14th International Congress
THE "NEW FRONTIERS"
OF ARRHYTHMIAS 2000

Jan. 29 - Feb. 5, 2000
Marilleva, Trento, Italy

RT-22

Molecular bases of juvenile sudden cardiac death

Silvia G. Priori, Marina Cerrone.
Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, Pavia, Cardiology Division, IRCCS, Policlinico S. Matteo Hospital, Pavia, Italy

Introduction

Several human diseases are genetically determined, either directly through a single genetic defect (monogenic diseases), or indirectly due to the inheritance of several traits acting as predisposing factors. In the last decade a large number of new genes has been identified and linked to human diseases. As a consequence, molecular biology is playing a growing role in clinical medicine, providing new diagnostic methods and new therapeutic perspectives.

The most important progresses of molecular genetics have occurred in the understanding of monogenic disorders, i.e. those diseases caused by a single defect. Most of these diseases are rare, however they are regarded as a model to devise strategies for the applications of genetic to more complex traits such as cancer and other leading causes of death and morbidity. In cardiology, highly prevalent diseases such as atherosclerosis, hypertension and coronary artery diseases are clustered in families and a positive “family history” is frequently present in affected individuals. The pattern of inheritance of these diseases however is not mendelian: the clinical phenotype could be modeled as resulting from the algebraic sum of “predisposing“ and “protective” inherited factors. In the future, when several of the genes contributing to the phenotype of these “complex” diseases are available, genetic parameters will be used to predict susceptibility to cardiac diseases.

One interesting approach for the understanding of “complex” traits is that of studying the distribution of polymorphisms and mutations of genes that cause monogenic disorders. The hypothesis being tested is that “sub-clinical” forms of monogenic disorders may manifest the clinical phenotype only after exposure to specific “triggering factors”.

Monogenic disorders associated to sudden cardiac death (hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, long QT syndrome, Brugada syndrome) have provided a working hypothesis toward the understanding of susceptibility genes for cardiac electrical instability^1,2.

In this article, we will review the current knowledge regarding the molecular mechanisms of mendelian disorders associated to sudden cardiac death focusing on the implications for the understanding of juvenile non coronary sudden cardiac death.