Short-term synchronized retroperfusion before reperfusion reduces infarct size after prolonged ischemia in dogs.

BACKGROUND: Previous studies have demonstrated that synchronized coronary venous retroperfusion (SRP) can restore blood flow to the ischemic myocardium, resulting in infarct size reduction and improvement of the left ventricular function. Despite the nutritive blood flow achieved by SRP being relatively limited, SRP has been shown to improve washout of by-products from the ischemic myocardium. The aim of this study was to investigate whether short-term SRP immediately prior to reperfusion would attenuate the deteriorative phenomena following reperfusion. METHODS AND RESULTS: Closed-chest anesthetized dogs underwent 3 hours of left anterior descending coronary artery (LAD) occlusion. The dogs were then randomized into two groups: (1) control group (n = 9), in which the occlusion was immediately followed by 3-hour reperfusion; or (2) SRP group (n = 9), in which SRP was started 3 hours after occlusion and maintained for 30 minutes with sustained occlusion followed by 2.5-hour reperfusion with simultaneous discontinuation of SRP. There were no statistical differences between the groups in global hemodynamics and degree of ischemia measured by radiolabeled microspheres. Myocardial infarct size (triphenyltetrazolium method) expressed as percentage of risk area was significantly smaller in the SRP group (24 +/- 7%, mean +/- SEM) than in the control group (54 +/- 9%). The extent of myocardial hemorrhage expressed as percentage of infarct size was also significantly reduced in the SRP group (3 +/- 2%) compared with the control group (24 +/- 6%). The increase in end-diastolic wall thickness in the ischemic area after reperfusion assessed by two-dimensional echocardiography was significantly less in the SRP group. Blood flow measurements after reperfusion demonstrated the occurrence of no-reflow phenomenon only in the control group. Histological examination revealed extensive myocardial hemorrhages only in the control group, which extended into the nonnecrotic myocardium in four of nine hearts and extensive contraction band necrosis compared with the SRP group. CONCLUSIONS: Short-term SRP prior to reperfusion can reduce infarct size, myocardial hemorrhage, wall swelling, and no-reflow phenomenon. The mechanism of this beneficial effect is not clear but might be due to gradual reperfusion and washout of by-products from the ischemic myocardium before fully oxygenated arterial blood reperfusion.

Local beta-adrenergic blockade does not reduce infarct size after coronary occlusion and reperfusion: a study of coronary venous retroinfusion of metoprolol.

Previous studies have demonstrated pronounced ischemic zone myocardial concentrations of metoprolol following coronary venous retroinfusion in pigs with coronary artery ligation. The effect of coronary venous retroinfusion of metroprolol on myocardial infarct size was studied in 16 pentobarbital-anesthetized open-chest pigs undergoing 60-minute occlusion of the left anterior descending coronary artery followed by 3 hours of reperfusion. Pigs in the experimental group (n = 8) were given 0.4 mg/kg (1.0 mg/ml) of metroprolol via the anterior interventricular vein over a period of 5 minutes, beginning immediately after coronary occlusion followed by 0.2 mg/kg/hr intravenously. Control pigs (n = 8) received the same volume of saline as the treated group. The risk area and the necrotic area were assessed by monastral blue dye and triphenyl tetrazolium chloride staining, respectively. Metoprolol did not influence hemodynamics. Plasma concentrations of metoprolol were within therapeutic levels. The administration of the beta-blocker resulted in a trend toward reduced norepinephrine concentrations, both in the aorta and coronary vein after coronary occlusion, but it did not prevent norepinephrine overflow following reperfusion. Infarct size expressed as a percentage of the risk area was 77 +/- 11% in the control group and 75 +/- 12% (mean +/- SD; NS) in the treated group. Thus, metoprolol retroinfusion did not reduce infarct size and did not prevent catecholamine overflow after reperfusion. It is concluded that the beneficial effects of metroprolol in acute infarction are probably unrelated to local beta-adrenergic blockade, at least in the pig, an animal with a paucity of coronary collateral blood flow.

Preservation of regional myocardial ultrasonic backscatter and systolic function during brief periods of ischemia by synchronized coronary venous retroperfusion.

