Biomechanical properties of reperfused transmural myocardial infarcts in rabbits during the first week after infarction. Implications for left ventricular rupture.

Left ventricular (LV) rupture potential was studied after transmural myocardial infarction (MI) in rabbits by measuring 1) the tensile strength of infarcted tissue strips, 2) the force required to initiate a tear (tear threshold) in the central infarcted region, and 3) the intracavitary pressure required to rupture the infarcted ventricle. During the first week after MI, infarcts resulting from a permanent coronary occlusion were compared with infarcts reperfused "late" (i.e., 3 hours) after coronary occlusion with a resultant hemorrhagic transmural infarct but no reduction in infarct size. The reperfused hemorrhagic infarcted strips had less tensile strength than strips from permanently occluded infarcts in the initial 24 hours after MI (16 +/- 1 versus 24 +/- 3 g/mm2, p less than 0.05), but the tear threshold and response to increased LV pressure were not influenced by infarct reperfusion at this time. By 3 days after MI, reperfused infarcts had equal tensile strength, had greater resistance to infarct tearing, and could withstand a greater LV distending pressure compared with permanently occluded infarcts. By 5 days after MI, reperfused infarcts maintained a greater tear threshold but had less tensile strength than permanently occluded infarcts, although all infarct values were equivalent or greater than normal LV values. By 7 days after MI, reperfused and permanently occluded infarcts were equally strong by all measurements. Thus, late reperfusion of transmural infarcts increased resistance to infarct tearing and LV rupture above that of nonreperfused permanently occluded infarcts by 3 days after MI and enhanced tissue strength after an initial 24-hour vulnerable period. These findings suggest that late reperfusion may accelerate myocardial healing after MI.     

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.     

Pulmonary edema formation after myocardial infarction and coronary reperfusion: intravascular and extravascular pulmonary fluid volumes. IV

Two studies were performed to assess the importance of coronary reperfusion on pulmonary capillary endothelial permeability in 34 anesthetized dogs. The response of intravascular pulmonary blood volume (PBV) and extravascular lung water (EVLW) was examined using indicator-dilution and postmortem (wet weight/dry weight) techniques. In the first study, six dogs served as sham controls, seven were occluded (LAD) for 45 min, and seven occluded for 45 min and reperfused for 15 min. While PBV was similar in each group, EVLW was greater in the reperfused than nonreperfused dogs (9.5 +/- 0.7 cc/kg vs 8.1 +/- 0.8 cc/kg; P less than .05), and both occluded groups were greater (P less than .01) than the control animals (7.0 +/- 1.0 cc/kg). Similar trends in postmortem wet weight/dry weight data were observed when compared with the in vivo EVLW data. In a second study of 14 open-chest dogs, an LAD ligation was held for 45 min in 14 dogs. In seven dogs, reperfusion was allowed for 15 min. A left atrial (LA) balloon was then inflated in all 14 dogs, increasing left atrial pressure to 25 mmHg in each dog for 90 min. Once again, PBV was similar in both groups, but EVLW was greater at the matched level of LA pressure elevation (14.6 +/- 3.2 cc/kg nonreperfused vs 18.7 +/- 4.1 cc/kg reperfused dogs; P less than .01). Again, postmortem data confirmed these data. Thus, we conclude coronary occlusion accelerates EVLW formation independent of LA pressure. Edema formation is worsened by coronary reperfusion, suggesting that the washout of myocardial toxins from the ischemic myocardium alters endothelial permeability.(ABSTRACT TRUNCATED AT 250 WORDS)     

Detection of myocardial reperfusion by analysis of serum creatine kinase isoforms

Serum creatine kinase (CK) MM isoforms were determined by chromatofocusing in 22 patients with acute myocardial infarction undergoing intracoronary thrombolysis. In 13 patients with successful coronary recanalization within 3.6 +/- 1.0 (SD) h after onset, time to peak CK activity occurred 13 +/- 3 h after onset which was significantly shorter (p less than 0.01) than that in 9 patients without coronary recanalization (20 +/- 4 h). The proportion of CK MM-A, the myocardial isoform, in serum in the reperfused group at 6, 10, and 14 h after onset (53 +/- 9, 38 +/- 5, and 27 +/- 4%, respectively) was always significantly lower (p less than 0.01) than that in the nonreperfused group (69 +/- 7, 59 +/- 8, and 43 +/- 4%). During the same period, the proportions of CK MM-B and CK MM-C, the converted isoforms derived intravascularly from MM-A by circulating carboxypeptidase, in the reperfused group were always significantly higher (p less than 0.01) than those in the nonreperfused group. The ratios of MM-A% to MM-B% and MM-A% to MM-C% amplified the differences between the two groups. At 10 h after onset, these ratios clearly differentiated the reperfused and the nonreperfused group at the values of 1.0 (MM-A/MM-B) and 3.0 (MM-A/MM-C) with the diagnostic sensitivity of 85% and 92%, respectively. Thus, myocardial reperfusion was detectable noninvasively by analysis of serum CK MM isoforms during the early stage of acute myocardial infarction.     

