Background:
Congenital long- or short-QT syndrome may lead to life-threatening ventricular tachycardia and sudden cardiac death. Apart from rare disease-causing mutations in ion channels, common genetic variations in the neuronal nitric oxide synthase (NOS1) regulator NOS1AP, have recently been associated with QT interval variations in a human whole-genome association study. In fact, NOS1AP SNPs have been linked to increases in QTc intervals and sudden cardiac death. We therefore speculate that myocardial NOS1AP overexpression may lead to a decrease of the QTc interval and an increased susceptibility to rhythm disorders.
Methods and Results:
We generated transgenic mice (TG) with a conditional myocardial NOS1AP overexpression and focused on electrical alterations. Conditional overexpression of NOS1AP resulted in a 147% ventricular increase in TG mice compared to WT littermates. NOS1AP was mainly located at the sarcolemma where it interacted with NOS1 and the L-type Ca2+- channel. HW/BW ratio, ventricular ANP expression, ventricular cross-sectional area and collagen deposition were not altered in NOS1AP mice under baseline conditions.
However, NOS1AP overexpressing mice showed a clear decrease of QTc intervals (33 vs. 48 ms). They were more prone to bradycardia (resting heart rate 467 bpm vs. 666 bpm). Atrial programmed stimulation repeatedly caused atrial tachycardia. Ventricular programmed stimulation caused VT in some mice with NOS1AP overexpression.
We also investigated the functional effect of the human rs16847548 (T/C). We found that this SNP decreased NOS1AP promoter activity in a viral NOS1AP luciferase assay, suggesting that this SNP downregulates NOS1AP expression in humans.
Conclusion:
Myocardial overexpression of NOS1AP leads to a significant shortening of the QTc interval with an increased susceptibility to atrial and ventricular rhythm disorders. SNP rs16847548 in NOS1AP resulted in downregulation of NOS1AP expression which provides an explanation for elongation of QTc intervals. In summary, not only a mutation in ion channels itself but also genetic alterations in expression of ion channel modifiers, such as NOS1AP, have an impact on QTc intervals.
Noninvasive Ventricular Programmed Stimulation
