Left ventricular hypertrophy secondary to chronic pressure overload or volume overload is associated with abnormalities of perfusion, contractile function and bioenergetics under basal conditions or during periods of stress. Previous studies correlating bioenergetic and functional characteristics have been perfused in open chest, surgically stressed animals or isolated perfused heart preparations, although studies correlating perfusion and contractile function have been performed in intact awake animals. This study will be carried out in chronically instrumented closed chest dogs to determine whether abnormalities of myocardial bioenergetics, systolic function and glucose metabolism previously described in isolated heart preparations and open chest animals also occur in hypertrophied myocardium operating under physiological conditions, and compare the bioenergetic consequences of pressure and volume overload hypertrophy under basal conditions and during stress induced by pacing, inotropic stimulation and exercise. Severe left ventricular hypertrophy (LVH) secondary to pressure overload will be produced by banding the ascending aorta in young dogs, while volume overload hypertrophy will be produced by creating mitral regurgitation. Myocardial blood flow will be measured in LVH and control groups with radioactive microspheres, transmural systolic function with the pulsed Doppler technique, and creatine phosphate (CP), ATP, inorganic phosphate (Pi) and 2-deoxyglucose-6- phosphate (as an index of glucose uptake) with transmural spatially localized 31P NMR spectroscopy. Glucose metabolism and Krebs cycle activity will be assessed with 13C NMR spectroscopy. We postulate that under basal conditions a transmural CP/ATP gradient exists with CP lowest in the subendocardium in LVH hearts but not in normal hearts. To determine whether the lower CP/ATP ratio is the result of persistent subendocardial underperfusion in LVH, intracoronary adenosine will be administered to increase blood flow and determine whether this gradient results from inadequate subendocardial perfusion. To determine whether subendocardial underperfusion during tachycardia produces bioenergetic abnormalities and contractile dysfunction in LVH, measurements will be repeated during pacing at rates of 200 and 240 beats/minute. To determine whether an exaggerated increase of oxygen consumption during inotropic stimulation in LVH hearts results in alteration of high energy phosphates, measurements will be repeated during dobutamine infusion at a rate of 15 and 30 mu g/kg/min intravenously. To examine whether heavy exercise causes subendocardial stunning in LVH hearts, hemodynamic and function measurements will be repeated during exercise, and NMR studies will be performed immediately after exercise, and daily until spectra have returned to baseline. Transmural systolic function will be monitored and correlated with blood flow and high energy phosphate measurements. To determine whether LVH is associated with abnormalities of glucose metabolism, the rate of uptake and distribution of 2-deoxyglucose (monitored as the appearance of 2- deoxyglucose-6-phosphate) will be monitored and the disposition of 13C glucose will be evaluated. Lastly the applicability of the 13C labeled acetate NMR technique for evaluating tricarboxylic acid cycle turnover rates will be tested in an in vivo model by comparing oxidative rates calculated by NMR techniques with directly measured MVO2.
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