2006 Thomas W. Smith Memorial Lecture—From a Girl to a Mouse: A Journey in the Rhythm of the Heart
In the past 10 years, impressive advancements have occurred in the understanding of genetic bases of cardiac arrhythmias. This field has evolved into truly “translational” science in which the flow of data from bench to bedside has promoted advancements in basic electrophysiology and in clinical arrhythmology alike. As a paradigm of the fruitful integration between basic and clinical science in this area, I will present the story of the discovery of the molecular basis of catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare arrhythmogenic disorder characterized by adrenergically induced polymorphic ventricular tachycardia and sudden death in children. After being profoundly involved in the management of a little girl who experienced cardiac arrest, we diagnosed CPVT and initiated the search for the gene of this disease. We discovered that CPVT is caused by mutations in the cardiac ryanodine receptor’s gene (RyR2), a key protein implicated in the control of intracellular calcium. In vitro functional characterization demonstrated that the mutant RYR2 releases calcium from the sarcoplasmic reticulum during diastole, thus causing life-threatening arrhythmias. We developed a knock-in mouse model of CPVT that carries the same mutation identified in our patients, and this model is now an important source of data contributing to the understanding of CPVT and helping in the assessment of novel therapeutic strategies. Thus, the little girl is now hoping that the mouse will help doctors find a better treatment for her disease.