This study examines the effects of brief periods of ischemia on average and cardiac cycle-dependent variation of regional ultrasonic backscatter paralleled with changes in regional myocardial contraction, and to what extent these changes could be reversed by synchronized coronary venous retroperfusion. In five closed-chest dogs, the left anterior descending coronary artery was occluded on four occasions for a 2-minute period and retroperfusion was applied randomly to two of the coronary occlusions. Complete functional recovery was allowed between the occlusions. Two-dimensional echocardiographic images were obtained before and at the peak of the 2-minute occlusion period. Regional myocardial contraction as measured by fractional area change and systolic wall thickening during untreated occlusions decreased from 33.9 +/- 14.0% to -0.15 +/- 6.2%, and from 22.0 +/- 1.8% to -17.9 +/- 2.2%, whereas during retroperfusion-treated occlusions it changed from 37.4 +/- 8.5% to only 23.4 +/- 11.2% (p less than 0.005 versus baseline), and from 24.1 +/- 2.8% to only 12.7 +/- 2.0% (p less than 0.005 versus baseline), corresponding to a preservation of 62% and 52% of baseline regional contraction, respectively. Average regional gray level (arbitrary units) during untreated coronary occlusions exhibited a significant increase in the ischemic regions, from 5.6 +/- 2.7 at baseline to 11.5 +/- 4.4 during occlusion (p less than 0.005); during retroperfusion-treated occlusions, average gray level increased from 4.7 +/- 3.6 to only 6.3 +/- 3.6 (NS). Untreated coronary artery occlusions resulted in a systolic increase in gray level in the ischemic region, followed by a diastolic decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

Retrograde coronary venous administration of recombinant tissue-type plasminogen activator: a unique and effective approach to coronary artery thrombolysis.

Recent studies of interventional therapy by way of the coronary venous system have demonstrated that it can protect acutely ischemic myocardium. To evaluate the efficacy of coronary venous retroinfusion compared with systemic intravenous administration of recombinant tissue-type plasminogen activator (rt-PA), 14 dogs were studied with a copper coil-induced thrombus in the left anterior descending coronary artery. The rt-PA (24,000 fluorescence units/kg) was administered continuously, either intravenously (n = 8) or retrogradely (n = 6), for 30 min beginning 60 min after coronary occlusion. Thrombolysis was determined by repetitive coronary angiography. All dogs were killed 3 h after termination of rt-PA infusion and infarct size was measured by the triphenyltetrazolium chloride staining technique. Complete thrombolysis occurred in five of the six dogs in the retroinfusion group and four of the eight dogs in the systemic intravenous infusion group. Partial lysis was achieved in two dogs treated by intravenous infusion. Lysis did not occur in one dog treated with retroinfusion and in two dogs treated with intravenous infusion. Time to thrombolysis was 13.4 +/- 2.3 min in the retroinfusion group versus 27.8 +/- 4.8 min in the intravenous group (p less than 0.001). Myocardial functional recovery in the ischemic zone measured by two-dimensional echocardiography 60 min after reperfusion was significant only in the retroinfusion group (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary venous retroinfusion of deferoxamine reduces infarct size in pigs.

The efficacy of coronary venous retroinfusion of the iron chelator deferoxamine was studied in 24 pentobarbital-anesthetized open chest pigs with a 60 min occlusion of the left anterior descending coronary artery followed by 3 h of reperfusion. Eight retrogradely treated pigs were given 10 mg/kg body weight of deferoxamine by way of the anterior interventricular vein and eight systemically treated pigs received the same doses of deferoxamine intravenously. Drug infusions lasted for 5 min, beginning 15 min before reperfusion. Eight control pigs received systemic intravenous saline solution. Myocardial area at risk and necrotic area were assessed by the monastral blue dye and the triphenyltetrazolium chloride staining method, respectively. There were no significant differences in hemodynamics or regional myocardial function (sonomicrometry) among the groups. Infarct size expressed as percent of risk area was 73.9 +/- 13.5% in the control group, 70.6 +/- 16.4% in the systemically treated group and 48.5 +/- 21.4% (p less than 0.05) in the retrogradely treated group. In conclusion, deferoxamine significantly reduced infarct size after coronary occlusion only when given regionally by way of the coronary vein. Because there was no significant hemodynamic effect caused by deferoxamine infusion, it is suggested that this drug prevents postischemic reperfusion injury by a direct cardioprotective effect.

