Comparative effects of nicardipine, a new calcium antagonist, on size of myocardial infarction after coronary artery occlusion in dogs

To examine whether nicardipine, a dihydropyridine derivative, limits size of myocardial infarction, and to compare the protective effects of nicardipine administered before and early and late after coronary artery occlusion, 99mTc-labeled albumin microspheres were injected into the left atrium during 5 min temporary coronary artery occlusion to determine the extent of the hypoperfused zone (the area at risk). The coronary arteries were then reperfused for 45 min before 6 hr permanent coronary artery occlusion. Fifteen minutes before permanent occlusion, dogs were randomly assigned to a control group (n = 11), a pretreatment group (n = 9), which received at this point 10 micrograms/kg of nicardipine as a loading dose followed by a continuous infusion of 8 micrograms/kg/hr for 6 hr, an early treatment group (n = 9), in which nicardipine treatment was initiated 15 min after occlusion, or a late treatment group (n = 8), in which nicardipine administration was delayed for 3 hr. Six hours after coronary artery occlusion, the hearts were excised and the left ventricle of each was cut into 3 mm thick slices and stained with triphenyltetrazolium chloride. The extent of myocardial necrosis was measured by planimetry of the unstained areas. Thereafter, the same slices were autoradiographed and the extent of the hypoperfused zone was measured by planimetry of the "cold spot." The extent of the hypoperfused zone was identical among the four groups. In the control group, the ratio of the extent of myocardial necrosis to the extent of the hypoperfused zone was 95.8 +/- 3.8% (mean +/- SEM). However, it was significantly smaller in the pretreatment group (59.9 +/- 13.3%, p less than .05) and the early treatment group (49.0 +/- 10.6%, p less than .01) than in the control group. In the late treatment group, this value was not different from that in the control group (86.5 +/- 7.1%). There was a close inverse correlation between reduction of infarct size and the extent of the hypoperfused zone in the pretreatment and early treatment groups. Thus, nicardipine administered before or early after coronary artery occlusion limited infarct size by 37% to 49%, whereas when administration was delayed for 3 hr infarct size was not reduced. Furthermore, nicardipine had more striking effects on the ischemic myocardium of dogs with small hypoperfused zones than on that of dogs with large hypoperfused zones.     

Does the extent of the zone at risk after coronary artery occlusion influence the percentage of the zone that evolves to infarction?

To examine whether the extent of the zone at risk for infarction after coronary artery occlusion influences the percentage of the zone that evolves to necrosis in the absence of intervention, 99mTc-labeled albumin microspheres were injected into the left atrium 1 min after coronary occlusion in 34 dogs. Six hours after occlusion, the left ventricle was cut into 3-mm-thick slices for triphenyltetrazolium chloride staining and autoradiography. The extent of myocardial necrosis and hypoperfused zone was measured by planimetry and expressed as a percentage of the total volume of the left ventricle. The extent of myocardial necrosis and hypoperfused zone varied widely from 8 to 40% and 14 to 43% of the left ventricle, respectively. However, there was a close correlation between infarct size (IS, percent of left ventricle) and the extent of hypoperfused zone (HZ, percent of left ventricle): IS = 0.89x (HZ) - 0.21 (r = 0.909, SEE = 3.02, p less than 0.01). The ratio of infarct size to the extent of hypoperfused zone was 87.9 +/- 2.3%. Dogs with large hypoperfused zones (greater than or equal to 30% of the left ventricle) had a significantly greater ratio of infarct size to the extent of the hypoperfused zone (95.3 +/- 2.4%, n = 11, p less than 0.05) than dogs with small hypoperfused zones (less than 30% of the left ventricle; 84.3 +/- 3.0%, n = 23). Moreover, the ratio was greater than or equal to 90% in all but one dog (91%) with large hypoperfused zones, but in only 10 of 23 dogs (43%) with small hypoperfused zones (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Sustained beneficial effects of gallopamil (D600) on size of myocardial infarction 24 hours after coronary artery occlusion in dogs

