Postischemic Myocardium Research Articles

Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction.

We investigated myocardial perfusion dynamics after thrombolysis and its clinical implications. We studied 39 patients with acute anterior myocardial infarction (AMI). Myocardial contrast echocardiography (MCE) was performed before and immediately after successful reflow with intracoronary injection of sonicated Ioxaglate. The average segmental score by two-dimensional echocardiography (graded 0, normal, to 3, akinetic/dyskinetic) and global ejection fraction (left ventricular ejection fraction, LVEF%) by left ventriculography were measured at 1 day and at 4 weeks after reflow. Hypokinesis in the infarct region was assessed by the centerline method and expressed in terms of standard deviations (regional wall motion [RWM]: SD/chord) of normal. Immediately after reflow, 30 of 39 patients (group A) showed significant contrast enhancement within the risk area. The other nine patients (23%, group B), however, showed the residual contrast defect in the risk area (myocardial no reflow). There were no significant differences in the elapsed time, angiographic collateral grade, and degree of residual stenosis between group A and group B. Before reflow, both groups exhibited similar levels of global and regional left ventricular function. Improvement in global (LVEF, average segmental score) and regional left ventricular function was greater in group A than in group B (average segmental score, 0.44 +/- 0.41 versus 0.97 +/- 0.36, p less than 0.01; LVEF, 56.4 +/- 13.4 versus 42.7 +/- 8.9, p less than 0.05; RWM, -1.87 +/- 0.85 versus -3.18 +/- 0.52, p less than 0.005). MCE demonstrates that angiographically successful reflow cannot be used as an indicator of successful myocardial reperfusion in AMI patients. The residual contrast defect in the risk area demonstrated immediately after reflow is a predictor of poor functional recovery of the postischemic myocardium.

Increase in myofilament separation in the “stunned” myocardium

This study explores the effects of ischemic reperfusion injury on the radial separation distance between thick and thin myofilaments. The left anterior descending coronary artery was occluded for 5 mins and reperfused for 10 mins twelve times repetitively in 6 dogs. At the end of a final 90 min reperfusion period, the hearts were fixed by perfusion with glutaraldehyde, and subepicardial and subendocardial tissue from both normal and ischemic areas were prepared for transmission electron microscopy. Quantitative analysis of inter-filament distance (IFD) was performed on micrographs of transverse sections. The center-to-center IFD was calculated from the numerical density of thick filaments at the A band level using a hexagonal array conversion formula. Sarcomere length was measured on micrographs of longitudinal sections. The results showed that center-to-center thick IFD in the stunned subendocardium was 43.9 ± 0.8 nm which was significantly greater than the control distance of 40.6 ± 0.4 nm ( P<0.001) from normal zone tissue. Thick IFD in the subepicardium was also significantly different: 43.4 ± 0.6 nm in the stunned tissue as compared with 39.0 ± 0.7 nm in the non-ischemic tissue ( P<0.001). Sarcomere length in the normally perfused subendocardium was 2.01 ± 0.07 μm and was increased to 2.20 ± 0.08 μm in the stunned subendocardium ( P<0.005). Sarcomere length in the normal and the stunned subepicardium was also different: 2.02 ± 0.04 vs. 2.10 ± 0.09 μm ( P<0.005). The significant increase in spatial separation between the contractile filaments may affect optimal cross-bridge force generation at the molecular level. Myocardial performance in stunned myocardium is likely to be affected by these geometric alterations. The longer “unstressed” sarcomere lengths in stunned myocardium are suggestive of cytoskeletal abnormalities in the post-ischemic myocardium.

