Opening of the primary cardiac sodium channel, encoded by SCN5A, is responsible for rapid myocyte depolarization that initiates the cardiac cycle and underlies fast conduction in the heart. Mutations in the gene have been associated with a range of phenotypes, including long QT syndrome, Brugada syndrome, conduction disease, dilated cardiomyopathy (DCM) and atrial fibrillation. Out of hundreds of mutations linked to these disease states, only a handful have been clearly associated with DCM and heart failure and the underlying mechanisms are not understood. This proposal builds on our work establishing murine models of sodium channel-related disease to test the overall hypothesis that SCN5A mutations initiate the DCM phenotype through mechanisms directly related to electrophysiologic dysfunction; notably, this distinguishes SCN5A-related DCM from other forms of the disease. In mice with D1275N, a mutation associated with human DCM, our major findings are decreased peak sodium current, near normal gating, striking conduction delay by ECG and optical mapping, decreased abundance of the channel protein especially along the lateral myocyte border, and age-dependent development of DCM. By contrast, other mouse lines with equivalent or greater decreases in peak sodium current do not display conduction abnormalities or DCM. Accordingly, in Specific Aim 1, we will test multiple competing hypotheses to explain this apparent paradox: specific experiments will address the roles of intracellular ionic homeostasis versus abnormalities in conduction, and their underlying mechanisms, as generators of the DCM phenotype. Unlike D1275N, the DCM-associated R222Q mutation displays striking gating changes in vitro and patients display very frequent drug-sensitive ventricular ectopic activity and develop DCM.
In Specific Aim 2, we will contrast mechanisms whereby R222Q and D1275N cause DCM and test the hypothesis that suppression of ectopic activity improves or reverses the DCM phenotype. Heart failure affects more that 4 million people in the United States and studies to identify molecular subsets represent an important step to tailoring mechanism-based therapy.
Heart failure affects more than 4 million people in the United States; with health care costs above $30 billion a year and is a leading cause of cardiovascular and all-cause mortality. This proposal addresses the mechanisms of dilated cardiomyopathy (DCM) and heart failure as a result of mutations in SCN5A; a gene known to play a role in heart rhythm control and more recently implicated in DCM.
|Kroncke, Brett M; Yang, Tao; Kannankeril, Prince et al. (2018) Exploiting ion channel structure to assess rare variant pathogenicity. Heart Rhythm 15:890-894|
|Kroncke, Brett M; Glazer, Andrew M; Smith, Derek K et al. (2018) SCN5A (NaV1.5) Variant Functional Perturbation and Clinical Presentation: Variants of a Certain Significance. Circ Genom Precis Med 11:e002095|
|Yang, Tao; Meoli, David F; Moslehi, Javid et al. (2018) Inhibition of the ?-Subunit of Phosphoinositide 3-Kinase in Heart Increases Late Sodium Current and Is Arrhythmogenic. J Pharmacol Exp Ther 365:460-466|
|Yang, Zhenjiang; Prinsen, Joseph K; Bersell, Kevin R et al. (2017) Azithromycin Causes a Novel Proarrhythmic Syndrome. Circ Arrhythm Electrophysiol 10:|
|Roden, Dan M (2016) Pharmacogenetics of Potassium Channel Blockers. Card Electrophysiol Clin 8:385-93|
|Roden, Dan M (2014) Pharmacology and Toxicology of Nav1.5-Class 1 anti-arrhythmic drugs. Card Electrophysiol Clin 6:695-704|
|Roden, Dan M (2014) The Brugada ECG and schizophrenia. Circ Arrhythm Electrophysiol 7:365-7|
|Roden, Dan M; Knollmann, Björn C (2014) Dantrolene: from better bacon to a treatment for ventricular fibrillation. Circulation 129:834-6|