Acute effects of delayed reperfusion on myocardial infarct shape and left ventricular volume: a potential mechanism of additional benefits from thrombolytic therapy

The purpose of this study was to characterize the effects of late reperfusion on myocardial infarct shape and to quantitate associated changes in left ventricular volume. Reperfusion was delayed until there was no salvage of ischemic myocardium. Dogs underwent 6.5 h of left anterior descending coronary artery occlusion (n = 5) or 5.5 h of occlusion and 1 h of reperfusion (n = 5). Infarct shape was measured with pairs of ultrasonic crystals implanted circumferentially in the mid myocardium. Infarct stiffness was determined from end-diastolic pressure-segment length curves produced by aortic clamping. Left ventricular volume was measured with three pairs of endocardial ultrasonic crystals and the effect of infarct shape change on left ventricular volume was determined. Infarct size, expressed as a percent of the area at risk, was similar in reperfused (97 +/- 1%) and nonreperfused (98 +/- 1%) hearts. After coronary artery occlusion, infarct segments became akinetic and functional dilation, measured as end-diastolic ultrasonic crystal separation, increased to a similar extent in reperfused (24 +/- 7%) and nonreperfused (19 +/- 3%) hearts. In 13 additional dogs that underwent reperfusion and instrumentation with endocardial ultrasonic crystals for volume measurement, left ventricular volume increased 42 +/- 6% over the preocclusion level (p less than 0.001). Within minutes of reperfusion, the infarct stiffened, infarct dilation decreased to 1 +/- 4% over the baseline preocclusion level (p less than 0.05 vs. prereperfusion) and left ventricular volume decreased to 16 +/- 11% over the baseline level (p less than 0.01 vs. postocclusion). Thus, coronary artery reperfusion reverses initial infarct dilation. Changes in infarct dilation occur immediately after reperfusion and are accompanied by infarct stiffening and a decrease in left ventricular volume. Reperfusion can affect infarct shape and stiffness at a point in time when myocardial salvage is no longer possible.     

Effect of intracoronary diltiazem on infarct size and regional myocardial function in the ischemic reperfused canine heart

This study was designed to investigate whether intracoronary diltiazem given before reperfusion could enhance myocardial salvage in the canine heart. Twenty-five dogs were subjected to 90 min of coronary occlusion followed by 4 h of reperfusion. The dogs were assigned to one of three experimental groups. The early diltiazem group received intracoronary diltiazem into the distal coronary bed at the onset of coronary occlusion and for 60 min after reperfusion. The late diltiazem group received the same amount of drug beginning 15 min before reperfusion and the control group received saline solution for 90 min of occlusion and 60 min of reperfusion. Infarct size expressed as a percent of the area at risk was significantly smaller in the early and late diltiazem groups (15.6 +/- 3.6% and 21.2 +/- 5.1%, respectively) than in the control group (49 +/- 4.6%) (p less than 0.05). Intracoronary diltiazem restored systolic function of the stunned, previously ischemic tissue to essentially normal preocclusion values. Segmental shortening after reperfusion averaged 21.6% in the early diltiazem group versus 0 +/- 1.7% and 7.3 +/- 4% for the control and late diltiazem groups, respectively (p less than 0.05). Low dose intracoronary diltiazem did not alter hemodynamic variables or myocardial blood flow but did improve segmental shortening 2 and 6 h after reperfusion. These data indicate that intracoronary diltiazem given during occlusion or just before reperfusion increases the salvage of myocardium compared with the salvage achieved by reperfusion alone. These results also suggest that intracoronary diltiazem given during the ischemic period enhances systolic contractile function of postischemic stunned myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Streptokinase improves reperfusion blood flow after coronary artery occlusion

