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KMID : 1011920140150020004
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International Journal of Arrhythmia
2014 Volume.15 No. 2 p.4 ~ p.16
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Arrhythmogenic Mechanisms of Autoimmune Myocarditis Associated with Inflammation and Ca2+/Calmodulin-Dependent Protein Kinase II Activation
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Park Hye-Rim
Park Hye-Won
Lim Ji-Su
Oh Su-Jung
Park Sung-Ha
Park Hui-Nam
Lee Moon-Hyoung
Joung Bo-Young
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Abstract
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Rationale: Fatal arrhythmia is a frequent cause of death in patients with acute myocarditis.
Objective: To investigate the arrhythmogenic mechanisms of myocarditis.
Methods and Results: Autoimmune myocarditis was induced by injection of porcine cardiac myosin (2 mg) into the footpads of adult Sprague-Dawley rats on days 1 and 8 (Myo; n=15). Uninjected rats were used as controls (control; n=15). In an additional group of rats, corticosteroid (6 mg) was injected into the gluteus muscle prior to injection of porcine cardiac myosin on days 1 and 8 (MyoS; n=15). In the Myo group, 5 out of 15 rats (33%) died suddenly at 17 ± 2 days after induction of myocarditis, and 5 of the 10 surviving rats (56%) exhibited arrhythmia. No control rats died or exhibited arrhythmia (p=0.02). Compared with the control group, action potential duration (APD; 98 ± 7 vs. 152 ± 52 ms, p=0.03), APD dispersion (6 ± 2 vs. 24 ± 4 ms, p<0.001), the pacing cycle length for discordant alternans (90 ± 9 vs. 198 ± 22 ms, p<0.001), and the frequency of ventricular tachycardia (p=0.003) were increased in the Myo group. These arrhythmogenic effects were attenuated in the MyoS group, however. Expression of high-mobility group box protein 1 (HMGB1), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) was increased in Myo rats compared with controls, and this was attenuated in MyoS rats. An increase in phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII), ryanodine receptor type 2 and phospholamban activity were also observed in the Myo group relative to controls, though this was similarly attenuated in MyoS animals.
Conclusions: The arrhythmogenic mechanisms of myocarditis involve increased APD, APD dispersion and discordant alternans. These arrhythmogenic effects may be related to the increase in inflammatory markers and CaMKII activation, as indicated by the attenuating effects of an antiinflammatory steroid.
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KEYWORD
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myocarditis, arrhythmia, inflammation, Ca2+/calmodulin-dependent protein kinase II
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