Abstract
We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls.
Highlights
Heart failure (HF) is a major health issue, affecting 5.7 million people in the United States [1]
A number of etiologic factors, such as coronary artery disease, hypertension, valvular disease, alcohol, chemotherapy, and rare deleterious genetic mutations can lead to cardiac injury that results in HF but little is known about how common genetic variants contribute to HF progression
Global gene expression profiling of left ventricular (LV) tissues from control and ISO-treated mice was performed to identify genes whose expression was correlated to HF traits and to identify expression quantitative trait loci (eQTL) to prioritize candidate genes
Summary
Heart failure (HF) is a major health issue, affecting 5.7 million people in the United States [1]. Irrespective of the primary insult, compensatory adrenergic and renin-angiotensin activation augment heart rate (HR), contractility and fluid retention to maintain adequate cardiac output and preserve organ function, which in turn leads to chronic maladaptive cellular growth and irreversible myocardial injury, furthering HF progression [3]. Such molecular, cellular and extracellular changes, manifested clinically as changes in size, shape and function of the heart, is known as cardiac remodeling and is one of the most important clinical determinants of HF progression. Understanding how common genetic variation modifies the pathophysiology of HF progression in terms of cardiac remodeling will likely provide insights in the design of novel therapeutics to improve survival and life quality of HF patients
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