Certain patients with coronary artery disease (CAD) may have neither ST depression nor chest pain during exercise despite the presence of myocardial ischemia. The frequency and characteristics of such electrocardiographically and symptomatically silent ischemia were studied in 171 patients with both angiographically documented CAD and scintigraphically documented ischemia. Fifty-six (33%) of 171 patients had neither ST depression nor chest pain (Group N), and 115 (67%) had ST depression and/or chest pain (Group P). The two groups were similar with respect to age, gender. the prevalence of prior infarction. and peak systolic blood pressure. Group N patients, however, had a higher mean peak heart rate and rate-pressure product, less severe scintigraphic ischemia. a lower lung thallium-201 uptake, and a smaller number of diseased vessels. Stepwise discriminant analysis showed a history of effort angina, lung thallium-201 uptake. and scintigraphic severity of ischemia to be significant discriminators between Groups N and P. In conclusion, electrocardiographically and symptomatically silent ischemia may be common during exercise in patients with CAD, and less severe ischemia may be one of important determinants.

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We studied alterations in respiratory activity of mitochondria (Mt) in non-infarcted myocardium (NIZ) under severe pump failure complicated by acute myocardial infarction (AMI). Dogs in which AMI was induced were divided into two groups; one in which left ventricular systolic pressure (LVPs) was maintained higher than 70% of preligation level (ND group); and one in which LVPs was diminished to less than 70% (D group). Regional myocardial blood flow (MBF) in NIZ reduced significantly in proportion to decreases in LVPs and cardiac output (CO). State -III activity and RCR decreased in proportion to reductions in MBF. LVPs, and CO in Mt from NIZ of D group. Complex-I and DNP-stimulated ATPase activities were also reduced in NIZ of D group. Morphologic studies revealed slight swelling and fusion of mitochondria in NIZ cells of D group, but no changes such as the appearance of a dense deposit indicating ischemic damage were seen. Pump failure in AMI is likely to be caused partly by impaired function of Mt in NIZ induced by hypoperfusion. Improvement of metabolic impairment in NIZ is important in the treatment of pump failure.

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The present study was designed to examine whether activation of Na⁺/H⁺ exchange and subsequent massive Ca²⁺ influx via Na⁺/Ca²⁺ ex-change are involved in the pathogenesis of myocardial reperfusion injury. We tested the effects of 1 mM amiloride, which is known to inhibit both Na⁺/H⁺ and Na⁺/Ca²⁺ exchange, and 3 μM 5-(N-ethyl-N-isopropyl) amiloride (EIPA), which is known to act as a specific inhibitor against Na⁺/H⁺ exchange, on the incidence of ventricular arrhythmias, isovolumic left ventricular function and creatine kinase (CK) release during reperfusion after 15 or 30 min of global ischemia in the isolated and perfused guinea pig heart. Treatment of a normally perfused heart with amiloride decreased heart rate significantly and tended to increase coronary flow and left ventricular developed pressure (LVDP), whereas treatment with EIPA decreased all of these 3 measurements significantly. Treatment with amiloride or EIPA for 15 min before ischemia, and during reperfusion after 15 min of ischemia, under electrical pacing at 240 rpm to eliminate a negative chronotropic effect abolished ventricular tachycardia (VT) and ventricular fibrillation (VF) during reperfusion associated with highly significant inhibition of increases in left ventricular end-diastolic pressure (LVEDP) and CK release. Amiloride or EIPA pretreatment also inhibited the incidence of VF and increases in LVEDP and CK release significantly during reperfusion after 30 min of ischemia. However, amiloride was more effective in preventing these events than EIPA. The treatment with amiloride or EIPA only during reperfusion after 15 or 30 min of ischemia also decreased the incidence of VF and inhibited the increases in LVEDP and CK release significantly, though less effectively than the pretreatment modality. These results suggest that EIPA prevents ventricular arrhythmias, contracture and myocardial cellular injury during reperfusion after 15 min of ischemia by inhibiting Na⁺/H⁺ ex-change, while amiloride exerts more powerful protection against these events than EIPA during reperfusion after 30 min of ischemia by inhibiting both Na⁺/H⁺ and Na⁺/Ca²⁺ exchange.

