Abstract:
Persistent elevation of Ca(2+) influx due to prolongation of the action potential (AP), chronic activation of the β-adrenergic system and molecular remodeling occurs in stressed and diseased hearts. Increases in Ca(2+) influx are usually linked to prolonged myocyte action potentials and arrhythmias. However, the contribution of chronic enhancement of Cav1.2 activity on cardiac electrical remodeling and arrhythmogenicity has not been completely defined and is the subject of this study. Chronically increased Cav1.2 activity was produced with a cardiac specific, inducible double transgenic (DTG) mouse system overexpressing the β2a subunit of Cav (Cavβ2a). DTG myocytes had increased L-type Ca(2+) current (ICa-L), myocyte shortening, and Ca(2+) transients. DTG mice had enhanced cardiac performance, but died suddenly and prematurely. Telemetric electrocardiograms revealed shortened QT intervals in DTG mice. The action potential duration (APD) was shortened in DTG myocytes due to significant increases of potassium currents and channel abundance. However, shortened AP in DTG myocytes did not fully limit excess Ca(2+) influx and increased the peak and tail ICa-L. Enhanced ICa promoted sarcoplasmic reticulum (SR) Ca(2+) overload, diastolic Ca(2+) sparks and waves, and increased NCX activity, causing increased occurrence of early and delayed afterdepolarizations (EADs and DADs) that may contribute to premature ventricular beats and ventricular tachycardia. AV blocks that could be related to fibrosis of the AV node were also observed. Our study suggests that increasing ICa-L does not necessarily result in AP prolongation but causes SR Ca(2+) overload and fibrosis of AV node and myocardium to induce cellular arrhythmogenicity, arrhythmias, and conduction abnormalities.
摘要:
由于动作电位(AP)的延长,Ca(2)内流的持续升高,β-肾上腺素能系统的慢性激活和分子重塑发生在压力和患病的心脏中。Ca(2)内流的增加通常与延长的肌细胞动作电位和心律失常有关。然而,Cav1.2活性的慢性增强对心脏电重构和致心律失常的作用尚未完全确定,是本研究的主题.Cav1.2活性的长期增加是由心脏特异性产生的,过表达Cavβ2a亚基(Cavβ2a)的诱导型双转基因(DTG)小鼠系统。DTG肌细胞L型Ca(2+)电流(ICa-L)增加,肌细胞缩短,和Ca(2+)瞬变。DTG小鼠的心脏表现增强,却突然过早地死去.遥测心电图显示DTG小鼠QT间期缩短。由于钾电流和通道丰度的显着增加,DTG肌细胞的动作电位持续时间(APD)缩短。然而,DTG肌细胞中缩短的AP不能完全限制过量的Ca(2)流入,并增加了峰值和尾部ICa-L。增强的ICa促进肌浆网(SR)Ca(2)过载,舒张期Ca(2+)火花和波,NCX活动增加,导致早期和延迟后去极化(EAD和DAD)的发生率增加,这可能导致室性早搏和室性心动过速。还观察到可能与房室结纤维化有关的房室阻滞。我们的研究表明,增加ICa-L并不一定会导致AP延长,但会导致SRCa(2)超负荷和AV结和心肌纤维化,从而引起细胞心律失常,心律失常,和传导异常。