Hohendanner Felix, Walther Stefanie, Maxwell Joshua T, Kettlewell Sarah, Awad Sawsan, Smith Godfrey L, Lonchyna Vassyl A, Blatter Lothar A
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, 60612, USA.
J Physiol. 2015 Mar 15;593(6):1459-77. doi: 10.1113/jphysiol.2014.283226. Epub 2014 Dec 22.
Impaired calcium (Ca(2+)) signalling is the main contributor to depressed ventricular contractile function and occurrence of arrhythmia in heart failure (HF). Here we report that in atrial cells of a rabbit HF model, Ca(2+) signalling is enhanced and we identified the underlying cellular mechanisms. Enhanced Ca(2+) transients (CaTs) are due to upregulation of inositol-1,4,5-trisphosphate receptor induced Ca(2+) release (IICR) and decreased mitochondrial Ca(2+) sequestration. Enhanced IICR, however, together with an increased activity of the sodium-calcium exchange mechanism, also facilitates spontaneous Ca(2+) release in form of arrhythmogenic Ca(2+) waves and spontaneous action potentials, thus enhancing the arrhythmogenic potential of atrial cells. Our data show that enhanced Ca(2+) signalling in HF provides atrial cells with a mechanism to improve ventricular filling and to maintain cardiac output, but also increases the susceptibility to develop atrial arrhythmias facilitated by spontaneous Ca(2+) release.
We studied excitation-contraction coupling (ECC) and inositol-1,4,5-triphosphate (IP3)-dependent Ca(2+) release in normal and heart failure (HF) rabbit atrial cells. Left ventricular HF was induced by combined volume and pressure overload. In HF atrial myocytes diastolic [Ca(2+)]i was increased, action potential (AP)-induced Ca(2+) transients (CaTs) were larger in amplitude, primarily due to enhanced Ca(2+) release from central non-junctional sarcoplasmic reticulum (SR) and centripetal propagation of activation was accelerated, whereas HF ventricular CaTs were depressed. The larger CaTs were due to enhanced IP3 receptor-induced Ca(2+) release (IICR) and reduced mitochondrial Ca(2+) buffering, consistent with a reduced mitochondrial density and Ca(2+) uptake capacity in HF. Elementary IP3 receptor-mediated Ca(2+) release events (Ca(2+) puffs) were more frequent in HF atrial myoctes and were detected more often in central regions of the non-junctional SR compared to normal cells. HF cells had an overall higher frequency of spontaneous Ca(2+) waves and a larger fraction of waves (termed arrhythmogenic Ca(2+) waves) triggered APs and global CaTs. The higher propensity of arrhythmogenic Ca(2+) waves resulted from the combined action of enhanced IICR and increased activity of sarcolemmal Na(+)-Ca(2+) exchange depolarizing the cell membrane. In conclusion, the data support the hypothesis that in atrial myocytes from hearts with left ventricular failure, enhanced CaTs during ECC exert positive inotropic effects on atrial contractility which facilitates ventricular filling and contributes to maintaining cardiac output. However, HF atrial cells were also more susceptible to developing arrhythmogenic Ca(2+) waves which might form the substrate for atrial rhythm disorders frequently encountered in HF.
钙（Ca(2+)）信号受损是心力衰竭（HF）时心室收缩功能降低和心律失常发生的主要原因。在此我们报告，在兔HF模型的心房细胞中，Ca(2+)信号增强，并且我们确定了其潜在的细胞机制。Ca(2+)瞬变（CaTs）增强是由于肌醇-1,4,5-三磷酸受体诱导的Ca(2+)释放（IICR）上调以及线粒体Ca(2+)摄取减少。然而，增强的IICR，连同钠钙交换机制活性增加，也促进了以致心律失常Ca(2+)波和自发动作电位形式的自发Ca(2+)释放，从而增强了心房细胞的致心律失常潜能。我们的数据表明，HF中增强的Ca(2+)信号为心房细胞提供了一种改善心室充盈和维持心输出量的机制，但也增加了因自发Ca(2+)释放而发生房性心律失常的易感性。
我们研究了正常和心力衰竭（HF）兔心房细胞中的兴奋-收缩偶联（ECC）和肌醇-1,4,5-三磷酸（IP3）依赖性Ca(2+)释放。通过容量和压力联合过载诱导左心室HF。在HF心房肌细胞中，舒张期[Ca(2+)]i升高，动作电位（AP）诱导的Ca(2+)瞬变（CaTs）幅度更大，主要是由于中央非连接肌浆网（SR）的Ca(2+)释放增强，并且激活的向心传播加速，而HF心室CaTs降低。较大的CaTs是由于IP3受体诱导的Ca(2+)释放（IICR）增强和线粒体Ca(2+)缓冲减少，这与HF中线粒体密度和Ca(2+)摄取能力降低一致。与正常细胞相比，HF心房肌细胞中基本的IP3受体介导的Ca(2+)释放事件（Ca(2+)微泡）更频繁，并且在非连接SR的中央区域更常检测到。HF细胞中自发Ca(2+)波的总体频率更高，并且更大比例的波（称为致心律失常Ca(2+)波）触发了AP和整体CaTs。致心律失常Ca(2+)波的更高倾向是由增强的IICR和肌膜钠-钙交换活性增加使细胞膜去极化的联合作用导致的。总之，数据支持这样的假设，即在左心室衰竭心脏的心房肌细胞中，ECC期间增强的CaTs对心房收缩力产生正性肌力作用，这有助于心室充盈并有助于维持心输出量。然而，HF心房细胞也更容易发生致心律失常Ca(2+)波，这可能构成HF中常见的房性心律失常的基础。