Effect of reperfusion on electrocardiographic and enzymatic infarct size: results of a randomized multicenter study of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) versus intracoronary streptokinase in acute myocardial infarction

The effect of early coronary artery reperfusion on ECG and enzymatic parameters was examined in 240 patients with acute myocardial infarction. These patients had participated in a randomized trial comparing intravenous anisoylated plasminogen streptokinase activator complex (APSAC) (n = 123) and intracoronary streptokinase (n = 117) therapy. Reperfusion occurred in 59 of 115 (51%) patients receiving APSAC and 67 of 111 (60%) patients receiving streptokinase (p = NS). There was greater early resolution of ST segment elevation in the reperfused than in the nonreperfused patients (p less than or equal to 0.003) and more rapid Q wave evolution (p less than or equal to 0.03). Sigma Q was lower in reperfused than in nonreperfused patients at 8 hours (1.41 +/- 1.18 versus 2.11 +/- 2.10 mV; p less than or equal to 0.05) and at 24 hours (1.43 +/- 1.25 mV versus 2.08 +/- 1.88 mV; p less than or equal to 0.02). Time to peak level was shorter in the reperfused patients for creatine kinase (CK) (10.7 +/- 5.5 hours versus 14.9 +/- 5.9 hours; p less than 0.0001) and lactic acid dehydrogenase (LDH) (29.6 +/- 13.6 hours versus 34.4 +/- 10.5 hours; less than or equal to 0.03) enzymes. Peak LDH-1 was lower in the reperfused group (274 +/- 149 U/L versus 341 +/- 173 U/L; p less than or equal to 0.04). Reperfusion at a mean of 3.9 hours after the onset of infarction was associated with more rapid resolution of ST segment elevation, faster Q wave evolution, smaller ECG infarct size, earlier cardiac enzyme release, and smaller enzymatic infarct size than later or no reperfusion.     

Effects of early and later reperfusion on healing speed of experimental myocardial infarct

The effects of reperfusion on myocardial infarct healing in the rabbit were analyzed using two morphometric indexes: the ratio of the volume of the organized portion of infarct to the volume of the whole infarct (%O/I), and the ratio of the minimal thickness of the infarct zone to the normal zone thickness (thinning ratio). In the nonreperfused infarcts, %O/I increased from 43.8 +/- 3.1% (mean +/- SEM) at 48 h to 85.7 +/- 2.5% at seven days, which supported the validity of this index. The thinning ratio was 0.50 +/- 0.03 at 48 h and did not change during the following five days. In other groups of rabbits, the coronary artery was temporarily occluded for 30 mins (early reperfusion) or 60 mins (late reperfusion), and the hearts were analyzed at 72 h or seven days. Early reperfusion limited infarct size as a percentage of the area at risk (%I/AAR) by approximately 50%, but late reperfusion did not. In both nonreperfused and reperfused infarcts, %O/I correlated significantly with absolute infarct size. Furthermore, the regression lines of the relationship of infarct size to %O/I of early and late reperfused infarcts shifted towards higher %O/I values compared with that of nonreperfused infarcts at seven days, which suggested accelerated organization. However, such a regression line shift by reperfusion was not detected at 72 h after infarction. The thinning ratio was higher in early reperfused infarcts compared to nonreperfused or late perfused infarcts, and there was a weak inverse correlation between thinning ratio and %I/AAR when the data of reperfused and nonreperfused infarcts were pooled.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serial nuclear magnetic resonance imaging of acute myocardial infarction with and without reperfusion