Percutaneous cooling of ischemic myocardium by hypothermic retroperfusion of autologous arterial blood: effects on regional myocardial temperature distribution and infarct size.

The effects of synchronized coronary venous retroperfusion of cooled autologous arterial blood on regional myocardial temperature distribution and infarct size were studied in open chest dogs with 3.5 h of left anterior descending coronary artery occlusion. After 30 min of occlusion, the dogs were randomly assigned to one of three groups: 1) untreated control group (n = 5), 2) normothermic retroperfusion group (infusion temperature 32 degrees C) (n = 7), and 3) hypothermic retroperfusion group (infusion temperature 15 degrees C) (n = 7). Regional myocardial temperatures were measured by using needle-tipped thermistors stabbed in the 1) anterior wall distal to the occlusion site, 2) anterior wall proximal to the occlusion site, 3) left lateral wall, 4) posterior wall, and 5) right ventricular free wall. Rectal and pulmonary artery temperatures were also measured. In the hypothermic retroperfusion group, the anterior wall temperature decreased rapidly by 5 degrees C at 15 min of retroperfusion (p less than 0.05 vs. normothermic retroperfusion or untreated control groups), whereas the temperature at other sites decreased with a linear trend over time. Myocardial temperatures in the ischemic area (distal anterior wall) were generally lower than those in the other sites during the first 60 min of hypothermic retroperfusion and the largest intramyocardial temperature difference (3.6 degrees C) was found at 15 min after retroperfusion. Infarct size expressed as a percent of the risk area was significantly smaller in the hypothermic retroperfusion group (6.2 +/- 3.3%) than in the control (64.9 +/- 14%) or normothermic retroperfusion groups (24.1 +/- 6.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary venous retroperfusion support during high risk angioplasty in patients with unstable angina: preliminary experience.

Synchronized coronary venous retroperfusion was used during coronary balloon angioplasty to support the ischemic myocardium of 20 patients with unstable angina and anatomy at high risk of a coronary event. Hemodynamics and left ventricular function were the major end points of the study. Coronary venous catheterization and retroperfusion were successfully performed in 15 patients. The target vessel was an unprotected left main artery in 2, left anterior descending artery in 10, left circumflex coronary artery in 1 and right coronary artery in 2 patients. A nonsupported balloon inflation (mean 44 +/- 13 s) was compared with a later retroperfusion-supported inflation (mean 145 +/- 21 s). Right anterior oblique left ventriculograms, aortic blood pressure, pulmonary artery pressure and thermodilution cardiac output were obtained before and during peak untreated and treated balloon inflations and on completion of angioplasty. All patients had either a baseline left ventricular ejection fraction less than 0.40 or greater than 40% of contracting myocardium estimated to be at risk for severe ischemia during angioplasty. The cardiac (liters/min per m2) and stroke work (g.m/m2) indexes decreased from mean baseline values of 2.5 +/- 0.52 and 52 +/- 15 to 1.7 +/- 0.47 and 27 +/- 12 (mean +/- SD), respectively, during nonsupported balloon inflations but decreased only to 2.1 +/- 0.52 (p less than 0.01 vs. nonsupported) and to 36 +/- 14 (p = 0.01 vs. nonsupported), respectively, during retroperfusion-supported inflations. Ejection fraction (n = 8) decreased from a baseline value of 55 +/- 13% to 27 +/- 7.3% during nonsupported inflations but only to 39 +/- 10% during retroperfusion-supported inflations (p = 0.01 vs. nonsupported). Regional wall motion (area change) in the ischemic (target) region was reduced from a baseline value of 49 +/- 17% to 11 +/- 16% during nonsupported inflations but only to 27 +/- 15% during retroperfusion-supported inflations (p less than 0.01 vs. nonsupported). All but two patients had a favorable hemodynamic response to retroperfusion. There were no serious adverse effects related to the procedures and no hospital deaths. It is concluded from this preliminary study that coronary venous retroperfusion appears to be safe, to provide hemodynamic support and to improve left ventricular function during angioplasty in patients with unstable angina and anatomy at high risk of a coronary event.

