Hermann H. Klein

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)

Na+/H+ Exchange Inhibitor Cariporide Attenuates Cell Injury Predominantly During Ischemia and Not at Onset of Reperfusion in Porcine Hearts With Low Residual Blood Flow

BackgroundThis study investigated whether myocardial protection by inhibition of Na+/H+ exchange (NHE) occurs during ischemia and/or during reperfusion. Methods and ResultsThe left anterior descending coronary artery was occluded in 32 pigs for 60 minutes and then reperfused for 24 hours. Infarct sizes (nitroblue tetrazolium [NBT] stain, histology) were determined at the end of the experiments. An extracorporeal bypass was used to achieve a constant residual blood flow of 3 mL/min in the myocardium at risk during ischemia. The NHE-1 inhibitor cariporide or distilled water was infused into the extracorporeal bypass system. In group 1, active treatment was administered from the onset of ischemia until 10 minutes of reperfusion (n=8). In group 2, active treatment was infused during the first 30 minutes of ischemia only (n=8). The group 3 animals (n=8) received intracoronary cariporide after 45 minutes of ischemia until 10 minutes of reperfusion. The control animals (group 4, n=7) were treated similarly to group 1 animals, with the cariporide solution being replaced by distilled water. Infarct sizes of group 1 (NBT stain, 41.5±20%; histology, 44.6±12%) and group 2 (NBT stain, 33.5±14%; histology 34.9±15%) differed significantly (at least P =0.012) from infarct sizes of group 3 (NBT stain, 71.6±15%; histology, 69.2±12%) and the control group (NBT stain, 76±9%; histology 72.4±12%). Cariporide treatment in group 1 and group 2 significantly improved functional recovery after 24 hours of reperfusion. ConclusionsMyocardial protection by cariporide is predominantly achieved by NHE inhibition during ischemia and not during early reperfusion.

The effect of two different diltiazem treatments on infarct size in ischemic, reperfused porcine hearts.

The effect of diltiazem on the development of infarcts was investigated in porcine hearts. The left anterior descending coronary artery was occluded in each of 32 anesthetized pigs for 75 min and was reperfused for 4 hr. Diltiazem (15 micrograms/kg X min) was infused in 11 pigs for 30 min before occlusion (therapy A) and in another eight pigs before reperfusion (therapy B). Eleven pigs served as controls. Tissue concentrations of adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD) were determined in transmural needle biopsy samples taken from the ischemic apex after 70 min of ischemia. The infarct size, expressed as the ratio of the infarcted tissue over the area at risk of necrosis multiplied by 100, amounted to 79 +/- 20% in the control group. Although there was no significant difference between hemodynamics in the control and the treated groups, pretreatment with diltiazem significantly reduced infarct size (53 +/- 26%; p = .025). Reduction of infarct size by therapy B did not reach the required level of significance (66 +/- 33%). The ischemic loss of ATP and NAD was significantly lower in the pretreated group, which further indicates that the beneficial effect of diltiazem was exerted primarily during ischemia and not during reperfusion.

Time delay of cell death by Na+/H+-exchange inhibition in regionally ischemic, reperfused porcine hearts.

Studies in different preparations have suggested that Na+/H+ exchange is one mechanism causally involved in cell death in myocardial ischemia and reperfusion. The time delay of cell death by pretreatment with the Na+/H+-exchange inhibitor HOE642, cariporide (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate), was investigated in regionally ischemic, reperfused porcine hearts. HOE642 (1 mg/kg) was injected intravenously in 14 thoracotomized pigs 10 min before occlusion of the left anterior descending coronary artery (45 min of ischemia, six pigs; 70 min of ischemia, six pigs; 90 min of ischemia, two pigs). Ischemia was followed by 24 h of reperfusion. Six animals (45 min of ischemia) served as controls. Infarct size was determined as a ratio of infarcted (tetrazolium stain, histology) to ischemic myocardium (dye technique), and regional myocardial function was assessed by sonomicrometry. HOE642 did not affect global hemodynamic parameters. In the pretreated group with 45 min of ischemia, HOE642 significantly decreased histochemical infarct size from 51.2 +/- 12.6% (control group) to 13.2 +/- 12% (p < 0.005) and histologic infarct size from 44.5 +/- 9% to 17.1 +/- 7% (p < 0.005). Recovery of regional systolic shortening after 24 h of reperfusion was improved from 2 +/- 6% (control group) to 12 +/- 7% (p = 0.02). In addition, myocardial contracture and increase in heart rate during early reperfusion were attenuated. When ischemia was prolonged to 70 min after pretreatment with HOE642, infarct size, recovery of systolic shortening, myocardial contracture, and increase in heart rate did not differ from those of the control group. Pretreatment with HOE642 increased the tolerance to ischemia/reperfusion by approximately 20-25 min. Inhibition of Na+/H+ exchange appears to be very promising in the clinical treatment of acute myocardial ischemia and reperfusion.

