Delayed afterdepolarization in intact canine sinoatrial node as a novel mechanism for atrial arrhythmia

INTRODUCTION: Recent evidence indicates that spontaneous sarcoplasmic reticulum Ca release and Na-Ca exchanger current activation contribute to the sinoatrial node (SAN) automaticity. These findings suggest that SAN activity may share mechanisms that underlie both automaticity and triggered activity. The aim of this study is to test the hypothesis that spontaneous, nonvoltage gated, intracellular Ca (Ca(i)) elevation may induce delayed afterdepolarization (DAD) in intact SAN during isoproterenol infusion. METHODS AND RESULTS: We simultaneously mapped Ca(i) and membrane potential in 31 isolated Langendorff-perfused canine right atriums (RA). Isoproterenol increased heart rate and late diastolic Ca(i) elevation (LDCAE) of the superior SAN, leading to consistent SAN automaticity in all 31 RAs. However, DAD-like diastolic depolarizations (DD) were transiently observed in 4 RAs during isoproterenol infusion. These DAD-like DDs were preceded by LDCAE, but did not trigger a full action potential. The LDCAE preceding DAD-like DDs had smaller amplitude (0.41 ± 0.08 AU vs 0.48 ± 0.07 AU, P = 0.001) and less steep slopes (3.7 ± 1.3 AU/s vs 4.8 ± 1.4 AU/s, P = 0.001) than that of sinus beats. The coupling interval of DAD-like DDs was longer than that of the preceding normal beats (407 ± 48 ms vs 371 ± 44 ms, P = 0.002). CONCLUSION: The isoproterenol-induced LDCAE of superior SAN induced a full action potential in most cases. However, if the LDCAE was too small to trigger an action potential, then it induces only DAD-like DD. The failure of DAD-like DD to consistently trigger a sinus beat is a novel mechanism of atrial arrhythmogenesis.ope