To compare nuclear magnetic resonance (NMR) image-derived T1 and T2 changes during evolving infarction, 14 dogs were studied serially: (1) 1 to 2 hours after left anterior descending coronary occlusion, (2) 2 to 3 hours after coronary occlusion (n = 7) or in the first hour after reperfusion following 2 hours of occlusion (n = 7), and (3) 5 days and (4) 21 days after occlusion/reperfusion. In addition, the extent of T1 and T2 abnormalities was compared to the extent of infarction as determined histologically for each set of images. With sustained coronary occlusion, an increase versus control values (T1 = 351 +/- 11 msec; T2 = 41 +/- 2 msec) was observed in the second hour after occlusion (T1 = 448 +/- 51 msec; T2 = 51 +/- 8 msec), gradually reaching a maximum by day 5 (T1 = 490 +/- 64 msec; T2 = 63 +/- 9 msec). By 21 days, T1 had decreased to 427 +/- 43 msec and T2 to 55 +/- 11 msec. However, with myocardial reperfusion, an abrupt increase in both T1 and T2 occurred compared to prereperfusion values in the first hour after release of occlusion, from 445 +/- 32 msec to 555 +/- 65 msec and from 52 +/- 5 msec to 65 +/- 8 msec, respectively. Subsequently, T1 remained elevated whereas T2 normalized. Only on day 21 images was there a good correlation between the extent of T1 and T2 abnormalities and infarct size, in both nonreperfused (r = 0.87; p less than 0.05), and reperfused (r = 0.89; p less than 0.01) dogs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term protection of ischaemic myocardium by nitroglycerin ointment

To assess whether the reduction in ischaemic injury during acute myocardial infarction induced by nitroglycerin (NTG) results in a decrease in tissue necrosis, 96 rats were assigned to two groups. The first group (n = 34) was sham-operated. The second group of 62 rats was randomised in a ratio of 2:1 into control (n = 43) and treated (n = 19) subgroups following coronary artery occlusion. Treated animals received an application of 2% NTG ointment every 8 h immediately post-occlusion. All rats were killed 48 h after coronary artery occlusion and total creatine kinase activity (CK) of the left ventricle (LV) was measured. Infarct size calculated by CK depletion was 65.2 +/- 14.3% (mean +/- SD) of LV in control rats, and 51.6 +/- 14.0% of LV in NTG-treated (p less than 0.02). In a further series of 46 rats with coronary occlusion, the area of infarcted myocardium 21 days post-occlusion was assessed by planimetry on histological sections. In rats with control occlusion (n = 22), the extent of infarction was 30.6 +/- 4.8% of LV, and in NTG-treated rats (n = 24) it was 16.2 +/- 5.8% of LV (p less than 0.001). The amount of scar tissue in the infarcted myocardium 21 days post-occlusion was also determined by measuring LV hydroxyproline and collagen content in an additional 32 rats randomly assigned to a control (n = 11), a NTG-treated (n = 9) and a sham-operated group (n = 12).(ABSTRACT TRUNCATED AT 250 WORDS)     

Post-ischemic cardiac chamber stiffness and coronary vasomotion: the role of edema and effects of dextran

Contributions of edema to left ventricular (LV) chamber stiffness and coronary resistance after ischemia were studied in isolated buffer-perfused rabbit hearts, with constant LV chamber volume, subjected to 30 min global ischemia and 60 min reperfusion. During reperfusion hearts were perfused with standard buffer or with 3% dextran to increase oncotic pressure and decrease water content. LV chamber volume was adjusted to an initial diastolic pressure (LVEDP) of 10 mmHg. In nonischemic hearts (n = 6) LVEDP was 11 +/- 0.3 mmHg and water content was 5.0 +/- 0.1 ml/g dry weight after 90 min of perfusion. In untreated ischemic hearts (n = 8) LVEDP was 51 +/- 4 mmHg and water content was 6.0 +/- 0.1 ml/g dry weight after 60 min reperfusion (P less than 0.001 v. nonischemic). In dextran-treated ischemic hearts (n = 8) LVEDP was 38 +/- 3 mmHg (P less than 0.05 v. untreated ischemic) and water content was 5.2 +/- 0.1 ml/g dry weight (P less than 0.001 v. untreated ischemic). Coronary resistance in untreated ischemic hearts increased by 26% from 2.0 +/- 0.06 to 2.6 +/- 0.06 mmHg/ml/min after 60 min reperfusion. In treated hearts coronary resistance increased by 16% from 1.9 +/- 0.09 to 2.2 +/- 0.09 mm/Hg/ml/min (P less than 0.01 v. untreated ischemic). To determine whether the decrease in coronary resistance with dextran could be ascribed to active vasodilation, dilator responses to 2 min hypoxia or 10(-4)M adenosine were tested in nonischemic and reperfused ischemic hearts. Dilator responses were stable in nonischemic hearts or hearts reperfused after 15 min ischemia but after 30 min ischemia the dilator response to hypoxia was reduced by 72% (P less than 0.025) and the dilator response to adenosine was eliminated (P less than 0.02). Thus the response to dextran was unlike that of a direct vasodilator. These data suggest that myocardial edema plays a significant role in maintaining increased ventricular chamber stiffness and coronary resistance during reperfusion after ischemia.     

