The relationships of high energy phosphates, tissue pH, and regional blood flow to diastolic distensibility in the ischemic dog myocardium.

Abstract

SUMMARY. Myocardial ischemia due to increased oxygen demand (pacing tachycardia plus critical coronary stenoses) alters diastolic distensibility and relaxation more than ischemia of comparable duration due to coronary occlusion. To investigate the relationship between myocardial diastolic function and metabolism, we compared myocardial high energy phosphate content, tissue pH, and regional blood flow for these two types of ischemia in anesthetized open-chest dogs. Myocardial biopsies were done with a high-speed air-turbine biopsy drill, permitting rapid (<1-second) freezing of tissue samples from both nonischemic and ischemic areas, while myocardial pH was measured with a hydrogen ion-selective polymer membrane implanted in the subendocardium. After 3 minutes of pacing tachycardia in dogs with critical coronary stenoses (demand-type ischemia, n = 14), regional systolic function (% segment shortening by ultrasonic crystals) was mildly depressed (from 19 ± 2% control to 13 ± 2% post-pacing, P < 0.01), while left ventricular diastolic pressure-segment length relations shifted upward, indicating decreased distensibility of the ischemic myocardial segment. Associated with these changes in function, subendocardial adenosine triphosphate decreased (from 31.3 ± 1.5 to 27.9 ± 1.0 nmol/mg protein, P < 0.01), as did creatine phosphate (53.8 ± 2.1 to 39.6 ± 2.5 nmol/mg protein, P < 0.01), while myocardial pH declined slightly (ApH = -0.14 ± 0.02, P < 0.01). In contrast, at 3 minutes of coronary artery occlusion (primary ischemia, n = 14), regional segment shortening was replaced by systolic bulging (% shortening decreased from 17 ± 2% to -2 ± 1% during occlusion, P < 0.01), while left ventricular pressure-segment length relations were not shifted upward, and there was no decrease in diastolic distensibility of the ischemic segment. With coronary artery occlusion, subendocardial adenosine triphosphate declined slightly (33.2 ± 0.5 to 29.2 ± 2.0 nmol/mg, P < 0.05), while creatine phosphate decreased substantially (51.1 ± 2.3 to 7.8 ±1.4 nmol/mg protein, P < 0.01). Myocardial pH fell strikingly (ApH = -0.33 ± 0.03, P < 0.01), and the decline was 236% of that seen with demand-type ischemia. Regional myocardial blood flow (microsphere technique) showed a decreased endocardial:epicardial (endo:epi) ratio (1.04 ± 0.04 control vs. 0.40 ± 0.05 during pacing, P < 0.01) and absolute subendocardial flow (1.02 ± 0.47 to 0.47 ± 0.05 ml/min per g, P < 0.01) with demand-type ischemia. However, subendocardial blood flow in demand-type ischemia was still much greater than flow during coronary artery occlusion (0.10 ± 0.03 ml/min per g, P < 0.01). In summary, diastolic dysfunction was prominent during ischemia caused by increased oxygen demand, but was minimal during ischemia due to primary coronary flow reduction of equal duration. The diastolic dysfunction could not be explained simply by adenosine triphosphate depletion, which was modest and similar with both types of ischemia. Protection against diastolic dysfunction in primary ischemia m...

Mechanisms underlying ischemic diastolic dysfunction: relation between rigor, calcium homeostasis, and relaxation rate

“…The results support a mechanism of ATP depletion directly affecting cross-bridge detachment underlying increased diastolic chamber stiffness during ischemia. However, previous studies, including ours (10,23,37), have failed to demonstrate a lower average tissue [ATP] in hearts subjected to either supply or demand ischemia, in which an increase in diastolic chamber stiffness occurred, compared with hearts subjected to similar ischemia, in which no increase in diastolic tension occurred. Thus the degree of diastolic dysfunction sustained failed to correlate with the level of depletion of high-energy phosphates during ischemia (32).…”

Lack of Direct Role for Calcium in Ischemic Diastolic Dysfunction in Isolated Hearts

“…Several studies have demonstrated that subendocardial ischemia is more severe than subepicardial ischemia for a given decrease in CPP. 15,16 Similarly, recent 31 P-NMR studies of isolated hearts subjected to global lowflow ischemia have identified 2 regions of different degrees of acidosis, whereby the extent of increase in LV end-diastolic pressure correlated closely with the size of the more severely acidotic (presumably subendocardial) region. 18 Ultrastructural studies of isolated rabbit hearts subjected to global low-flow ischemia have shown a marked degree of heterogeneity, with some myocytes in rigor juxtaposed to adjacent cells with near-normal ultrastructure.…”

“…14 Our observed decrease in the average myocardial ATP level of 30% to 50% during ischemia, concomitant with an increase in LV end-diastolic pressure, is consistent with rigor formation in the subendocardium, where the decrease in [ATP] would be greater than the average myocardial decrease. 15,16 Metabolic factors might contribute to rigor development at such modest decreases in ATP. Metabolites of the creatine kinase reaction, such as a decrease in CP and an increase in ADP, can affect rigor tension development and stiffness.…”

Contributions of [Ca2+]i, [Pi]i, and pHi to altered diastolic myocyte tone during partial metabolic inhibition.

“…It is possible that this or a similar mechanism accounts for the difference in effects ofdemand vs. supply ischemia on left ventricular compliance. A comparative study of 3-min periods ofsupply ischemia (coronary artery occlusion) and demand ischemia (coronary stenoses with pacing tachycardia) has revealed some metabolic differences that have the potential to affect diastolic compliance (45). Relative to demand ischemia, supply ischemia resulted in greater tissue acidosis (pH decreased -0.33 vs. -0.14 pH U) and a threefold greater decrease in subendocardial creatine phosphate (CP) content (decrease of 43 vs. 14 nmol/mg protein from a preischemic control value of 52).…”