Abstract 2357: Integrin Alpha7, a Novel Determinant of QT Duration and Lethal Ventricular Arrhythmias in Mouse and Man
The genetic determinants of QT interval variation and sudden cardiac death (SCD) are incompletely defined. Mutations causing monogenic disease as well as common gene variants have been shown to contribute to both. Electrical conduction throughout the myocardium and hence impulse propagation and QT interval are contingent upon correct myocyte attachment to the extracellular matrix. Integrins are key proteins in this attachment process and we therefore investigated the role of the major cardiac isoform, integrin alpha7, in determining QT interval and predisposition to SCD. In a mouse model of integrin alpha7 deletion (α7−/−), premature sudden death occurred in all animals. α7−/− mice displayed prolonged QTc interval (α7−/−: 31±0.89ms, α7+/+: 24±0.49ms; n=6; p<0.0001, QTc=QT/(RR/100)1/2) by 3 months of age. In addition, 10 month old α7−/− mice exhibited spontaneous episodes of polymorphic ventricular tachycardia, prolonged QTc duration and increased QRS interval. The altered rhythm was associated with downregulation of N-cadherin and connexin 43. Furthermore, α7−/− mice demonstrated increased propensity to drug-induced arrhythmias: treatment with ouabain in combination with isoprenaline induced ventricular tachycardia, ventricular fibrillation and subsequently death in 6 month old α7−/− mice, but not in α7+/+ mice. In data from a published genome-wide association study of QT interval in the general population, we identified 34 single nucleotide polymorphisms (SNPs) within ITGA7. A Q-Q-plot demonstrated a clear overrepresentation of QT duration associated SNPs amongst them. The strongest association was with rs6581076 (α = +0.58±0.23 ms QTc, p= 9.58 × 10−3). In conclusion, alterations in the integrin α7 gene are linked to QT interval variation in humans and are associated with long QT syndrome and lethal ventricular arrhythmias in mice. Firstly, the mouse data provide a mechanistic link between the locus and the candidate gene in the human study, thus considerably strengthening the hypothesis that integrin α7 variation is causally related to QT interval variation and lethal arrhythmias. Secondly, they reveal a novel role for integrin α7 in the modulation of QT duration, ventricular arrhythmias and sudden death.