Response of reperfusion-salvaged, stunned myocardium to inotropic stimulation

The purpose of this study was to determine whether myocardium salvaged by reperfusion following coronary occlusion could respond to inotropic stimulation by dopamine. Mongrel dogs underwent a 2-hour occlusion of the proximal left anterior descending coronary artery, followed by reperfusion for 5 or 28 hours. Dopamine (5 to 10 micrograms/kg/min) or dextrose was administered 1 hour or 24 hours after the onset of reperfusion. Serial, computer-assisted, two-dimensional echocardiographic determination of percentage of systolic wall thickening (%SWT) and cross-sectional ejection fraction (% delta area) were used to evaluate the response to treatment. Myocardium in the region of central ischemia contracted poorly after 1 hour of reperfusion (mean %SWT = 1.3 +/- 13.3% [mean +/- SD] compared to preocclusion value of 43.6 +/- 18.5%, p less than 0.001) and tended to thin at 24 hours of reperfusion (mean %SWT = -6.0 +/- 12.3%, p less than 0.001). After 1 hour of reperfusion, dopamine produced a greater than fourfold improvement in %SWT within the reperfused zone (to 15.3 +/- 7.3%, p less than 0.05). After 24 hours of reperfusion, dopamine again produced an improvement in %SWT (to 5.8 +/- 12.5%, p less than 0.05). There were no significant changes in %SWT with dextrose infusion. Thus, dopamine stimulates the reperfusion-salvaged but noncontracting (stunned) myocardium to contract as early as 1 hour after reperfusion.     

Does reperfusion extend necrosis? A study in a single territory of myocardial ischemia--half reperfused and half not reperfused

The purpose of this study was to confirm or disprove the existence of reperfusion-induced extension of necrosis. To avoid the effect of the variability of collateral circulation when groups of dogs are compared, we compared the effect of reperfusion and nonreperfusion on myocardial necrosis in a single ischemic territory, half of which was reperfused and half of which was not. The left anterior descending coronary artery (LAD) territory between its last diagonal branch and the apex was studied because it was found to have uniform collateral blood flow. In 20 dogs, the LAD was occluded for 90-240 minutes to produce necrosis of different degrees of transmurality. Before release of this occlusion, the LAD was occluded distally halfway to the apex to keep the distal half nonreperfused. After 5 minutes of proximal reperfusion. Monastral blue dye was injected into the left atrium for demarcation of the reperfused region, and the heart was arrested, excised, cut parallel to the LAD, and placed into triphenyl tetrazolium chloride (TTC) solution for delineation of the region of necrosis. The validity of TTC staining under the conditions of this study was confirmed by light and electron microscopy. The transmurality of necrosis, measured within 1 or 0.5 cm on either side of the boundary, ranged from 30% to 88% of wall thickness and was not different in the reperfused compared with the nonreperfused region (paired t test). Reperfusion did not advance the epicardial edge of necrosis compared with the nonreperfused region. In conclusion, at 5 minutes after reperfusion, comparison of necrosis in the reperfused and nonreperfused halves of a single ischemic territory could not demonstrate an extension of necrosis by reperfusion.     