Measurement of regional glucose metabolic rates in reperfused myocardium

Regional myocardial glucose utilization was measured with [18F]fluorodeoxyglucose (FDG) and positron emission tomography in normal and postischemic tissue after 3 h of intracoronary balloon occlusion in closed-chest chronically instrumented anesthetized dogs. Estimates of glucose metabolic rates were made using the Sokoloff model, assuming the lumped constant to be unchanged in reperfused tissue. Myocardial sectors were classified as normal, reversibly injured, or infarct containing based on occlusion blood flow images and postmortem histology. Occlusion flow, measured by microspheres, was reduced by 38% in reversibly injured and 74% in infarct-containing sectors, recovering to 91 and 66%, respectively, 1 h postreperfusion. One month postreperfusion, flow was normal in reversibly injured sectors but remained depressed at 60% in infarct-containing sectors. Glucose utilization at baseline was homogeneous, averaging 0.8 mumol.g-1.min-1. After 3 h of reperfusion following occlusion of the left anterior descending coronary artery, regional glucose metabolic rate was increased 60% relative to baseline in normal myocardium but not in postischemic sectors, leading to an enhancement of FDG uptake in normal relative to postischemic myocardium. At 24 h postreperfusion, the glucose metabolic rate decreased in normal remote tissue to 46% of baseline levels, probably reflecting increased plasma free fatty acid levels, but was not significantly altered in reversibly injured myocardium, leading to enhanced FDG uptake in reversibly injured relative to normal myocardium. Subsequently, glucose metabolism in normal and postischemic sectors was not significantly different. Prolonged relative enhancement of glucose metabolic rate in postischemic tissue was found when the glucose metabolic rate in normal myocardium was low. Myocardial glucose utilization correlated with hg, the rate constant for FDG phosphorylation under all conditions (r = 0.88).

Coronary pressure-flow, pressure-function, and function-myocardial oxygen consumption relations in postischaemic myocardium

The aim was to study coronary pressure-flow, pressure-myocardial wall motion and myocardial wall motion-myocardial oxygen consumption relations in postischaemic myocardium with prolonged myocardial dysfunction (stunned myocardium) in comparison with normal myocardium. Regional myocardial wall thickening was measured with ultrasonic crystals, and postischaemic myocardial dysfunction was achieved by occlusion of a carotid-left anterior descending coronary artery bypass (15 min) and reperfusion (30 min). Coronary perfusion pressure was decreased in 10 mm Hg steps by constricting the bypass before and after producing postischaemic myocardial dysfunction. At each constriction step, coronary flow, regional wall thickening, and regional myocardial oxygen consumption in the area perfused by the left anterior descending artery were measured. 12 anaesthetised open chest mongrel dogs, weighing 12-16 kg, were studied. At the basal level, myocardial wall thickening of postischaemic myocardium was depressed compared to normal myocardium, at 18.5(SD 8.9)% v 1.3(7.1)%, p less than 0.01. With coronary stenosis, wall thickening gradually decreased at a coronary pressure below 60 mm Hg in normal myocardium, but remained unchanged until mean coronary pressure was reduced to 50 mm Hg in postischaemic myocardium. Myocardial wall thickening of postischaemic myocardium was always more depressed than normal myocardium. At any level of coronary pressure, coronary flow in postischaemic myocardium was not different from normal myocardium. There was no difference in regional myocardial oxygen consumption between normal and postischaemic myocardium at any level of coronary pressure. However, regional myocardial oxygen consumption in postischaemic myocardium was higher than in normal myocardium performing similar levels of myocardial wall thickening. The coronary pressure-function relation but not the pressure-flow relation changed in postischaemic myocardium after a 15 min coronary occlusion. Regional myocardial oxygen consumption was relatively increased in postischaemic myocardium.

