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B-YIA2-01 MECHANO-ARRHYTHMOGENICITY IS ENHANCED IN LATE REPOLARISATION DURING ISCHEMIA AND DRIVEN BY A TRPA1-, CALCIUM-, AND REACTIVE OXYGEN SPECIES-DEPENDENT MECHANISM

      Background

      Cardiac dyskinesis during ischemia results in arrhythmias via mechanically-induced changes in electrophysiology (‘mechano-arrhythmogenicity’). While cellular mechanisms of mechano-arrhythmogenicity are unknown, ischemic alterations in voltage-Ca2+ dynamics may create a vulnerable period (VP) for mechano-arrhythmogenicity during late repolarisation.

      Objective

      Determine cellular mechanisms of mechano-arrhythmogenicity in ischemia and define the importance of the VP.

      Methods

      Rabbit LV myocytes were paced at 1Hz and rapidly stretched (10-18% increase in sarcomere length over ∼110ms) during diastole or the VP in control (CTL) or simulated ischemic (SI) conditions. Drugs were used to buffer Ca2+ (BAPTA), stabilise ryanodine receptors (dantrolene), block mechano-sensitive TRPA1 (HC-030031) or KATP channels (glibenclamide), or to chelate (NAC), block (DPI), or increase (fluorophore photoexcitation) reactive oxygen species (ROS) production. Voltage-Ca2+ dynamics were simultaneously monitored by dual fluorescence imaging with a single camera-optical splitter system to assess the VP (= Ca2+ transient - action potential duration). Diastolic Ca2+ was measured with ratiometric imaging.

      Results

      The VP was longer in SI than CTL (146±7 vs 54±8ms; n=50 cells, N=6 rabbits; p<0.0001). Mechano-arrhythmogenicity during the VP was greater in SI compared to CTL (7 vs 1% of stretches induced arrhythmias; n=50, N=6; p<0.005) but was similar in diastole. Arrhythmias during the VP were more complex than in diastole (100 vs 69% had sustained activity; n=50, N=6; p<0.05). In the VP, arrhythmia incidence was reduced by BAPTA (2%; p<0.05), HC-030031 (1%; p<0.005), NAC (1%; p<0.005), or DPI (2%; p<0.05), while dantrolene had no effect. Fluorophore photoexcitation caused an increase during both the VP and diastole (29 and 14%, n=42, N=4; p<0.05). Glibenclamide reduced the size of the VP (109±6ms; p<0.0001), with an associated decrease in arrhythmia incidence (2%, n=50, N=6; p<0.05). SI increased diastolic Ca2+ (9±1%, n=25, N=5; p<0.0001), which was not prevented by NAC or HC-030031.

      Conclusion

      Mechano-arrhythmogenicity in ischemia is enhanced during the VP and involves TRPA1, Ca2+, and ROS, representing potential anti-arrhythmic targets.