CELLULAR AND MOLECULAR MECHANISMS INVOLVED IN THE ARRHYTHMOGENESIS OF THE HYPERTROPHIC CARDIOMYOPATHY

Hypertrophic cardiomyopathy (HCM) is considered one of the most severe inherited cardiomyopathies for its lethality. Although compatible with long life, there is a constant risk of sudden death. Sudden deaths in HCM can occur at any age, even in subjects who have been asymptomatic all their life. The annual rate of sudden death ranges 2-3%, being as high as 4-6% in children. The most common cause of death is likely lethal cardiac rhythm disturbances producing cardiac arrest. Some factors, such as severe exertion, are known to predispose to sudden death, but efficient methods to predict which patients are mostly susceptible to fatal arrhythmias have not been developed yet. On the other side, drugs ordinarily used for the suppression of ventricular arrhythmias may even exacerbate the problem. Thus, the comprehension of arrhythmogenic mechanisms in HCM is crucial to treat and prevent rhythm disturbances. They are thought to occur when a trigger interacts with an abnormal substrate in the myocardium, which favors its propagation and produces ventricular fibrillation. In HCM, as well as in acquired cardiomyopathies due to hypertension, coronary artery disease or infarction, both the microscopic structure of cardiac tissue and cellular properties are markedly altered as a consequence of a process named cardiac remodeling. Our research group has been studying cellular electrical abnormalities associated with myocardial hypertrophy for many years. Luckily, many alterations occurring at a cellular level are similar in inherited and acquired cardiomyopathies, in humans as well as in animal models. In fact, cardiac electrophysiological remodeling is typically associated with the re-entry of cells into a fetal program, i.e., return to a primordial profile. These similarities allow studying molecular mechanisms responsible for electrophysiological remodeling in animal models, and comparing them with human cardiomyopathies. This is the approach of our research program.