Streptokinase is an effective thrombolytic agent which, with early restoration of coronary blood flow, has the potential for limiting infarct size. Distinct from thrombolysis, we studied the effects of streptokinase on reperfusion coronary blood flow and infarct size. Open-chest anesthetized canines underwent a 90 minute snare occlusion of the left circumflex coronary artery followed by release and reperfusion through a critical stenosis for 6 hours. The animals were assigned randomly to two groups. Intracoronary streptokinase [group 1 (n = 8): 6000 IU/kg in 3 ml of saline] or saline [group 2 (n = 8): 3 ml of saline] was infused at 0.05 ml/min for 60 minutes beginning 30 minutes before reperfusion. Coronary blood flow was stable in group 1 during reperfusion, while in group 2 it fell during 6 hours of reperfusion (30 +/- 4 ml/min to 18 +/- 2 ml/min, P = 0.05). The ST-segment elevation on the limb lead II electrocardiogram 15 minutes after coronary artery occlusion was similar in both groups (group 1: 3.9 +/- 0.6 mV, group 2: 2.3 +/- 0.5 mV), suggesting the extent of myocardial ischemia was also similar in both groups. The infarct sizes were similar when expressed both as a percent of the total left ventricular mass [(IZ/LV) group 1: 17 +/- 2.5%, group 2: 17.5 +/- 2.5%] or as a percent of the area at risk of infarction [(IZ/AR) group 1: 39 +/- 6%, group 2: 39 +/- 5%]. In both groups, the mass of left ventricle dependent on the blood flow distribution of the left circumflex coronary artery was similar when compared to total left ventricular mass [(AR/LV) group 1: 41 +/- 3%, group 2: 44 +/- 4%]. These results demonstrate that streptokinase maintains reperfusion coronary blood flow through a critical stenosis at a rate similar to baseline levels. Despite the fact that coronary blood flow remained stable with streptokinase during reperfusion, infarct size was not limited after 90 minutes of fixed coronary artery occlusion in this canine model of myocardial injury.     

Limitation of myocardial infarct size by superoxide dismutase as an adjunct to reperfusion after different durations of coronary occlusion in the pig

Superoxide dismutase (SOD) has been documented to limit myocardial infarct size in the richly collateralized dog heart. This study was designed to explore this concept in a low-collateralized animal model. A blind, randomized, placebo-controlled protocol was used in 65 pentobarbital-anesthetized pigs subjected to closed-chest left anterior descending coronary artery occlusion for 30 (n = 22), 60 (n = 22), and 90 (n = 14) minutes followed by reperfusion up to 24 hours from the start of occlusion. Another seven control pigs were subjected to 24 hours of permanent occlusion. A total dose of 9 mg/kg bovine CuZn SOD was administered as a bolus injection immediately before reperfusion followed by a 1-hour infusion. Infarct size was assessed by tetrazolium staining. Myocardium at risk and collateral flow were determined by using cerium-141-labeled microspheres (15 microns) during the occlusion. After 30 minutes of occlusion, infarct sizes in placebo versus SOD-treated animals were 45.5 +/- 15.7% vs. 23.8 +/- 15.6% of myocardium at risk (p = 0.007). The corresponding values after 60 minutes of occlusion were 78.6 +/- 9.3% vs. 66.9 +/- 14.6% (p = 0.035). SOD administered after 90 minutes of occlusion did not limit infarct size (88.5 +/- 4.8% vs. 92.3 +/- 5.2%). Twenty-four hours of coronary occlusion resulted in infarction of 92.4 +/- 4.2% of myocardium at risk. (All values are mean +/- SD.) Ventricular fibrillation occurred in only nine pigs distributed equally between SOD and placebo. The results indicate that CuZn SOD has the potential to further improve the myocardial salvage established by reperfusion of an ischemic pig heart territory. However, the narrow time window for limiting infarct size in the pig by reperfusion is not much extended by SOD.     

In vivo delineation of myocardial hypoxia during coronary occlusion using fluorine-18 fluoromisonidazole and positron emission tomography: a potential approach for identification of jeopardized myocardium

Previous studies have demonstrated that the positron-emitting fluorine-18 (18F)-labeled fluoromisonidazole is a specific tracer of myocardial hypoxia. Its fractional extraction is enhanced in ischemic or hypoxic myocardium but returns to baseline levels on reperfusion and recovery of normal function. Thus, this agent might be useful in delineating acutely hypoxic but potentially salvageable myocardium. Accordingly, to delineate the relation between the myocardial extraction of 18F-fluoromisonidazole after intravenous administration and the time of antecedent ischemia in vivo, uptake of tracer was measured with positron emission tomography and direct postmortem tissue analysis in 14 dogs in which tracer was administered within 3 h of coronary occlusion (a time associated with marked potential for salvage on reperfusion); in 4 dogs after 6 h of coronary occlusion (a time associated with minimal salvage of myocardium on reperfusion); and in 8 dogs after greater than 24 h of coronary occlusion (to delineate uptake in tissue that is irreversibly damaged). The residual fraction (that is, the amount of tracer extracted and retained in a region) in ischemic myocardium in the dogs in which 18F-fluoromisonidazole was administered within 3 h after occlusion averaged (+/- standard deviation) 23 +/- 18%, which was higher than the residual fraction in myocardium subjected to ischemia for either 6 or greater than 24 h before tracer administration (12 +/- 7% and 5 +/- 2%, respectively, p less than 0.01 for both). Retention of tracer in remote normal myocardium averaged 2 +/- 1%.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of cytochrome C on the extent of myocardial infarction and regional function of the ischemic myocardium

