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

Abstract

BackgroundCardiac dyskinesis in regional ischemia results in arrhythmias through mechanically-induced changes in electrophysiology ( mechano-arrhythmogenicity) that involve ischemic alterations in voltage-calcium (Ca2+) dynamics, creating a vulnerable period (VP) in late repolarisation. ObjectiveTo determine cellular mechanisms of mechano-arrhythmogenicity in ischemia and define the importance of the VP. Methods and ResultsVoltage-Ca2+ 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 KATP 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 Ca2+ (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 Ca2+ imaging revealed that SI increased diastolic Ca2{+/-} (+9{+/-}1%, p<0.0001), which was not prevented by HC-030031 or NAC. ConclusionIn ischemia, mechano-arrhythmogenicity is enhanced specifically during the VP and is mediated by ROS, TRPA1, and Ca2+.