Abstract 19785: Altered Qtc Intervals and Risk of Arrhythmias Arise in Mice Overexpressing Nitric Oxide Synthase Adapter Protein Nos1ap
Rationale: Cardiac depolarization is reflected by the QT interval duration. If prolonged, shortened or otherwise unregularly it may predispose individuals to ventricular tachycardia and sudden cardiac death (SCD). Whole-genome association studies (WGAS) linked genetic variations in the gene for neuronal nitric oxide synthase adapter protein NOS1AP to alterations in QTc intervals and SCD.
Hypothesis: We hypothesize NOS1AP mutations result in reformed neuronal nitric oxide synthase NOS1 interactions resulting in modified L-type-Ca2+ channel modulation which downstream tempers with QTc intervals and increases susceptibility to rhythm disorders and SCD.
Methods and results: We generated conditional double transgenic mice overexpressing 6xHN-NOS1AP under control of the cardiac-specific amyh7 promotor and under control of doxycycline (Tet-Off system). These animals were then investigated with the main focus upon electrophysiology. Heart rates were similar in induced vs. non-induced animals. NOS1AP overexpression resulted in arrhythmia already under basal conditions; we observed ventricular fibrillation and tachycardia in these animals. 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. Telemetry again showed ventricular tachycardia or ventricular fibrillation. We additionally investigated the functional effect of the human SNP rs16847548 (T/C) located in the NOS1AP promoter. We found that this SNP significantly impaired NOS1AP transcriptional activity in vitro, suggesting 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 sudden cardiac death. SNP rs16847548 in NOS1AP resulted in less NOS1AP promoter activity as seen 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 seem to have an impact on QTc intervals.
Author Disclosures: T. Williams: None. D. Oppelt: None. P. Arias-Loza: None. M. Abesser: None. J. Schmitt: None. O. Ritter: None.
- © 2016 by American Heart Association, Inc.