Myocytes oxygenation and high energy phosphate levels during hypoxia.

Decrease of ambient oxygen level has been used in myocytes culture experiments in examining the responsiveness to stress secondary to hypoxia. However, none of these studies measure the myocytes oxygenation levels resulting in ambiguity as to whether there is insufficient oxygen delivery. This study examined the hypothesis that at a basal myocardial work state, adequate myocyte oxygenation would be maintained until extremely low arterial pO2 levels were reached. Myocyte pO2 values in normal dogs were calculated from the myocardial deoxymyoglobin (Mb- δ) levels using (1)H-spectroscopy (MRS) and were normalized to Mb-δ obtained after complete LAD occlusion. During Protocol 1 (n = 6), Mb-δ was measured during sequential reductions of the oxygen fraction of inspired gas (FIO2) from 40, 21, 15, 10, and 5%, while in protocol 2 (n = 10) Mb-δ was measured at FIO2 of 3%. Protocol 3 (n = 9) evaluated time course of Mb-δ during prolonged exposure to FIO2 of 5%. Myocardial blood flow (MBF) was measured with microspheres and high energy phosphate (HEP) levels were determined with (31)P-MRS. MVO2 progressively increased in response to the progressive reduction of FIO2 that is accompanied by increased LV pressure, heart rate, and MBF. Mb-δ was undetectable during FIO2 values of 21, 15, 10, and 5%. However, FIO2 of 3% or prolonged exposure to FIO2 of 5% caused progressive increases of Mb-δ which were associated with decreases of PCr, ATP and the PCr/ATP ratio, as well as increases of inorganic phosphate. The intracellular PO2 values for 20% reductions of PCr and ATP were approximately 7.4 and 1.9 mmHg, respectively. These data demonstrate that in the in vivo system over a wide range of FIO2 and arterial pO2 levels, the myocyte pO2 values remain well above the K(m) value with respect to cytochrome oxidase, and oxygen availability does not limit mitochondrial oxidative phosphorylation at 5% FIO2

Hemodynamic Data.

<p>Values are means ± SD. * P<0.05 vs Baseline.</p><p>Hemodynamic Data.</p

Relationship of PCr with pO₂.

<p>Relationship of PCr with pO₂.</p

Relationship of ATP with pO₂.

<p>Relationship of ATP with pO₂.</p

Myocardial PCr/ATP and Pi/PCr Data.

<p>Values are means ± SE. * P<0.05 vs. Baseline. † P<0.01 vs. Baseline.</p><p>Myocardial PCr/ATP and Pi/PCr Data.</p

Myocardial blood flow, oxygen consumption, and arterial - venous blood gas data.

<p>Values are Mean±SD, * p<0.05 vs. Baseline.</p><p>Myocardial blood flow, oxygen consumption, and arterial - venous blood gas data.</p

Relationship of Myocardial Blood Flow and Tissue Oxygenation with Oxygen Fraction of Inspired Gas.

<p>DMB  =  level of deoxymyoglobin normalized to total LAD occlusion; MBF  =  myocardial blood flow rate (ml per minute per gram myocardium measured by microspheres at each experimental conditions). *, p<0.01 VS Baseline; #, p<0.01 VS. LAD occlusion.</p

Long-term preservation of myocardial energetic in chronic hibernating myocardium

We previously reported that the myocardial energetic state, as defined by the ratio of phosphocreatine to ATP (PCr/ATP), was preserved at baseline (BL) in a swine model of chronic myocardial ischemia with mild reduction of myocardial blood flow (MBF) 10 wk after the placement of an external constrictor on the left anterior descending coronary artery. It remains to be seen whether this stable energetic state is maintained at a longer-term follow-up. Hibernating myocardium (HB) was created in minipigs (n = 7) by the placement of an external constrictor (1.25 mm internal diameter) on the left anterior descending coronary artery. Function was assessed with MRI at regular intervals until 6 mo. At 6 mo, myocardial energetic in the HB was assessed by 31P-magnetic resonance spectrometry and myocardial oxygenation was examined from the deoxymyoglobin signal using 1H-magnetic resonance spectrometry during BL, coronary vasodilation with adenosine, and high cardiac workload with dopamine and dobutamine (DpDb). MBF was measured with radiolabeled microspheres. At BL, systolic thickening fraction was significantly lower in the HB compared with remote region (34.4 ± 9.4 vs. 50.1 ± 10.7, P = 0.006). This was associated with a decreased MBF in the HB compared with the remote region (0.73 ± 0.08 vs. 0.97 ± 0.07 ml·min−1·g, P = 0.03). The HB PCr/ATP at BL was normal. DpDb resulted in a significant increase in rate pressure product, which caused a twofold increase in MBF in the HB and a threefold increase in the remote region. The systolic thickening fraction increased with DpDb, which was significantly higher in the remote region than HB (P < 0.05). The high cardiac workload was associated with a significant reduction in the HB PCr/ATP (P < 0.02), but this response was similar to normal myocardium. Thus HB has stable BL myocardial energetic despite the reduction MBF and regional left ventricular function. More importantly, HB has a reduced contractile reserve but has a similar energetic response to high cardiac workload like normal myocardium