a systems genetics approach to gain understanding of the regulatory mechanisms underlying the role of in DCM.

Progressive Left Ventricular Remodeling for Predicting Mortality in Children With Dilated Cardiomyopathy: The Pediatric Cardiomyopathy Registry.

Background: Pediatric dilated cardiomyopathy often leads to death or cardiac transplantation. We sought to determine whether changes in left ventricular (LV) end-diastolic dimension (LVEDD), LV end-diastolic posterior wall thickness, and LV fractional shortening (LVFS) over time may help predict adverse outcomes.

Methods And Results: We studied children up to 18 years old with dilated cardiomyopathy, enrolled between 1990 and 2009 in the Pediatric Cardiomyopathy Registry.

Utility of Left and Right Ventricular Strain in Arrhythmogenic Right Ventricular Cardiomyopathy: A Prospective Multicenter Registry.

Background: Imaging evaluation of arrhythmogenic right ventricular cardiomyopathy (ARVC) remains challenging. Myocardial strain assessment by echocardiography is an increasingly utilized technique for detecting subclinical left ventricular (LV) and right ventricular (RV) dysfunction. We aimed to evaluate the diagnostic and prognostic utility of LV and RV strain in ARVC.

Dyslipidemia and cardiovascular disease among childhood cancer survivors: a St. Jude Lifetime Cohort report.

Background: Childhood cancer survivors have increased risk of dyslipidemia and atherosclerotic cardiovascular disease (CVD). The aim of this study was to evaluate the prevalence and associated cardiovascular risks of specific lipid abnormalities among childhood cancer survivors.

Methods: Comprehensive lipid panel measurements were obtained from 4115 5-year survivors, with 3406 (mean age at evaluation = 35.

Expression Levels of the Gene in the Heart Are Highly Associated with Cardiac and Glucose Metabolism-Related Phenotypes and Functional Pathways.

Background: Troponin-I interacting kinase encoded by the gene is expressed in nuclei and Z-discs of cardiomyocytes. Mutations in were identified in patients with cardiac conduction diseases, arrhythmias, and cardiomyopathy.

Methods: We performed cardiac gene expression, whole genome sequencing (WGS), and cardiac function analysis in 40 strains of BXD recombinant inbred mice derived from C57BL/6J (B6) and DBA/2J (D2) strains.

Elevated Copeptin Levels Are Associated with Heart Failure Severity and Adverse Outcomes in Children with Cardiomyopathy.

In children with cardiomyopathy, the severity of heart failure (HF) varies. However, copeptin, which is a biomarker of neurohormonal adaptation in heart failure, has not been studied in these patients. In this study, we evaluated the correlation of copeptin level with functional HF grading, B-type natriuretic peptide (BNP), and echocardiography variables in children with cardiomyopathy.

Cardiac imaging and biomarkers for assessing myocardial fibrosis in children with hypertrophic cardiomyopathy.

Background: Myocardial fibrosis, as diagnosed on cardiac magnetic resonance imaging (cMRI) by late gadolinium enhancement (LGE), is associated with adverse outcomes in adults with hypertrophic cardiomyopathy (HCM), but its prevalence and magnitude in children with HCM have not been established. We investigated: (1) the prevalence and extent of myocardial fibrosis as detected by LGE cMRI; (2) the agreement between echocardiographic and cMRI measurements of cardiac structure; and (3) whether serum concentrations of N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) and cardiac troponin-T are associated with cMRI measurements.

Methods: A cross-section of children with HCM from 9 tertiary-care pediatric heart centers in the U.

Cardiac copper content and its relationship with heart physiology: Insights based on quantitative genetic and functional analyses using BXD family mice.

Background: Copper (Cu) is essential for the functioning of various enzymes involved in important cellular and physiological processes. Although critical for normal cardiac function, excessive accumulation, or deficiency of Cu in the myocardium is detrimental to the heart. Fluctuations in cardiac Cu content have been shown to cause cardiac pathologies and imbalance in systemic Cu metabolism.

Echocardiography phenotyping in murine genetic reference population of BXD strains reveals significant QTLs associated with cardiac function and morphology.

The genetic reference population of recombinant inbred BXD mice has been derived from crosses between C57BL/6J and DBA/2J strains. The DBA/2J parent exhibits cardiomyopathy phenotypes, whereas C57BL/6J has normal heart. BXD mice are sequenced for studying genetic interactions in cardiomyopathies.

Progressive Reduction in Right Ventricular Contractile Function Attributable to Altered Actin Expression in an Aging Mouse Model of Arrhythmogenic Cardiomyopathy.

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder of desmosomal dysfunction, and PKP2 (plakophilin-2) has been reported to be the most common disease-causing gene when mutation-positive. In the early concealed phase, the ACM heart is at high risk of sudden cardiac death before cardiac remodeling occurs because of mistargeted ion channels and altered Ca handling. However, the results of pathogenic PKP2 variants on myocyte contraction in ACM pathogenesis remain unknown.

The genetic architecture of pediatric cardiomyopathy.

To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history.