Altered Load Dependence of Postischemic Myocardium

Intermittent myocardial ischemia can produce areas of postischemic ("stunned") myocardium in the heart of the human with coronary artery disease. These areas are no longer ischemic, but have diminished contractile performance. Although the effects of loading conditions on systolic contraction of normal, ischemic, and failing myocardium have been investigated in great detail, the way in which load affects contraction of postischemic myocardium is not known. The aim of this study was to determine in anesthetized dogs how loading conditions affect the systolic function of a region of myocardium after 10 min of ischemia and 1 h of reperfusion. Sets of piezoelectric crystals were implanted in a test zone and in a remote zone of myocardium. Measurements of systolic wall thickening were made during nine combinations of left atrial pressure (3, 6, and 9 cmH2O) and mean arterial pressure (70, 90, and 110 mmHg). One set of measurements was made under baseline conditions, and a second set was made after 10 min of coronary occlusion and 1 h of reperfusion. Ischemia and reperfusion reduced wall thickening in the test zone 36 +/- 3% and diminished the response to increases in preload. In contrast, the response of the test zone to changes in afterload was unchanged. An interaction between the test zone (in which depressed contraction was observed) and the surrounding myocardium (in which enhanced function was observed) produced the appearance of a regional wall motion abnormality as afterload increased. These results emphasize that the load dependence of postischemic myocardium differs from that of normal myocardium and must be taken into account in clinical studies in which regional contraction is used to monitor the heart for ischemia.

Increased sensitivity of postischemic myocardium to negative inotropic effects of Na + -antagonistic drugs

Increased sensitivity of postischemic myocardium to negative inotropic effects of Na + -antagonistic drugs

The relationship between regional blood flow and contractile function in normal, ischemic, and reperfused myocardium

The prevailing paradigm of coronary physiology and pathophysiology is that a balance between blood flow (i.e., supply) and function (i.e., demand) exists under normal conditions and that an imbalance between supply and demand occurs during ischemia. However, this paradigm is derived largely from studies relating changes in total coronary inflow to global ventricular function. The present article examines the relationship between myocardial blood flow and function on a regional level and proposes that a change may be needed in the current paradigm of coronary pathophysiology. In normal myocardium, considerable heterogeneity of regional blood flow exists, indicating either similar heterogeneity of metabolic demand and function or questioning the precision of metabolic coupling between flow and function. After the onset of ischemia, a transient imbalance between the reduced blood flow and function may exist. However, myocardial function rapidly declines and during early steady-state ischemia regional myocardial blood flow and function are once again evenly matched. Such supply-demand balance may persist over prolonged periods of ischemia enabling the myocardium to remain viable through reduction of energy expenditure for contractile function, i.e., to "hibernate". Whereas in "hibernating" ischemic myocardium, regional myocardial blood flow and function are both reduced but appropriately matched to one another, flow and function appear to be largely uncoupled in reperfused "stunned" myocardium. The clinical identification of viable but ischemic (hibernating) and postischemic (stunned) myocardium is of utmost importance in patients undergoing reperfusion procedures. A new paradigm of coronary and myocardial pathophysiology, encompassing a regional as well as a global view of perfusion and function, will have to include explanations for phenomena such as myocardial hibernation and myocardial stunning.

Effects of the New Class-III Antiarrhythmic Drug D-Sotalol on Contractile Function of Postischemic Myocardium

The hemodynamic effects of the new class-III antiarrhythmic drug D-sotalol (2 mg/kg i.v.) on postischemic myocardium were investigated in comparison with the actions of the racemic D,L-sotalol (2 mg/kg i.v.) in rats. Drug infusion (7 min) was started 20 min after 3 x 4 min of global ischemic injury (oxygen deficiency). The left ventricular isovolumic pressure-generating capacity at the beginning of infusion was reduced by 15%, indicating postischemic dysfunction. Infusion of D-sotalol caused a highly significant (p less than 0.01) reduction of the left ventricular pressure-generating capacity (to 58 +/- 5%), as well as of the dp/dtmax (to 21 +/- 3%). Stroke volume (to 66 +/- 6%), ejection fraction (to 62 +/- 7%), and cardiac output (to 51 +/- 6%) were also decreased (p less than 0.01). Fifteen minutes after infusion a partial renormalization of the hemodynamic measures (dp/dtmax 41 +/- 5%; stroke volume 94 +/- 8%) was observed. Infusion of the racemic D,L-sotalol caused similar hemodynamic changes (left ventricular pressure-generating capacity 60 +/- 2%, dp/dtmax 25 +/- 2%), indicating its cardiodepressant action. In contrast to prior findings on normal myocardium, our present results indicate that D-sotalol, a potential new class-III antiarrhythmic drug, has a considerable negative inotropic effect on postischemic myocardium.

