VARIABILITY IN THE RISK FOR ARRHYTHMIAS AND SUDDEN DEATH IN THE LONG QT SYNDROME. IDENTIFICATION AND ROLE OF MODIFIER GENES

In genetic disorders as in common cardiac diseases many patients die suddenly and unexpectedly. Of those with an acute myocardial infarction, 5% do not even arrive alive at the hospital. Why does this occur only in some patients? We try to answer these questions by using, as a model, a monogenic arrhythmogenic disease, the long QT syndrome. Our hypothesis is that a genetic predisposition to react to stress (pain, exercise, emotions) with different responses of the autonomic nervous system results in varying amounts of catecholamines (substances released by the nervous system) reaching the heart. Catecholamines acting on hearts electrically unstable can cause sudden death within few minutes. We are testing our hypothesis in the long QT syndrome (LQTS), a genetic disease which we have studied for 35 years. LQTS is a leading cause of sudden cardiac death in the young, produced by at least 6 different genes. The most common genetic variant is called LQT1 and most LQT1 patients who have life-threatening arrhythmias do so under conditions of physical (running, swimming) or emotional stress. This is because their mutations create a condition in which catecholamines become extremely dangerous. We will study the DNA of 2 different LQT1 populations, all “founder populations” as they descend from a single common ancestor and include several families, in which all affected individuals share the same identical mutation. Founder populations are ideal for the study of modifier genes. If our hypothesis is correct, we will be able to identify those LQT1 patients at highest risk and to implement aggressive preventive strategies. These “modifier genes” are probably the same acting in patients with myocardial infarction. This might have profound implications for preventing sudden cardiac death.