Abstract 1699: Possible Ionic Mechanism of Contractile Dysfunction in Brugada Syndrome
The Brugada syndrome is a form of arrhythmias that is associated with high incidence of sudden cardiac deaths. It is linked to mutations of the SCN5A gene and a reduction of the cardiac sodium current. The disease is believed to account for at least 4% of all sudden death. Understanding the pathophysiology of the disease is essential for the development of effective treatment strategy. It is believed that that the mechanism of Brugada syndrome is entirely electrical in nature. An alternative view is that the electrical abnormality of the syndrome has a possible morphological base. Wall motion abnormalities of the right ventricle (RV) have been detected in Brugada syndrome patients, and it is postulated that the motion abnormalities may indicate the existence of subtle structure or morphological changes of the RV, which may contribute to the arrhythmogenic substrate. The mechanism of the motion or contractile abnormality is currently unknown. We hypothesize that the RV contractile abnormality can be accounted for by the cellular electrical alterations of the syndrome. We used TTX 1 to 5 μM to partially block the Na current in RV ventricular cells to create a Brugada syndrome-like setting. This resulted in accentuation of the phase 1 repolarization or collapse of the action potential (AP) plateau in the RV epicardial cells, but not in RV endocardial or LV cells. The dynamic clamp technique was used to quantitatively examine the interplay between INa and Ito in generating the above cellular electrical alternations. Simultaneous measurement of AP morphology and cellular mechanical properties of RV cells showed that the TTX-induced accentuation of phase 1 notch is associated with a reduction of cell contractility and delay in Ca transient peak, while collapse of the AP plateau completely suppressed the cell contraction and significantly blunted the Ca transient. Blockade of Ito in RV epicardial cells by dynamic clamp restored the TTX induced electrical and mechanical alterations, pointing to the potential of Ito blockade as a therapeutic strategy for treatment of the disease. We concluded that the contractile abnormality in Brugada syndrome can be accounted for by the cellular electrical alterations, and is not necessarily an indication of morphological abnormalities.