Diltiazem at reperfusion reduces neutrophil accumulation and infarct size in dogs with ischaemic myocardium

The aim was to demonstrate the ability of diltiazem to protect the ischaemic myocardium in the course of coronary reperfusion, and to establish if an interaction with neutrophils is implied. Ischaemia was induced by occluding the left anterior descending coronary artery for 90 min followed by 6 h of reperfusion with a residual critical stenosis left in place. Three groups were studied: group 1 (control) received a saline perfusion; group 2 was given a bolus injection of 400 micrograms.kg-1 of diltiazem 10 min before reperfusion, followed by 4 micrograms.kg-1.min-1 perfusion until termination of experiment; group 3 was made neutropenic by injecting a neutrophil antiserum produced in rabbits and was then treated with diltiazem, as in the second group. 60 mongrel dogs of either sex were allocated at random into one of the three groups the day before the experiment. Diltiazem plasma concentrations ranged from 68.6(SEM 10.0) to 102.5(15.2) micrograms.litre-1 during the study. Transmural collateral blood flow, measured with 153Gd microspheres 15 min after occlusion, and area at risk, evaluated by Evans blue perfusion, did not differ among the three groups. Infarct size, estimated by triphenyltetrazolium staining of heart slices and expressed as a percentage of area at risk, was less (p less than 0.05) in the diltiazem [20.5(5.2)%] and diltiazem plus neutropenia [17.6(5.4)%] groups compared to controls [39.8(6.9)%] but neutropenia added no significant benefit to diltiazem alone. The animals treated with diltiazem alone had lower serum creatine kinase levels than controls, at 5719(891) v 14,333(2885) IU.litre-1, p less than 0.05. The neutrophilia seen in controls was virtually absent in diltiazem dogs. Myocardial neutrophil accumulation estimated by scintigraphy of 111In labelled autologous neutrophils was much less in diltiazem than in control dogs, at 3948(1228) v 11,021(2081) 111In-neutrophil.g-1 of infarct, p less than 0.02. Diltiazem given during reperfusion reduces infarct size by a mechanism that includes an inhibition of neutrophil accumulation in the post-ischaemic myocardium.

Gas chromatographic-mass spectrometric analysis of lipoxygenase products in post-ischemic rabbit myocardium

Leukotriene B 4 (LTB 4) is a potent chemotactic compound for neutrophils and is thought to be an important mediator of myocardial ischemia-reflow injury. We have measured LTB 4 in rabbit cardiac tissue following ischemia-reflow using a sensitive and specific gas chromatographic-mass spectrometric (GC-MS) assay. The concentration of LTB 4 in rabbit myocardium following 45 min ischemia and 3 h reflow was 48.7 ± 12.5 pg/g, significantly higher than in non-ischemic tissue from the same animal (17.5 ± 3.9 pg/g). These concentrations were at least an order of magnitude lower than previously reported values assessed by radioimmunoassay (RIA). Compared with the GC-MS method, RIA greatly overestimated LTB 4 concentrations in cardiac tissue. The capacity of post-ischemic myocardium to produce lipoxygenase products, LTB 4, 5-, 12- and 15-HETEs was also assessed following incubation of myocardium ex vivo with calcium ionophore. In all animals ischemic cardiac tissue produced greater amounts of LTB 4, 5-, and 12-HETEs than non-ischemic myocardium and 12-HETE was the major product. Neutrophils that have accumulated in the injured tissue may be a major source of these products. However, in contrast to cardiac tissue, isolated rabbit neutrophils stimulated with A23187 produced 5-HETE as the major product with very little 12-HETE formed. These latter findings suggest that cells other than neutrophils may contribute to the production of lipoxygenase products during myocardial ischemia-reflow injury.