The effects of cytochrome C, an electron carrier in the process of oxidative phosphorylation, on infarct size and regional left ventricular function after a coronary artery occlusion were investigated. Thus, in 30 dogs, 1 minute after left anterior descending coronary artery occlusion, 99mTc-labeled albumin microspheres (8 mCi) were injected into the left atrium for subsequent assessment of the hypoperfused zone, that is, the area at risk of infarction. Fifteen minutes after coronary artery occlusion, dogs were randomized into a control group (n = 15) and a cytochrome C-treated group (n = 15). The latter immediately received cytochrome C, 2.5 mg/kg intravenously. Six hours after coronary artery occlusion the dogs were sacrificed and their left ventricles were cut into 3 mm thick slices. Infarct size was determined by triphenyltetrazolium chloride staining and measured by planimetry. The same slices were then submitted to autoradiography and the hypoperfused zone was then measured by planimetry. The hypoperfused zone was 22 +/- 2% and 23 +/- 2% of the left ventricle in the control and treated groups, respectively (NS), indicating that the extent of myocardium at risk before treatment was similar. The extent of the hypoperfused zone which evolved to necrosis was 90 +/- 3% in the control group but only 50 +/- 7% in the treated group (p less than 0.001). Myocardial salvage in the treated group was paralleled by improvement in systolic wall thickness of the ischemic segment as measured by two-dimensional echocardiography. Thus, cytochrome C reduced the extent of myocardial necrosis by 44% and improved systolic function of the ischemic myocardium.     

Improved regional myocardial blood flow, left ventricular unloading, and infarct salvage using an axial-flow, transvalvular left ventricular assist device. A comparison with intra-aortic balloon counterpulsation and reperfusion alone in a canine infarction model.

BACKGROUND. It has been suggested that left ventricular unloading at the time of reperfusion provides superior infarct salvage over reperfusion alone. The purpose of this study was to show that the Hemopump transvalvular axial-flow left ventricular assist device provides superior left ventricular unloading, ischemic zone collateral blood flow, and infarct size reduction compared with intra-aortic balloon counterpulsation and reperfusion alone. METHODS AND RESULTS. Eighteen dogs were instrumented with regional myocardial function sonomicrometers in the ischemic and control zones. The left anterior descending coronary artery just distal to the first diagonal branch was instrumented with a silk snare and Doppler flow probe. Additionally, pressure catheters were placed in the left atrial appendage, left ventricular apex, and ascending aorta for hemodynamic measurements. Regional myocardial blood flow was determined by using 15-microns radioactive microspheres. Measurements were made in the control state, immediately after coronary occlusion, at 1 and 2 hours after coronary occlusion, with reperfusion, and 1 hour after reperfusion. In treated animals, left ventricular assistance was maintained during the entire period of occlusion and reperfusion. The Hemopump was associated with a significant decrease in left ventricular systolic and diastolic pressure, whereas mean arterial pressure was maintained. Intra-aortic balloon counterpulsation resulted in no significant changes in left ventricular systolic pressure and a modest decrease in left ventricular diastolic pressure. Regional unloading as assessed by sonomicrometers was significant in the Hemopump animals and absent in the balloon pump animals. Absolute regional myocardial blood flow in the ischemic zone increased slightly (p = 0.002) in the Hemopump animals and did not change in the balloon pump animals. Infarct size expressed as percentage of the zone at risk was 62.6% in the control animals, 27.22% in the balloon pump animals, and 21.7% in the Hemopump animals. CONCLUSIONS. Mechanical unloading of the ventricle during ischemia and reperfusion appears to result in significant infarct salvage compared with reperfusion alone. The Hemopump appears to provide superior left ventricular systolic and diastolic unloading compared with intra-aortic counterpulsation in a canine model.     

