Mechano-arrhythmogenicity is enhanced during late repolarisation in ischemia and driven by a TRPA1-, calcium-, and reactive oxygen species-dependent mechanism

ABSTRACT Background Cardiac dyskinesis in regional ischemia results in arrhythmias through mechanically-induced changes in electrophysiology (‘mechano-arrhythmogenicity’) that involve ischemic alterations in voltage-calcium (Ca 2+ ) dynamics, creating a vulnerable period (VP) in late repolarisation. Objective To determine cellular mechanisms of mechano-arrhythmogenicity in ischemia and define the importance of the VP. Methods and Results Voltage-Ca 2+ dynamics were simultaneously monitored in rabbit ventricular myocytes by dual-fluorescence imaging to assess the VP in control and simulated ischemia (SI). The VP was longer in SI than in control (146±7 vs 54±8ms; p <0.0001) and was reduced by blocking K ATP channels with glibenclamide (109±6ms; p <0.0001). Cells were rapidly stretched (10-18% increase in sarcomere length over 110-170ms) with carbon fibres during diastole or the VP. Mechano-arrhythmogenicity, associated with stretch and release in the VP, was greater in SI than control (7 vs 1% of stretches induced arrhythmias; p <0.005) but was similar in diastole. Arrhythmias during the VP were more complex than in diastole (100 vs 69% had sustained activity; p <0.05). In the VP, incidence was reduced with glibenclamide (2%; p <0.05), by chelating intracellular Ca 2+ (BAPTA; 2%; p <0.05), blocking mechano-sensitive TRPA1 (HC-030031; 1%; p <0.005), or by scavenging (NAC; 1%; p <0.005) or blocking reactive oxygen species (ROS) production (DPI; 2%; p <0.05). Ratiometric Ca 2+ imaging revealed that SI increased diastolic Ca 2± (+9±1%, p <0.0001), which was not prevented by HC-030031 or NAC. Conclusion In ischemia, mechano-arrhythmogenicity is enhanced specifically during the VP and is mediated by ROS, TRPA1, and Ca 2+ .