This R21 application will assess the feasibility of using RNA amplified from left ventricular (LV) biopsies of patients during coronary artery bypass graft (CABG) surgery, in order to identify gene expression signatures of early cardiac remodeling. As a first attempt to obtain a gene signature from pre-symptomatic patients, this represents a novel area of investigation with the potential to enhance health-related research. With the aging of the US population, and improved survival of older patients after myocardial infarction (MI), heart failure is a huge public health challenge. It is the primary diagnosis for hospitalization of people over 65: The population-attributable risk for heart failure is 62% from coronary artery disease (CAD), 17% from smoking, and 10% from hypertension. Once individuals develop symptoms of heart disease, remodeling of the heart has already occurred. We propose to improve treatment by identifying molecular pathways that are novel therapeutic targets for early prevention of this remodeling process, in patients with ischemic heart disease. Despite increasing use of microarrays, we have little knowledge of early changes in the human cardiac transcriptome in asymptomatic patients with cardiac dysfunction that could lead to failure. This is in large part because insufficient tissue is available for RNA hybridization to arrays, except from explanted failing hearts or during ventricular assist device (VAD) surgery. However, when cardiac dysfunction has progressed to full blown failure, the complex early, compensatory and late molecular changes cannot be disentangled. We propose a novel approach - to obtain gene expression profiles from amplified RNA of LV biopsies from CABG patients with ischemic heart disease at all stages of heart failure - presymptomatic to severe - in order to distinguish gene expression profiles that foreshadow heart failure in asymptomatic patients (ACC/AHA stages A and B), in patients with impaired cardiac function (stage C) and patients with severe failure (stage D). Our laboratory now successfully performs (two-step) amplification of ng amounts of RNA from biopsy-sized cardiac specimens. We also developed a new clinical data collection tool to allow stratification of patients according to clinical and lifestyle variables.
Specific Aims are (1): to test the feasibility of identifying cardiac gene expression signatures of patients with ischemic heart disease, as a function of increasing severity of heart failure; (2): to test the feasibility of identifying the contribution of a preventable risk factor (smoking) to the transcriptome of at risk patients with ischemic heart disease and thus assess the ability to segregate patients according to risk factors. These studies will break new ground by identifying novel applications for gene profiling from nanogram quantities of RNA from asymptomatic patients, will help identify gene signatures of early stages in cardiac disease development, and will constitute a first step towards pre- emptive medicine. These pilot studies will help identify gene expression signatures from pre-symptomatic patients with incipient heart failure. This will provide an important first step towards our goal of pre-emptive or preventative medicine. In this manner, in the future, patients can be aggressively treated before significant disease progression occurs. ? ? ? ? ? ?