Acute reduction in functional infarct expansion with late coronary reperfusion: assessment with quantitative two-dimensional echocardiography

Reperfusion performed too late to salvage myocardium decreases chronic infarct expansion in experimental animals. However, the acute effects of delayed reperfusion are not known. Twenty-two dogs underwent 3 (n = 8), 4 (n = 8) or 6 h (n = 6) of circumflex artery occlusion followed by 3 h of reperfusion. Effects of reperfusion on diastolic expansion were assessed in two ways: 1) change in mean radius of curvature of the infarct segment, and 2) change in the ratio of the length of the diameter from the center of the infarct zone to the opposite wall (septal-lateral diameter) to the length of the diameter perpendicular to this (anteroposterior diameter). Effects on systolic expansion were examined with quantitative two-dimensional echocardiographic systolic thickening analysis. Delayed reperfusion produced an immediate decrease in diastolic infarct expansion. The ratio of septal-lateral/anteroposterior diameters, which had increased with occlusion from a preocclusion baseline of 0.98 +/- 0.06 to 1.13 +/- 0.08 (p less than 0.001), decreased with reperfusion to 1.02 +/- 0.07 at 15 min and 1.03 +/- 0.08 at 3 h of reperfusion (p = 0.001). This was due solely to a decrease in the septal-lateral diameter. The radius of curvature of the infarcted segment increased from 2.1 +/- 0.5 cm before reperfusion to 2.74 +/- 0.8 cm at 15 min and 2.6 +/- 0.85 cm at 3 h of reperfusion (p = 0.009). This occurred despite a significant (13.6%) decline in end-diastolic cavity area and is compatible with flattening of the reperfused infarct region. Systolic infarct expansion also improved slightly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional differences in postischemic recovery in the stunned canine myocardium

To determine if differences exist in the degree of ischemic damage and in postischemic recovery when different coronary arteries are occluded and reperfused, 40 barbital-anesthetized dogs were subjected to brief 15-minute periods of coronary artery occlusion followed by 3 hours of reperfusion ("stunned" myocardium) of the left anterior descending (LAD) or the left circumflex (LCX) coronary arteries. Myocardial segment shortening (%SS) in the subendocardium of nonischemic and ischemic reperfused areas was measured by sonomicrometry, and regional myocardial blood flow was measured by radioactive microspheres. Transmural tissue biopsies were taken at the end of reperfusion for the measurement of adenine nucleotides and total tissue water content. Arterial and local coronary venous blood samples were collected during preocclusion, during occlusion, and at 30 and 180 minutes of reperfusion for determination of blood oxygen content and oxygen consumption in the ischemic area. During occlusion, subendocardial blood flow (LAD flow = 0.11 +/- 0.02; LCX flow = 0.15 +/- 0.04 ml/min/gm), myocardial oxygen consumption (LAD = 2.4 +/- 0.7; LCX = 2.7 +/- 0.7 ml/min/100 gm), and areas of the left ventricle at risk (LAD = 27.4 +/- 2.3%; LCX = 32.4 +/- 2.4) were similar in both groups, thus indicating equivalent degrees of ischemia. There were no differences between groups in hemodynamics throughout the experiment or in the loss of myocardial high-energy phosphates or increase in total tissue water in the ischemic reperfused area at 3 hours of reperfusion. There was a significantly greater loss (p less than 0.05) of systolic wall function during LAD versus LCX occlusion and a greater recovery of segment function from 5 minutes throughout 1 hour of reperfusion after LCX occlusion (p less than 0.05), with no difference in %SS at 2 and 3 hours following reperfusion. Thus, although similar changes occurred in blood flow, metabolite parameters, tissue edema, wall function, and overall hemodynamics when either the LAD or LCX perfusion territories were occluded and reperfused, the loss of systolic wall function and recovery of segment shortening were more variable after regional stunning of the LCX perfusion bed. These data suggest that evaluation of pharmacologic or surgical interventions to improve postischemic functional recovery may be more reliably performed when the LAD coronary artery is the vessel occluded.     

Limitation of the area of necrosis induced by quinacrine after coronary occlusion in the dog