To examine whether gallopamil (D600), a methoxy derivative of verapamil, has sustained beneficial effects on the ischemic myocardium, its effects on the size of myocardial infarction determined 6 hours (protocol 1) and 24 hours (protocol 2) after left anterior descending coronary artery occlusion were compared in anesthetized, open-chest dogs. To quantify the extent of the hypoperfused zone, Tc-99m- or In-111-albumin microspheres were injected into the left atrium 1 minute after occlusion. Fifteen minutes after occlusion, dogs were randomly assigned to a control group or a gallopamil-treated group that received immediately after assignment 0.08 mg/kg of gallopamil followed by a continuous infusion of 0.2 mg/kg/hr for 6 hours. Six or 24 hours after occlusion, the left ventricle was cut into 3 mm thick slices for triphenyltetrazolium chloride staining and autoradiography. There were no differences in the extent of the hypoperfused zone among the four groups. In both protocols 1 and 2 the ratio of the extent of myocardial necrosis to the extent of the hypoperfused zone was significantly smaller in the treated groups (56.7 +/- 6.7% [n = 8], p less than 0.01 and 72.3 +/- 5.3% [n = 6], p less than 0.05 for protocols 1 and 2, respectively) than in the control groups (100.7 +/- 6.0% [n = 7] and 95.2 +/- 4.3% [n = 5] for protocols I and II, respectively). Thus gallopamil administered early after coronary artery occlusion had beneficial effects on the ischemic myocardium, which were sustained for at least 24 hours after the onset of infarction.     

Relation of myocardial salvage to size of myocardium at risk in dogs

Infarct size varies in untreated animals subjected to coronary artery occlusion at the same anatomic site. The relation between the hypoperfused zone and the magnitude of myocardial salvage when different pharmacologic interventions are used remains to be established. Thus, in 95 anesthetized dogs, 1 minute after left anterior descending coronary occlusion, technetium-99m-labeled albumin microspheres (8 mCi) were injected into left atrium for the assessment of the hypoperfused zone. Fifteen minutes after coronary occlusion 42 dogs were randomized into a control group and 53 into a treated group. In the treated group, 6 dogs received nifedipine, 0.35 micrograms/kg followed by 2.4 micrograms/kg/hour; 7 received diltiazem, 0.2 mg/kg followed by 0.9 mg/kg/hour; 13 received bepridil, 2.5 mg/kg; 9 received cytochrome C, 2.5 mg/kg; 8 received rutosides, 200 mg/kg; and 10 received nifedipine plus cytochrome C. All drugs were administered intravenously. At 6 hours the dogs were killed and their hearts were cut into 3-mm-thick slices. Infarct size was determined by triphenyltetrazolium chloride staining; the hypoperfused zone was delineated by autoradiography. The dogs were retrospectively subgrouped as follows: those with small hypoperfused zones, i.e., less than 15% of the left ventricle (controls n = 8, treated n = 7) and those with large hypoperfused zones, i.e., more than 15% of the left ventricle (controls n = 34, treated n = 46). In dogs with large hypoperfused zones, treatment salvaged 42 +/- 3% of the myocardium destined to undergo necrosis, whereas in those with small hypoperfused zones 78 +/- 10% of myocardium was salvaged (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative effects of propranolol, timolol and metoprolol on myocardial infarct size after experimental coronary artery occlusion

