Ca2+/calmodulin-dependent protein kinase II increases the susceptibility to the arrhythmogenic action potential alternans in spontaneously hypertensive rats

• Published in: American journal of physiology. Heart and circulatory physiology 2014-07, Vol.307 (2), p.H199-H206
• Main Authors: Mitsuyama, Hirofumi, Yokoshiki, Hisashi, Watanabe, Masaya, Mizukami, Kazuya, Shimokawa, Junichi, Tsutsui, Hiroyuki
• Format: Article
• Language: English
• Subjects: Action Potentials; Animals; Anti-Arrhythmia Agents - pharmacology; Benzylamines - pharmacology; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Cardiac Pacing, Artificial; Cardiomegaly - enzymology; Cardiomegaly - etiology; Cardiomegaly - physiopathology; Disease Models, Animal; Heart Ventricles - drug effects; Heart Ventricles - enzymology; Heart Ventricles - physiopathology; Hypertension - complications; Hypertension - drug therapy; Hypertension - enzymology; Hypertension - physiopathology; Male; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sulfonamides - pharmacology; Threonine; Time Factors; Ventricular Fibrillation - enzymology; Ventricular Fibrillation - etiology; Ventricular Fibrillation - physiopathology; Ventricular Fibrillation - prevention & control
• ISSN: 1522-1539
• DOI: 10.1152/ajpheart.00387.2012

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. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is known to modulate the function of cardiac sarcoplasmic reticulum and play an important role in Ca(2+) cycling. We thus aimed to determine the role of CaMKII in the increased susceptibility to APD-ALT and arrhythmogenesis in the hypertrophied heart. 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. APD-ALT was evoked at significantly lower pacing rate in SHR compared with WKY (382 ± 43 vs. 465 ± 45 beats/min, P < 0.01). These changes in APD-ALT in SHR were completely reversed by KN-93 (1 μmol/l; n = 5), an inhibitor of CaMKII, but not its inactive analog, KN-92 (1 μmol/l; n = 5). 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). Western blot analyses indicated that the CaMKII autophosphorylation at Thr287 was significantly increased in SHR compared with WKY. The increased susceptibility to APD-ALT and VF during rapid pacing in hypertrophied heart was prevented by KN-93. CaMKII could be an important mechanism of arrhythmogenesis in cardiac hypertrophy.