Useful insights into mechanisms of catecholaminergic polymorphic ventricular tachycardia

Sep 5 2006

World Congress of Cardiology Report - Familial genetic defects are responsible for several cases of unexpected sudden cardiac death in young and otherwise healthy individuals.

This discovery has been made possible through the integration of clinical cardiology and molecular biology over the past decade.

Among these inherited diseases, the Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), even if rare, is highly lethal. CPVT is caused by genetic mutations in a cardiac protein, the ryanodine receptor, responsible for the regulation of calcium in the heart. The mutations cause an increase in the amount of calcium in the heart that can facilitate the occurrence of lethal arrhythmias. Individuals who carry these mutations have a structurally normal heart and a normal ECG in resting conditions, but they develop arrhythmias during physical and/or emotional stress. Mortality in the absence of therapy is 30% before age 40.

The only available medical therapy so far is beta-blockers. However, they are not highly effective, since 50% of the patients continue to have arrhythmias during medical treatment. In this case, an implantable cardioverter defibrillator (ICD) is the only alternative option, even for young children. Under some circumstances this raises tough ethical questions.

Since in resting conditions the patients do not show anomalies in the ECG, the diagnosis if often made with a stress-test or a Holter-ECG. CPVT is characterized by a very peculiar arrhythmia called bidirectional ventricular tachycardia.

Unfortunately, the electrophysiological mechanisms that underlie arrhythmias in the setting of CPVT are poorly understood. The use of experimental models, therefore, could be useful in unravelling those mechanisms, providing new tools for a better management of patients.

In 2001, the group of Dr. Silvia Priori, in Pavia, Italy, discovered the genetic bases of CPVT. Subsequently, the same group developed a mouse model that carried a common mutation associated with CPVT, in order to investigate the characteristics of the disease at the molecular level.

In 2005, Cerrone et al. published the first results of this model, demonstrating that during stress the mouse developed the same kind of lethal arrhythmias described in CPVT patients. A typical example of ventricular tachycardia recorded in this mouse is similar to the human tachycardia.

Thus this mouse is a reliable model to study the mechanisms of arrhythmias in CPVT.

Recently, a collaboration has been set between the group of Dr Priori in Pavia and the group of Dr. Jose’ Jalife in Syracuse, NY. The aim is to study the CPVT using optical mapping, a highly sophisticated state of the art imaging technique. Dr. Jalife is a world-renowned expert in this field.

Optical mapping is a technique that allows us to visualize arrhythmias in the isolated heart through the use of particular dyes that are sensitive to the changes in voltage that occur in the heart. The signal is recorded by a fast camera, digitized and later analyzed.

We discovered with optical mapping that during normal rhythm, the CPVT mouse heart displays the same characteristics described earlier in the human heart. Furthermore, we were able to increase our understanding of the mechanisms that underlie the different arrhythmias that characterize CPVT. As an example, we now know that ventricular tachycardia in this mouse model was due to a focal source arising from a highly localized area of the ventricle.

On the other hand, the mechanism that underlie sudden cardiac death is not focal, but reentry. Our data allowed us also to record some examples of bidirectional ventricular tachycardia, the one typical of CPVT, where the origin of the beat alternates between the left and the right ventricle.

In conclusion, the development and optical mapping studies of the CPVT mouse model has provided very useful insights into the mechanisms of this rare, yet highly fatal, disease.