Reversal of chronic regional myocardial dysfunction (hibernating myocardium) by synchronized diastolic coronary venous retroperfusion during coronary angioplasty.

A 62 year old man with previous myocardial infarction, an occluded right coronary artery and a 90% stenosis of the left anterior descending coronary artery underwent angioplasty with the support of coronary venous retroperfusion of arterial blood during the procedure. In two of four angioplasty balloon dilations of the left anterior descending coronary artery, synchronized diastolic retroperfusion of the coronary veins with arterial blood was applied to protect the severely dysfunctioning myocardium from additional ischemia. Two-dimensional echocardiography was used to monitor and quantitate alterations in left ventricular function. Retroperfusion of arterial blood resulted in immediate improvement in ischemic zone wall motion despite the totally occluded artery during balloon dilation. Echocardiographic images recorded after angioplasty showed a marked improvement in contraction of the previously dyskinetic segments, with changes similar to those seen during balloon dilations with synchronized diastolic coronary venous retroperfusion. Thus, in this patient, viability of chronically dysfunctioning myocardium could be demonstrated by the improvement in regional wall motion during retroperfusion. This technique could eventually be of value to elucidate the anatomic location of viable myocardium while maintaining adequate left ventricular systolic function during coronary artery interventions in the catheterization laboratory.

Sequential noninvasive assessment of left ventricular size, regional wall thickness and function during 3 hours of coronary artery occlusion and reperfusion: differential effects of reflow in dogs with small vs large areas at risk.

1. The present study was undertaken to determine noninvasively the sequential changes in left ventricular (LV) size, wall thickness and regional contractile function occurring during 3 h of proximal left anterior descending coronary artery occlusion (CAO), and their modification by reperfusion (REP) over a 7-day period. 2. Twenty, closed-chest, anesthetized dogs underwent CAO for 3 h and were reperfused for 7 days. Hemodynamics (aortic, LV pressure, LV dP/dt) and regional LV function were measured sequentially during CAO and reperfusion. The animals were killed at 7 days and infarct size was measured using the triphenyl-tetrazolium-chloride technique. Regional function (systolic fractional area change, FAC) was measured in 40 LV segments of 5 two-dimensional echo short-axis planes (8 segments per section). 3. At three hours of CAO, 14 dogs developed extensive areas of akinesis or dyskinesis in more than 6 segments (Group I, large risk area), whereas 6 dogs developed akinesis or dyskinesis in 6 segments or less (Group II, small risk area). Four dogs died between 12 and 48 h after REP in Group I and none of Group II died. Recovery of regional function after REP was significantly different between Groups I and II: in hypokinetic segments, FAC improved from 16.7 +/- 0.9% (mean +/- SEM) at 3 h of CAO to 25.4 +/- 3.2% at 24 h and to 34.9 +/- 2.0% at 7 days (66.3 +/- 3.4% of baseline) after REP in Group I; in Group II, FAC increased from 16.6 +/- 1.5% at 3 h of CAO to 48.5 +/- 7.4% at 24 h and to 52.4 +/- 1.6% (92.7 +/- 2.8% of baseline) at 7 days after REP. In akinetic/dyskinetic segments, FAC increased from -9.2 +/- 2.4% at 3 h of CAO to 8.2 +/- 2.6% at 72 h and to 8.3 +/- 3.2% (15.1 +/- 5.8% of baseline) at 7 days of REP in Group I; in Group II, FAC rose significantly from -7.6 +/- 1.6% at 3 h of CAO to 39.9 +/- 7.3% at 24 h and to 50.8 +/- 4.3% (89.2 +/- 4.9% of baseline) at 7 days after REP. There was a significant inverse correlation between the magnitude of compensatory hyperkinesis in the nonischemic wall and the extent of hypokinesis at 60 min (r = -0.82, P less than 0.001), but this correlation was less significant at 24 h (r = -0.64, P less than 0.01), 72 h (r = -0.53, P less than 0.02), and 7 days (r = -0.50, P less than 0.05) after REP.(ABSTRACT TRUNCATED AT 400 WORDS)