Effect of superoxide dismutase on infarct size and postischemic recovery of myocardial contractility and metabolism in dogs

The effects of superoxide dismutase treatment on infarct size, postischemic recovery of contractile function and tissue content of high energy phosphates were examined in a canine model of myocardial ischemia and reperfusion. Ischemia was induced by thrombotic occlusion of a coronary artery and reperfusion was achieved by intravenous thrombolysis. Average duration of ischemia was 90 min. Fifty closed chest anesthetized dogs were randomized to receive either superoxide dismutase (34,000 IU/min intravenously) or placebo, starting approximately 30 min before and continuing for 30 min into the reperfusion phase. Left ventricular ejection fraction and regional segmental shortening of the postischemic area were calculated from contrast angiograms after 4 h, 48 h and 1 week of reperfusion. Tissue content of high energy phosphates was determined from transmural biopsy after 4 h and 1 week. Infarct size was measured by planimetry of dye-stained heart slices. In the superoxide dismutase and placebo-treated groups, respectively, the mortality rate was 25% and 16%, collateral flow 20 +/- 10 and 23 +/- 18 ml/min per 100 g, area at risk 25 +/- 6% and 26 +/- 7% of the left ventricle and infarct size 28 +/- 19% and 36 +/- 27% of the area at risk. Multiple regression analysis failed to show any beneficial effect of superoxide dismutase treatment on infarct size. Left ventricular ejection fraction, regional segmental shortening of the postischemic area and tissue content of high energy phosphates recovered to a similar extent and at a similar rate in both treated and placebo groups up to 1 week after reperfusion. Thus, in this model of coronary occlusion and reperfusion superoxide dismutase treatment is of no benefit.     

Enhanced thrombolysis,reduced coronary reocclusion and limitation of infarct size with liposomal prostaglandin E1in a canine thrombolysis model

Objectives. The purpose of this study was to test the hypothesis that liposomal prostaglandin E₁(TLC C-53) would result in more rapid thrombolysis, less reocclusion and smaller infarct size when administered with heparin and streptokinase in a canine thrombolysis model.Background. In experimental animals, prostaglandin E₁has been shown to augment thrombolysis, improve coronary flow and reduce infarct size when infused directly into the left atrium. TLC C-53 is a stable preparation of prostaglandin E₁bound by phospholipid microspheres that produces fewer adverse hemodynamic effects during intravenous use.Methods. To investigate the effects of TLC C-53 on coronary patency and infarct salvage, we studied 30 conditioned open chest dogs. After coil-induced left anterior descending coronary artery occlusion and 1 h of clot maturation, the dogs were randomly assigned to receive a 10-min intravenous infusion of either TLC C-53 (2 μg/kg body weight) or placebo. Both groups then received intravenous heparin and streptokinase. Hemodynamic variables and Doppler coronary flow were monitored, and myocardial blood flow was determined using radioactive microspheres. Infarct size was assessed with triphenyltetrazolium chloride staining.Results. Thrombolysis time was accelerated from 79 ± 38 to 47 ± 9 min (mean ± SD), and coronary patency was greater (100% vs. 50%) with TLC C-53 than with placebo (p < 0.05). Moreover, for arteries that recanalized, coronary Doppler flow and myocardial perfusion were more severely impaired with placebo. Infarct size as a percent of the area at risk was higher (p < 0.05) with placebo (51 ± 15%) than with TLC C-53 (33 ± 14%). Neutrophil infiltration into ischemic myocardium determined by myeloperoxidase assay was also significantly greater in the placebo group.Conclusions. TLC C-53 administered intravenously before thrombolytic therapy resulted in a significant acceleration of thrombolysis time, improvement in coronary patency and blood flow during reperfusion and a reduction in infarct size.     

Amelioration of ischemia- and reperfusion-induced myocardial injury by the selective estrogen receptor modulator, raloxifene, in the canine heart

