By applying new techniques of quantitative physiology, detailed studies of energetics and mechanics in the failing left ventricle are proposed to provide insight into the pathophysiology of cardiac failure and improved ability to direct interventions such as afterload reduction and valve replacement or repair in the failing heart. Although cardiac failure remains the leading cause of death in the United States, our current understanding of the pathophysiology and optimal management of the failing heart remains hampered by the lack of practical measures of cardiac performance independent of the load changes that accompany cardiac failure, by inability to quantify metabolic to mechani- cal energy transfer relationships, and by technical difficulties in maintaining a stable animal models of congestive heart failure. This laboratory is uniquely suited to overcoming these barriers in having over 10 years of experience with chronic animal preparations and having led the development of new models myocardial creep, metabolic to mechanical energy transfer relationships, and cardiac performance relationships which are load-insensitive. Using chronically implanted, conscious animals, 3 different pathophysiologic mechanisms of heart failure will be studied: aortic stenosis (pressure overload), mitral insufficiency, (cardiac overload), and ventricular pacing (rate overload). In each of these models, left ventricular energetics will be assessed using the new technique of thermodilution calorimetry and new models relating myocardial oxygen consumption to total mechanical energy and to pressure-volume area. Systolic and diastolic mechanics will be quantified using linear Frank-- Starling relationships, the end-systolic pressure-volume relationship, and measures of passive myocardial properties such as creep. Ventriculoarterial coupling will be examined during pharmacologic manipulation of afterload and inotropic state using established and newly developed models to quantify ventricular load intrinsic and extrinsic to the ventricle itself. Issues to be quantitatively examined include: 1) whether the failing heart """"""""wastes"""""""" oxygen or in fact consumes less oxygen for a given energy load, 2) how systolic ventricular and myocardial per- formance in the failing heart are affected by hypertrophy and dilation, 3) how myocardial creep affects diastolic changes in failure, and 4) whether the failing heart is more sensitive to afterload than the normal heart, and 5) how to best time such interventions as valve replacement to avoid irreversible changes in heart failure.
