title: Ca2+/calmodulin-dependent protein kinase II increases the susceptibility to the arrhythmogenic action potential alternans in spontaneously hypertensive rats.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mitsuyama
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan yokoshh@med.hokudai.ac.jp.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yokoshiki
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Mizukami
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Shimokawa
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002304:Cardiac Pacing, Artificial; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D006973:Hypertension / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013449:Sulfonamides / Q000494:pharmacology; D013912:Threonine; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D000096926:Benzenesulfonamides
chemical_list: D000889:Anti-Arrhythmia Agents; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D013912:Threonine; C072105:KN 93; D000096926:Benzenesulfonamides
keywords: APD alternans; CaMKII; cardiac hypertrophy