TGF-β ₁ -Mediated Fibrosis and Ion Channel Remodeling Are Key Mechanisms in Producing the Sinus Node Dysfunction Associated With SCN5A Deficiency and Aging

Abstract

Background-Mutations in the cardiac Na ϩ channel gene (SCN5A) can adversely affect electric function in the heart, but effects can be age dependent. We explored the interacting effects of Scn5a disruption and aging on the pathogenesis of sinus node dysfunction in a heterozygous Scn5a knockout (Scn5a ϩ/Ϫ ) mouse model. Methods and Results-We compared functional, histological, and molecular features in young (3 to 4 month) and old (1 year) wild type and Scn5a ϩ/Ϫ mice. Both Scn5a disruption and aging were associated with decreased heart rate variability, reduced sinoatrial node automaticity, and slowed sinoatrial conduction. They also led to increased collagen and fibroblast levels and upregulated transforming growth factor-␤ 1 (TGF-␤ 1 ) and vimentin transcripts, providing measures of fibrosis and reduced Nav1.5 expression. All these effects were most noticeable in old Scn5a ϩ/Ϫ mice. Na ϩ channel inhibition by Nav1.5-E3 antibody directly increased TGF-␤ 1 production in both cultured human cardiac myocytes and fibroblasts. Finally, aging was associated with downregulation of a wide range of ion channel and related transcripts and, again, was greatest in old Scn5a ϩ/Ϫ mice. The quantitative results from these studies permitted computer simulations that successfully replicated the observed sinoatrial node phenotypes shown by the different experimental groups. Conclusions-These results implicate a tissue degeneration triggered by Nav1.5 deficiency manifesting as a TGF-␤ 1 -mediated fibrosis accompanied by electric remodeling in the sinus node dysfunction associated with Scn5a disruption or aging. The latter effects interact to produce the most severe phenotype in old Scn5a ϩ/Ϫ mice. In demonstrating this, our findings suggest a novel regulatory role for Nav1.5 in cellular biological processes in addition to its electrophysiologic function. (Circ Arrhythm Electrophysiol. 2011;4:397-406.) Key Words: sinoatrial node Ⅲ aging Ⅲ remodeling Ⅲ ion channels Ⅲ Nav1.5 protein S inus node dysfunction (SND) is associated with abnormal impulse formation and propagation in the sinoatrial node (SAN). It presents clinically as sinus bradycardia, sinus pause or arrest, atrial chronotropic incompetence, and SAN exit block. 1 It affects Ϸ1 in 600 cardiac patients aged Ͼ65 years and is responsible for Ϸ50% of the 1 million permanent pacemaker implants per year worldwide. 2,3 Although SND occurs most commonly in elderly patients in the absence of clinically apparent accompanying cardiac disease, 2 its pathogenesis is unclear. Nevertheless, experimental animal models do show structural, electrophysiological, and ion channel remodeling with age. 2,4 -7 Furthermore, genetic defects in ion channels that include those involving human Nav1.5 have been associated with familial sick sinus syndrome, a rare congenital form of SND. 8 -10 Finally, genetic defects in SCN5A also are associated with progressive (ie, agedependent) cardiac conduction disease (PCCD), which often is accompanied by SND. 10,11 Clinical Perspective on p 406The clinical s...

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