The effects of equiblocking doses of three beta-adrenergic blocking agents, propranolol, timolol and metoprolol, on myocardial infarct size were evaluated in 28 dogs after acute experimental coronary artery occlusion. Heart rate, arterial pressure and arterial free fatty acid concentration were measured in an attempt to evaluate their effects on the extent of myocardial injury. The zone at risk of infarction in each dog 1 minute after left anterior coronary artery occlusion was assessed by injecting highly radioactive albumin microspheres into the left atrium, and the hypoperfused zone was determined by autoradiography. After 15 minutes, the dogs were randomized into four groups: control dogs (n = 7), propranolol-treated dogs (1.2 mg/kg intravenously, n = 7), timolol-treated dogs (0.2 mg/kg intravenously, n = 7) and metoprolol-treated dogs (1.2 mg/kg intravenously, n = 7). After 6 hours, the dogs were killed. The left ventricle was sliced and stained with triphenyl-tetrazolium chloride for measurement on infarct size. The same slices were then autoradiographed for measurement of the hypoperfused zone. The percent of hypoperfused zone that evolved to infarction (the ratio of infarct size to hypoperfused zone) was 90.4 +/- 1.9% in the control group, 72.4 +/- 2.4% in the propranolol-treated dogs (p less than 0.05 versus control group); 57.9 +/- 4.4% in the timolol-treated dogs (p less than 0.01 versus control group; p less than 0.05 versus propranolol) and 54.4 +/- 3.7% in the metoprolol-treated dogs (p less than 0.01 versus control group; p less than 0.05 versus propranolol). Thus, propranolol, timolol and metoprolol reduced myocardial infarct size in dogs by 20, 36 and 40%, respectively, after experimental coronary artery occlusion. Metoprolol and timolol protected the ischemic myocardium more effectively than did propranolol.     

The effect of acute hypercholesterolemia on myocardial infarct size and the no-reflow phenomenon during coronary occlusion-reperfusion

The goal of this study was to determine the effects of acute hypercholesterolemia on the evolution of myocardial infarction in a preparation of coronary occlusion-reperfusion. New Zealand white rabbits were fed a 2% cholesterol-enriched diet for 3 days (plasma cholesterol 329 +/- 70 mg/dl), or maintained on the control diet (plasma cholesterol 67 +/- 12 mg/dl). Temporary (30 min) coronary artery occlusion was performed in open-chest rabbits with a suture snare. The snare was released to permit reperfusion. When the animals were killed 5.5 hr later, left ventricles were cut into 3 mm slices. Infarct size was determined by planimetry of tetrazolium-stained slices while the area at risk of infarction (hypoperfused zone) was determined by planimetry of the "cold spots" on autoradiograms of the slices that contained 99m Tc-labeled microspheres that had been injected 1 min after occlusion. Infarct size, expressed as percent of the hypoperfused zone, was 42.8 +/- 1.3% (n = 10) in the control group and was increased by approximately 100% in cholesterol-fed animals to 83.7 +/- 2.0% (n = 10, p less than .001). To test the hypothesis that vascular obstruction (no reflow) might account for the larger infarct size, thioflavin S was injected immediately before the animals were killed to demarcate perfused myocardium in three additional groups of animals: standard chow-fed rabbits (n = 5), cholesterol-fed rabbits (n = 5), and standard chow-fed rabbits that, in addition, received an infusion of isoproterenol (0.1 microgram/kg/min, n = 6), an intervention believed to increase infarct size through a mechanism not dependent on the no-reflow phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between the extent of the hypoperfused zone of the myocardium and the occurrence of ventricular fibrillation

Ventricular fibrillation and subsequent death frequently occur so soon after coronary artery occlusion that infarct size cannot be determined; thus the systematic study of their relationship is impossible. Recently, however, a technique has been developed that permits the assessment, in vivo, of the extent of the myocardial hypoperfused zone (HZ). Accordingly, in 55 open-chest dogs, 99mTc-labeled (8 mCi) albumin microspheres (15 microns in diameter) were injected into the left atrium 1 minute after coronary artery occlusion. The zone of hypoperfusion was analyzed in 28 dogs that had ventricular fibrillation (group A) and 27 dogs that had no ventricular fibrillation (group B). In group B, the HZ was 26.3 +/- 1.7% of the left ventricle vs 31.6 +/- 1.3% of the left ventricle in group A (p less than 0.05), showing that ventricular fibrillation occurred in dogs with larger zones of hypoperfusion.     