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We investigated the vasodilator effects of captopril (CAP) on the systemic capacitance and resistance vessels by measuring changes in the mean circulatory pressure (MCP) and total peripheral resistance (TPR) that occurred in response to the intravenous injection of CAP (1mg/kg) in open-chest dogs. The following five groups of dogs received CAP: (1) Group of untreated dogs. (2) TSA Group in which the dogs were subjected to total spinal anesthesia (TSA). (3) Ang II Group in which the dogs received a continuous intravenous infusion of angiotensin II (Ang II). (4) APR+Ang II Group in which the dogs received a continuous intravenous infusion of Ang II after pretreatment with aprotinin (APR, 25.000 K.I.E.). a kallikrein inhibitor. and (5) IND+APR+Ang II Group in which the dogs received a continuous intravenous infusion of Ang II after pretreatment with indomethacin (IND, 5mg/kg), a prostaglandin synthesis inhibitor, and APR. 1) CAP significantly decreased TPR and MCP in the untreated Group. 2) CAP significantly decreased TPR and MCP in the TSA Group. There were no significant differences in percentage change of TPR (%ΔTPR) and percentage change of MCP (%ΔMCP) between the untreated and TSA Groups. 3) In the Ang II Group. CAP decreased the elevated TPR significantly. but hardly affected the elevated MCP. 4) CAP significantly decreased TPR without significant change in MCP in the APR+Ang II Group. The%ΔTPR was significantly smaller in this Group than in the Ang II Group. 5) CAP significantly decreased TPR without significant change in MCP in the IND+APR+Ang II Group. The %ΔTPR was significantly smaller in this Group than in the Ang II Group. When one compares the arterial system with the venous system, this study suggests that the kinin-kallikrein system activating action of CAP partly contributes to its vasodilator action on the systemic resistance vessels.

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In order to understand the pathophysiology of myocardial stunning, reversibility, accumulation and continuity of ischemic myocardial damage after reperfusion should be studied. Then, to analyze these three factors, myocardial function, metabolism and morphology under ischemia and reperfusion were studied in anesthetized, open-chest dogs. When myocardial ischemia was induced by occlusion of the left anterior descending coronary artery, percentage regional systolic shortening (%SS) of ischemic myocardium sharply decreased and became stable 10min after occlusion. After reperfusion, ischemic myocardium showed active shortening after within 30-min occlusion, but did not after more than 60-min occlusion. During 90-min of ischemia, extracellular K⁺ concentration (Ke) steeply increased for first 10min and was almost stable for next 10min. Then, Ke straighthy in-creased till 90min. Metabolic rates, calculated from myocardial tissue CO₂ and pH, steeply increased for first 20min and sharply decreased for next 10min. After 30min, these two variables were almost stable, near zero. By electron-microscopy with cytochemistry, distribution of Na/K ATPase to myocardial cell membrane was observed to be almost after 15-min occlusion but distinctly sparse with destruction of cell membrane after 30-min occlusion. Therefore, irreversible myocardial damage appears after about 20-min ischemia and is almost complete after 60min. Reversibility of damage to ischemic myocardium after reperfusion may mainly occur within 60-min ischemia. Although stunned myocardium in a narrow sense is may appear after reperfusion within less than 20-min of ischemia, stunned myocardium in a broad sense may appear within less than 60-min ischemia. When reversible myocardial ischemia (4- or 15-min occlusion) was repeated after short time intervals (20-min reperfusion), %SS of ischemic myocardium was gradually decreased with each ischemic episode. Active shortening of ischemic myocardium disappeared after more than two episodes of 15-min occlusion. Fluctuation of PCO₂, pH and Ke of ischemic myocardium was gradually depressed with each occlusion. Metabolic viability of ischemic myocardium was cumulatively depressed by repeated brief occlusion. Naturally, myocardial damage was more severe after repeated 15-min occlusion than after 4-min occlusion. Accumulation of ischemic myocardial damage may arise as brief ischemia, which only induces reversible damage, is repeated. At last, continuity of ischemic myocardial damage was studied. The effect of 5-min occlusion to %SS of ischemic myocardium was apparently reversed after 90-min reperfusion. Early contractile failure was advanced even after very short duration of ischemia. Thus, myocardial function will be latently damaged. Fluctuation of PCO₂, pH and Ke was still depressed, thus, metabolic viability of ischemic myocardium will be latently depressed. This phenomenon, continuity of latent myocardial damage, is very important condition preceding myocardial stunning.

