Spatial heterogeneity of energy turnover in the heart

Abstract

Local myocardial blood flow varies substantially in spite of a rather homogeneous morphology. To further elucidate this paradox, the spatial heterogeneity of tricarboxylic acid cycle turnover (J(TCA), micromol min(-1) g(-1)) and coronary flow was assessed at a high spatial resolution (6x6x6 mm3) in the open chest dog. Local flow differed more than 2.5-fold between individual samples in each heart (n=7). Out of 1,500 myocardial samples, 1/10 received less than 60% and another 1/10 more than 138% of the normalized mean. In low- and high-flow samples, pyruvate uptake and metabolism were analyzed by 13C NMR spectroscopy. Following [3-13C]pyruvate infusion (2 mM, 12 min), glutamate [4-13C]/[3-13C] was significantly greater in low-flow (2.21+/-0.75, 40 samples) than in high-flow (1.64+/-0.49, 39 samples) areas. This suggests that there are major differences in J(TCA). Glutamate, citrate and lactate content positively correlated with flow. Anaplerotic pathways contributed a fraction similar to J(TCA) in low- and high-flow areas, as demonstrated by isotopomer analysis after 60 min of [3-13C]pyruvate application. Mathematical model analysis of NMR data and relevant pool sizes revealed that J(TCA) and thus myocardial oxygen consumption (MVO2) in high-flow areas exceed values in low-flow areas at least threefold. Thus low and high metabolic states normally coexist within the well perfused heart, suggesting that there is considerable spatial heterogeneity of cardiac energy generation and work.

Pattern differences between distributions of microregional myocardial flows in crystalloid- and blood-perfused rat hearts

“…On the basis of the sequential application of microspheres, early studies demonstrated that a temporal flow difference in a given region was relatively small compared with a spatial flow difference. Thus the distribution of regional myocardial flows has been considered quite stable (25,37,45), matching with local energy turnover and gene/ protein expression (11,27,39). However, at the presently focused microvascular levels, temporal fluctuations of regional flows seem to be comparable in magnitude to spatial flow variations as shown in CV and CA differences between bloodbolus-and blood-60 s-perfused hearts.…”

Myocardial O2consumption in porcine left ventricle is heterogeneously distributed in parallel to heterogeneous O2delivery

“…Fits with the full multiplet model were only accepted when the overall coefficient of variation (CV) was Ͻ25%. In case, this multiplet method did not lead to an acceptable fit of the model to the peak data because of low multiplet intensity relative to the NMR noise, we applied the simplified strategy to estimate J TCA by fitting the mean of the G2 and G3 peaks, divided by the total of the G4 peaks [ratio method (12,41); FC2 ϭ 0.6]. The value of glutamate was fixed at the biochemical assay value.…”

“…A similar method has recently been applied to demonstrate that regions with the 10% highest flow have significantly higher V O 2 than regions with the 10% lowest flow in the canine left ventricle (12). In this study, we applied our new 13 C method to measure the profile of V O 2 in small tissue areas in the normal in situ porcine left ventricle for the full range of blood flow.…”

“…From J TCA and F C2 V O 2 was computed. For the remaining 24 samples, J TCA was estimated by using the ratio method (12,41). The additional parameters were fixed at the mean values obtained from fits to the multiplets (CV Ͻ25%); see Table 3.…”

High-resolution imaging reveals a limit in spatial resolution of blood flow measurements by microspheres

“…In one dog, differently colored fluorescent microspheres (15 m, 250,000/kg) were then applied on days 1-3 via the atrial catheter while blood was simultaneously withdrawn from the aorta (10 ml/ min) into a virtual reference organ. For cardiac excision, the animal was anesthetized as previously described (10). In the other dog, radioactive microspheres were applied for local flow determinations in the alert animal.…”