Paradoxical toxicity of cardioplegic compounds on ischemic cardiomyocyte using optimal design strategy.
BACKGROUND
The aim of this study was to evaluate the effects of major components of cardioplegic solutions on myocardial tissue submitted to prolonged cold ischemia.


METHODS
Our methodology was based on the simultaneous testing in the same series of experiments of many compounds (19 in number), which were included in the composition of 20 established solutions. All the experiments were performed by a matricial-predefined protocol that allows the evaluation of the protective or toxic effects of each of these 19 compounds. Pig hearts were removed and left ventricular myocardiums were cut into 320 pieces. For each solution tested, 8 pieces of myocardial tissue were incubated at 4 degrees C for 24 hours and 8 other pieces were incubated for 72 hours. At the end of incubation period, tissue injury was assessed by measuring the leakage of myocardial enzymes(glutamic-oxaloacetic transaminase, lactate dehydrogenase, creatine phosphokinase) into the incubation medium. Initially, the effects of each solution were evaluated, and then a mathematical analysis was performed and the effects of each compound deduced.


RESULTS
After the 24-hour incubation period, pyruvate (5 mmol/liter), polyethylene glycol (5 mmol/liter), Ala-Gln (20 mmol/liter), and reduced glutathione (3 mmol/liter) showed toxic effects, whereas ethanol (1%) and calcium chloride (2 mmol/liter) seemed to be protective. After 72 hours' incubation, similar data were obtained; dextran 70 (0.57 mmol/liter) was also found to be deleterious.


CONCLUSIONS
The results revealed surprising myocardial toxicity (enzymatic release) from components included in cardioplegic solutions. Some components would induce metabolic activation during prolonged hypothermic ischemia, which may be inappropriated and which may perhaps exacerbate damages by increasing membrane ruptures. This concept confirms eventual discrepant effects of preservative compounds on cardiomyocyte membrane during deep hypothermia, according to the metabolic state of the cell.
Ferrera
René
R
INSERM, Institut National pour la Santé et la Recherche Médicale, EMI-U 0226, Lyon, France. ferrera@lyon.inserm.fr
Michel
Pierre
P
Ovize
Michel
M
D000818:Animals; D002122:Calcium Chloride; D002314:Cardioplegic Solutions; D002470:Cell Survival; D015925:Cryopreservation; D004151:Dipeptides; D000431:Ethanol; D005978:Glutathione; D006321:Heart; D017202:Myocardial Ischemia; D009206:Myocardium; D032383:Myocytes, Cardiac; D019188:Organ Preservation Solutions; D011092:Polyethylene Glycols; D011773:Pyruvates; D012107:Research Design; D013552:Swine
D002314:Cardioplegic Solutions; D004151:Dipeptides; D019188:Organ Preservation Solutions; D011773:Pyruvates; D000431:Ethanol; D011092:Polyethylene Glycols; D005978:Glutathione; D002122:Calcium Chloride; C054122:alanylglutamine