Salvage of ischemic myocardium by prostacyclin during experimental myocardial infarction

The effects of prostacyclin (PGI2) on infarct size and regional myocardial blood flow were studied in 28 anesthetized dogs subjected to 5 hours of coronary occlusion. A region of myocardial hypoperfusion was defined by injection of dye into the left atrium just before sacrifice. Infarct size was determined by planimetry of left ventricular slices after incubation in triphenyl tetrazolium chloride. The animals received either PGI2 in Tris buffer solution (20 to 40 ng/kg per min, n = 14) or Tris buffer alone (control, n = 14) beginning 10 minutes after anterior descending coronary artery occlusion. During PGI2 infusion, mean arterial pressure decreased by 8%, but heart rate was unchanged. Infarct size was significantly less (p less than 0.005) in PGI2-treated dogs compared with the control group, both as percent of left ventricle (8.1 versus 17.7%) and as percent of the hypoperfused zone (39.8 versus 77.3%). No significant changes in regional myocardial blood flow occurred over the 5 hour infusion period in either group. Thus, under the conditions of this study, prostacyclin appeared to protect ischemic myocardium by a direct flow-independent mechanism.     

Intermittent coronary sinus occlusion in dogs: reduction of infarct size 10 days after reperfusion

Intermittent balloon occlusion of the coronary sinus was applied to 11 open chest dogs subjected to 3 hours of ligation of the left anterior descending coronary artery followed by 8 to 12 days of reperfusion. Anticoagulants were not given during the reperfusion period. Risk region was assessed by planimetry of autoradiographs made from ventricular slices. Infarct size was equivalent when assessed by planimetry of ventricular slices before and after staining with triphenyltetrazolium chloride. In the seven survivors, 30 +/- 8% of the risk region was infarcted. Seven of 11 control dogs survived (p = NS); 75 +/- 4% of the risk region was infarcted in the control animals (p less than 0.01 versus treated survivors). Light microscopic inspection of specimens stained with hematoxylin-eosin confirmed the border between necrotic and preserved myocardium. Thrombus was observed in the coronary sinus in all survivors in the treatment group. These findings confirm earlier short-term studies that demonstrated a potent anti-ischemic effect of intermittent coronary sinus occlusion. At the same time, coronary sinus thrombosis warrants caution in the application of this technique to myocardial ischemia in humans.     

Myocardial protection with autoperfusion during prolonged coronary artery occlusion

Passive transcatheter coronary arterial perfusion, i.e., autoperfusion, has been introduced for clinical use to ameliorate short episodes of myocardial ischemia during percutaneous transluminal coronary angioplasty. The primary goal of this study was to evaluate the cardioprotective effect of autoperfusion after prolonged coronary artery occlusion. Accordingly, in 24 anesthetized dogs, either the left anterior descending or left circumflex coronary artery was occluded for 6 hours. The dogs were randomized to a control group subjected to coronary artery occlusion alone (n = 13) or to a group treated with transcatheter autoperfusion (n = 11). The hypoperfused zone, i.e., risk area and infarct size, were measured by autoradiography and triphenyltetrazolium chloride staining, respectively. The hypoperfused zone was 30 +/- 2% and 29 +/- 2% in the control and treated (NS) groups, respectively. When infarct size was expressed as a percent of the hypoperfused zone, it was 84 +/- 5% in the control group and 25 +/- 9% in the group treated with transcatheter autoperfusion (p less than 0.001), showing a reduction of 70%. In addition, an in vitro study showed pressure-dependent flow during autoperfusion as reflected by close linear relationship between perfusion pressure and flow (Flow = 0.54 X Pressure + 16.16, r = 0.99, n = 16). These data suggest that although passive coronary arterial perfusion for 6 hours after coronary occlusion does not prevent myocardial necrosis, it markedly reduces myocardial infarction in the canine model.     

