Adenylyl cyclase (AC) has long been recognized as a pivotal effector molecule in cardiac myocytes and other cells. In 1998 we showed that the amount of adenylyl cyclase sets a limit on the ability of cardiac myocytes to generate cAMP. Subsequent studies showed that AC gene expression has a pronounced favorable effect on cardiovascular function in normal and failing hearts, including increased global left ventricular (LV) function, increased survival and prevention of deleterious remodeling. Data from our laboratory indicate that AC expression also is associated with reduced mortality in acute myocardial infarction. We propose a clinical trial of intracoronary delivery of an adenovirus encoding adenylyl cyclase type VI (ACVI) in patients with congestive heart failure (CHF). These studies stem from extensive preclinical data that we have obtained during the initial four years of the current Program (now submitted for renewal). We expect to be treating patients in Year 5 of the current Program, having achieved all but the final regulatory milestones. We project that this first trial will be complete in Year 3 of the proposed Program. Performing vector development and preclinical studies in parallel with the clinical study will enable a seamless transition to the conduct of a Phase 2 study using a regulated expression vector during the five year tenure of the proposed renewal award. I.B. Hypothesis. Intracoronary delivery of an adenovirus encoding ACVI will improve heart function and reduce symptoms in patients with Class III/IV congestive heart failure. Specific Aim 1. To determine the safety and potential efficacy of intracoronary delivery of an adenovirus encoding ACVI in patients with Class III/IV heart failure in a Phase 1/Phase 2 clinical trial. Specific Aim 2. To determine the safety and efficacy of intracoronary delivery of an adenovirus encoding ACVI (with regulated expression) in patients with Class III/IV heart failure in a Phase 2 clinical trial.