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To investigate excitation-contraction coupling in stunned myocardium, intracellular free calcium concentration ([Ca²⁺]_i) was measured before and after ischemia in perfused hearts using gated ¹⁹F NMR and the Ca²⁺ indicator 5F-BAPTA. Maximal Ca²⁺-activated force was also measured in parallel experiments. Stunned myocardium was created by reperfusion after 15 min global ischemia at 37°C in isolated ferret hearts. In stunned myocardium, peak [Ca²⁺]_i was paradoxically higher than that in control, but maximal Ca²⁺-activated pressure was lower in stunned hearts. These results indicate that contractile failure in stunned myocardium is due to a decrease in the myofilament sensitivity to Ca²⁺ as well as to a decrease in maximal Ca²⁺-activated force; failure of activator Ca²⁺ delivery cannot be implicated. The role of intracellular calcium overload in the pathogenesis of stunned myocardium was also investigated. Time-averaged ¹⁹F NMR measutements directly revealed the increase in [Ca²⁺]_i during ischemia and in the early phase of reperfusion. The strategies to prevent Ca overload during reperfusion with modified reperfusate succeeded in preserving contractile function. Transient Ca overload without ischemia induced by different causes, i.e., high [Ca]₀ perfusion, ventricular fibrillation or treatment with adriamycin, also produced contractile dysfunction that outlasted the interventions themselves. Thus, we propose that transient Ca overload during ischemia and early reperfusion initiates long-lasting contractile dysfunction in stunned myocardium.

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Reperfusion after reversible ischemia has been shown to result in prolonged depression of contractile function ("myocardial stunning"). Recent studies suggest that oxygen free radicals may mediate postischemic dysfunction. Since heart sarcolemmal membranes, which contain several types of enzymes. ion channels and receptors play important roles to maintain cell functions, the pre-sent study was undertaken to examine the effects of oxygen free radicals on heart sarcolemmal membrane functions in vitro. In the presence of a superoxide anion radical-generating system (2mM xanthine plus 0.03 U/ml xanthine oxidase), sarcolemmal Ca²⁺-stimulated ATPase activity and ATP-dependent Ca²⁺ accumulation were inhibited in an incubating time-dependent manner. Both lipid peroxidation (r=0.82) and sulthydryl group content (r=0.95) showed significant correlations with Ca²⁺-stimulated ATPase activity. ATP-indenpendent Ca²⁺ bindings were increased upon treating the membranes with xanthine plus xanthine oxidase. Voltage-dependent Ca²⁺-channels were also affected by oxygen free radicals. The maximal number of binding sites (Bmax) for [³H]-nitrendipine binding was depressed without any changes in dissociation constant (Kd). The effects of oxygen free radicals on adrenergic receptors were more complex. Bmax for [³H]-dihydroalprenolol (DHA) binding (β-receptor) was increased whereas Bmax for [³H]-prazosin binding (α₁-receptor) was de-creased after incubating the membrane with xanthine plus xanthine oxidase. Kd for [³H]-DHA or [³H]-prazosin binding was increased. Superoxide dismutase showed protective effects on the changes in these membrane functions due to xanthine plus xanthine oxidase. It is suggested that oxygen free radicals damage heart sarcolemmal mambrane functions which may lead to cardiac dysfunction. in the stunned myocardium.

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^<123>I-Metaiodobenzylguanidine (¹²³I-MIBG) uptake in the stunned myocardium was investigated in open chest dogs. ¹²³I-MIBG is a tracer taken up in presynaptic adrenergic vesicles and reflects the function of the myocardial sympathetic nervous system. This study revealed that in the stunned myocardium without infarct, ¹²³I-MIBG uptake was normal up to 40 minutes of ischemia and that exogenous noradrenaline improved deteriolated regional wall motion with increased uptake of ¹²³I-MIBG. However, uptake of ¹²³I-MIBG per flow decreased with infarct in ischemic areas, and it showed a linear relation with regional wall motion. Thus, in the absence of infarction ¹²³I-MIBG is a tracer to differentiate stunning from more severe ischemia with persistent wall motion abnormality. Normal uptake and storage of ¹²³I-MIBG in the stunned condition suggests that catecholamine release or second effector mechanism may replate to the mechanism.

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To clarify the relationship beween 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 (0.2mg/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 ( Δ-shortening) lowered at 5 min after reperfusion and augmented progressively. But, Δ-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 α-2 receptor mediated negative feed-back mechanism would play an important role in these diminished NE release.

