Cardiovascular dysfunction resulting from primary abnormalities of the heart or vessels is often compounded by their adverse interaction. This proposal tests the hypothesis that pathologic vascular loading typical of aging or atherosclerotic disease (reduced compliance and enhanced systolic wave reflections) adversely affects left ventricular mechanical function, energetic efficiency, and coronary supply/demand balance. It is further hypothesized that these effects can critically limit net cardiovascular function and reserve capacity when the ventricle itself has concomitant disease that reduces chamber function and/or limits coronary flow reserve. Two canine preparations are used: a) an in situ preparation in which most all of the thoracic aorta is surgically bypassed by a stiff plastic conduit; and b) an isolated blood perfused preparation in which real impedance spectra (not a simplified hydraulic model) are loaded onto a beating heart, and coronary perfusion is controlled open-loop (fixed mean pressure) or closed-loop (pulsatile pressure determined from computer calculated arterial pressure). To test the importance of concomitant ventricular disease, data will be obtained in the following heart models: normal and increased inotropic state, regional and global ischemia, hypertrophic (from chronic hypertension), and cardiomypathic (from chronic tachycardia pacing). Ventricular function is assessed by pressure-volume relations, using indices such as the end-systolic pressure-volume relation, stroke work-end-diastolic volume relation, and dP/dt/max at matched preload to assess contractility. Myocardial oxygen consumption is determined from coronary sinus flow (ultrasound flowmeter) and arterial-venous difference (on-line spectraphotometry). Cardiac efficiency is assessed by the relation between oxygen consumption and total pressure-volume area. In addition, myocardial oxygen consumption required to maintain a given cardiac output at an adequate mean perfusion pressure is determined. It is anticipated these experiments will yield new and important information regarding the mechanisms whereby pathologic vascular-cardiac interaction limits system function and capacity. This understanding is essential towards improving both pharmacologic and mechanical assist therapies used to treat cardiovascular disease.
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