Abstract 194: Heart Failure-Associated Increases in CaMKII Activity Facilitate Abnormal Impulse Induction
Background: Accumulating evidence implicates CaMKII (Ca/calmodulin-dependent protein kinase II) in heart failure (HF)-related ventricular arrhythmias. Recent studies have demonstrated that inhibition of CaMKII abolishes ventricular tachycardia (VT) independent of action potential duration (APD) shortening; underlying mechanisms, however, are poorly understood. To test this, we studied the effects of CaMKII inhibition on AP morphology and impulse conduction in failing ventricular myocytes.
Methods: Using the whole-cell patch clamp technique, we studied freshly dissociated ventricular myocytes from a mouse model of pressure-overload heart failure (HF). In addition, we employed a novel coupling-clamp technique to electrically couple 2 cardiomyocytes via variable conductances (Gc) or to couple a myocyte (Gsac) to a fixed voltage source (E = −10 mV).
Results: Application of Gsac induced EADs and automaticity reproducibly in ventricular myocytes from failing heart (n=38/38) as compared with sham-operated controls (6/58). Increased amplitude of L-type Ca2+ current (ICa) and slowed ICa inactivation were observed in HF, suggestive of Ca2+ channel phosphorylation by CaMKII. Also, Ca2+-induced ICa facilitation, a known consequence of CaMKII activation, was abolished in HF myocytes. Consistent with this, CaMKII enzymatic activity in isolated HF myocytes was significantly increased (4.1±0.5 pmol/min/μg, p<0.05) compared with sham-operated controls (1.7±0.6). In experiments to test the role of CaMKII in HF arrhythmogenesis, we found that inhibition of CaMKII (10μM KN93) abolished EADs and automaticity in HF myocytes. KN93 had no effect on AP propagation, i.e. the critical Gc for successful AP conduction was unchanged. However, a dramatic increase in excitation threshold was observed in response to CaMKII inhibition. In contrast, APD30 and APD90 were not changed.
Conclusion: Enhanced electrical activity in HF is associated with increased CaMKII activity and the consequent facilitation of ICa. These data suggest that inhibition of CaMKII abolishes ventricular arrhythmias by suppressing abnormal impulses and lowering cardiomyocyte excitability.