Effects of nisoldipine on recovery of coronary blood flow, sarcoplasmic reticulum function and other biochemical parameters in post-ischaemic porcine myocardium

The effects of nisoldipine (0.1 μg/kg/min; n = 9) or its solvent ( n = 9) were studied in pigs, in which left anterior descending coronary artery (LADCA) blood flow in both groups was reduced to 20% of baseline for 60 min and reperfused for 2 hr. Infusions were started at 30 min of ischaemia and lasted throughout reperfusion. In both groups, flow reduction abolished regional contractile function and caused similar decreases in the level of creatine phosphate (CP; by 70%) and the energy charge (from 0.91 to 0.69), mean arterial blood pressure (by 25%), LVdP/d t max (by 30%) and cardiac output (by 30%). During ischaemia LADCA blood flow slightly increased (from 14 ± 8 to 24 ± 6mL/min/ 100 g; P < 0.05) in the nisoldipine-treated animals, resulting in an increase in CP to 91 ± 24% of baseline and preventing further decreases in energy charge, as observed in the solvent-treated animals. After 2 hr of reperfusion in neither group return of contractile function of the post-ischaemic myocardium was observed. Post-ischaemic blood flow in the nisoldipine-treated pigs increased from 24 ± 6 mL/min/100 g to 76 ± 14 mL/min/100 g and from 19 ± 6 mL/min/100 g to 41 ± 6 mL/min/100 g in the solvent-treated animals (P < 0.05) after 2 hr of reperfusion. Myocardial work was significantly higher in the nisoldipinetreated animals (111 ± 15 mmHg.L/min as compared to 69 ± 14 mmHg.L/min in the solvent-treated pigs after 2 hr of ischaemia). The energy charge of the post-ischaemic myocardium was similar for both groups (0.84 ± 0.02 for the nisoldipine-treated and 0.83 ± 0.03 for the solvent-treated animals). The rate of sarcoplasmic reticular Ca 2+ uptake of the non-ischaemic segment of the nisoldipine-treated animals was 61% higher (P < 0.05) than that of the solvent-treated animals. In the post-ischaemic myocardium similar rates of Ca 2+ uptake were found in both groups, but the activities were markedly lower as compared to the non-ischaemic myocardium. It is concluded that nisoldipine increases blood flow during reperfusion, which may have been caused by coronary vasodilatation. However, attenuation of the “no-reflow” phenomenon also contributed, since more rapid rephosphorylation of ADP leading to an increase in CP during ischaemia may have preserved jeopardized cells. Moreover, nisoldipine increases the sarcoplasmic reticular Ca 2+ pump activity independent of ischaemia, which may have contributed in reducing the Ca 2+ overload.

Ventricular wall motion and NE release in post-ischemic reperfused myocardium.

To clarify the relationship between post-ischemic myocardial dysfunction and local cardiac sympathetic nerve function, we measured regional myocardial length and norepinephrine (NE) release during sympathetic nerve stimulation in 32 mongrel dogs. Coronary occlusion was produced by balloon occluder for 15 min and reperfused for 60 min. Dogs were divided into 3 groups as follows; Group 1 (n = 14): Sympathetic nerve stimulation, Group 2 (n = 9): Pre-treatment with yohimbine hydrochloride (0.2 mg/kg) and sympathetic nerve stimulation, Group 3 (n = 9): Exogenous NE administration. Sympathetic nerve stimulation or NE infusion were performed before occlusion and after reperfusion. In group 1, the extent of the increase in systolic shortening during sympathetic nerve stimulation (delta - shortening) lowered at 5 min after reperfusion and augmented progressively. But, delta-shortening at an early reperfusion period did not reduce in group 2 and 3. NE release from the ischemic myocardium decreased in group 1 and did not recover for 60 min. When the cardiac sympathetic nerve was denervated with 90% phenol solution, NE release further decreased in group 1. On the other hand, NE release did not decrease in group 2. These results indicate that the response to sympathetic nerve stimulation decreased in post-ischemic reperfused myocardium and this was due to diminished NE release. It was considered that sympathetic nerve conduction was not completely impaired in post-ischemic myocardium and pre-synaptic alpha-2 receptor mediated negative feedback mechanism would play an important role in these diminished NE release.

