S. Lindert

Combined treatment with vitamins E and C in experimental myocardial infarction in pigs

The effect of two different combined treatments with vitamin E acetate and vitamin C on infarct size and recovery of regional myocardial function was investigated in ischemic, reperfused porcine hearts. The left anterior descending coronary artery was distally ligated in 30 thoracotomized pigs for 45 minutes followed by 3 days of reperfusion. Infarct size was determined as the ratio of infarcted (tetrazolium stain) to ischemic (dye technique) myocardium. Regional myocardial function was assessed by sonomicrometry. Ten pigs received vitamin E acetate (12 gm intravenously three times for 1 week) before ischemic and vitamin C (4.4 gm intravenously) before reperfusion (therapy A). Another 10 pigs were treated with vitamin E acetate (12 gm intraarterially) and vitamin C (4.4 gm intravenously) during ischemia (therapy B). An additional 10 pigs served as a control group. Global hemodynamics did not differ significantly among the groups before and during ischemia. Mean plasma concentrations of vitamin E amounted to 107 micrograms/ml in group A, 16 micrograms/ml in group B, and 0.9 micrograms/ml in the control group at the onset of reperfusion. Therapy A reduced the size of the infarct from 73 +/- 12% to 47 +/- 16% of the region at risk (p less than 0.005) and improved regional systolic shortening from 0 +/- 7% to 11 +/- 6% at 3 days after reperfusion (p less than 0.01). Therapy B decreased the size of the infarct to 64 +/- 9% of the region at risk (p = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Cell death in ischemic, reperfused porcine hearts: a histochemical and functional study

SummaryThe temporal development of infarcts was histochemically and functionally determined in porcine hearts. In one series of experiments (22 pigs), the distal third of the left anterior descending coronary artery (LAD) was transiently occluded for periods between 20 and 90 min and was reperfused for another 24h. At the end of the experiments, the infarcted myocardium of four tissue slices was determined with a tetrazolium stain and related to the risk region which was delineated by a fluorescent dye. Infarcts started to develop in the ischemic septum and the subendocardial layer of the free anterior wall between 20 and 35 min of ischemia. Thereafter, infarctions progressed rapidly from the inner towards the outer layer at risk. The jeopardized anterior left ventricular wall became almost completely infarcted within 60 min of ischemia. In a second series of experiments (10 pigs) recovery of systolic shortening was studied with implanted ultrasonic crystals over 3 weeks of reperfusion. At the end of the experiments, systolic shortening was about 75% of baseline level when ischemia had lasted between 20 and 35 min. Almost no recovery was observed when the occlusion time lasted 45 to 60 min. This study suggests that the assessment of myocardial infarction with a tetrazolium stain after 24 h of reperfusion corresponds very well with functional recovery after 3 weeks of reperfusion. Furthermore, determination of regional myocardial function of the ischemic, reperfused segment in the chronic stage may be considered an additional tool to evaluate therapeutic effects on infarct size in this model.

Intracoronary superoxide dismutase for the treatment of “reperfusion injury” A blind randomized placebo-controlled trial in ischemic, reperfused porcine hearts

SummaryThe effect of recombinant human superoxide dismutase (rh-SOD) on infarct size was investigated in porcine hearts. The left anterior descending coronary artery was occluded in each of 24 anesthetized pigs for 45 min and reperfused for 24 h. The animals were randomly assigned to either rh-SOD (n=12) or placebo treatment (n=12). 2 min before reperfusion, an intracoronary (i.c.) infusion of rh-SOD (total dose: 2000 U/kg) or placebo was started which lasted for up to 45 min reperfusion. At the end of the experiment, the infarcted myocardium was assessed using a tetrazolium stain (NBT) and related to the risk region which was determined with a fluorescent dye. Two pigs of the SOD group and one of the control group died before the end of the experiments. Except for a lower calculated myocardial oxygen consumption and a lower dp/dtmax in the SOD group during ischemia, hemodynamic parameters of the two groups did not differ significantly. rh-SOD i.c. treatment during reperfusion did not reduce infarct size significantly. Infarct size amounted to 74±13% in the control group and to 66±19% in the treated group. The incidence of reperfusion arrhythmias was not affected by rh-SOD treatment. It is concluded that i.c. rh-SOD treatment at the beginning of reperfusion neither significantly reduces infarct size nor diminishes the incidence of reperfusion arrhythmias in this preparation.

