The impaired tolerance of the recently infarcted rat heart to cardioplegic arrest: The protective effect of orotic acid

Abstract

After myocardial infarction, a reduced mass of non-infarcted myocardium remains to maintain cardiac output. This acutely stressed, non-infarcted myocardium exhibits many metabolic disturbances, and undergoes a process of acute hypertrophy. These stress-induced disturbances may reduce the tolerance of the heart to the global ischaemia of cardioplegic arrest and may explain the increased mortality and morbidity associated with cardiac surgery in patients with recent myocardial infarction. We postulated that orotic acid, a pyrimidine precursor which augments the rate of protein synthesis during hypertrophy, might improve the response of the recently infarcted heart to cardioplegic arrest. Myocardial infarction was induced in rats by coronary ligation, and after 2 days or 3 days the hearts were excised and perfused on the working heart apparatus. After measurement of work capacity, the hearts underwent 1 hour of hypothermic cardioplegic arrest. Post-arrest function was then measured and expressed as a percentage of the pre-arrest value. A group of sham-operated, non-infarcted hearts served as controls. There were two distinct findings: 1. (1) when subjected to hypothermic cardioplegic arrest 2 days after myocardial infarction, hearts recovered only 49% of pre-arrest function, compared with 80% recovery in non-infarcted controls ( P < 0.001). Three days after infarction, recovery had improved to 68% ( P < 0.01 vs. 2 days, P < 0.05 vs. non-infarcted). 2. (2) Treatment with oral orotic acid following infarction augmented recovery from cardioplegic arrest to 83%, 2 days after infarction ( P < 0.001 vs. untreated) and to 87%, 3 days after infarction ( P < 0.01 vs. untreated). These findings indicate that the recently infarcted heart has reduced tolerance to global ischaemia, that orotic acid therapy improves this tolerance and hence may improve the results of urgent cardiac surgery in patients with acute myocardial infarction.