Augmentation of regional function in nonischemic myocardium during coronary occlusion measured with two-dimensional echocardiography

Increased regional left ventricular function frequently occurs in the nonischemic myocardium after acute coronary occlusion. To further define the regional and global effects of this increased remote function in the ischemic left ventricle, 22 dogs were studied with two-dimensional echocardiography before and 1 h after left circumflex coronary artery occlusion. Two groups of dogs were identified with and without compensatory increased regional left ventricular function, defined as regional wall thickening in the nonischemic zone greater than 2 SD above baseline. After coronary occlusion, nonischemic wall thickening was 76 +/- 15% in the hyperfunction group (n = 11) and 45 +/- 14% in the nonhyperfunction group (n = 11) (p less than 0.001). Despite similar left ventricular end-diastolic cavity areas and equivalent degrees of ischemic wall thinning, dogs with increased left ventricular function in the nonischemic myocardium had a smaller extent of circumferential left ventricular dysfunction (136 +/- 33 versus 170 +/- 43 degrees, p less than 0.001) and a higher area ejection fraction (38 +/- 9% versus 27 +/- 6%, p less than 0.001). These functional differences occurred despite similar myocardial areas at risk by autoradiography (41 +/- 6% versus 37 +/- 12%, p = NS). The data suggest that increased left ventricular function in the nonischemic myocardium determines the global functional impact of acute coronary occlusion and, through interaction with adjacent myocardium, modifies the extent of circumferential left ventricular dysfunction.     

Does antiplatelet therapy enhance myocardial salvage after coronary reperfusion?

The aim of this study was to test the hypothesis that either the cyclooxygenase inhibitor aspirin or the thromboxane A2 receptor antagonist sulotroban exerts a direct myocardial effect that enhances myocardial salvage afforded by reperfusion. Accordingly, 21 anesthetized dogs underwent suture occlusion of the left anterior descending coronary artery. At 2.5 h after occlusion, all dogs received intravenous streptokinase (20,000 U/kg body weight over 30 min) and were randomized to the following groups: group I (n = 7) received no additional treatment, group II (n = 7) received aspirin (5 mg/kg intravenously) and group III (n = 7) received sulotroban (10 mg/kg followed by 10 mg/kg per h intravenously). At 3 h after occlusion, the dogs underwent coronary reperfusion for the next 3 h. Myocardial infarct size as a percent of the hypoperfused zone was similar among dogs in group I (42 +/- 8%), group II (41 +/- 10%) and group III (45 +/- 11%). The incidence and the extent of myocardial hemorrhage were similar in all three study groups. Infarct size as a percent of the hypoperfused zone was significantly smaller in dogs without hemorrhage irrespective of treatment (35 +/- 9% versus 63 +/- 5%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Autoradiographic method for measuring the ischemic myocardium at risk: effects of verapamil on infarct size aftr experimental coronary artery occlusion.

Investigation of the efficacy of pharmacologic agents affecting myocardial infarct size after coronary artery occlusion is complicated by the variability of collateral flow among experimental animals which results in variability of infarct size. To overcome this difficulty, we developed an autoradiographic method to delineate the ischemic area at risk of necrosis after coronary artery occlusion and we invetigated the potential protective effect of a calcium antagonist verapamil. The left anterior descending coronary arteries of 25 barbiturate-anesthetized dogs were occluded. Thirty minutes later, highly radioactive human albumin microspheres labeled with 99mTc were injected into the left atrium. One hour after coronary artery occlusion, dogs were randomized to control or treated groups; the latter received a 0.2 mg/kg loading dose and 0.6 mg/kg per hr maintenance dose of verapamil intravenously. Eight hours after coronary artery occlusion, the dogs were killed, the hearts were excised, and the left ventricle was sectioned parallel to the atrioventricular groove; infarct size was determined planimetrically after incubation in triphenyl tetrazolium chloride. The slices were then exposed to high-speed x-ray film with image-enhancing screens. The percentage of left ventricle that was ischemic, as determined by planimetry of autoradiographs, was similar in treated and control animals (36.6 +/- 2.0% compared to 37.3 +/- 2.8%, respectively). Of the ischemic area, 92.0 +/- 4.3% was infarcted in control animals and 70.5 +/- 5.1% was infarcted in treated animals (P < 0.01). Thus, this autoradiographic method using 99mTc-labeled human albumin microspheres is useful in delineating the area of ischemia after coronary artery occlusion and in evaluating the efficacy of pharmacologic agents designed to protect ischemic myocardium. Verapamil, administered 1 hr after coronary artery occlusion, is effective in limiting infarct size.     

