Ischemic Myocardial Metabolism Research Articles

Notoginsenoside R1 Regulates Ischemic Myocardial Lipid Metabolism by Activating the AKT/mTOR Signaling Pathway.

Ischemic heart diseases are responsible for more than one-third of all deaths worldwide. Radix notoginseng is widely used to treat ischemic heart disease in China and other Asian countries, and notoginsenoside R1 (NGR1) is its characteristic and large-amount ingredient. However, the potential molecular mechanisms of NGR1 in improving ischemic heart diseases are unclear. In this study, we combined pharmacological evaluation with network pharmacology, myocardial proteomics, and conventional molecular dynamics (MD) simulation to explore the cardio-protection mechanisms of NGR1. Our results revealed that NGR1 improved the echocardiographic, tissue pathological, and serum biochemical perturbations in myocardial ischemic rats. The network pharmacology studies indicated that NGR1 mainly regulated smooth muscle cell proliferation, vasculature development, and lipid metabolism signaling, especially in the PI3K/AKT pathway. Myocardial proteomics revealed that the function of NGR1 was focused on regulating metabolic and energy supply processes. The research combined reverse-docked targets with differential proteins and demonstrated that NGR1 modulated lipid metabolism in ischemic myocardia by interacting with mTOR and AKT. Conventional MD simulation was applied to investigate the influence of NGR1 on the structural stabilization of the mTOR and AKT complex. The results suggested that NGR1 can strengthen the affinity stabilization of mTOR and AKT. Our study first revealed that NGR1 enhanced the affinity stabilization of mTOR and AKT, thus promoting the activation of the AKT/mTOR pathway and improving lipid metabolic abnormity in myocardial ischemic rats.

Shenfu decoction as adjuvant therapy for improving quality of life and hepatic dysfunction in patients with symptomatic chronic heart failure

Ethnopharmacological relevanceShenfu decoction (SFD) is a water extract of the dried root or root stalk of Panax ginseng C. A. Mey (Asian ginseng) and the lateral root of Aconitum carmichaeli Debx (prepared by Fuzi, Heishunpian in Chinese). It has been used to treat heart failure for over a thousand years. The main active components of SFD, ginsenosides and higenamine, enhance heart contractility, increase the coronary blood supply, improve ischemic myocardial metabolism, scavenge free radicals and protect myocardial ultrastructure. Aim of the studyTo investigate the effect of SFD on quality of life (QOL) and hepatic function in symptomatic chronic heart failure (CHF) patients. Materials and methodsForty patients enrolled in the study were randomized into two groups: an SFD group (18 cases) and a control group (22 cases). All the patients received standard heart failure therapy, and the SFD group patients were also treated with Shenfu granules for 14 days as an adjunctive therapy. The effects of SFD on QOL, plasma alanine aminotransferase (ALT) level, cardiac function, left ventricular ejection fraction (LVEF) and tumor necrosis factor-α (TNF-α) level were studied. ALT threshold in hepatic injury are 21U/L for men and 17U/L for women. ResultsMinnesota Living with Heart Failure Questionnaire (MLHFQ) scores were improved by 35.27±10.72 vs. 23.87±11.96 in the SFD and control groups respectively (p<0.01). Subgroup analysis of the MLHFQ results demonstrated that both physical and emotional scores were significantly higher in the SFD group (21.00±5.66 vs. 16.75±6.25, p<0.05; 4.64±4.84 vs. 1.13±2.85, p<0.05). Circulating ALT was significantly decreased by SFD (13.3IU/L vs. 0.6IU/L, p<0.01). The grading of cardiac function and LVEF were increased by 1.6±0.5 vs. 1.1±0.3 and 18%±13% vs. 8%±8% in the SFD and control groups respectively (p<0.05 and p<0.05). The level of TNF-α declined more in SFD than control group (64.8±5.0 to 57.6±4.1, p<0.05; vs. 61.6±5.9 vs. 57.7±3.2. p>0.05). ConclusionCompared with standard heart failure treatment, oral SFD as an adjuvant therapy significantly improved QOL and hepatic injury in CHF patients.