Phospholipase activation has been suggested to represent one of the most relevant biochemical steps toward irreversible myocardial injury during ischemia. Accordingly, the time-course of myocardial phospholipid degradation was studied in 167 rats surviving coronary artery occlusion randomly divided into 83 controls and 84 treated with the phospholipase inhibitor quinacrine (75 mg/Kg s.c. every 8 h). The animals were sacrificed at different times ranging from 2 to 48 h post-occlusion and phospholipids and creatine kinase activity (CK) were measured on the supernatant of the left ventricular homogenates. In control animals a rapid fall in phospholipid concentration (from 1.33 +/- 0.12 to 0.67 +/- 0.05 microgram P/mg of protein) and CK activity (from 9.84 +/- 0.49 to 6.93 +/- 0.60 IU/mg of protein) was observed within 4 hours post-occlusion; these parameters remained almost unchanged throughout the rest of the study. In quinacrine-treated animals left ventricular phospholipids and CK also fell during the first hours post-occlusion; however, 24 and 48 h after the occlusion they were significantly higher than in controls (phospholipids: 0.99 +/- 0.05 vs 0.62 +/- 0.04 microgram P/mg of protein, p less than 0.001, and CK: 7.76 +/- 0.54 vs 4.99 +/- 0.37 IU/mg of protein, p less than 0.001, at 48 h). The effect of quinacrine on the extent of necrosis was then assessed in 13 anesthetized dogs undergoing ligation of the left anterior descending coronary artery. To measure the area at risk (RZ), 99Tc-PP labeled albumin microspheres were injected into the left atrium 5 min after coronary occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Early differentiation of infarcted and noninfarcted reperfused myocardium in dogs by quantitative analysis of regional myocardial echo amplitudes

This study tests the hypothesis that ischemic but viable reperfused myocardium can be differentiated from infarcted reperfused myocardium by regional analysis of myocardial echo amplitudes. In eight closed-chest, anesthetized dogs, the left anterior descending coronary artery was occluded for 3 hours, followed by 1 hour of reperfusion, and sacrifice. Infarct size was measured by the triphenyl tetrazolium chloride technique in a 1-cm-thick mid-left ventricular transverse slice, and matched with a corresponding end-diastolic two-dimensional echo short-axis cross-section. Outlining of epi- and endocardial surfaces, along with construction of a mid-myocardial outline, allowed measurements of regional myocardial echo intensities and grey-level histograms in subendo- and subepicardial regions. In 36 eventually infarcted subendocardial segments (greater than 20% wall necrosis), average pixel intensity (arbitrary units) was 73.7 +/- 33.1 (SD) in control, 75.8 +/- 33.0 at 3 hours of occlusion, and 107.8 +/- 40.9 at 5 minutes, 105.5 +/- 38.9 at 15 minutes, and 101.1 +/- 37.6 at 60 minutes postreperfusion P less than 0.05 vs. control or occlusion); intensity in normal segments (no or less than 20% wall necrosis) was 60.0 +/- 18.6 in control, 57.4 +/- 20.3 at 3 hours of occlusion, and 63.5 +/- 14.8, 68.0 +/- 27.9, and 64.2 +/- 22.3 at 5, 15, and 60 minutes postreperfusion, respectively (no significant change). The skew of the grey-level distribution in infarcted subendocardial segments did not change from control (0.49 +/- 0.72) to 3 hours of occlusion (0.41 +/- 0.52), but decreased (shift to higher echo amplitude) significantly at 5 minutes (-0.31 +/- 0.53), 15 minutes (-0.22 +/- 0.50), and 60 minutes (-0.28 +/- 0.45) after reperfusion (P less than 0.05 vs. control or occlusion); in normal subendocardial segments, there was no significant change throughout the study. In 31 partly infarcted subepicardial segments (greater than 50% wall necrosis), changes in postreperfusion echo amplitudes were less significant. Average pixel intensity was 71.3 +/- 28.6 in control, 71.8 +/- 29.2 after coronary occlusion, and 89.2 +/- 35.3, 83.7 +/- 37.5, and 85.6 +/- 34.9 at 5, 15, and 60 minutes after reperfusion, respectively. It is concluded that reperfusion of irreversibly injured myocardium is associated with consistent early increase in regional myocardial echo intensities and changes in the grey-level distribution. Such alterations might be used to detect the extent of tissue necrosis within minutes after reperfusion.     