BACKGROUND: 17 beta-estradiol reduces myocardial infarct size which is mediated by nitric oxide (NO) and the opening of Ca (2+)-activated K+ (KCa) channels. Raloxifene, a selective estrogen receptor modulator, demonstrates acute coronary artery vasorelaxing effects. Whether raloxifene reduces ischemia/reperfusion injury and what mechanisms are involved in the cardioprotective effects were investigated. METHODS: Infarct size was measured in open-chest dogs following occlusion of the left anterior descending coronary artery for 90 min and subsequent reperfusion for 6 hr. The incidence of ventricular fibrillations during reperfusion period was also observed. Infusion of raloxifene and/or other drugs into the left anterior descending coronary artery was initiated 10 min before coronary occlusion and continued until 1 hr after reperfusion started without an occlusion period. RESULTS: Infarct size was reduced in the raloxifene (5 micrograms/kg/min) group compared with the control group (6.8 +/- 4.2% vs 40.9 +/- 3.9% of the area at risk, p < 0.01). Either NG-nitro-L-arginine methyl ester, the inhibitor of NO synthase (infarct size: 22.8 +/- 5.4%, p < 0.05 vs raloxifene or the control) or charbdotoxin, the blocker of KCa channels (infarct size: 23.5 +/- 5.1%, p < 0.05 vs raloxifene or the control), partially attenuated the infarct size-limiting effect, and combination of both agents completely abolished the effect (infarct size: 37.7 +/- 5.8%). The incidence of ventricular fibrillations was also less in the raloxifene group than in the control group(11% vs 44%, p < 0.05). CONCLUSIONS: Raloxifene reduces myocardial infarct size and the incidence of ventricular fibrillations by NO- and the opening of KCa channels-dependent mechanisms in canine hearts.     

Experimental and clinical investigations for the time interval from onset of symptoms to the coronary reperfusion

To clarify the relationship between time interval from the onset of coronary occlusion to the reperfusion and reperfusion rates or left ventricular function, an experiment with 113 mongrel dogs was carried out. Coronary thrombi experimentally induced within 4 hours in 63 dogs were rapidly lysed by intracoronary thrombolytic agent (Experiment 1). Infarct size was investigated in 17 dogs. The infarct size (% of left ventricle) in 9 dogs with 4-hour reperfusion following 2-hour coronary occlusion was significantly smaller than that in 8 dogs with 6-hour occlusion (12.0 +/- 7.9 vs 19.1 +/- 8.7% respectively p less than 0.05) (Experiment 2). The infarct size in 8 dogs with 7-day reperfusion following 2-hour occlusion was also significantly reduced compared to that in 7 dogs with 7-day occlusion (16.3 +/- 7.4 vs 28.5 +/- 8.9%, respectively p less than 0.02) (Experiment 3). The infarct size in 11 dogs with 4-hour reperfusion with verapamil administration following 2-hour occlusion was significantly reduced compared to that in 7 dogs with 6-hour occlusion without verapamil (5.5 +/- 1.9 vs 20.3 +/- 3.3%, respectively p less than 0.01) (Experiment 4). In experiment 3, anterior wall motion also was assessed by contrast ventriculography and infarct related areas in reperfused group was found to be improved compared to non-reperfused group at 7 days after infarction. In clinical studies, 121 patients who were admitted within 12 hour of onset of symptoms, were investigated to evaluate reperfusion rates and left ventricular function. The reperfusion rate of young age thrombus within 3 hours was 89% of 18 patients with completely occluded coronary artery. It was 77% of the 52 patients with 3 to 6 hour occlusion and 72% of the 18 patients with over 6 hour occlusion. There was a tendency towards high reperfusion rates in younger thrombus. In patients who were recanalized within 3 hours from the onset of symptoms ejection fraction of left ventricle at the chronic stage had a significantly higher percentage when compared to the unsuccessful group. Wall motion of infarct-related areas in patients who were thrombolysed within 6 hours was improved compared to the unsuccessful group. Administration of verapamil during reperfusion in patients with acute myocardial infarction suppressed rapid CK release and sigma CK. Thus, young age thrombus can be lysed easily, earlier recanalization after coronary occlusion can reduce infarct size and improve left ventricular function. Reinforced administration of verapamil during reperfusion can also reduce infarct size.     

Infarct resorption, compensatory hypertrophy, and differing patterns of ventricular remodeling following myocardial infarctions of varying size