Assessing ischemic myocardial metabolism in vivo with hyperpolarized 13C: relating the metabolic perturbation to the area at risk

Background The high metabolic activity of the heart makes it particularly suited to the use of hyperpolarized (HP) 13C methods to non-invasively detect and characterize metabolic changes that occur during ischemia/reperfusion (I/R). Energy metabolism in ischemic rat hearts has been previously interrogated with HP 13C-labelled pyruvate ex vivo, and its hyperpolarized metabolites have been imaged in the ischemic pig heart in vivo. In both cases, a decrease in the conversion to labelled bicarbonate was observed vs. conversion to lactate, consistent with the expected decrease in pyruvate oxidation. Here, our aim was to establish this I/R model in rats and to correlate metabolic changes with the area at risk. Methods

Prevention of ventricular fibrillation during acute myocardial ischemia: control of free fatty acids.

Fatal ventricular fibrillation is a common complication of acute coronary syndromes. Effective preventive measures are not available. Immediate restriction of free fatty acid availability should optimize ischemic myocardial metabolism, reduce ventricular vulnerability, and increase glucose utilization. Rapid inhibition of lipoprotein lipase activity will achieve this. The clinical effects of antilipolytic treatment require further study.

Effects of OG-VI, a nucleoside-nucleotide mixture, on ischemic myocardial metabolism in dogs.

OG-VI is a solution composed of 30 mmol/l inosine, 30 mmol/l sodium 5'-guanylate, 30 mmol/l cytidine, 22.5 mmol/l uridine, and 7.5 mmol/l thymidine, which is known to improve myocardial stunning. To study the effect of OG-VI on myocardial energy and carbohydrate metabolism during ischemia. Ischemia was induced in pentobarbital-anesthetized open-chested dogs for 3 min by left anterior descending coronary artery ligation. Saline, 1.2 mmol/kg per min OG-VI, or 12 mmol/kg per min OG-VI was infused at 0.1 ml/kg per min, starting 30 min before the onset of ischemia. The myocardium was extracted 3 min after the onset of ischemia, and used to determine the tissue levels of energy and carbohydrate metabolites. Ischemia decreased the levels of ATP and fructose 1,6 diphosphate significantly, and increased those of AMP, glucose 6 phosphate, fructose 6 phosphate and lactate. OG-VI infusion preserved the adenine nucleotide levels significantly in 3 min ischemic hearts, and attenuated the ischemia-induced alteration of carbohydrate metabolism. OG-VI may improve the myocardial metabolic derangement induced by ischemia.

Effects of thoracic epidural anesthesia on changes in ischemic myocardial metabolism induced by intracoronary injection of endothelin in dogs

Thoracic epidural anesthesia (TEA) has been reported to alleviate ischemic damage to the myocardium. Endothelin, an endothelium-derived peptide and a potent coronary vasoconstrictor, may contribute to poor cardiac perfusion and ischemia. The objective was to examine regional myocardial metabolism during ischemia caused by intracoronary injection of endothelin with and without TEA. The three experimental groups and three treatments were randomized. All studies were conducted in a university research laboratory. Thirty anesthetized dogs comprised the study groups. Study animals were divided into three groups of 10 animals each identified as normal saline (NS); TEA; and TEA + blood pressure controlled (TEA + BPC). The NS group had 0.5 mL/kg of normal saline injected into the T4-5 epidural space. The TEA group had 0.5 mL/kg of saline containing 1% lidocaine injected into the T4-5 space. The TEA + BPC group had blood pressure and heart rate maintained at pre-epidural injection values by partially occluding the descending aorta and by atrial pacing. Endothelin (15 pmol/kg) was bolus injected into the left anterior descending (LAD) artery of each heart. Systolic and diastolic blood pressure, heart rate, and LAD coronary blood flow (CBF) were monitored. Three minutes after injection of endothelin, myocardial tissue was sampled from the distribution of the LAD artery and from the control, left circumflex (LCx) artery. ATP, ADP, AMP, lactate, and pyruvate were measured by enzymatic methods. It was found that in each group endothelin consistently decreased LAD CBF, but the decrease was less in the TEA + BPC group. In the tissue distribution of the LAD, the levels of ATP and energy charge potential were lower, and the level of lactate was higher in the NS group than in the TEA or the TEA + BPC groups (p < 0.01). These results confirm that (1) endothelin injected into the LAD artery decreases CBF and causes selective myocardial ischemia in a fashion similar to intravascular stenosis of the LAD rather than to mechanical occlusion and (2) TEA, with or without pressure support, lessens the degree of regional ischemia induced by injection of endothelin in the LAD.

