Abstract 2662: Delayed Afterdepolarization in Intact Canine Sinoatrial Node as a Novel Mechanism for Atrial Arrhythmia

Background - Recent evidence indicates that spontaneous sarcoplasmic reticulum (SR) Ca release and Na-Ca exchanger current ( I NCX ) activation contribute to the sinoatrial node (SAN) automaticity. These findings suggest that automaticity and triggered activity share the same mechanism. However, delayed afterdepolarization (DAD) has not been reported in intact SAN. Methods and Results - We simultaneously mapped intracellular Ca (Ca i ) and membrane potential (Vm) in 21 Langendorff-perfused canine right atrium (RA) at baseline and during isoproterenol (ISO) infusion with spatial resolution of 0.35 × 0.35 mm 2 /pixel and temporal resolution of 1 ms/frame. ISO infusion increased heart rate and late diastolic Ca i elevation (LDCAE) of the superior SAN, leading to consistent SAN automaticity in 17 RAs. However, intermittent transient late diastolic depolarization was observed in 4 RAs when ISO dose was increased from 0.1 to 0.3 μ mol/L. These diastolic depolarizations were preceded by LDCAE, and were not followed by a full action potential. Therefore, they were consistent with the definition of DADs. An ectopic pacemaker then antidromically activated the SAN, resulting in atrial arrhythmia. Further increase of ISO dose eliminated DADs. The DADs occurred either intermittently (n=19) or in an alternans patterns (n=18). The cycle lengths closed by ectopic beats were longer than those closed by normal sinus beats (407±48 ms, vs. 371±44 ms, p=0.002). To further explore the mechanisms of DADs, we performed computer simulation using the Maltsev model of the SAN (AJP 2009). The DADs are observed when either the I CaL or I NCX were reduced by 50% while SR Ca uptake was increased by 50%. Further increase of these currents produced consistent SAN activation. These findings suggest that I CaL inhibition by increased SR Ca release may play a role in the transient appearance of DADs during intermediate dose of ISO. Conclusions - Intermediate dose ISO infusion may induce DADs in the SAN. While a robust LDCAE may induce sufficiently large DADs to trigger sinus beats, I CaL inhibition by increased SR Ca release during intermediate dose ISO infusion may result in DADs that are too small to activate SAN. These findings indicate that triggered activity underlies SAN automaticity.