Ventricular arrhythmias, increased cardiac calmodulin kinase II expression, and altered repolarization kinetics in ANP receptor deficient mice

Cardiac hypertrophy is associated with ventricular arrhythmias and sudden death. The molecular mechanisms that predispose the hypertrophied heart to arrhythmias are not well understood. In mice, deletion of the gene coding for the atrial natriuretic peptide receptor, guanylyl cyclase A (GC-A–/–), causes arterial hypertension, cardiac hypertrophy and sudden death. We used this mouse model to study molecular mechanisms of arrhythmias in the hypertrophied heart. Right and left ventricular monophasic action potential durations (APD) were recorded in isolated, Langendorff-perfused hearts during pacing from the right atrium and ventricle. The atrioventricular (AV) node was ablated to provoke bradycardia. Intracellular Ca2+ transients were measured in isolated INDO-1 loaded ventricular myocytes. Cardiac expression of Ca2+/calmodulin-dependent protein kinase II (CaMKII) was analyzed by western blotting. Polymorphic ventricular arrhythmias (pVT) occurred spontaneously after mechanical AV block in 20/45 hearts from 12-month-old GC-A–/– mice (P < 0.05), but neither in age-matched GC-A+/+ hearts nor in hearts from 3-month-old mice of either genotype. Triggered activity preceded pVT. APD were prolonged and systolic Cai2+ levels were increased in GC-A–/– hearts independently of age. In 12-month-old GC-A–/– hearts only, dispersion of APD and expression levels of CaMKII were increased. CaMKII expression was particularly increased in hearts with pVT. Direct inhibition of CaMKII activation by KN93 (0.5 or 2 μM) or inhibition of Ca2+/calmodulin-dependent activation of CaMKII by W-7 (25 μM) suppressed pVT in GC-A–/– hearts (P < 0.05) while prolonging APD. The combination of increased CaMKII activity and altered action potential characteristics facilitates ventricular arrhythmias in hypertrophic GC-A–/– hearts.