P-278 - Effect of efonidipine hydro-chrolide, a novel calcium antagonist, on ischemic myocardial metabolism.

P-278 - Effect of efonidipine hydro-chrolide, a novel calcium antagonist, on ischemic myocardial metabolism.

Effects of Bunitrolol on Ischemic Myocardial Energy Metabolism in Dogs

The effect of bunitrolol, a β-adrenergic blocking agent having intrinsic sympathomimetic activity, on ischemic myocardial metabolism was examined in anesthetized dog hearts. Ischemia was induced by ligating the left anterior descending coronary artery for 3 or 30 min. Bunitrolol (0.3 or 1.0 mg/kg of body weight) was injected intravenously 5 min before the onset of ischemia. Ischemia reduced myocardial high-energy phosphate levels and changed the levels of glycolytic intermediates. Bunitrolol at a dose of 0.3 mg/kg significantly decreased heart rate, whereas the drug at a dose of 1.0 mg/kg did not. This result suggests that intrinsic sympathomimetic activity is observed only at a high dose of bunitrolol. Pretreatment with bunitrolol at 0.3 but not 1.0 mg/kg attenuated the myocardial metabolic changes caused by 3 min of ischemia. After 30 min of ischemia, a beneficial effect of bunitrolol on the ischemic myocardium was not observed. These results suggest that bunitrolol may lessen the ischemic influence on the myocardium in the early stage of ischemia and that intrinsic sympathomimetic action may not have a beneficial effect on the ischemic myocardium.

Effects of iloprost, a PGI2 derivative, on ischemic myocardial energy and carbohydrate metabolism in dogs.

Effects of iloprost, which is a stable prostacyclin analogue, on the ischemic myocardium were examined in the open-chest dog heart in terms of biochemical parameters. Ischemia was initiated by ligating the left anterior descending coronary artery. When the coronary artery was ligated for 3 min, the levels or glycogen, fructose-1,6-diphosphate (FDP), adenosine triphosphate and creatine phosphate decreased, and the levels of glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), lactate, adenosine diphosphate and adenosine monophosphate increased. During ischemia, therefore, energy charge potential was significantly decreased from 0.89 +/- 0.01 to 0.82 +/- 0.01, and ([G6P] + [F6P])/[FDP] and [lactate]/[pyruvate] ratios were significantly increased from 1.75 +/- 0.30 to 29.05 +/- 5.70 and 13 +/- 3 to 393 +/- 112, respectively. Iloprost (0.1, 0.3, or 1 microgram.kg-1) was injected intravenously 5 min before the onset of ischemia. Iloprost (0.1, 0.3, and 1 micrograms.kg-1) reduced the ischemia-induced decrease in energy charge potential to 94, 74, and 86%, respectively, the increase in ([G6P] + [F6P])/[FDP] to 38, 29, 32%, respectively, and the increase in [lactate]/[pyruvate] to 67, 45, 65%, respectively. These results suggest that iloprost lessens the myocardial metabolic derangements produced by ischemia, and the most potent effect was obtained at the dose of 0.3 microgram.kg-1.

Effects of MCI-176, a new quinazolinone calcium antagonist, on myocardial energy and carbohydrate metabolism in ischemic dog hearts

The effect of 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-6-isopropoxy-4(3 H)-quinazolinone hydrochloride (MCI-176), a calcium antagonist, on ischemic myocardial metabolism was studied in dog hearts subjected to an occlusion of the left anterior descending coronary artery (LAD) for 3 or 30 min. MCI-176 (0.03 or 0.1 mg/kg), when injected i.v. 5 min before occlusion, increased coronary blood flow and decreased systematic aortic pressure. When the LAD was ligated, the levels of creatine phosphate, ATP, total adenine nucleotides and energy charge potential decreased in the ischemic myocardium. Three minutes after ischemia, MCI-176 (0.1 mg/kg) significantly (P < 0.05) diminished these impairments of energy metabolism. Even 30 min after ischemia, pretreatment with MCI-176 tended to lessen the depletion of ATP and total adenine nucleotides, although these effects were not statistically significant. Myocardial ischemia produced a breakdown of glycogen, an accumulation of lactate, and an inhibition of glycolytic flux through phosphofructokinase reaction. MCI-176 (0.1 mg/kg) significantly (P < 0.05) reduced these alterations of carbohydrate metabolism after 3 min of ischemia. These results suggest that pretreatment with MCI-176 reduces the impairments of myocardial energy and carbohydrate metabolism in ischemic dog hearts, suggesting that the drug is capable of improving the imbalance between oxygen supply and oxygen demand in the ischemic myocardium.

