Progressive Loss of Myocardial ATP Due to a Loss of Total Purines During the Development of Heart Failure in Dogs

Abstract

Background —Whether myocardial ATP content falls in heart failure is a long-standing and controversial issue. The mechanism(s) to explain any decrease in ATP content during heart failure have not been identified. Methods and Results —Cardiac dysfunction, heart failure, and a prolonged steady state of heart failure were induced by chronic right ventricular pacing for 1 to 2 weeks, 3 to 4 weeks, and 7 to 9 weeks in dogs. Cardiac function and myocardial O 2 consumption (MV̇ o 2 ) were measured with the dogs in the conscious state. ATP, total purine, and creatine were measured in biopsy specimens obtained at each stage. ATP and the total purine pool progressively fell at rates of 0.12 and 0.15 nmol · mg protein −1 · d −1 , despite an increase in MV̇ o 2 . The rate of loss of creatine was 1.06 nmol · mg protein −1 · d −1 , 7 times faster than the depletion of total purine. Conclusions —(1) ATP contents progressively decreased during heart failure as a result of a loss of the total purine pool. The loss of purines may be due to inhibition of de novo purine synthesis. (2) Loss of creatine is an early marker of heart failure and may serve as a compensatory mechanism minimizing the reduction of the total purine pool in the failing heart.