Early phase acute myocardial infarct size quantification: validation of the triphenyl tetrazolium chloride tissue enzyme staining technique

Gross histochemical delineation of myocardium which has lost dehydrogenase enzyme activity has been shown to facilitate macroscopic recognition of necrotic myocardium. The present study was undertaken to assess the accuracy of the triphenyl tetrazolium chloride (TTC) technique for quantitating myocardial infarct size very early after coronary occlusion. In 16 closed-chest dogs the left anterior descending coronary artery was occluded with an intra-arterial balloon. Twelve dogs were killed 6 hours after occlusion, their hearts excised, cut from apex to base into 1 cm thick slices, and incubated in TTC. Whole-mount histologic sections of each slice were prepared. Myocardial infarct size was measured by planimetry of photographs of each gross slice and histologic section using classical criteria of necrosis. Myocardial infarct size determined in 54 slices by the TTC technique and histologically was similar (25 +/- 16% vs 27 +/- 16% of the left ventricular mass, mean +/- SD) with close correlation between the two methods (r = 0.91). Four dogs were killed 3 hours after occlusion and TTC stained and unstained myocardium was studied by electron microscopy. When the TTC technique identified necrosis so did electron microscopy. Areas identified by the TTC technique as non-necrotic were either normal or only ischemic by electron microscopy. Thus, using TTC, necrosis can be quantitated reliably 6, and even 3 hours after coronary occlusion, before histologic changes are clearly diagnostic. This technique represents a reliable, practical means for quantitation of recent infarction and for studying the evolution of ischemic injury in its early phase.     

Long-term preservation of ischemic myocardium in the dog by hyaluronidase

The administration of hyaluronidase is a promising intervention to protect the ischemic myocardium in man, but evidence of the extent to which it may reduce the ultimate size of an infarct is not well-defined. Hence, open chest, anesthetized dogs were randomized into 10 control dogs which received saline and eight treated dogs which received three doses of hyaluronidase (500 NF units/kg I.V.) at 15 minutes, 2 hours and 24 hours after occlusion of the left anterior descending coronary artery (CAO). Regional myocardial blood flow (RMBF) assessed by the microsphere technique was measured 12 minutes after CAO. The chest was then closed and the dogs were allowed to recover. Twenty-one days after CAO, the hearts were excised, divided into 1 cm thick slices and incubated in triphenyl tetrazolium chloride. Infarct size was then determined by planimetry. The left ventricular myocardium was divided into multiple samples for RMBF analysis. In control dogs 23.2 +/- 2% of the left ventricle was infarcted, compared to only 9 +/- 2.8% (P less than 0.001) in hyaluronidase-treated dogs. RMBF in noninfarcted myocardium directly adjacent to the infarct was similar to that in the normal zone remote from the infarct in the control dogs; however, in the hyaluronidase-treated dogs, blood flow in the myocardium adjacent to the infarct was significantly reduced to 68% of normal (P less than 0.01) in the outer myocardial wall and to 86% of normal (P less than 0.02) in the inner myocardial wall, which indicates that this tissue, at least in some part, was in jeopardy, but was salvaged by hyaluronidase. Epicardial electrocardiographic data showed that three weeks after CAO, Q waves were less frequent and smaller in hyaluronidase compared to untreated dogs. Preservation of the frequency and magnitude of R waves was greater in the hyaluronidase-treated group at three weeks. We conclude that hyaluronidase resulted in long-term preservation of the ischemic myocardium.     

