NCX is an important determinant for premature ventricular activity in a drug-induced model of AndersenTawil syndrome

Abstract

Aims AndersenTawil syndrome (ATS1)-associated ventricular arrhythmias are initiated by premature ventricular activity (PVA) resulting from diastolic Ca 2 (CaD) accumulation. We hypothesized that relatively high Na Ca 2 exchanger (NCX) expression coupled with slower Ca 2 uptake may constitute an arrhythmogenic substrate during drug-induced ATS1 (DI-ATS1). Methods and resultsDI-ATS1 was induced with 10 mol/L BaCl2 and 2 mmol/L [K]o. Ca 2 transients and action potentials were optically mapped from Langendorff-perfused guinea pig ventricles. Intracellular Ca 2 handling was modulated by either direct NCX inhibition with 5 mol/L KB-R7943 or by sarcoplasmic reticulum Ca 2-ATPase (SERCA2a) inhibition with cyclopiazonic acid (CPA). During DI-ATS1, PVA was more frequent in left ventricular (LV)-base (LVB) vs. LV-apex (LVA) (2.2 ± 0.8 vs. 0.6 ± 0.3 PVA/10 min), consistent with greater CaD (1.65 ± 0.13 vs. 1.42 ± 0.09 normalized-CaD units) and western blot-assessed NCX protein expression (81.2 ± 30.9) in LVB relative to LVA. Further, regions of high NCX (LVB) evidenced a shorter PVA coupling interval relative to regions of low NCX expression (LVA, 67.7 ± 3.5 vs. 78.5 ± 3.6). Inhibiting NCX during DI-ATS1 lowered the incidence of ventricular tachycardias (VTs, 0 vs. 25) and PVA (1.5 ± 0.4 vs. 4.3 ± 1.4 PVA/10 min), but it did not affect PVA coupling intervals in LVB nor LVA (70.8 ± 4.3 vs. 73.8 ± 2.5). Conversely, inhibition of SERCA2a with CPA, thereby increasing the role of NCX in Ca 2 handling, significantly increased the incidence of VTs and PVA relative to DI-ATS1 alone, while decreasing the PVA coupling interval in all regions. ConclusionPVA preferentially occurs in regions of enhanced NCX expression with relatively slower Ca 2 uptake and during perfusion of CPA which further reduces sarcoplasmic reticular Ca 2 uptake. © 2011 The Author.