Sequential noninvasive assessment of left ventricular size, regional wall thickness and function during 3 hours of coronary artery occlusion and reperfusion: differential effects of reflow in dogs with small versus large areas at risk

The present study was undertaken to determine noninvasively the sequential changes in left ventricular (LV) size, wall thickness and regional contractile function occuring during 3 h of proximal left anterior descending coronary artery occlusion (CAO), and their modification by reperfusion (REP) over a 7-day period. Twenty, closed-chest, anesthetized dogs underwent CAO for 3 h and were reperfused for 7 days. Hemodynamics (aortic, LV pressure, LV dP/dt) and regional LV function were measured sequentially during CAO and reperfusion. The animals were killed at 7 days and infarct size was measured using the triphenyl-tetrazolium-chloride technique. Regional function (systolic fractional area change, FAC) was measured in 40 LV segments of 5 two-dimensional echo short-axis planes (8 segments per section). At three hours of CAO, 14 dogs developed extensive areas of akinesis or dyskinesis in more than 6 segments (Group I, large risk area), whreas 6 dogs developed akinesis or dyskinesis in 6 segments of less (Group II, small risk area). Four dogs died between 12 and 48 h after REP in Group I and none of Group II died. Recovery of regional function after REP was significantly different between Groups I and II: in hypokinetic segments, FAC improved from 16.7 + or - 0.9% (mean + or - SEM) at 3 h of CAO to 25.4 + or - 3.2% at 24 h and to 34.9 + or - 2.0% at 7 days (66.3 + or - 3.4% of baeline) after REP in Group I; in Group II, FAC increased from 16.6 + or - 1.5% at 3 h of CAO to 48.5 + or - 7.4%...

Post-reperfusion function evaluated using two-dimensional echocardiography in dog: systolic/diastolic function vs percent necrosis.

Two-dimensional echocardiography (2DE) was performed in nine dogs with three hour proximal occlusion of the left anterior descending coronary artery and seven day reperfusion for sequentially mapping systolic functions (Seg-FAC%: percent segmental fractional area change) and diastolic functions (Seg-VLAC: mean velocity of segmental luminal area change) of eight segments in a mid-papillary left ventricular short-axis cross-section. The corresponding segment functions on 2DE to the most profoundly affected segment were evaluated by triphenyl-tetrazolium-chloride staining seven days post reperfusion, and categorized in two groups in terms percent mural necrosis (N%): N% greater than or equal to 40% in group A and N% less than 40% in group B, respectively. Seg-FAC% showed a significant difference between the two groups seven days post reperfusion (13.4 +/- 9.4% in group A, 53.3 +/- 7.7% in group B), while Seg-VLAC showed significant differences in the groups at three hours post occlusion (-1.6 +/- 2.1 cm2/sec in group A and 3.2 +/- 2.6 cm2/sec in group B) and seven days post reperfusion (0.48 +/- 4.7 cm2/sec in group A and 7.5 +/- 2.4 cm2/sec in group B). At seven days post reperfusion, Seg-VLAC correlated negatively with N% (r = -0.94), while Seg-FAC% did not with N% (r = -0.58). It was concluded that Seg-VLAC, after three hours' occlusion, predicts the recovery of the regional left ventricular function seven days after reperfusion; and Seg-VLAC, seven days after reperfusion can estimate the regional transmurality of necrosis thereafter.

Complete and delayed reversal of a large dyskinetic area with early spontaneous reperfusion during evolving myocardial infarction.

Sequential angiographic studies have shown that spontaneous reperfusion occurs in approximately 30 to 40% of patients during evolving myocardial infarction. However, it is difficult to establish the effects of spontaneous reperfusion on left ventricular function. We report the case of a 65 year old woman with clinical features of acute myocardial infarction with early spontaneous reperfusion and complete recovery of ventricular function 1 year later.

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.