OBJECTIVES: We sought to identify advantages of contrast-enhanced magnetic resonance imaging (MRI) in studying postinfarction ventricular remodeling. BACKGROUND: Although sequential measurements of ventricular volumes, internal dimensions, and total ventricular mass have provided important insights into postinfarction left ventricular remodeling, it has not been possible to define serial, directionally opposite changes in resorption of infarcted tissue and hypertrophy of viable myocardium and effects of these changes on commonly used indices of remodeling. METHODS: Using gadolinium-enhanced MRI, the time course and geometry of changes in infarcted and noninfarcted regions were assessed serially in dogs subjected to coronary occlusion for 45 min, 90 min, or permanently. RESULTS: Infarct mass decreased progressively between three days and four to eight weeks following coronary occlusion; terminal values averaged 24 +/- 3% of those at three days. Radial infarct thickness also decreased progressively, whereas changes in circumferential and longitudinal extent of infarction were variable. The ability to define the circumferential endocardial and epicardial extents of infarction allowed radial thinning without epicardial expansion to be distinguished from true infarct expansion. The mass of noninfarcted myocardium increased by 15 +/- 2% following 90-min or permanent occlusion. However, the time course of growth of noninfarcted myocardium differed systematically from that of infarct resorption. Measurements of total ventricular mass frequently failed to reflect concurrent changes in infarcted and noninfarcted regions. Reperfusion accelerated infarct resorption. Histologic reductions in nucleus-to-cytoplasm ratios corresponded with increases in noninfarcted ventricular mass. CONCLUSIONS: Concurrent directionally opposite changes in infarcted and noninfarcted myocardium can be defined serially, noninvasively, and with high spatial resolution and full ventricular coverage following myocardial infarction.     

Quantification of myocardial infarction during coronary occlusion and myocardial salvage after reperfusion using cardiac imaging with technetium-99m hexakis 2-methoxyisobutyl isonitrile

Myocardial imaging with technetium-99m hexakis 2-methoxyisobutyl isonitrile was investigated as a means to assess myocardial infarct size during coronary occlusion and to quantify the extent of salvaged myocardium after coronary occlusion followed by reperfusion. Open chest dogs underwent either a permanent coronary artery occlusion (Group 1, n = 16) or a 2 h occlusion followed by reperfusion (Group 2, n = 15). Animals in both groups were killed 48 h after occlusion. During coronary occlusion, 23 of the 25 dogs that survived the coronary occlusions had abnormal myocardial scintigrams. The scintigraphic perfusion defect size correlated well with the pathologic infarct size (r = 0.85 and 0.95 by planar and tomographic imaging, respectively). The planar scintigraphic defect size, but not the tomographic defect size, overestimated the pathologic size. The planar scintigraphic defect size observed during coronary occlusion was markedly reduced 48 h after reperfusion (24.8 +/- 12.8% to 10.6 +/- 9.7% of the left ventricle, p less than 0.003). The uptake of technetium-99m hexakis 2-methoxyisobutyl isonitrile in the ischemic myocardium increased significantly 48 h after reperfusion (p less than 0.003) and correlated with the increase in regional myocardial blood flow, as assessed by radioactive microspheres (r = 0.83, p less than 0.01). Thus, myocardial imaging with technetium-99m hexakis 2-methoxyisobutyl isonitrile allows reliable demonstration of the presence of acute infarction, estimation of infarct size and quantification of the extent of salvaged myocardium after coronary reperfusion.     

Effects of nicardipine, a calcium antagonist, on myocardial salvage and high energy phosphate stores in reperfused myocardial injury

The current study determined the effectiveness of nicardipine, a 1,4-dihydropyridine calcium antagonist, in preserving reperfused myocardium in a cat model of temporary coronary occlusion and ascertained if replenishment of myocardial phosphate stores during reperfusion as defined by phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy was indicative of salvage. Twenty open chest, anesthetized cats were studied with use of a snare ligature around the proximal left anterior descending coronary artery, with a coil sutured to the epicardial surface overlying the distribution of the artery. Peak areas of phosphocreatine, inorganic phosphate and adenosine triphosphate (ATP) NMR signals were measured during 1 h of occlusion followed by 1.5 h of reperfusion. Infarct size and jeopardy area were determined in vitro by simultaneous infusion of phthalocyanine blue dye and triphenyltetrazolium chloride into the aorta and the left anterior descending coronary artery, respectively, after 5 h of myocardial reperfusion. Nicardipine-treated and control groups had similar jeopardy area values (41.2 +/- 1.6% versus 47.4 +/- 3.1% of the left ventricle), but infarct area was significantly reduced in the nicardipine-treated group (3.2 +/- 1.1% versus 24.9 +/- 7.5% of jeopardy area, p less than 0.01). High energy phosphate compounds remained markedly altered during reperfusion in both groups. No significant improvement in phosphocreatine or inorganic phosphate recovery was observed in animals pretreated with nicardipine despite an 87% reduction in infarct size. Myocardial ATP was greater during reperfusion in the nicardipine-treated compared with the control group (average over initial 90 min of reperfusion 58 +/- 6% versus 46 +/- 3% of baseline values, p less than 0.05), suggesting improved recovery of ATP. However, the measured levels of high energy phosphate compounds during reperfusion and their ratios did not correlate with infarct size and thus were not predictive of myocardial salvage.     