Antiinflammatory Agent BW 755 C in Ischemic Reperfused Porcine Hearts

The effect of the antiinflammatory compound BW 755 C on myocardial infarctions was evaluated in regionally ischemic reperfused hearts of 35 pigs. The left anterior descending coronary artery was occluded distally in 23 anesthetized pigs for 45 min and was reperfused for 24 h. The BW 755 C (10 mg/kg) was intravenously injected prior to ischemia in seven pigs (group A). A second dose of BW 755 C (5 mg/kg) was given after 4 h of reperfusion. Group B consisted of eight animals. They were treated with BW 755 C immediately before (10 mg/kg i.v.) and after 4 h of reperfusion (5 mg/kg). Another eight pigs served as controls. At the end of the experiments, infarct size was determined as the ratio of the infarcted myocardium (tetrazolium stain) over the risk region (fluorescent dye). Leukocyte infiltration of the risk region was histologically quantitated in one slice of each experiment. In a second set of experiments recovery of regional myocardial function of the risk region was determined by sonomicrometry during 2 weeks of reperfusion. The BW 755 C (10 mg/kg) was injected intravenously in six pigs before ischemia and at a dose of 5 mg/kg after 4 h of reperfusion. Six pigs served as controls. Hemodynamic parameters and total leukocyte blood count did not differ between the groups. Treatment protocol of group A reduced the infarct size from 72 ± 13% (control group) to 50.9 ± 12% (p < 0.005). Infarct size of group B (65 ± 16%) did not differ from control experiments. Leukocyte infiltration of the risk region was only attenuated in group A (p = 0.01) compared with the control group. The treatment protocol of group A, however, did not decrease the transmural extent of necrosis after 2 weeks of reperfusion. Furthermore, this therapy did not improve functional recovery of the risk region, suggesting that the beneficial effect observed after 24 h of reperfusion was later lost. It is concluded that BW 755 C, when given before ischemia and after reperfusion, limits myocardial infarct size determined after 24 h of reperfusion. This, however, does not necessarily imply ultimate salvage of jeopardized myocardium because the same treatment did not improve regional myocardial function and the transmural extent of necrosis after 2 weeks of reperfusion.

Effect of intracoronary superoxide dismutase on regional function in stunned myocardium.

This study investigates the ischemic-time dependency of dysfunction in reversibly ischemic myocardium and the effect of postischemic oxygen free radical scavenging thereupon. In open chest pigs, occlusion of the distal left anterior descending coronary artery (LAD) for 4 (n = 5), 8 (n = 5), or 12 min (n = 5) resulted in paradoxical systolic and diastolic regional function, measured by ultrasonic crystals. With onset of reperfusion, systolic shortening (SS) and diastolic lengthening (DL) normalized completely in the 4− and 8-min groups, followed by a significant decrease to 50% control in the 8-min group. In the I2-min group, recovery of SS and DL was only partial. In two further groups, animals received an intracoronary infusion of either recombinant human superoxide dismutase (SOD, n = 6) or placebo (n = 6), starting with reperfusion after an 8-min LAD occlusion. SOD improved recovery of SS compared with placebo (p < 0.05), but DL and the depression of SS during later reperfusion were not influenced. Mitochondrial function after 90 min of reperfusion was not impaired in ischemicreperfused compared to control myocardium. We conclude that the degree of postischemic dysfunction increases with the duration of ischemia. Oxygen free radical scavenging by SOD, starting not before reperfusion, fails to prevent myocardial stunning. Mitochondrial function is intact in such myocardium.

Effect of α-tocopherol (vitamin E) in a porcine model of stunned myocardium

Oxygen free radicals have been suggested to cause the myocardial damage resulting in the prolonged contractile depression following brief periods of regional is chemia. In pigs, we infused the natural antioxidant a-tocopherol as its water-soluble acetate [0.3 g/kg intravenously (i.v.), n = 6] three times during 1 week, prior to thoracotomy, 8-min distal left anterior coronary artery (LAD) occlusion and 90-min reperfusion. Plasma levels of a-tocopherol [high-performance liquid chromatography (HPLC)] on the experimental day were 148.91 ± 21.47 μg/ml as compared to preinfusion control of 0.51 ± 0.14 μg/ml. Myocardial levels of a-tocopherol were elevated to 93.15 ± 14.78 μg/g as compared to 4.08 ± 0.60 μ.g/g in the control group (n = 6). Malondialdehyde levels in ischemic-reperfused myocardium of the treatment group were insignificantly lower (441.96 ± 59.55 nmol/g) as compared to the control group (500.9 ± 72.72 nmol/g). Heart rate was significantly higher in the treatment group by the end of the experiments (135 ± 10 vs. 105 ± 4 beats/min, p < 0.01). Regional segment shortening (SS, sonomicrometry) became normal within I min of reperfusion in both the treatment and the control group. During the following 10 min, SS decreased to 52 ± 6% of pre-is chemic control in the α-tocopherol group and to 54 ± 7% in the control group (NS). SS remained at these depressed values throughout the reperfusion period. Pre-treatment with the antioxidant α-tocopherol resulted in a tendency to lower lipid peroxidation products but did not prevent development of contractile depression in re-versibly ischemic reperfused myocardium.

The effect of intracoronary diltiazem on regional myocardial function and development of infarcts in porcine hearts

SummaryThe effect of intracoronary (i.c.) pretreatment with diltiazem on regional myocardial function and the development of infarcts was investigated in regionally ischemic, reperfused porcine hearts. The left anterior descending coronary artery (LAD) was distally ligated in 16 pigs for 20–90 min followed by 24 h of reperfusion. Eight pigs were treated with increasing doses of i.c. diltiazem (0.375 mg/min, 0.75 mg/min, 1 mg/min) prior to ischemia. Eight pigs served as controls. Regional myocardial function was assessed by implanted ultrasonic crystals. Infarct size was determined as ratio of infarcted (tetrazolium stain) to ischemic myocardium (dye technique). I.c. diltiazem mainly depressed early systolic shortening (isovolumetric contraction) and lengthening during the first half of diastole. Pretreatment with this calcium antagonist significantly delayed the development of infarcts. In control experiments, a mean infarct size of 74% was found after 45-min ischemia. At that time no infarction was observed in the treated group, where infarcts started to evolve after 60-min ischemia. It is concluded that the favorable action of i.c. diltiazem can mainly be ascribed to a reduced myocardial oxygen consumption at the onset of ischemia.