Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
Circ Res. 2013 May 10;112(10):1334-44. doi: 10.1161/CIRCRESAHA.113.301055. Epub 2013 Mar 26.
The Ca(2+) sensitivity of the myofilaments is increased in hypertrophic cardiomyopathy and other heart diseases and may contribute to a higher risk for sudden cardiac death. Ca(2+) sensitization increases susceptibility to reentrant ventricular tachycardia in animal models, but the underlying mechanism is unknown.
To investigate how myofilament Ca(2+) sensitization creates reentrant arrhythmia susceptibility.
Using hypertrophic cardiomyopathy mouse models (troponinT-I79N) and a Ca(2+) sensitizing drug (EMD57033), here we identify focal energy deprivation as a direct consequence of myofilament Ca(2+) sensitization. To detect ATP depletion and thus energy deprivation, we measured accumulation of dephosphorylated Connexin 43 (Cx43) isoform P0 and AMP kinase activation by Western blotting and immunostaining. No differences were detected between groups at baseline, but regional accumulation of Connexin 43 isoform P0 occurred within minutes in all Ca(2+)-sensitized hearts, in vivo after isoproterenol challenge and in isolated hearts after rapid pacing. Lucifer yellow dye spread demonstrated reduced gap junctional coupling in areas with Connexin 43 isoform P0 accumulation. Optical mapping revealed that selectively the transverse conduction velocity was slowed and anisotropy increased. Myofilament Ca(2+) desensitization with blebbistatin prevented focal energy deprivation, transverse conduction velocity slowing, and the reentrant ventricular arrhythmias.
Myofilament Ca(2+) sensitization rapidly leads to focal energy deprivation and reduced intercellular coupling during conditions that raise arrhythmia susceptibility. This is a novel proarrhythmic mechanism that can increase arrhythmia susceptibility in structurally normal hearts within minutes and may, therefore, contribute to sudden cardiac death in diseases with increased myofilament Ca(2+) sensitivity.
肌球蛋白丝对 Ca2+的敏感性在肥厚型心肌病和其他心脏病中增加，可能导致心脏性猝死的风险增加。Ca2+敏化增加了动物模型中折返性室性心动过速的易感性，但潜在机制尚不清楚。
研究肌球蛋白丝 Ca2+敏化如何导致折返性心律失常易感性。
使用肥厚型心肌病小鼠模型（肌钙蛋白 T-I79N）和一种 Ca2+敏化药物（EMD57033），我们发现肌球蛋白丝 Ca2+敏化直接导致局部能量剥夺。为了检测 ATP 消耗，从而检测能量剥夺，我们通过 Western blot 和免疫染色来测量去磷酸化连接蛋白 43（Cx43）同工型 P0 的积累和 AMP 激酶的激活。在基线时，各组之间没有差异，但在所有 Ca2+敏化的心脏中，在异丙肾上腺素挑战后体内和快速起搏后分离的心脏中，几分钟内就会出现 Connexin 43 同工型 P0 的局部积累。荧光素黄染料扩散表明在 Connexin 43 同工型 P0 积累区域的缝隙连接偶联减少。光学映射显示，只有横向传导速度减慢，各向异性增加。用 blebbistatin 使肌球蛋白丝 Ca2+脱敏可防止局部能量剥夺、横向传导速度减慢和折返性室性心律失常。
肌球蛋白丝 Ca2+敏化可在增加心律失常易感性的条件下迅速导致局部能量剥夺和细胞间偶联减少。这是一种新的致心律失常机制，可在几分钟内增加结构正常心脏的心律失常易感性，并可能因此导致 Ca2+敏感性增加的疾病中心脏性猝死。