Positron emission tomography demonstrates that coronary sinus retroperfusion can restore regional myocardial perfusion and preserve metabolism

Positron emission tomography was used to image blood flow and metabolic tracers in risk zone myocardium after left anterior descending coronary artery occlusion during synchronized coronary venous retroperfusion. Six control and seven intervention open chest dogs had occlusion of the mid left anterior descending coronary artery. Synchronized retroperfusion commenced 25 min later. Flow tracers (rubidium-82 and nitrogen-13 ammonia) were injected retrogradely. Three hours after coronary occlusion, fluorine-18 (F-18) deoxyglucose uptake in the control and treatment groups was compared. At 200 min of occlusion, infarct size was assessed. Retrograde flow tracer uptake was observed in the risk zone in the seven intervention dogs. Fluorine-18 deoxyglucose uptake in the risk zone was increased in five of the six intervention dogs but was reduced in five of the six control dogs. The risk zone to normal zone F-18 deoxyglucose count ratio was higher in the intervention than the control group (1.13 +/- 0.39 vs. 0.59 +/- 0.51; p less than 0.05). The endocardial subsegment risk zone to normal zone F-18 deoxyglucose count ratio was also significantly higher in the intervention group. Percent infarction in the risk zone was 70% lower in the group treated with synchronized retroperfusion than in the control group (18.4 +/- 22.6% vs. 61.2 +/- 25.4%; p less than 0.02). Thus, positron emission tomography revealed that retroperfusion could deliver oxygenated blood and maintain metabolism in risk zone myocardium. Infarct size was limited to 30% of that of control. In acute closure of the left anterior descending coronary artery, synchronized retroperfusion might be considered for maintaining viability of the jeopardized myocardium if the artery cannot be reopened rapidly.     

Effects of previous myocardial infarction on measurements of reactive hyperemia and the coronary vascular reserve

The measurement of coronary vascular reserve by the reactive hyperemic response to ischemia has been advocated as a practical method of assessing the physiologic significance of coronary stenoses. Because the concept of measuring coronary blood flow during maximal vasodilation assumes a normal arteriolar network and viable myocardium, the presence of previous myocardial infarction may cause a significant decrease in the coronary reserve unrelated to the severity of a coronary stenosis itself. To determine the potential importance of this effect, rest and hyperemic coronary blood flow were measured in 14 dogs in the regions subtended by the left anterior descending and left circumflex coronary arteries. One hour occlusion of the left anterior descending artery followed by reperfusion was performed in 10 dogs; the 4 remaining dogs in which no occlusion was performed served as control animals (group 3). One week later, rest and hyperemic blood flow measurements were repeated in all 14 dogs. Of the 10 dogs undergoing left anterior descending artery occlusion, 5 had a large infarct (group 1) and 5 had a small infarct (group 2). In group 1 in the 1 week study, both the coronary reserve in the left anterior descending artery zone and the ratio of the coronary reserve in this zone and the left circumflex artery zone decreased compared with values before occlusion (from 425 +/- 134 to 150 +/- 34% and from 1.56 +/- 0.40 to 0.68 +/- 0.31, respectively; both p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo nuclear magnetic resonance imaging of myocardial perfusion using the paramagnetic contrast agent manganese gluconate

