Intercellular Communication and Cardiac Arrhythmias

描述(申请人提供)：心血管疾病是西方世界的一个主要健康问题，仅在美国每年就估计有50万人死亡。心脏性猝死背后的潜在机制仍然知之甚少。许多类型的心血管疾病，包括缺血性心脏病和心力衰竭，都与广泛的纤维化有关。心脏纤维化发展过程中的一个关键事件是成纤维细胞向活跃表型或肌成纤维细胞的转化。成纤维细胞激活是否会导致不同的电表型，从而使心脏对心律失常事件易感，这一问题仍有待探索。在这项建议中，我们将研究从梗塞组织分离的成纤维细胞的电学表型。我们还将致力于确定新的治疗方法，旨在改变这些细胞的电表型。赠款的总体目标是确定预防、延迟或限制心脏成纤维细胞的激活是否具有潜在的有益的抗心律失常效果。我们提出了三个特定的目标：特定的目标1是确定从梗死心脏分离的成纤维细胞在心肌细胞和成人成纤维细胞的异种细胞培养中影响冲动增殖和心律失常发生的潜力。我们假设心脏损伤改变了成纤维细胞的电学表型，这是通过异种细胞培养的高分辨率光学图谱来评估的。特异目的2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细胞间偶联水平增加和静息膜电位变化的共同作用的结果。具体目的3是确定HMG-CoA还原酶抑制剂的多效性作用之一是否包括改善梗塞组织的传导特性和挽救从梗塞心脏分离的成纤维细胞的电表型。为此，我们假设他汀类药物的抗纤维化特性将减弱成纤维细胞激活的电生理效应，如在离体梗死心脏和心肌细胞和成纤维细胞的异细胞培养中所评估的那样。为了实现这些目标，我们将结合分子生物学和细胞电生理技术，以及器官和细胞水平的高分辨率光学标测技术。公共卫生相关性：心血管疾病是一个主要的健康问题，据估计，美国每年有50万人死于心血管疾病。纤维化与多种形式的心血管疾病有关，并可能导致致命性心律失常的发生。成纤维细胞的激活是否会改变电生理底物的问题仍有待探讨。在这项提案中，我们将研究成纤维细胞的激活，并确定旨在改变其电表型的新的治疗方法。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is a major health problem accounting for an estimated 500,000 deaths each year in the United States. Fibrosis is associated with many forms of cardiovascular disease and may contribute to the development of lethal arrhythmias. The question of whether fibroblast activation alters the electrophysiological substrate remains to be explored. In this proposal, we will investigate fibroblast activation and identify new therapeutic approaches designed to alter their electrical phenotype.