Relation of change in wall motion and glucose metabolism after coronary artery bypass grafting. Assessment with positron emission tomography.

Regional myocardial glucose metabolism was assessed by positron emission tomography (PET) in stunned myocardium. PET perfusion and metabolic imaging using N-13 ammonia and F-18 deoxyglucose (FDG) was performed before and 5-7 weeks after coronary artery bypass grafting (CABG) in 23 patients with coronary artery disease. Of 22 asynergy segments showing increased FDG uptake preoperatively, the postoperative PET showed a decrease in FDG uptake in 16 segments (73%) and persistent uptake in 6 segments (27%). The improvement in asynergy was observed in all of the segments showing postoperative decrease in FDG uptake, while it was observed in only 50% of those with persistent FDG uptake (p less than 0.01). On the other hand, 4 of 5 segments showing a new FDG uptake postoperatively revealed deterioration of wall motion abnormality. These data suggest that an increase in exogenous glucose utilization may often persist in postischemic myocardium. Improvement in regional function seems to be associated with the improvement in metabolic abnormality after CABG.

Improvement of postischemic contractile dysfunction of dog heart by MC1-154, a novel cardiotonic agent

The effects of MC1-154, a cardiotonic agent which has direct effects on cardiac myofilaments, on postischemic contractile dysfunction were studied in dog heart subjected to a 30-min occlusion of the left anterior descending coronary artery followed by reperfusion, and compared with the effects of milrinone and dobutamine, that have largely cyclic AMP-dependent mechanisms of action. Regional myocardial contractility (segment shortening) and tissue ATP levels were severely depressed in reperfused myocardium. MCI-154 (0.3 and 1 μg/kg per min) improved the regional function of postischemic myocardium and decreased left ventricular end-diastolic pressure and systemic aortic pressure when infused i.v. from 30 min after reperfusion. The improvement of regional function caused by MCI-154 (1 μg/kg per min) was more pronounced than that caused by milrinone (1 μg/kg per min) or dobutamine (1 μg/kg per min), although the drugs produced an equal increase in cardiac performance (peak positive left ventricular dP/dt). These results suggest that MCI-154 produces a more pronounced improvement of regional myocardial function than milrinone and dobutamine, presumably by increasing the responses of the contractile protein system to Ca 2+. In this respect, MCI-154 would be of much benefit for the treatment of postischemic left ventricular dysfunction.

Evidence for decreased coronary flow reserve in viable postischemic myocardium.