Use of left ventricular function as an end point of thrombolytic therapy.

In recent acute myocardial infarction, early reperfusion of the infarct-related artery by intracoronary or intravenous thrombolytic therapy induces a significant limitation of infarct size, provided reperfusion occurs within a time frame that myocardial salvage can still be expected. Limitation of infarct size reduces scar tissue formation, aneurysm formation, infarct zone expansion, left ventricular volume enlargement, and eventually results in higher left ventricular ejection fraction. Infarct size limitation and left ventricular function preservation occur with all thrombolytic agents currently in clinical use: streptokinase, alteplase and, more recently, anistreplase. When anistreplase is compared with conventional heparin therapy, a 31% reduction in infarct size is found (estimated from single photon emission computed tomography, or SPECT). This translates into a significant preservation of left ventricular ejection fraction as observed in anistreplase-treated patients compared with heparin-treated patients (0.53 +/- 0.13 vs 0.47 +/- 0.12, p less than 0.002). In comparative trials of 2 thrombolytic agents, anistreplase was demonstrated to be as efficient as alteplase on left ventricular ejection fraction preservation and infarct size limitation.     

Treatment of reperfusion injury with intracoronary calcium channel antagonists and reduced coronary free calcium concentration in regionally ischemic, reperfused porcine hearts

The effect of intracoronary diltiazem, EGTA (ethylene-bis-(beta-aminomethylether)-N,N'-tetraacetic acid), nifedipine, verapamil and isotonic saline solution as placebo on reperfusion injury was investigated in regionally ischemic, reperfused porcine hearts. The left anterior descending coronary artery was distally occluded for 45 min and was reperfused for 3 days. Intracoronary infusion was started immediately before reperfusion and continued during 45 min of reperfusion. Infarct size was determined as the ratio of infarcted (tetrazolium stain) to ischemic myocardium (dye technique). Regional systolic shortening was assessed by sonomicrometry. Apart from left ventricular end-diastolic pressure before ischemia and during 45 min of reperfusion, global hemodynamic values in the five treatment groups did not differ; in particular, calculated left ventricular oxygen consumption before and during ischemia was equally low. Intracoronary EGTA decreased coronary venous free calcium concentration to about 70% of baseline value. Infarct size was reduced from 76 +/- 10% (control group, n = 8) to 60 +/- 10% (p less than 0.01) by intracoronary diltiazem (n = 8) and to 55 +/- 15% (p less than 0.01) by intracoronary EGTA (n = 8). Insignificant reductions in infarct size were found after treatment with intracoronary verapamil (63 +/- 18%, n = 8) and intracoronary nifedipine (68 +/- 9%, n = 7). Regional systolic shortening of the risk region, which did not differ among the groups before occlusion and during ischemia, recovered to the greatest extent in the EGTA-treated pigs (p less than 0.01 compared with values in the control group). Treatment with intracoronary calcium antagonists resulted in only marginal improvement of systolic shortening.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of propranolol and diltiazem alone and in combination on the recovery of left ventricular segmental function after temporary coronary occlusion and long-term reperfusion in conscious dogs

We evaluated the ability of propranolol and diltiazem alone and in combination to enhance the recovery of left ventricular (LV) segmental function during 1 month of reperfusion after two temporary occlusions of the left anterior descending coronary artery (LAD) in conscious dogs instrumented with ultrasonic crystals for the measurement of regional net systolic wall thickening (NET). LV segments were classified according to their contractile function after 1 hr of LAD occlusion: class 1, greater than 67% of preocclusion (control) NET; class 2, 0% to 66.9%; class 3, less than 0% (paradoxical systolic wall thinning). Propranolol (1 mg/kg iv) or diltiazem (20 micrograms/kg/min) was given 65 min after LAD occlusion in dogs that had 2 (group I) or 4 hr (group II) of LAD occlusion. Diltiazem plus propranolol (same doses) were given to another group of dogs that underwent 4 hr (but not 2) of LAD occlusion. Untreated control dogs received 25 ml of saline and underwent 2 or 4 hr of LAD occlusion. The NET of class 2 and 3 segments in group I control dogs increased significantly during 1 month of reperfusion, from 32 +/- 5% and -43 +/- 6% to 66 +/- 9% and 26 +/- 9%, respectively (p less than .05). Neither diltiazem nor propranolol enhanced the long-term recovery of these segments in group I dogs. However, diltiazem prevented further deterioration of contractile dysfunction observed in control dogs immediately after reperfusion in both segment classes. The NET of class 2 segments in group II control dogs after 4 weeks of reperfusion remained at levels observed during LAD occlusion: 30 +/- 4% to 37 +/- 12%. Class 3 NET increased from -33 +/- 5% to 12 +/- 12% with 1 month of reperfusion, but these segments were essentially akinetic. Propranolol or diltiazem alone did not produce significant overall increases in NET, but diltiazem again prevented further declines in NET of class 2 and 3 segments during early reperfusion. However, the combination of diltiazem and propranolol significantly enhanced overall recovery of class 2 NET in group II dogs (44 +/- 3% to 88 +/- 7%) and prevented the worsening of NET associated with early reperfusion. Compared with untreated dogs, propranolol plus diltiazem also significantly decreased the extent of histologic necrosis in class 2 and 3 segments as well as the macrohistochemically determined infarct size in group II dogs.(ABSTRACT TRUNCATED AT 400 WORDS)     

