MiP2005: Session 2

Mitochondrial Physiology Network 10.9: 205-26 (2005) - download pdf

 

Spatial profiles of mitochondrial oxygen consumption in myocardium in situ during ischemia.

DJC Alders1, JABJ Groeneveld1, Johannes HGM van Beek1,2

1VU University Medical Centre, Amsterdam; 2Ctr. Medical Systems Biology, Leiden/Amsterdam, The Netherlands. - hans.vanbeek@vumc.nl

    In the normal heart myocardial blood flow and oxygen consumption are both heterogeneous, but highly matched to each other. Myocardial ischemia and infarction as a result of coronary stenosis are major causes of death in humans. Myocardial infarction may show a patchy pattern. We investigated how oxygen delivery, as reflected by coronary blood flow, matches to oxygen consumption at the local level during increasing partial coronary stenosis of the left anterior descending (LAD) artery in porcine left ventricle.

    In in vitro and in vivo myocardium we have demonstrated that TCA cycle and other metabolic fluxes can be quantitated from a single high-resolution carbon-13 NMR spectrum in a small tissue sample, making it possible to assess spatial patterns of oxygen consumption [1,2]. Heart muscle samples are taken exactly 5.5 min after the start of infusion of 13-enriched acetate. A high-resolution NMR spectrum is obtained from tissue sample extracts, showing single carbon NMR peaks, often split into multiplets due to J-coupling between adjacent isotopes. The NMR free induction decays are analyzed in the time domain and yield absolute line intensities. The multiplet intensities are analyzed by a model for isotope traffic in the TCA cycle and communicating amino acid pools. The 160 differential equation model is integrated for each point on a trajectory in parameter space to find an optimal fit. Flux quantitation therefore depends on a pre-steady-state of carbon-13 isotope enrichment in glutamate.

    In small (<1 ml) tissue samples, blood flow was measured with radioactive microspheres, and oxygen consumption in the same sample with the carbon-13 method. In one group of animals LAD pressure was 65-70 mmHg downstream of the stenosis (group I, n = 7), and in another group LAD pressure was 30-35 mmHg (group II, n = 7). During normal perfusion, blood flow (~5 ml∙min-1∙g-1 dry mass) and oxygen consumption (~19 mmol∙min-1∙g-1 dry mass) are well correlated (r=0.85). In group I, blood flow decreased by 31.9 % on average during stenosis, in group II by 40.9 %. The correlation between blood flow and oxygen consumption on a local level decreased markedly with decreasing blood flow and with decreasing LAD pressure downstream of the stenosis.

    We conclude that during progressing partial coronary occlusion, in addition to the global decrease of the oxygen supply-to-consumption ratio, oxygen delivery to oxygen consumption matching is increasingly heterogeneous. This implies that local vasodilation reserve is not uniformly matched to regional demand and that during stenosis some areas are more affected by ischemia than others.

     Supported by the Netherlands Heart Foundation, grant no. 96.127

1.  Beek JHGM van, Mil HGJ van, Kanter FJJ de, King RB, Alders DJC, Bussemaker JA (1999) 13C-NMR double labeling method to quantitate local myocardial oxygen consumption using frozen tissue samples. Am. J. Physiol. 277: H1630-H1640.

2.  Alders DJC, Groeneveld ABJ, De Kanter FJJ, Beek JHGM van (2004) Myocardial oxygen consumption in porcine left ventricle is heterogeneously distributed in parallel to heterogeneous oxygen delivery. Am. J. Physiol. 287: H1353-H1361.


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