Effects of regression of left ventricular hypertrophy following atenolol or bunazosin therapy on ischemic cardiac function and myocardial metabolism in spontaneously hypertensive rats.

The effects of regression of left ventricular hypertrophy following atenolol and bunazosin therapy on ischemic cardiac function and myocardial metabolism in spontaneously hypertensive rats (SHR) were studied. Atenolol (50 mg/kg/day) and bunazosin (5 mg/kg/day) were administered to SHR from 19 to 26 weeks of age, whereas tap water was given to control SHR and normotensive Wistar-Kyoto rats (WKY). Both atenolol and bunazosin significantly decreased arterial blood pressure and significantly decelerated the increase in left ventricular weight in SHR. At the end of the long-term treatment, hearts were removed and perfused by the working heart technique for 15 min, and then global ischemia was induced for either 10 or 30 min. The ischemic heart was reperfused for 30 min. The pressure-rate product and the extent of recovery of the coronary flow after reperfusion following 30 min of ischemia in the bunazosin-treated SHR were significantly higher than those in the control SHR and the atenolol-treated SHR. The levels of adenosine triphosphate (ATP), creatine phosphate (CrP), and energy charge potential in the SHR heart reperfused after 30 min of ischemia were significantly lower than those in the reperfused WKY. Both atenolol and bunazosin improved the restoration of ATP and CrP in SHR after reperfusion following 30 min of ischemia. In conclusion, antihypertensive therapy with either atenolol or bunazosin was effective in preventing cardiac hypertrophy and ischemic damage caused by different mechanisms. Factors resulting from stimulation of the cardiac alpha 1 adrenoceptor may play an important role in the development of hypertensive cardiac hypertrophy, just as factors resulting from stimulation of the beta 1-adrenoceptor do.

Effects of Lidocaine on Ischemic Myocardial Metabolism Assessed by 31P-NMR in the Isolated Perfused Rat Heart.

Using an isolated perfused rat heart preparation, the protective effects of lidocaine and diltiazem on ischemic derangements of myocardial energy metabolism were studied with 31P-nuclear magnetic resonance spectroscopy. The hearts were perfused with a solution containing lidocaine (4.27 x 10(-5), 12.80 x 10(-5) M) or diltiazem (2.22 x 10(-7), 2.22 x 10(-6) M) for 15 min prior to the induction of global ischemia. The decrease in myocardial oxygen consumption rate, assessed as the product of heart rate and left ventricular systolic pressure (HR x LVP), was greater in diltiazem-treated than in lidocaine-treated hearts. Diltiazem and lidocaine significantly retarded the fall in myocardial pH during ischemia and improved ATP recovery after reperfusion. There was a good correlation between suppression of HR x LVP observed before induction of ischemia and decreased drop in pH during the early phase of ischemia in the diltiazem-treated groups (r = -0.78, p less than 0.01), but not in the lidocaine-treated groups. These results indicate that the beneficial effects of diltiazem on the ischemic myocardium are due primarily to the cardio-depressant effects. The beneficial effects of lidocaine cannot, however, be explained solely on the basis of the depression of oxygen consumption.

