MITOCHONDRIAL DYSFUNCTION AND ARRHYTHMIC RISK: POSSIBLE NEW THERAPIES FOR SUDDEN DEATH


Samuel C. Dudley, M.D., Ph.D., Brown University and Lifespan Cardiovascular Institute, Providence, RI, USA

Mitochondria are essential to providing ATP thereby satisfying the energy demand of the incessant electrical activity and contractile action of cardiac muscle. Emerging evidence indicates that mitochondrial dysfunction can adversely affect cardiac electrical functioning by impairing the intracellular ion homeostasis and membrane excitability through reduced ATP production and excessive reactive oxidative species (ROS) generation, resulting in increased propensity to cardiac arrhythmias. Recent work by our group has demonstrated that increased cytosolic NADH, because of cardiomyopathy and mitochondria dysfunction, results in decreased INa. This work suggests a link between metabolism and INa. The deleterious effect of NADH accumulation on INa can be ameliorated with NAD+, the oxidized form of the nucleotide. NAD+ supplementation acts via a membrane surface receptor to decrease mitochondrial ROS and raise sodium channel levels. Myocardial infarction (MI) and angiotensin II are also associated with mitochondrial ROS production and decreased expression of Cx43, the principal gap junction protein responsible for propagating current in ventricles. Inhibition of mitochondrial ROS or downstream, activated c-Src improved Cx43 levels and conduction velocity and lowered arrhythmia inducibility in arrhythmic mouse models. These results suggest that myocardial injury is associated with decreased conduction velocity secondary to reduced INa and Cx43. Raising these ion channel levels by reducing mitochondrial ROS production may be a new paradigm of antiarrhythmic therapy.