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

Familial hypertrophic cardiomyopathy (fHCM) 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 fHCM 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 fHCM 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 fHCM, as well as in acquired cardiomyopathies, both the microscopic structure of cardiac tissue and cellular properties are markedly altered as a consequence of a process named cardiac remodeling. What is the signal leading from a gene defect to the clinical disease is an open question, but its comprehension is crucial to prevent or reduce the progression of fHCM; this is one of the aims of our projects. Progression of the disease leads to a deterioration of patient’s condition and increased risk of sudden death. Experimental methodologies currently used in our lab allow ascertaining the presence of electrical abnormalities directly in cardiac cells from fHCM patients, by using tissue specimens routinely removed during corrective surgery. These studies will allow to get deeper insight into the molecular mechanisms favoring arrhythmias and to plan novel therapeutic strategies.