Intercellular Communication and Cardiac Arrhythmias

项目摘要/摘要 心血管疾病是西方世界的一个主要健康问题，仅在美国就如此 据估计，每年有50万人死亡。突如其来背后的潜在机制 心源性死亡仍然知之甚少。包括缺血性在内的多种类型的心血管疾病 心脏病和心力衰竭与广泛的纤维化有关。世界上最重要的事件之一 心脏纤维化的发展是成纤维细胞向活跃表型或 肌成纤维细胞。成纤维细胞激活是否会导致不同的电表型的问题 这使得心脏容易受到心律失常事件的影响，这一点仍有待探索。在这项提案中，我们 将研究从梗塞组织分离的成纤维细胞的电学表型。我们也会努力工作 寻找新的治疗方法，旨在改变这些患者的电学表型 细胞。赠款的总体目标是确定预防、拖延或 限制心脏成纤维细胞的激活具有潜在的抗心律失常作用。我们有 提出了三个特定的目标：特定的目标1是确定分离的成纤维细胞的潜能 心肌梗死对异种细胞培养的脉冲传播和心律失常的影响 肌细胞和成体成纤维细胞。我们假设心脏损伤改变了心脏的电表型。 成纤维细胞通过异种细胞培养的高分辨率光学图谱进行评估。具体目标2 目的是确定成纤维细胞激活的电生理机制。在这里，我们假设 从梗塞组织分离的成纤维细胞的电生理表型是由于 细胞间偶联水平的提高和静息状态的改变的联合作用 膜电位。具体目标3是确定多效效应中的一种 HMG-CoA还原酶抑制剂包括改善脑梗塞组织的传导特性和 挽救从梗死心脏分离的成纤维细胞的电学表型。为了实现这一目标，我们 假设他汀类药物的抗肝纤维化作用将减弱其电生理效应。 离体梗死心脏和异种细胞心肌细胞培养中成纤维细胞活性的评估 和成纤维细胞。为了实现这些目标，我们将利用分子生物学和 细胞电生理技术，以及高分辨率光学测绘技术 器官和细胞水平。

PROJECT SUMMARY/ABSTRACT Cardiovascular disease is a major health problem in the western world and in the United States alone accounts for an estimated 500,000 deaths each year. The underlying mechanisms behind sudden cardiac death remain poorly understood. Many types of cardiovascular disorders including ischemic heart disease and heart failure are associated with extensive fibrosis. A critical event in the development of cardiac fibrosis is the transformation of fibroblasts into an active phenotype or myofibroblast. The question of whether fibroblast activation results in a different electrical phenotype that makes the heart susceptible to arrhythmic events remains to be explored. In this proposal, we will investigate the electrical phenotype of fibroblasts isolated from infarcted tissue. We will also work toward identifying new therapeutic approaches designed to alter the electrical phenotype of these cells. The overall aims of the grant are directed at determining whether preventing, delaying or limiting the activation of cardiac fibroblasts has potential beneficial antiarrhythmic effects. We have proposed three specific aims: Specific Aim 1 is to determine the potential of fibroblasts isolated from infarcted hearts to influence impulse propagation and arrhythmogenesis in heterocellular cultures of myocytes and adult fibroblasts. We hypothesize that cardiac injury alters the electrical phenotype of fibroblasts as assessed by high resolution optical mapping of heterocellular cultures. Specific Aim 2 is to determine the electrophysiological mechanisms of fibroblast activation. Here we hypothesize that the electrophysiological phenotype of fibroblasts isolated from infarcted tissue results from the combined effect of an increase in the level of intercellular coupling and a change in the resting membrane potential. Specific Aim 3 is to determine whether one of the pleiotropic effects of the HMG-CoA reductase inhibitors includes improving the conduction properties of infarcted tissue and rescuing the electrical phenotype of fibroblasts isolated from infarcted hearts. In this aim, we hypothesize that the anti-fibrotic properties of statins will attenuate the electrophysiological effects of fibroblast activation as assessed in isolated infarcted hearts and heterocellular cultures of myocytes and fibroblasts. To achieve these aims, we will utilize a combination of molecular biological and cellular electrophysiological techniques, as well as high resolution optical mapping technology at the organ and cellular levels.