心選択生β‐遮断薬Ｂｅｔａｘｏｌｏｌのイヌ虚血心筋エネルギー代謝および糖代謝変化に対する作用

The effect of betaxolol, a beta 1-adrenoceptor antagonist, on ischemic myocardial metabolism was studied in dog hearts subjected to an occlusion of the left anterior descending coronary artery for 10 or 30 min. Betaxolol (0.1 or 0.3 mg/kg) was injected i.v. 5 min before ischemia. Betaxolol decreased heart rate, (+)dp/dt, coronary flow and blood pressure. Coronary occlusion decreased the levels of creatine phosphate, adenosine triphosphate, total adenine nucleotides and energy charge potential in the ischemic myocardium. Ten minutes after ischemia, betaxolol significantly diminished these impairments of energy metabolism. Even 30 min after ischemia, a higher dose of betaxolol significantly inhibited the depletion of total adenine nucleotides. Myocardial ischemia produced a breakdown of glycogen, an accumulation of lactate and an inhibition of glycolytic flux through the phosphofructokinase reaction. Betaxolol also reduced these alterations of carbohydrate metabolism 10 min after ischemia. These results indicate that betaxolol delays the onset of myocardial metabolic change from aerobic to anaerobic during ischemia and hence reduces the severity of myocardial ischemic injury.

Alleviation of myocardial dysfunction and abnormal lactate metabolism during coronary stenosis in dogs by ICI 118,551

Hemodynamic parameters, segment shortening in the ischemic myocardium and cardiac lactate extraction were estimated in the presence of a critical coronary stenosis, before and after administration of the selective β 2-adrenoceptor antagonist, ICI 118,551, or the β 1-adrenoceptor antagonist, atenolol, to anesthetized dogs. ICI 118,551 (0.2 and 0.5 mg/kg i.v.) and atenolol (0.2 mg/kg i.v.) produced significant decreases in both heart rate (by 6, 14 and 20% of the predrug value, respectively) and maxLVdP/dt (by 15, 26 and 24% of the predrug value, respectively). ICI 118,551 (0.5 mg/kg) and atenolol significantly improved the impaired shortening of the myocardial segment when compared with the change seen after saline administration. ICI 118,551 at both doses and atenolol significantly increased depressed cardiac lactate extraction while saline did not. Increasing heart rate by pacing abolished the beneficial effects of ICI 118,551 and atenolol on ischemic myocardial segment shortening and lactate metabolism. The data suggest that not only β 1- but also β 2-adrenoceptor blockade may contribute to the amelioration of myocardial ischemia in a model of coronary stenosis.

Effect of flunarizine on ischemic myocardial metabolism in dogs

The effect of flunarizine, a calcium entry-blocker, on the ischemic myocardial metabolism of the open-chest dog heart was examined and compared to that of diltiazem. During ischemia, initiated by ligating the left anterior descending coronary artery, the metabolism of the myocardium switched from aerobic to anaerobic; the levels of glycogen, fructose-1,6-diphosphate (FDP), adenosinetriphosphate and creatinephosphate decreased, and the levels of glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), lactate, adenosine diphosphate and adenosine monophosphate increased during 3 min of ischemia. The calculated energy charge potential decreased, and the ([G6P] + [F6P]/[FDP] ratio and the lactate/pyruvate ratio were increased by ischemia. Flunarizine (0.3 or 1 mg/kg) or diltiazem (0.1 mg/kg) was injected i.v. 5 min before the start of ischemia. Pretreatment with either flunarizine or diltiazem reduced the decrease in the energy charge potential and the increase in the ([G6P] + [F6P])/[FDP] ratio during ischemia. Flunarizine (1 mg/kg) and diltizem (0.1 mg/kg) reduced the accumulation of lactate due to ischemia, leading to a decrease in the lactate/pyruvate ratio. Flunarizine and diltiazem may lessen the influence of ischemia on the myocardial tissue.

O-211 - Effects of lidocaine on the ischemic myocardial metabolism assessed by 31p-NMR in the isolated perfused rat heart

O-211 - Effects of lidocaine on the ischemic myocardial metabolism assessed by 31p-NMR in the isolated perfused rat heart