Preconditioning causes improved wall motion as well as smaller infarcts after transient coronary occlusion in rabbits

BACKGROUND. A brief coronary occlusion before a more prolonged occlusion results in less myocardial infarction than the longer occlusion alone. However, the effects of this preconditioning on recovery of systolic function after coronary occlusion have not been determined. METHODS AND RESULTS. Ultrasonic crystals implanted in rabbit myocardium measured segment length in the distribution of a branch of the left coronary artery that was fitted with a snare occluder. Rabbits were randomly allocated to either nonpreconditioned or preconditioned groups. Rabbits in the latter group underwent preconditioning with a 5-minute coronary occlusion followed by 10 minutes of reperfusion. Then the coronary artery was occluded for 20 minutes in all rabbits, after which it was allowed to reperfuse for 90 minutes. The hearts were then excised, and infarct size was measured by staining with triphenyltetrazolium chloride. During coronary occlusion, all hearts except one demonstrated either akinesis or paradoxical bulging. Five minutes after release of the 20-minute occlusion, active shortening had returned in the preconditioned rabbits and averaged 27.9 +/- 16.6% of baseline shortening. At the same time, paradoxical lengthening persisted in nonpreconditioned rabbits (-15.5 +/- 19.8% of baseline). By the end of the 90-minute reperfusion period, segment shortening averaged 40.1 +/- 8.4% of baseline in preconditioned rabbits and only 6.2 +/- 12.0% in nonpreconditioned rabbits (p less than 0.05). Infarct size as a percentage of risk area was significantly smaller in preconditioned rabbits as well (3.0 +/- 1.6% versus 28.8 +/- 7.0%, p less than 0.002) and likely accounted for the improved shortening. CONCLUSIONS. We conclude that a brief coronary occlusion before a more prolonged occlusion results in not only reduced infarct size but also significantly better recovery of systolic function.     

More rapid thrombolysis with coronary venous retroinfusion of streptokinase compared with intravenous administration. An experimental study in canines

The efficacy of coronary venous retroinfusion vs intravenous administration of streptokinase was compared in 20 closed chest dogs with copper coil induced thrombosis of the left anterior descending coronary artery. Streptokinase was continuously infused for 60 min (100 IU kg-1 min-1) starting 60 min after coronary artery occlusion. Time to clot lysis was determined by coronary angiography performed at 5 min intervals. Complete lysis occurred in eight out of 10 dogs receiving intravenous streptokinase and in all 10 dogs in the coronary venous group. Time to thrombolysis was significantly shorter with coronary venous retroinfusion (23 +/- 8 min) than after systemic infusion (62 +/- 26 min; P less than 0.001). Recovery of ischaemic zone left ventricular systolic function, studied by two-dimensional echocardiography, was significantly better in the animals that received retrograde streptokinase than in the group that received intravenous streptokinase (17 +/- 12% vs -2 +/- 16%; P less than 0.05). Myocardial necrosis expressed as a percentage of the risk area was 8 +/- 12% after retroinfusion of streptokinase compared with 32 +/- 25% (P less than 0.005) after intravenous administration. In conclusion, coronary venous administration of streptokinase was more effective than intravenous therapy as determined by more rapid clot lysis which resulted in improved functional recovery of the ischaemic myocardium and a significant reduction in myocardial necrosis.