Metabolic response to prolonged reduction of myocardial blood flow distal to a severe coronary artery stenosis.

Abstract

Limited data are available concerning the effects of mild-to-moderate, sustained reductions of coronary blood flow on myocardial aerobic metabolism. This study tested the hypothesis that a sustained flow reduction distal to a severe coronary artery stenosis may be well tolerated (after the initial insult is passed) because of gradual improvement in the balance between myocardial oxygen supply and demand. Studies were performed in eight sedated, closed-chest domestic swine that were instrumented with an artificial coronary arterial stenosis (80% diameter reduction). Hemodynamics, regional myocardial blood flow and oxygen, lactate, acid, and base metabolism were measured before stenosis and at 5, 20, 60, 120, and 180 minutes after stenosis insertion. Regional myocardial function (ultrasonic length sensors) was measured serially during 2 hours in three additional swine. After stenosis placement, endocardial and transmural flows declined (p<0.05) compared with flows before stenosis (from 1.54±0.37 to 0.73 ± 0.24 ml/min/g [mean ± SD] and from 1.44 ± 0.31 to 1.19 ± 0.25 ml/min/g, respectively). Thereafter, flows remained unchanged for the duration of the study. Similarly, prestenosis heart rate (135 ± 7 beats/min), aortic mean pressure (113 ± 17 mm Hg), and tension time index (27.1 ± 3.6 mm Hg * sec) remained constant for the duration of the study. In contrast, regional coronary venous pH declined (p<0.05) compared with prestenosis levels (7.35±0.02) 5 minutes after stenosis (7.28±0.04), but it returned to prestenosis levels during the next hour. Regional coronary venous Pco2 exhibited a similar pattern (i.e., acute increase during poststenosis with gradual return to prestenosis levels). Lactate consumption at prestenosis (36.7 ± 27.3 ,umol/min/100 g) changed to production 5 minutes poststenosis (-80.3 ± 46.8; p<0.05) and then gradually returned toward consumption during the ensuing 3 hours (1.6 ± 10.7 at 180 minutes, p<0.05 vs. 5 minutes). Regional myocardial oxygen consumption declined compared with prestenosis consumption (16.8 ±4.1 ml/min/100 g) at 5 minutes poststenosis (13.7±2.8, p<0.05) and remained unchanged thereafter. Regional shortening declined abruptly immediately after stenosis placement in a separate group of three animals and decreased further until a steady state was achieved 40 minutes after stenosis. Thus, the data demonstrate that metabolic indexes of myocardial ischemia improve over time in a clinically relevant animal model of human ischemic heart disease. Such changes occur in the absence of significant alterations in either regional myocardial blood flow or external determinants of myocardial oxygen demand. The mechanism that is involved likely is related to a time-dependent adjustment in which myocardial oxygen demand declines and stabilizes at a level more appropriate to reduced myocardial oxygen supply. (Circulation 1988;78:729-735) Recent advances in the treatment of patients with ischemic heart disease, notably coronary angioplasty and thrombolysis, at times From

Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning

“…156,157,159 Myocardial creatine phosphate content decreases during the first few minutes of ischemia induced by partial occlusion but then returns toward normal within 60 to 85 minutes. 157,159 Fedele et al 160 showed that within 5 minutes after placement of a partial stenosis in an animal model of acute hibernation (in which necrosis did not occur), there was a significant reduction in anterior interventricular vein pH. However, by 180 minutes after stenosis placement, the pH had recovered to normal.…”

Glucose metabolism distal to a critical coronary stenosis in a canine model of low-flow myocardial ischemia.

“…With this technique, hearts perfused aerobically with [1][2][3][4][5][6][7][8][9][10][11][12][13] C]glucose accumulate [3][4][5][6][7][8][9][10][11][12][13] C]alanine and [4][5][6][7][8][9][10][11][12][13] C]glutamate in proportion to rates of glycolysis and glucose-supported TCA cycle activity, respectively (18). Furthermore, the steady state [4][5][6][7][8][9][10][11][12][13] C] glutamate/ [3][4][5][6][7][8][9]…”

“…Under these conditions, intracellular pools of glucose metabolites reach steady state 13 C enrichments which are lower than plasma glucose, and whose absolute value is determined by the relative contributions of plasma glucose, versus other precursor molecules, to the pool. Thus, the cytosolic pyruvate pool accumulates [3][4][5][6][7][8][9][10][11][12][13] C]pyruvate in proportion to the fraction of total glycolytic substrate supplied by exogenous 13 C-glucose, relative to other carbon sources (e.g.,…”

Response of high-energy phosphates and lactate release during prolonged regional ischemia in vivo.

“…Recent investigations of prolonged myocardial ischemia, a potential model of hibernating myocardium, have demonstrated initial depression and subsequent metabolic recovery by some measures despite persistently depressed myocardial blood flow and function.4,5 Specifically, lactate production has been noted to increase initially and then decrease during prolonged ischemia in the perfused heart6 and the intact pig. 4 Although it has been shown that phosphocreatine (PCr) concentrations return to normal during 1 hour of mild ischemia, 5 prolonged ischemia has been shown to reduce ATP levels in proportion to the degree of flow reduction. 5,7 Thus, the effect of prolonged ischemia on tissue phosphates has not been adequately defined, and it is unknown whether changes in high-energy phosphates are dissociated from, or parallel, changes in lactate metabolism.…”