NMR STUDIES OF MYOCARDIAL HYPERTROPHY

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Nuclear Magnetic Resonance (NMR) spectroscopy, which permits the noninvasive, sequential evaluation of metabolites and cations, has been employed in the study of perfused hearts of small animals. Although 31P NMR has been used extensively to evaluate high energy phosphate metabolism, only a few studies of cardiac tissue have employed the NMR active isotopes 2H, 35C1, and 23Na, which permit the measurement of intracellular water and intracellular sodium. In addition, relatively few studies have exploited the potential of 31P NMR as a method to measure intracellular free Mg2+ and pH. Although the signals transducing increased hemodynamic load into myocardial growth remain unknown, increased intracellular Na+ has been implicated as at least one factor. Increased Na+ influx indirectly affects intracellular pH (via Na+/H+ exchange), intracellular free Ca2+ (via Na+:Ca2+ exchange), intracellular K+ (via Na+,K+-ATPase), and intracellular free Mg2+ (via Mg2+:Na+ cotransport). the long term objective of the research described in this proposal is to determine specific alterations in Na+ levels and transport properties which might signal the development (and reversal) of myocardial hypertrophy and the concomitant effects on other cation levels and transport systems. Myocardial hypertrophy is one of the long-term mechanisms of compensation for cardiac stress. However, hypertrophy accompanying aortic stenosis, hypertension, or congestive cardiomyopathies, initially an adaptive response, can result in heart failure due to inadequate of excessive growth or abnormal function. Left ventricular hypertrophy in hypertensive patients is associated with an almost 10-fold increase in the risk of developing congestive heart failure. A specific animal model of myocardial hypertrophy (aortic stenosis) will be studied (in vitro) using 2H, 23Na, 31P, and 35C1 NMR to measure intracellular cations and high energy phosphates and to define the changes in their chemical activities which occur during the course of hypertrophy. Image-localized (1H, 23Na, and 31P) NMR spectroscopy will also be employed in some of these studies to measure intracellular free magnesium, pH, high energy phosphates, sodium, and specific metabolites (ie. lactate) in various regions (left ventricle, right ventricle) of the heart.