虚血心筋ガス代謝よりみたｐｏｓｉｔｉｖｅ ｉｎｏｔｒｏｐｉｃ ａｇｅｎｔ適応の問題点

虚血心筋ガス代謝よりみたｐｏｓｉｔｉｖｅ ｉｎｏｔｒｏｐｉｃ ａｇｅｎｔ適応の問題点

Protective metabolic effects of propranolol during total myocardial ischemia

Clinical trials have shown an increase in survival in patients treated with beta blockers after infarction. In addition, the majority of patients undergoing myocardial revascularization are also treated preoperatively with beta blockers. It is commonly thought that beta blockers exert their protective effect primarily by decreasing heart rate and subsequent myocardial work. The present study was designed to determine whether beta blockade has any primary protective metabolic effects on globally ischemic myocardium. Thirty-four anesthetized dogs underwent total myocardial ischemia at 37 degrees C. High-energy nucleotide and lactate levels in left ventricular tissue samples were determined at control and at 15 minute intervals as well as at the onset of ischemic contracture in 24 dogs. Seventeen dogs were treated with propranolol before ischemia. The time to ischemic contracture in control dogs was 63.3 +/- 1.4 minutes compared with 75.9 +/- 2.2 minutes in the propranolol-treated group (p less than 0.01). In addition to significantly delaying the onset of ischemic contracture, propranolol also decreased the rate of anaerobic glycolysis during ischemia. Ischemic contracture occurred in the control group with an average adenosine triphosphate level of 1.26 +/- 0.08 mumol compared to 0.91 +/- 0.08 mumol/gm wet weight for the beta blocked group (p less than 0.0025). These are the first data suggesting that the protective effects of beta blockade may be related to a beneficial effect on ischemic myocardial metabolism allowing myocardium to survive with lower levels of adenosine triphosphate.

Effects of l- and d-propranolol on the ischemic myocardial metabolism of the isolated guniea pig heart, as studied by 31P-NMR.

Using 31P nuclear magnetic resonance (NMR) spectroscopy (acquisition time of 3 min), we studied the effects of l- and d-propranolol on the ischemic derangement of myocardial energy metabolism in the isolated perfused guinea pig heart. The myocardial pH and concentration of high-energy phosphate were used as measures of the energy metabolism. Cardiac pH progressively declined during ischemia from 7.41 +/- 0.04 to 7.13 +/- 0.05, 6.91 +/- 0.04, 6.74 +/- 0.04, and 6.61 +/- 0.04 (before ischemia and 3, 6, 9, and 12 min after ischemia, respectively). After 3 min of reperfusion, pH rapidly returned to 7.42 +/- 0.04. Creatine phosphate (CP) and adenosine triphosphate (ATP) contents were reduced, while inorganic phosphate (Pi) contents were increased during ischemia. Whereas CP and Pi contents were restored to the normal values after reperfusion, the recovery of ATP contents was poor. Both l- and d-propranolol (10(-6) M) significantly suppressed the fall of the myocardial pH. Changes in the high-energy phosphate contents were also attenuated by l- and d-propranolol. These results suggest that not only l-propranolol, but also d-propranolol can produce beneficial effects on the ischemic derangements of myocardial energy metabolism.

Effects of nifedipine on conduction delay during ventricular myocardial ischemia and reperfusion

Nifedipine has been suggested to have more potent slow channel blocking action than other agents of this type. However, its use in the treatment of cardiac arrhythmias has been limited. Electrophysiologic studies on AV conduction have shown that nifedipine lacks any significant effect. However, the action of the drug on intraventricular conduction has not been investigated with regard to its potential in the treatment of ventricular arrhythmlas especially during ischemia. Therefore, the effects of nifedipine on conduction delay during ischemia and reperfusion were assessed in the present study. Sixteen dogs (eight control and eight nifedipine-treated dogs) were used. Transmural electrodes were positioned in normal, ischemic, and reperfused tissue, and at the border of these segments. The left anterior descending artery was initially ligated below the second diagonal branch (first ligation) and 30 minutes later below the first diagonal branch (second ligation); the second ligation was released 30 minutes later. Conduction of electrically induced premature impulses from the midwall of the left ventricle was recorded at epicardial and endocardial sites. Conduction delay was measured from the stimulus artifact to the first high-frequency deflection in each zone in the anterograde (base to apex) and retrograde (apex to base) directions. Intravenous nifedipine 0.1 mg/kg was given over 10 minutes immediately after the first ligation. Nifedipine slightly decreased the magnitude of conduction delay in the ischemic myocardium at 15 minutes of ischemia, which corresponded with the peak plasma nifedipine level. However, conduction delay throughout the remainder of the study was essentially unaltered by nifedipine. In conclusion, though nifedipine may improve ischemic myocardial metabolism, infarct size, and hemodynamics, the effect on the electrophysiologic parameters affecting conduction was insignificant. This lack of any further deterioration in conduction in the ischemic and reperfused tissue by the drug further attests to its safety during acute myocardial ischemia.