Previous nuclear magnetic resonance (NMR) imaging studies have indicated that coronary occlusion does not produce sufficient changes in standard tissue relaxation times to allow the detection of acute ischemia. To identify acute myocardial perfusion abnormalities, the use of the paramagnetic agent manganese gluconate combined with calcium gluconate (MnGlu/CaGlu) was investigated in canine models of acute coronary artery occlusion. In vitro studies showed that MnGlu/CaGlu was a more efficient relaxing agent than gadolinium-DTPA (relaxivity of 7.8 versus 5.1 s-1 mM-1) and demonstrated affinity for normal myocardium. The distribution of MnGlu/CaGlu as measured by manganese-54 tracer studies was proportional to myocardial blood flow in both normal and ischemic tissue. Hearts excised from dogs after coronary artery occlusion and administration of 0.035 mM/kg MnGlu/CaGlu were imaged ex vivo using a relatively spin-lattice relaxation time (T1)-weighted gradient reversal technique (repetition time [TR] 50 ms and echo time [TE] 9 ms). These images showed increased signal intensity in the normally perfused myocardium with a mean signal intensity ratio of hypoperfused to normal myocardium of 0.55 +/- 0.12 (mean +/- SD). In vivo images obtained in nine dogs after coronary artery occlusion and administration of the same dose of MnGlu/CaGlu demonstrated the region of hypoperfused myocardium in six dogs with a signal intensity ratio of hypoperfused to normal myocardium of 0.64 +/- 0.23 (p less than 0.05 versus control). When a higher dose of 0.1 mM/kg MnGlu/CaGlu was utilized and in vivo imaging was performed using a relatively spin-spin relaxation time (T2)-weighted (TR gated, TE 60 ms) spin-echo sequence in six dogs, the signal intensity of normal myocardium was decreased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Limitation of myocardial infarct size by metabolic interventions that reduce accumulation of fatty acid metabolites in ischemic myocardium

The effects on myocardial damage of metabolic interventions by nicotinic acid, oxfenicine, or a combination of the two were assessed in open-chest dogs exposed to coronary artery occlusion for 6 hours. The accumulation of metabolites of free fatty acids (FFAs) was studied in tissue samples of the left ventricle taken 60 minutes after coronary occlusion in separate animals. The percentage of the hypoperfused zone that evolved to infarction was 96 +/- 3% (mean +/- SEM) in control dogs, 74 +/- 4% in dogs treated with nicotinic acid (p less than 0.05 vs control dogs), 72 +/- 2% in dogs treated with oxfenicine (p less than 0.05 vs control dogs), and 54 +/- 5% in dogs with combined nicotinic acid and oxfenicine (p less than 0.05 vs control dogs, p less than 0.05 vs nicotinic acid and oxfenicine). Arterial FFA concentration was markedly reduced in dogs treated with nicotinic acid and those treated with combination nicotinic acid and oxfenicine. The accumulation of long-chain acyl carnitine was substantially reduced in the ischemic myocardium after nicotinic acid, oxfenicine, and a combination of the two, whereas the lowering of long-chain acyl CoA was less pronounced. Thus, nicotinic acid and oxfenicine, which depress myocardial FFA metabolism by different mechanisms, both reduce myocardial infarct size and their effects are additive.     

The percentage of the ischemic risk zone infarcting following permanent coronary occlusion is independent of ischemic zone size

The relationship between the amount of myocardium rendered ischemic, the risk zone, and the percentage of that zone which ultimately infarcts (% I/R) was examined in the closed chest canine model. Twenty-three dogs were anesthetized with pentobarbital. A special cannula was inserted through a carotid artery into the left coronary ostium. A teflon bead was infused through the cannula, thus, embolizing a distal coronary branch. Two to 8 minutes after the coronary embolization, 20 million radiomicrospheres labeled with 141Ce (15 mu in diameter) were injected into the left ventricle. This allowed the collateral blood flow in the risk zone to be measured and defined the ischemic zone. The dogs were sacrificed either 24 or 48 hours after coronary occlusion and the hearts were excised and sectioned into 5 mm thick slices. The risk zones were visualized by microsphere autoradiography while the infarcts were visualized by triphenyl tetrazolium staining. The volumes of both zones were determined by planimetry. Experiments were retrospectively divided into either a small risk zone group (risk zones smaller than 18% of the ventricle, n = 13) or a large risk zone group (risk zones larger than 18% of the ventricle, n = 10). There was a very close correlation between the % I/R and collateral blood flow in both the small and the large risk zone groups (Y = 90.85-1.07X, r = -0.88 vs Y = 88.84-0.91X, r = -0.93). That correlation was not statistically different between the 2 groups. These findings indicate that risk zone size itself does not influence the percentage of the risk zone which is infarcted in this model.