Abstract 17820: Overexpression of Nos1ap Alters Qtc Intervals and Risk of Arrhythmias in Mice

Abstract

Rationale: The QT interval duration (QTc) reflects cardiac depolarization. It may predispose individuals to ventricular tachycardia and sudden cardiac death if prolonged (long QTc), shortened (short QTc) or otherwise unregularly. Whole-genome association studies have linked genetic variations in the neuronal nitric oxide synthase adapter protein NOS1AP to variations in QTc intervals and sudden cardiac death. Hypothesis: We hypothesize NOS1AP functions as an L-type-Ca2+ channel modulator via its interaction with the neuronal nitric oxide synthase NOS1. Therefore, alterations in myocardial NOS1AP expression should temper with QTc intervals and increase susceptibility to rhythm disorders. Methods and results: We generated conditional double transgenic mice by crossbreeding pTRE-6xHN-Nos1AP animals with α-MHC-tTA mice; NOS1AP expression is therefore restricted to cardiomyocytes and under control of doxycycline (Tet-Off system). NOS1AP overexpressing animals were investigated with the main focus upon electrophysiology. Heart rates were similar in induced and non-induced animals. NOS1AP overexpression resulted in arrhythmia already under basal conditions; we observed ventricular fibrillation and tachycardia. There was a clear decrease of QTc intervals in NOS1AP overexpressing mice paralleled by a significantly reduced survival (only 56% after 12 weeks vs 100% in non-induced mice. QTc alterations and accompanied deaths subsided upon readministration of doxycycline. We also investigated the functional effect of the human SNP rs16847548 (T/C). We found that this SNP decreased NOS1AP transcriptional activity in vitro and therefore suggest this leads to a decrease in NOS1AP expression in humans. Conclusion: Myocardial overexpression of NOS1AP leads to short QTc syndrome with increased susceptibility to atrial and ventricular rhythm disorders and cardiac death. SNP rs16847548 in NOS1AP resulted in less NOS1AP promoter activity in vitro which could explain the alteration in QTc intervals. In summary, not only mutations in ion channels themselves but also genetic alterations in the expression of ion channel modulators such as NOS1AP, have an impact on QTc intervals.