Stimulation Characteristics of a Steroid-Eluting Electrode Compared with Three Conventional Electrodes

Stimulation thresholds of a steroid‐eluting electrode (Medtronic CapSure 4003, 9 patients) were compared with three conventional electrodes (carbon‐tipped lead, Siemens‐Elema 423 S/60, 10 patients; Elgiloy‐tipped lead, Cordis Encor, 10 patients; platinum‐tipped lead, Telectronix Laserdish 030–276, 9 patients). Voltage thresholds were determined during implantation, 1–3 days, 6 weeks, and 6 months postimplantation. No significant difference among the four electrodes was found in regard to stimulation and sensing behavior during implantation. Compared to intraoperative measurements, mean increase in voltage threshold and absolute voltage thresholds were substantially Jess for the steroid‐eluting electrode than for the other tested electrodes 6 weeks and 6 months after implantation. The rheobasechronaxie product, a parameter of the stimulation performance of electrodes, underlined the superior pacing characteristics of the steroid‐eluting electrode. To achieve low chronic stimulation threshold by pharmacological means is an attractive direction for future electrode technology.

Physiologische Änderungen des Herz-Kreislauf-Systems in der Schwangerschaft

ZusammenfassungDie physiologischen Änderungen des Herz-Kreislauf-Systems in der Schwangerschaft bestehen insbesondere in einer Zunahme des Körperwassers und des Plasmavolumens, einer Abnahme des peripheren Widerstandes und einer Steigerung des Herzminutenvolumens bei etwa gleich bleibendem arteriellem Blutdruck. Die linksventrikuläre Kontraktionskraft und ihr erster Differentialquotient (dp/dt) bleiben unverändert.AbstractCardiovascular alterations during pregnancy are characterized by an increased vascular volumen, cardiac output, and heart rate, with a marked fall in vascular resistance. Cardiac output is about 40–50% higher during the third trimester. Even higher values of cardiac output are observed during uterine contractions in labor. In general, arterial blood pressure remains unaffected or demonstrates some tendency toward lower diastolic pressure. The higher blood volume is associated with a slight increase in left ventricular dimensions. Left ventricular contraction force and its first derivative remain unchanged. Many symptoms and findings during pregnancy are caused by the described changes, such as dyspnea on exertion, presyncope due to pressure on the inferior vena cava resulting in a decreased venous return to the heart, prominent jugular venous pulsation, leg edema, and ejection murmurs over the aorta and pulmonary artery. Paroxysmal nocturnal dyspnea, anginal chest pain, syncopy, anasarca, and diastolic heart murmurs require further evaluation.

Temporal and spatial development of infarcts in porcine hearts

SummaryWe investigated the temporal and spatial development of infarcts in porcine hearts to evaluate the time-dependent beneficial effect of reperfusion on infarct size. The left anterior descending coronary artery (LAD) was occluded in 17 pigs for different periods of time followed by 4 hours of reperfusion. Transmural needle biopsies subdivided into subendocardial and subepicardial halves were taken from the ischemic apex after 60 min of ischemia to determine the tissue concentrations of ATP and NAD. The myocardium-at-risk was assessed with a fluorescent dye injected into the right atrium at the end of the experiments, just after the LAD had been reoccluded. The excised hearts were cut into slices parallel to the heart basis. The ischemic myocardium was measured by planimetry of the nonfluorescent areas whereas the infarcted tissue was determined with the NBT stain and related to the area-at-risk. Ischemic cell death started in the jeopardized left ventricular subendocardial septum after about 30 min of ischemia. The further progress involved the right subendocardial septum and the subendocardium of the left anterior free wall. Already after 75 min of ischemia most of the myocytes-at-risk were irreversibly injured.Infarctions reached their final extent after 90–120 min of ischemia. These results indicate that in hearts without a significant collateral blood flow reperfusion can only reduce infarct size if its initiated within 60–75 min of ischemia. Like in canine hearts infarctions progress from the ischemic subendocardium towards the outer layers.

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.