POTENTIAL THERAPY FOR THE PREVENTION OF SUDDEN CARDIAC DEATH


Naranjan S. Dhalla, Ph.D., M.D.(Hon), St. Boniface General Hospital Research Centre, University of Mantioba, Winnipeg, Canada

Objectives: Although sudden cardiac death is a leading cause of mortality, the mechanisms for its pathogenesis as well as therapy for prevention are poorly understood.

Background: Since overactivation of sympathetic nervous system is invariably seen in subjects with high risk for sudden cardiac death, elevated levels of circulating catecholamine levels are considered to result in lethal ventricular arrhythmias and subsequent sudden cardiac death. Such arrhythmogenic effects of catecholamines are generally believed to occur by their actions on a-adrenoceptors in coronary arteries for inducing coronary spasm and subsequent myocardial ischemia as well as on ß-adrenoceptors in cardiomyocytes for stimulating cardiac function and producing defects in intracellular Ca2+-handling.

Methods and Results: Experimental evidence from our laboratory has revealed that excessive amounts of circulating catecholamines are oxidized to aminochromes, which are highly reactive quinine compounds. These oxidation products of catecholamines have been demonstrated to produce subcellular alterations, intracellular Ca2+-overload, coronary spasm, myocardial cell damage, depletion of high energy stores and ventricular arrhythmias. Furthermore, catecholamine-induced arrhythmias and ventricular fibrillation were associated with elevated levels of plasma adrenochromes; however, these changes were markedly attenuated by treatment of animals with different antioxidants.

Conclusions: The results suggest that oxidation of catecholamines under stressful conditions may result in sudden cardiac death and thus different antioxidants may be considered as potential therapy for its prevention.