Mitochondrial reactive oxygen species cause arrhythmias in hypertrophic cardiomyopathy

Abstract Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and caused by genetic variants that often increase sarcomeric Ca 2+ sensitivity. While Ca 2+ sensitization explains diastolic dysfunction, the genesis of ventricular arrhythmias is unresolved. Here, we show that HCM mutations or pharmacological interventions that increase myofilament Ca 2+ sensitivity generate bioenergetic mismatch and oxidative stress during β-adrenergic stimulation which provide a trigger and a substrate for arrhythmias. For any given sarcomere shortening that produces work and consumes ATP, less Ca 2+ stimulates the Krebs cycle to maintain mitochondrial NADH. This reverses the mitochondrial transhydrogenase to regenerate NADH from NADPH, supporting ATP production at the cost of NADPH-dependent antioxidative capacity. The ensuing overflow of reactive oxygen species (ROS) from mitochondria and glutathione oxidation induce spontaneous Ca 2+ release from the sarcoplasmic reticulum and Ca 2+ waves, well-defined triggers of arrhythmias. Furthermore, transhydrogenase-dependent ROS formation slows electrical conduction during β-adrenergic stimulation in vivo , providing a substrate for arrhythmias. Chronic treatment with a mitochondrially-targeted ROS scavenger abolishes the arrhythmic burden during β-adrenergic stimulation in HCM mice in vivo, while inducing mitochondrial ROS with a redox cycler is sufficient to induce arrhythmias in wild-type animals. These findings may lead to new strategies to prevent sudden cardiac death in patients with HCM.