Gene expression profiles in the failing human heart

描述（由申请人提供）： 心肌病性、完整的衰竭的人类心脏的进行性心肌功能障碍和重塑的机制尚不清楚。β受体阻滞剂相关的心肌功能改善和重塑逆转的机制也仍然未知。一般来说，导致进行性心肌衰竭和重构的病理生理机制可能涉及改变心肌基因表达的信号传导机制。类似地，β-阻断剂治疗后心肌功能改善和重塑的分子基础也可能是由于心肌基因表达的时间依赖性变化。最近的许多研究表明，为了有意义，基因调控和表达必须在完整的心脏中进行检查。本提案的总体目标是在患有心肌衰竭的人类受试者中鉴定与心肌功能变化相关的基因表达谱。该提案研究1）相对于非衰竭对照，衰竭人类心脏中超过12，000个基因的表达2）与β受体阻滞剂相关的心肌功能改善相关的基因表达变化。 使用微阵列分析，我们能够测量大量的基因在少量的人心室心肌，可以连续从完整的心脏右心室（RV）心肌内膜活检获得的表达。我们已经证明，在左心室和右心室功能一致的情况下，基因表达的方向性变化在RV游离壁，RV间隔肌内膜异位症，LV游离壁是相似的，表明RV间隔肌内膜异位症活检样本可用于研究RV或LV游离壁基因表达的变化。因此，这一建议有能力确定负责在完整的人类心脏的心肌细胞功能障碍的分子机制。此外，该提议能够提供与β受体阻滞剂相关的心肌功能障碍改善机制相关的信息。

DESCRIPTION (provided by the applicant): The mechanisms responsible for progressive myocardial dysfunction and remodeling of the cardiomyopathic, intact failing human heart are unknown. The mechanism(s) behind Beta-blocker related improvements in myocardial function and reversal of remodeling also remains unknown. In general, the pathophysiologic mechanisms responsible for progressive myocardial failure and remodeling are likely to involve signaling mechanisms, which alter myocardial gene expression. Similarly, the molecular basis for improvement in myocardial function and remodeling following treatment with Beta-blocking agents also is likely due to time-dependent changes in myocardial gene expression. Numerous recent studies have demonstrated that, in order to be meaningful, gene regulation and expression must be examined in the intact heart. The overall objective of this proposal is to identify, in human subjects with myocardial failure, gene expression profiles associated with changes in myocardial function. This proposal investigates 1) the expression of over 12,000 genes in the failing human heart relative to nonfailing controls 2)changes in gene expression associated with Beta-blocker related improvement in myocardial function. Using microarray analysis we are able to measure the expression of a large number of genes in small quantities of human ventricular myocardium that can be obtained serially from the intact heart by right ventricular (RV) endomyocardial biopsy. We have demonstrated that in situations where left and right ventricular function are concordant, directional changes in gene expression are similar in RV free wall, RV septal endomyocardium, and LV free wall, indicating that RV septal endomyocardial biopsy samples may be used to investigate changes in RV or LV free wall gene expression. Thus, this proposal has the ability to determine the molecular mechanisms responsible for myocyte dysfunction in the intact human heart. Furthermore, this proposal has the ability to provide information relevant to the mechanisms responsible for Beta-blocker-related improvements in myocardial dysfunction.