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Clinical features of 37 cases of stunned myocardium were studied. Mean duration of asynergy was 22.6±15.7 days. In all 11 cases of unstable angina without any significant serum creatine kinase leakage, the duration of asynergy was within 14 days. Related coronary lesions were reperfused (spontaneously or by interventional therapy) to TIMI grade II or higher. Transient Q waves were observed in 39% of all cases. Negative T waves tended to be prolonged, and persisted after disappearance of asynergy in 74% of all cases. ²⁰¹Tl uptake in the stunned area varied widely between individual cases (ranging from "absent" to "normal"), although it became normal in all cases in the chronic stage. Mal-distribution of ^99mTc-pyrophosphate (PYP) to the endocardial side of the stunned area was observed in 33%. In 186 cases of acute coronary syndrome, we studied whether or not reversibility of ischemia-disturbed myocardium could be predicted by simultaneous dual isotope SPECT, and found that ²⁰¹Tl-uptake in the chronic stage significantly improved in the region showing absence of ^99mTc-PYP accumulation or maldistribution of ^99mTc-PYP to the endocardial side, while reversibility of the region showing transmural ^99mTc-PYP accumulation and a dought pattern was poor. Ischemia-associated myocardial damage recovered to various degrees, and dual isotope SPECT was useful in evaluating the reversibility of such damage already at the acute stage.

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A method for the diagnosis of stunned myocardium has not yet been established, although it has been retrospectively demonstrated in patients after intracoronary thrombolysis, unstable angina, and coronary revascularization. In this study, radionuclide cardiac imaging was carried out to evaluate the existence of stunned myocardium. 1) Gated blood pool scanning was performed in patients undergoing intracoronary thrombolysis both at the time of reperfusion (Rp) and 10 days later. In the Rp<4 h group, about half of the initially abnormal segments showed complete improvement on quantitative wall motion analysis. which was more than in the Rp>4h and control groups. 2) In patients with acute myocardial ischemia. the correlation between thallium perfusion and regional wall motion was assessed semiquantitatively. In unstable angina, 5.8% of the ventricular wall segments showed dissociation between perfusion and wall motion (well-perfused asynergy). These segments had abnormal wall motion although perfusion was maintained. and were thought to be areas of stunned myocardium. 3) Fourteen dogs were studied using thallium and ¹²³I-β-methyl-iodophenyl pentadecanoic acid (BMIPP) fatty acid imaging to evaluate the relationship of perfusion to metabolism. In the reperfusion model, mismatching of the pattern of thallium and BMIPP uptake was observed. Reperfused myocardium probably has an increased triglyceride content, which is related to the degree of myocardial viability. In conclusion, stunned myocardium may be correctly diagnosed acutely on the basis of alterations in its perfusion. metabolism, and function by using radionuclide cardiac imaging.

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To evaluate the clinical relationship between stunned myocardium and the sympathetic nervous system. 6 patients who had stunned myocardium accompanied by T wave inversion underwent simultaneous ¹²³I-metaiodobenzyl guanidine (MIBG) scintigraphy and thallium scintigraphy. All patients showed abnormal filling defects on the MIBG scintigrams in the areas with stunned myocardium. but the thallium scintigrams were almost normal. The extent of the defects in these 6 patients was determined on the MIBG scintigrams using a Bull's eye display. The defects were found to be larger than those in 4 patients with angina pectoris, and those in 4 patients who had previously shown T wave inversion but had a normal electrocardiogram at the time of examination. Thus, it is suggested that sympathetic denervation is one of the mechanisms causing stunned myocardium.

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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 up-take 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<0.01). On the other hand. 4 of 5 sagments 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.

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To elucidate the relationship between lactate metabolism following reperfusion and restoration of left ventricular (LV) function, we assessed serial changes in transcardiac lactate metabolism following reperfusion therapy in 67 patients admitted to hospital within 6 h of the onset of acute anteroseptal myocardial infarction. Left ventriculograms taken about 30 min after reperfusion therapy revealed marked dyskinesis in the anteroapical region in all subjects. According to the regional ejection fraction (rEF), determined 4 weeks later as an index of LV function, patients were divided into 3 group: 1) Restored LV group: 28 patients with reperfusion and restored LV function (rEF>30%); 2) Poor LV group: 26 patients with reperfusion but poor LV function (rEF<30%); 3) Failure group: 13 patients with failed reperfusion and occluded left anterior descending coronary artery. Although there was no difference in elapsed time and time to peak creatine phosphokinase (CPK) between the former 2 groups, the Restored LV group demonstrated lower peak CPK values, suggesting that these patients had less myocardial injury. Immediately after reperfusion, both groups showed transcardiac lactate production. In the Restored LV group, aerobic lactate metabolism was restored early after reperfusion (at 6 h), while in the Poor LV group prolonged anaerobic lactate metabolism was observed. These results suggest that an early restoration of aerobic metabolism might be a sign of stunned and viable myocardium, and a sustained lactate production might relate to a sustained process of myocardial injury.

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