Heart failure (HF) and associated arrhythmic sudden cardiac death (SCD) are primary causes of morbidity and mortality worldwide, warranting further investigation of risk factors and pathogenic mechanisms. Precise regulation of cardiac ion channels governing heart rate and rhythm is vital, since slight changes in ion conductance can trigger arrhythmia, elevating one?s risk for SCD. The cardiac action potential is initiated by sodium current through the heart?s primary voltage-gated sodium channel, Nav1.5, encoded by SCN5A. Mutations that alter Nav1.5 function cause arrhythmic syndromes (Brugada, long QT, inherited conduction) and dilated cardiomyopathy (DCM), and common genetic variants within the SCN5A locus have been linked to subtle changes in electrocardiographic measures. However, the impact of altered SCN5A expression on the clinical course of HF and associated non-arrhythmic deaths remains to be thoroughly investigated. Prior studies have shown that SCN5A+/- haploinsufficient mice develop aging-related adverse myocardial remodeling, with increased fibrosis and conduction slowing. We recently discovered that these findings may translate to the clinical setting. Specifically, we identified a common genetic variant that bolsters the activity of a microRNA (miR) binding site within the terminal coding sequence (CDS) of SCN5A. We found that this variant is linked to reduced SCN5A mRNA levels (10-20%) in human hearts, and surprisingly, increased non-arrhythmic death in HF patients. A potential basis for this was identified upon our unexpected finding that SCN5A+/- mouse hearts exhibit increases in oxidative stress and fatty acid oxidation (FAO). These combined preliminary data provide a solid foundation for our central hypothesis that reduced cardiac SCN5A expression elevates one?s susceptibility to subclinical cardiac pathologies that transform into significant risk in the setting of HF. With the core concept being that low Nav1.5 is bad for your heart, our overarching goals are now to 1) define new pathways controlling Nav1.5 levels, 2) delineate how lower Nav1.5 adversely impacts cardiomyocytes, and 3) empirically test if reduced Nav1.5 worsens HF outcomes.
In Aim 1, we will characterize novel pathways that regulate SCN5A mRNA stability and translation via its CDS, an expansive region that remains largely underexplored for RNA regulatory functions.
In Aim 2, we will define the pathways by which reduced SCN5A expression in cardiomyocytes leads to elevated oxidative stress and FAO.
In Aim 3, we will determine if reduced SCN5A expression is sufficient to increase HF-related morbidity and mortality in SCN5A+/- haploinsufficient mice with surgically-induced cardiomyopathy. Overall, this work has strong potential to 1) fill significant knowledge gaps regarding the regulatory control of SCN5A at the RNA level, 2) transform our understanding of Nav1.5 functions beyond well-established roles in cardiac conduction, 3) reinforce the link between reduced SCN5A expression and worse HF, advancing from associative observations to empirical evidence, and 4) prompt future studies aimed at translating these findings towards improved identification and care of high-risk HF patients.

Public Health Relevance

Public Health Relevance: Heart failure and associated sudden cardiac death are leading causes of morbidity and mortality for both men and women worldwide. The prevalence and adverse societal impacts of heart failure are growing, costing our public healthcare system more than $30 billion annually. Heart failure coincides with significant changes in cardiac ion channel expression and function, and our overall goal is to better understand the mechanisms by which this occurs to 1) identify new risk factors predisposing patients to worse heart failure outcomes, and 2) devise novel therapies to prevent these changes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Balijepalli, Ravi C
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University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
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