Gene expression profiles in the failing human heart

描述(由申请人提供)： 心肌病的完整衰竭心脏的进行性心肌功能障碍和重塑的机制尚不清楚。β-受体阻滞剂改善心肌功能和逆转重构的机制(S)也尚不清楚。总的来说，导致进行性心肌衰竭和心肌重构的病理生理机制可能涉及改变心肌基因表达的信号机制。同样，β-受体阻滞剂治疗后改善心肌功能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。最近的大量研究表明，为了有意义，必须在完整的心脏中检测基因的调节和表达。这项建议的总体目标是确定在患有心肌衰竭的人类受试者中，与心肌功能变化相关的基因表达谱。这项建议调查了1)与正常对照相比，12,000多个基因在衰竭心脏中的表达情况；2)与Beta受体阻滞剂相关的心肌功能改善相关的基因表达变化。利用基因芯片分析技术，我们能够通过右室心内膜心肌活检从完整的心脏中连续获得少量人心肌组织中大量基因的表达。我们已经证明，在左、右心功能一致的情况下，右室游离壁、右室间隔心内膜心肌和左室游离壁基因表达的方向性变化是相似的，这表明右室间隔心内膜心肌活检标本可以用来研究右室或左室游离壁基因表达的变化。因此，这一建议有能力确定导致完整人类心脏心肌细胞功能障碍的分子机制。此外，这项建议能够提供与β-受体阻滞剂相关的改善心肌功能障碍的机制相关的信息。

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.