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Background Heart failure increases autonomic nerve activities and changes intracellular calcium (Ca i ) dynamics. Objective The purpose of this study was to investigate the hypothesis that abnormal Ca i dynamics are responsible for triggered activity in the pulmonary veins (PVs) during acetylcholine infusion in a canine model of heart failure. Methods Simultaneous optical mapping of Ca i and membrane potential was performed in isolated Langendorff-perfused PV–left atrial (LA) preparations from nine dogs with ventricular pacing-induced heart failure. Mapping was performed at baseline, during acetylcholine (1 μmol/L) infusion (N = 9), and during thapsigargin and ryanodine infusion (N = 6). Results Acetylcholine abbreviated the action potential. In four tissues, long pauses were followed by elevated diastolic Ca i , late phase 3 early afterdepolarizations, and atrial fibrillation (AF). The incidence of PV focal discharges during AF was increased by acetylcholine from 2.4 ± 0.6 beats/s (N = 4) to 6.5 ± 2.2 beats/s (N = 8; P = .003). PV focal discharge and PV–LA microreentry coexisted in 6 of 9 preparations. The spatial distribution of dominant frequency demonstrated a focal source pattern, with the highest dominant frequency areas colocalized with PV focal discharge sites in 35 (95%) of 37 cholinergic AF episodes (N = 8). Thapsigargin and ryanodine infusion eliminated focal discharges in 6 of 6 preparations and suppressed the inducibility of AF in 4 of 6 preparations. PVs with focal discharge have higher densities of parasympathetic nerves than do PVs without focal discharges ( P = .01), and periodic acid–Schiff (PAS)-positive cells were present at the focal discharge sites. Conclusion Ca i dynamics are important in promoting triggered activity during acetylcholine infusion in PVs from pacing-induced heart failure. PV focal discharge sites have PAS-positive cells and high densities of parasympathetic nerves.

Objectives The purpose of this study was to test the hypothesis that radiofrequency (RF) catheter ablation results in cardiac nerve sprouting. Background Nerve sprouting plays a role in cardiac arrhythmogenesis. Whether or not nerve sprouting occurs after RF catheter ablation is unclear. Methods We performed RF catheter ablation in the right atrium (RA) and right ventricle (RV) in 10 dogs, which then were sacrificed in 2 hours (acute group, n=5) or 1 month (chronic group, n=5). Seven normal dogs were used as control. Immunohistochemical staining for growth-associated protein 43 (GAP-43) was performed to measure growing (sprouting) nerves. Results A significant increase of GAP-43 immunoreactive nerve fiber density was observed at the RA ablation sites in 2 hours (4,410 ± 1,379 μm 2 /mm 2 ) and in 1 month (2,948 ± 666 μm 2 /mm 2 ) after ablation compared to controls (1,377 ± 471 μm 2 /mm 2 , P = .0001). At remote sites (>2 cm away from ablation sites) of RA, RF ablation also resulted in robust nerve sprouting in both the acute group (5,846 ± 3241μm 2 /mm 2 ) and the chronic group (6,030 ± 2226 μm 2 /mm 2 ). RF ablation in the RV did not increase nerve density at the ablation sites, but nerve density was increased at remote sites in 2 hours (1,345 ± 451 μm 2 /mm 2 , P = .0136) that was reduced down to the normal control level (722 ± 337 μm 2 /mm 2 ) in 1 month. Conclusions Nerve sprouting occurred within 2 hours after RF ablation in both the RA and RV and persisted for at least 1 month in the RA but not the RV. The increased GAP-43 + nerve densities developed at both the ablation and the remote sites.

Background Single strong premature electrical stimulation (S 2 ) may induce figure-eight reentry. We hypothesize that Ca current-mediated slow-response action potentials (APs) play a key role in the propagation in the central common pathway (CCP) of the reentry. Methods We simultaneously mapped optical membrane potential (V m ) and intracellular Ca (Ca i ) transients in isolated Langendorff-perfused rabbit ventricles. Baseline pacing (S 1 ) and a cathodal S 2 (40–80 mA) were given at different epicardial sites with a coupling interval of 135 ± 20 ms. Results In all 6 hearts, S 2 induced graded responses around the S 2 site. These graded responses propagated locally toward the S 1 site and initiated fast APs from recovered tissues. The wavefront then circled around the refractory tissue near the site of S 2 . At the side of S 2 opposite to the S 1 , the graded responses prolonged AP duration while the Ca i continued to decline, resulting in a Ca i sinkhole (an area of low Ca i ). The Ca i in the sinkhole then spontaneously increased, followed by a slow V m depolarization with a take-off potential of −40 ± 3.9 mV, which was confirmed with microelectrode recordings in 3 hearts. These slow-response APs then propagated through CCP to complete a figure-eight reentry. Conclusion We conclude that a strong premature stimulus can induce a Ca i sinkhole at the entrance of the CCP. Spontaneous Ca i elevation in the Ca i sinkhole precedes the V m depolarization, leading to Ca current-mediated slow propagation in the CCP. The slow propagation allows more time for tissues at the other side of CCP to recover and be excited to complete figure-eight reentry.