Early detection of myocardial reperfusion by assay of plasma MM-creatine kinase isoforms in dogs

To determine whether myocardial reperfusion can be detected promptly by changes in profiles of isoforms of MM-creatine kinase (CK) in plasma, coronary occlusion was induced in 30 conscious dogs and reperfusion was initiated after 1, 2, 3, or 4 hr in 21. The myocardial isoform of MM-CK, MMA, was quantified in serial plasma samples by chromatofocusing. Before coronary occlusion, MMA comprised 13 +/- 7% (SD) of the total CK activity in plasma. The percentage of MMA (MMA%) was elevated before reperfusion, but increased markedly and consistently to a peak of 52 +/- 13% (n = 21) between 30 min and 1 hr after the time of onset of reperfusion. The rate of increase in MMA% was significantly faster with reperfusion at 1 hr (1.44 +/- 0.42% min-1), 2 hr (1.28 +/- 0.45% min-1), or 3 hr (1.02 +/- 0.27% min-1) (p less than .001), but not with reperfusion at 4 hr (0.48 +/- 0.34% min-1) compared with the rate in nonreperfused control dogs (0.29 +/- 0.09% min-1). Furthermore, the rate of increase in MMA% was neither influenced by peak total CK activity (r = -.1) nor dependent on infarct size measured histochemically 24 hr after coronary occlusion (r = -.003). The time from coronary occlusion to the peak of MMA% was reduced by reperfusion at 1 to 3 hr compared with control, but this index was not identified as rapidly as the rate of increase in MMA%. Accordingly, characterization of the rate of increase in MMA% in plasma when reperfusion occurs early after the onset of myocardial infarction permits prompt, reliable, and noninvasive detection of myocardial reperfusion.     

Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow

The "no-reflow" phenomenon, the occurrence of areas with very low flow in hearts reperfused after ischemia, is thought to be largely established at the time of reperfusion as a result of microvascular damage induced by ischemia. In the present study we sought to determine whether additional impairment of tissue perfusion might also occur during the course of reperfusion. Open-chest dogs were subjected to 90 minutes of left circumflex coronary artery occlusion and reperfused for 2 minutes (n = 7) or 3.5 hours (n = 8). Myocardial perfusion was visualized in left ventricular slices following in vivo injection of the fluorescent dye thioflavin-S just before killing. The area of impaired perfusion (absent thioflavin) averaged 9.5 +/- 3.0% of the risk region in dogs reperfused for 2 minutes, whereas it was nearly three times as large in dogs reperfused for 3.5 hours (25.9 +/- 8.2% of the risk region, p less than 0.05). Serial measurements of flow by microspheres during reperfusion demonstrated zones within the postischemic myocardium that were hyperemic 2 minutes after reperfusion, with adequate flow still present at 30 minutes, but with a subsequent marked fall in perfusion. After 3.5 hours these areas showed negligible flow (0.13 +/- 0.3 ml/min/g) and no thioflavin uptake. Tissue samples showing postischemic impairment in perfusion has received virtually no collateral flow during ischemia (less than 0.01 ml/min/g), whereas collateral flow was significantly higher in adjacent thioflavin-positive zones (0.04 +/- 0.01 ml/min/g in endocardial samples and 0.07 +/- 0.02 ml/min/g in samples from the midmyocardium, p less than 0.001 vs. thioflavin-negative areas). Areas that showed late impairment of flow invariably demonstrated contraction band necrosis, which contrasted with the pattern of coagulation necrosis observed in areas of "true" (i.e., immediate) no-reflow. Intracapillary erythrocyte stasis and marked intravascular neutrophil accumulation (to levels greater than 20-fold that found after 2 minutes reperfusion) were typically observed in areas of delayed impairment to flow. Obstruction to flow at the capillary level was confirmed in additional dogs in which the heart was injected postmortem with silicone rubber to delineate the microvascular filling pattern. Areas of absent capillary filling were much more extensive after 3.5 hours than after 2 minutes reperfusion. Thus, this study shows that the occurrence of areas of markedly impaired perfusion in postischemic myocardium is related only in part to an inability to reperfuse certain areas on reflow. A more important factor is represented by a delayed, progressive fall in flow to areas that initially received adequate reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)     

Streptokinase thrombolysis in experimental coronary artery thrombosis: pattern of reflow and effect of a stenosis

We studied recanalization of an obstructed left circumflex coronary artery by streptokinase in open-chest anesthetized dogs. Thrombotic occlusion was induced by a 100 μA anodal current selectively delivered to the intimal surface of the vessel. Intracoronary streptokinase (50,000 U) or saline was infused over a 50-min period beginning at either 30 min or 90 min after occlusion. Continous recordings were made of antegrade circumflex flow and regional myocardial function, which was quantitated using sonomicrometer crystals in the regions of the left anterior descending and circumflex coronary arteries. In some experiments a fixed stenosis, having no effect on mean circumflex coronary artery blood flow, was placed at the site of subsequent thrombus formation. The presence of a stenosis decreased the weight of occlusive thrombi obtained from nonreperfused saline controls by 40% and increased the proportion of animals successfully reperfused by streptokinase from 13 to 76%. Streptokinase reduced thrombus mass by 44% in animals recanalized in the presence of the stenosis. On the average, reflow was established after 26 min of streptokinase infusion, was less in magnitude than pre-occlusion flow, and was unstable and intermittent, being marked by frequent reocclusions. Initiating treatment at 30 min or 90 min post-occlusion did not influence characteristics of the reflow. Return of myocardial contractility in the ischemic bed was not detected during the immediate reperfusion period in the majority of these experiments.     

