Abstract 12021: Ca2+/calmodulin-Dependent Protein Kinase II Increases the Susceptibility to the Arrhythmogenic Action Potential Alternans in Spontaneously Hypertensive Rat
Background: Action potential duration alternans (APD-ALT), defined as long-short-long repetitive pattern of APD, potentially leads to lethal ventricular arrhythmia. However, the mechanisms of APD-ALT in the arrhythmogenesis of cardiac hypertrophy remain undetermined. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is known to modulate the function of cardiac sarcoplasmic reticulum and play an important role in Ca2+ cycling. We thus aimed to determine the role of CaMKII in the increased susceptibility to APD-ALT and arrhythmogenesis in the hypertrophied heart.
Methods: APD was measured by high-resolution optical mapping in left ventricular (LV) anterior wall from normotensive Wistar-Kyoto (WKY; n=10) and spontaneously hypertensive rats (SHR; n=10) during rapid ventricular pacing.
Results: APD-ALT was evoked at significantly lower pacing rate in SHR compared to WKY (382 ± 43 bpm vs. 465 ± 45 bpm, p≤0.01) (Figure A). These changes in APD-ALT in SHR were completely reversed by inhibiting CaMKII by KN-93 (1 μmol/L; n=5), but not its inactive analog, KN-92 (1 μmol/L; n=5) (Figure A). The magnitude of APD-ALT was also significantly greater in SHR than WKY and was completely normalized by KN-93. Ventricular fibrillation (VF) was induced by rapid pacing more frequently in SHR than in WKY (60 vs. 10%; p≤0.05), which was also abolished by KN-93 (0%, p≤0.05) (Figure B). By western blot analysis, autophosphorylation of CaMKII at Thr287 was significantly increased in SHR compared to WKY (Figure C).
Conclusion: The increased susceptibility to APD-ALT and VF during rapid pacing in hypertrophied heart was dependent on CaMKII activation. CaMKII is an important mechanism of arrhythmogenesis in cardiac hypertrophy.
- © 2013 by American Heart Association, Inc.