Enhanced external counterpulsation (EECP) is a non-invasive modality for the treatment of symptomatic coronary disease (CAD) in patients who are not amenable to standard revascularization procedures. EECP is efficacious in decreasing angina episodes, nitrate usage, and hospitalizations, and increasing exercise tolerance and quality of life scores. However, the mechanism(s) underlying for the salutory benefits of EECP remain largely unknown. The popular concept is that EECP may promote collateral development and improve myocardial perfusion. This classical 'angiogenesis' understanding of EECP is a theory and has not been proven in humans. Indeed, there is inadequate data to support the central hypothesis that improved myocardial perfusion is the basis for clinical improvement after EECP. We propose an alternate hypothesis to explain the chronic clinical benefits of EECP. We hypothesize that extra-cardiac factors, such as peripheral arterial stiffness, endothelial dysfunction, and elevated myocardial oxygen demand are the therapeutic target for EECP. To date, the extra cardiac effects of EECP have received little attention and peripheral vascular adaptations to EECP have not been investigated. Specifically, we propose that EECP, by promoting lower extremity arterial """"""""runoff"""""""" and intermittent reactive hyperemia in the legs with each inflation/deflation cycle of the compressive cuffs, improves peripheral vascular function. We further hypothesize that EECP-induced changes in peripheral vascular biology will reduce ventricular work and myocardial oxygen demand in patients with CAD. To test our hypothesis we will randomly assign symptomatic patients with CAD to 35 1-hour sessions of EECP (n=30) or 35 1-hour sessions of sham-EECP (n=30). We will execute the following Specific Aims to determine whether: 1) EECP, as compared to standard care, improves arterial function in symptomatic patients with CAD; 2) EECP, as compared to standard care, improves endothelial function; 3) changes in vascular biology are accompanied by commensurate changes in myocardial oxygen demand; 4) changes in vascular biology are accompanied by commensurate changes in maximal oxygen consumption, ischemic threshold, and anginal classification; 5) changes in vascular biology are accompanied by commensurate changes in vasoactive agents; 6) changes in vascular biology are accompanied by commensurate changes in free radical production and total antioxidant defenses. Only through identification of specific mechanisms behind the efficacy of EECP, will this treatment oDtion receive acceptance by the clinical community in the treatment of svmptomatic CAD.