To try to unravel the complexity and heterogeneity of the "no-reflow" phenomenon and its underlying mechanisms, we studied tissue perfusion in reperfused heart muscle by using tracer microspheres in an anesthetized dog model of 90-minute coronary occlusion followed by reperfusion for 2 1/2 hours, 24 hours, or 1 week. Regional myocardial blood flow was determined both in basal flow conditions and during reactive hyperemia. The effect of intracoronary adenosine administration was examined, and the ultrastructure of postischemic myocardium was analyzed. In viable reperfused tissue (as delineated by triphenyltetrazolium chloride staining), reflow in basal conditions is unimpaired. Coronary flow reserve (as approximated by peak reactive hyperemic flow) is intact at the start of reperfusion, decreases by more than half after 2 1/2 hours, and recovers completely within 1 week. This impairment of coronary reserve can be relieved by intracoronary adenosine administration. On ultrastructural examination, the capillaries are patent. On the other hand, in irreversibly damaged myocardium, both the basal reflow impairment and the decrease in coronary flow reserve are severe and permanent. Coronary flow reserve is already decreased at the start of reperfusion, and the pharmacological intervention has no beneficial effect. Ultrastructurally, extracellular and intracellular edema invariably are present, whereas the vascular endothelium is damaged and the capillaries are packed with red blood cells. We conclude that the no-reflow phenomenon (i.e., mechanical obstruction to blood flow) is limited to infarcted tissue. In viable myocardium, however, coronary flow reserve is transiently diminished, probably because of washout and subsequent insufficient availability of the chemical mediator adenosine after breakdown and slow recovery of the precursor ATP pool.

Epinephrine-stimulated contractile and metabolic reserve in postischemic rat myocardium

Recovery of contractile function and of fatty acid oxidation may be delayed in viable postischemic myocardium. To determine whether a metabolic reserve is preserved after reperfusion of reversibly injured myocardium, we studied the effect of epinephrine on myocardial fatty acid oxidation in isolated rat hearts perfused retrogradely with erythrocyte enriched buffer containing albumin 0.4 mM, palmitate 0.4 mM, and glucose 11 mM. Hearts were subjected to 60 min of low-flow ischemia (5% of control flow) followed by 60 min of reperfusion. Five minutes following the onset of reperfusion, developed left ventricular pressure (DLVP) and oxidation of palmitate were reduced to 53% (p less than 0.01) and 46% (p less than 0.01), respectively, of values measured in nonischemic control hearts. Subsequently, DLVP and oxidation of palmitate gradually recovered to 78% (NS) and 91% (NS) by 60 min of reperfusion. Epinephrine 5.10(-1) M elicited an immediate stimulation of both contractile function and palmitate oxidation. Early after reperfusion stimulated DLVP and palmitate oxidation were still lower compared to values measured in control hearts exposed to the same concentration of epinephrine. Later than 15 min after the onset of reperfusion the response of DLVP and of palmitate oxidation to epinephrine no longer differed between control and reperfused hearts. These results indicate that viable postischemic myocardium exhibits a remarkable oxidative metabolic reserve. The observation provides further evidence for the view that impairment of myocardial energy production is not responsible for contractile dysfunction early after reperfusion.

Abnormal regulation of ATP synthesis during increased workload in postischemic myocardium R.W. Jeremy, V.P. Chacko, L.C. Becker. Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD, U.S.A.

Abnormal regulation of ATP synthesis during increased workload in postischemic myocardium R.W. Jeremy, V.P. Chacko, L.C. Becker. Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD, U.S.A.

Measurement of ATP synthesis rates by 31P‐NMR spectroscopy in the intact myocardium in vivo

The ability to measure ATP synthesis rates using 31P-NMR spectroscopy is demonstrated in the normal, ischemic, and postischemic myocardium in vivo. Cardiopulmonary bypass (CBP) was employed to induce 20 min of global myocardial ischemia, and to conduct magnetization transfer measurements during the ischemic episode and following reperfusion and return to normal circulation. For the first few minutes of ischemia, transfer of magnetization from ATP gamma to Pi was extensive and the resultant fractional reduction (delta M/M0) in the Pi resonance intensity reached approximately 100%. Subsequent to reperfusion and stabilization off CPB and on normal circulation, both the fractional reduction and the spin-lattice relaxation time, T1*, of the Pi resonance were determined when ATP gamma spins were saturated. Under these conditions, the unidirectional ATP synthesis rate was 0.41 +/- 0.09 (SEM, N = 4) mumol/s/g wet wt. The data suggest that in the canine myocardium in vivo, glycolytic enzymes mediate a very rapid exchange between Pi and ATP gamma-phosphates during early phases of ischemia; in the postischemic reperfused myocardium, however, the glycolytic contribution to the unidirectional Pi----ATP rate measured by NMR in vivo is relatively small compared to that observed in glucose-perfused, postischemic rat hearts.

