Kohlhaas, M.; Sequeira, V.; Parikh, S.; Dietl, A.; Richter, O.; Bay, J.; Bertero, E.; Schwemmlein, J.; Tian, Q.; Friedrich, F. W.; Flenner, F.; Nickel, A. G.; Alscher, F.; Nanadikar, M. S.; Venkataraman, R.; Baudenbacher, F. J.; Kappl, R.; Johnson, V.; Prates Roma, L.; Kasakow, A.; Hohl, M.; Laufs, U.; Hoth, M.; Katschinski, D. M.; Bohm, M.; Lipp, P.; Carrier, L.; Eschenhagen, T.; Knollmann, B. C.; Maack, C.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is caused by genetic variants that often increase sarcomeric Ca2+ sensitivity. While Ca2+ sensitization explains diastolic dysfunction, the genesis of ventricular arrhythmias remains unresolved. Here, we show that HCM mutations or pharmacological interventions that increase myofilament Ca2+ sensitivity generate bioenergetic mismatch and oxidative stress during {beta}-adrenergic stimulation, which provide a trigger and a substrate for arrhythmias. For any given sarcomere shortening that produces work and consumes ATP, less Ca2+ 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 Ca2+ release from the sarcoplasmic reticulum and Ca2+ waves, well-defined triggers of arrhythmias. Furthermore, transhydrogenase-dependent ROS formation slows electrical conduction during {beta}-adrenergic stimulation in vivo, providing a substrate for arrhythmias. Chronic treatment with a mitochondrially-targeted ROS scavenger abolishes the arrhythmic burden during {beta}-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.