LOCAL RATE OF MYOCARDIAL AEROBIC METABOLIC IN RELATION TO LOCAL BLOOD FLOW

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Myocardial blood flow is heterogeneously distributed, even in the normal heart, and is redistributed very heterogeneously during myocardial ischemia. It is of importance to determine the consequences of the heterogeneous blood flow distribution for local aerobic metabolic rate. However, for the animal laboratory no method to measure local oxygen consumption in several small myocardial regions simultaneously was available. Very recently we developed a method to determine the local rate of the tricarboxylic acid cycle (TCA cycle; Krebs cycle; citric acid cycle): we infuse for 5.0-5.5 min 13C-labeled acetate (or lactate or pyruvate) into the heart. Thereafter the left ventricular free wall is immediately freeze-clamped and divided into regions of about 0.5 g wet weight (or smaller), from which metabolites are extracted. The non-radioactive 13C-label is detected in TCA-cycle-related metabolites, mainly glutamate, using 13C-NMR-spectroscopy of the extracts. New is that the multiple-fine-str ucture of the 13C-resonance of glutamate is analyzed with models of the time course of 13C label distribution in the 32 isotopic isomers of glutamate. A simple model containing 2 intermediate pools and 36 differential equations and a more comprehensive model (6 intermediate pools, 132 differential equations) have been developed. The differential equations are integrated using an ODE solver under the simulation interface of the Resource. Parameter optimization yields the local rate of the TCA cycle in each small tissue region, from which the local oxygen consumption is then calculated. The metabolic rate is estimated independently of local substrate transport. Up to six physiological parameters can be estimated simultaneously from 9 13C-NMR multiple intensities measured on extracts of frozen myocardial samples. Local perfusion is independently measured with labeled microspheres. Thus we have found a solution to the classic problem how to measure the local oxygen consumption in relation to local blood flow. We will investigate the hyothesis that in the normal heart there is a close link between local metabolism and blood flow, but that during myocardial ischemia this ratio between supply and demand becomes much more heterogeneous. To test this hypothesis the local blood flow will be measured in relation to the local oxygen consumption in situ in hearts of pigs (normal, high work state due to dobutamine, partial coronary stenosis). Subendocardial, mid-myocardial and subepicardial cardiac muscle layers will be compared, but the remarkable heterogeneity within these layers is also closely investigated.