Excitation-contraction coupling in postischemic myocardium. Does failure of activator Ca2+ transients underlie stunning?

To elucidate the mechanism of contractile dysfunction in postischemic ("stunned") myocardium, time-resolved measurements of intracellular free Ca2+ concentration ([Ca2+]i) were made using gated 19F nuclear magnetic resonance in seven perfused ferret hearts loaded with the fluorinated Ca2+ indicator 5F-BAPTA. Left ventricular developed pressure decreased to 65 +/- 3% (mean +/- SEM) of control after 15 minutes of global ischemia at 37 degrees C. In stunned myocardium, diastolic [Ca2+]i (0.24 +/- 0.03 microM) was not changed from control (0.18 +/- 0.03 microM, p greater than 0.10), but peak [Ca2+]i (1.03 +/- 0.13 microM) was paradoxically higher than that in control (0.61 +/- 0.06 microM, p less than 0.02). The slope of the relation between developed pressure and Ca2+ transient amplitude in stunned myocardium was significantly lower than that in control (p less than 0.05), even after normalization by maximal Ca2(+)-activated pressure. These results indicate that contractile failure in stunned myocardium is due to a decrease in the myofilament sensitivity to Ca2+ as well as to the previously identified decrease in maximal Ca2(+)-activated force; failure of activator Ca2+ delivery cannot be implicated. The increase in the amplitude of Ca2+ transients would require that more ATP be spent in Ca2+ sequestration; thus, decreased efficiency of energy utilization in stunned myocardium would result.

The oxygen consumption paradox of “stunned myocardium” in dogs

The contractile state of the heart is a major determinant of myocardial oxygen consumption. Since regional myocardial contractility can be severely impaired following a transient coronary occlusion, post-ischemic myocardium is frequently assumed to consume less oxygen. To test this assumption, regional myocardial function and oxygen consumption were studied in anesthetized dogs during 2 h of myocardial reperfusion following either a 15-min (Group I) or 4-h (Group II) left anterior descending coronary artery occlusion. Both groups developed similar post-ischemic regional dysfunction characterized by paradoxical motion (negative shortening). Measured as a percent of baseline segment shortening, anterior wall function in Group I (n = 8) and Group II (n = 5) at 30 min of reperfusion was -33 +/- 11% and -34 +/- 16% (p = NS) and at 120 min was -23 +/- 9% and -40 +/- 16% (p = NS). However, the two groups showed a marked difference in regional myocardial oxygen consumption during reperfusion. Despite the abnormal wall motion, regional oxygen consumption in Group I at 30 and 120 min of reperfusion was unchanged from pre-ischemic levels as measured as a percent of baseline: 104 +/- 20% (p = NS) and 111 +/- 21% (p = NS). In contrast, regional oxygen consumption in Group II was markedly depressed from baseline at 30 and 120 min of reperfusion: 42 +/- 7% (p less than .01) and 40 +/- 8% (p less than .01). To determine whether the dissociation between regional myocardial oxygen consumption and function in Group I was related to mitochondrial uncoupling, six additional dogs were studied. Tissue samples were obtained from post-ischemic myocardium after 120 min of reperfusion following a 15-min coronary artery occlusion, and compared to non-ischemic myocardium. There were no differences in the in vitro mitochondrial respiratory rates or oxidative phosphorylation capacity between the post-ischemic and non-ischemic myocardium. Therefore, in the post-ischemic myocardium, significant depressions in regional contractility may not be associated with falls in oxygen consumption. Following a 15-min coronary artery occlusion, the injured myocardium maintains a paradoxically high oxygen consumption with normal mitochondrial function despite decreased contractility and abnormal wall motion.