Relation between myocardial glutathione content and extent of ischemia-reperfusion injury

The relation between the extent of myocardial injury sustained during reperfusion and total glutathione (GSH) content in the ischemic myocardium was examined in anesthetized open-chest pigs subjected to coronary occlusion for 45 minutes and reperfusion for 2 hours. In pigs infused with saline during reperfusion (n = 6) there was a decrease in myocardial GSH content from 380 +/- 48 micrograms/g in normally perfused myocardium to 182 +/- 36 micrograms/g in the ischemic reperfused myocardium (p less than 0.02). Myocardial infarct size (expressed as a percentage of the ischemic area) was 12.5 +/- 0.8%. There was a delay of recovery of contractile function before returning to 60% of preocclusion value. In pigs pretreated with buthionine sulfoximine (BSO) (n = 5), an inhibitor of cellular GSH synthesis, there was reduction in GSH content to 215 +/- 25 micrograms/gm in normally perfused myocardium and to 77 +/- 8 micrograms/gm in the ischemic reperfused myocardium. The extent of injury was greater as evidenced by an increase in infarct size to 30.4 +/- 4.0% (p less than 0.001), severe destructive changes in subepicardial ultrastructure, which were absent in saline-infused pigs, and persistence of dyskinesia throughout reperfusion. In pigs infused with glutathione intravenously (0.8 gm/kg) at a rate of 6.5 mg/kg/min (n = 6), 5 minutes before and continuously during reperfusion, there was an increase in GSH content to 582 +/- 67 micrograms/g in normally perfused myocardium and to 312 +/- 80 micrograms/g in ischemic reperfused myocardium. The increase in myocardial GSH was associated with a reduction in infarct size to 7.5 +/- 1.3% (p less than 0.05, compared with saline-infused pigs) and an early recovery of contractile function of the ischemic myocardium. GSH infusion into pigs pretreated with BSO (n = 4) failed to increase myocardial GSH content and failed to reduce the extent of myocardial injury. Thus, the extent of myocardial injury sustained during reperfusion is very dependent on the effectiveness of its antioxidant defenses. Markedly increased susceptibility to injury occurs when the GSH content in the ischemic myocardium becomes depleted.     

Effects of reperfusion on the regional contraction of ischemic and nonischemic myocardium following partial coronary obstruction

In 14 dogs the effects on regional tension (Walton-Brodie gauges) and length (mercury-in-silastic) following 50% reduction (52.9 +/- 2.1) in coronary flow for two hours and reperfusion afterwards for one hour were addressed. Within five minutes of partial coronary occlusion, ejection tension in the ischemic zone decreased to 36.3 +/- 7.2% (P less than 0.001) and total tension to 64.4 +/- 5.7% of control (P less than 0.001) while phasic segment length increased to 165.2 +/- 16.3% control. No further significant changes in regional tension or length were observed throughout the two hour period of partial occlusion. Ejection tension remained positive and segment length maintained systolic shortening during the ejection phase throughout the period of occlusion. Following reperfusion, ejection tension in the ischemic zone increased from 35.1 +/- 5.9 to 87.0 +/- 22.0% (P less than 0.05) and total tension increased from 56.6 +/- 5.4 to 70.2 +/- 7.2% (P less than 0.02) while segment length decreased from 149.3 +/- 6.5 to 105.7 +/- 5.7% (P less than 0.001) within five to 15 min of reperfusion. The improvement in both regional tension development and segment length shortening was maintained throughout the one hour period of reperfusion. No significant changes were seen in the nonischemic zone. The present experimental study suggests that partial coronary occlusion producing a 50% reduction in coronary blood flow results in regional contractile changes. These changes are reversible at least twice as long as those following complete occlusion.