Basic/Translational Science -> Cell Physiology, Pharmacology, and Signaling D-BT01 - Cardiac Electrophysiology Society (CES): Lunch and Young Investigator Award Poster Session (ID 41) Special Session

D-BT01-14 - Acute Ischemia Increases Mechano-arrhythmogenicity In Late Repolarisation Via TRPA1 Channels (ID 15)

Disclosure
 B.A. Cameron: Nothing relevant to disclose.
Audio File Upload

Abstract

Background: Ventricular arrhythmias in acute ischemia are a major cause of sudden death. In the whole heart, altered tissue mechanics contributes to premature excitation through a mechano-sensitive Ca2+-driven mechanism. This may be facilitated by temporal uncoupling of voltage and Ca2+ dynamics, creating a vulnerable period in late repolarization for stretch-induced arrhythmias, during which Ca2+ remains high in repolarizing cells.
Objective: Determine mechanisms of mechano-arrhythmogenicity during acute ischemia.
Methods: Isolated LV myocytes from rabbits (female, NZW) were paced at 1 Hz and exposed to normal Tyrode (NT) or simulated ischemia solution (SI) (hyperkalemia [15 mM K+], acidosis [pH 6.5], and metabolic inhibition [1 mM sodium cyanide, 20 mM 2-deoxyglucose]). Cells were transiently stretched (20-40 µm for 100 ms) during diastole or the vulnerable period using carbon fibres. Pharmacology was used to buffer Ca2+ (1 µM BAPTA), stabilize ryanodine receptors (1 µM dantrolene), or block stretch-sensitive TRPA1 channels (10 µM HC-030031). Voltage and Ca2+ were simultaneously monitored using di-4-ANBDQPQ (20 µM), Fluo-5F (5 µM) with a single EMCCD camera-optical splitter system.
Results: SI shortened action potential duration (APDNT=384 vs APDSI=219 ms; p<0.0001) more than Ca2+ transient duration (CaTDNT=424 vs CaTDSI=357 ms; p<0.0001), resulting in a longer vulnerable period (VP=CaTD-APD) in SI than NT (VPSI=146 ms vs VPNT=54 ms; n=50 cells each, N=6 and N=14 rabbits; p<0.0001). Stretch-induced arrhythmias (premature excitation and sustained activity) were greater in SI than NT only in the vulnerable period (1 vs 7% of stretches; n=40, N=5 each; p<0.005). BAPTA and HC-030031 in SI reduced this arrhythmia incidence (1%; n=40, N=5; p<0.005), but surprisingly BAPTA also increased arrhythmia incidence in diastole (9%; n=40, N=5; p<0.005), while dantrolene had no effect.
Conclusion: Acute ischemia results in a greater shortening of APD than CaTD, creating a vulnerable period for stretch-induced arrhythmias. Stretch during this period triggers arrhythmias through a mechanism involving TRPA1 channels. Mechano-arrhythmogenicity and TRPA1 may represent novel anti-arrhythmic targets in acute ischemia.
Collapse