Human Heart Failure: A Mechanistic Assessment of Altered Ventricular Function
Human heart failure is associated with high mortality and morbidity. From a functional viewpoint, the failing heart has low power (rate of doing work) and an inadequate cardiac output to meet the metabolic needs of the periphery. We use myothermal and mechanical techniques on specially prepared thin epicardial muscle strips from nonfailing (coronary bypass surgery) and failing (idiopathic dilated cardiomyopathy, NYHA IV) human hearts to assess the mechanistic basis for the depressed power and cardiac output. The isometric peak force, rate of force development, and rate of relaxation are reduced to 53%, 49%, and 54%, respectively, in the failing heart while the time to peak tension is increased by 15%. The total activity-related heat, initial heat, tension-dependent heat, tension-independent heat, and tension-independent heat rate were substantially and significantly reduced in the failing preparations. The ratio of total activity-related heat to initial heat is an index of the ability of mitochondria to resynthesize ATP from ADP and is found to be unchanged in the failing myocardium. The amount of calcium cycled per beat and the rate of calcium uptake can be calculated from the tension-independent heat. In the failing myocardium, both of these are reduced to 31% of nonfailing values. The average cross-bridge force time integral can be calculated from the fiber strip force-time integral divided by the number of cross-bridge cycles per half sarcomere per twitch. The latter is obtained from the tension-dependent heat. The average cross-bridge force-time integral is increased by 41% in the failing heart. The depression in isometric force correlates with the decrease in calcium cycled per beat. This in itself contributes to the reduced ventricular performance. Added to that, there is a blunting of the force-frequency relationship and a decrease in the velocity of unloaded shortening. These fundamental changes at the molecular level result in a decrease in power output of the ventricle and ultimately lead to the serious morbid and mortal consequences found in congestive heart failure.
KeywordsIsometric Force Muscle Strip Hypertrophy Heart Initial Heat Human Heart Failure
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