Alex Y. Tan

Neural Mechanisms of Paroxysmal Atrial Fibrillation and Paroxysmal Atrial Tachycardia in Ambulatory Canines

Background— The relationship between autonomic activation and the mechanisms of paroxysmal atrial fibrillation remains unclear. Methods and Results— We implanted a pacemaker and a radio transmitter in 7 dogs (group 1). After baseline recording, we paced the left atrium at 20 Hz for 1 week and then monitored left stellate ganglion nerve activity, left vagal nerve activity, and left atrial electrogram without pacing for 24 hours. This protocol repeated itself until sustained atrial fibrillation (>48 hours) was induced in 3±1 weeks. In another 6 dogs (group 2), we cryoablated left and right stellate ganglia and the cardiac branch of the left vagal nerve during the first surgery and then repeated the same pacing protocol until sustained atrial fibrillation was induced in 7±4 weeks (P=0.01). There were 4±2 episodes of paroxysmal atrial fibrillation per day and 10±3 episodes of paroxysmal atrial tachycardia per day in group 1. Simultaneous sympathovagal discharges were observed to immediately precede the onset of atrial arrhythmias in 73% of episodes. In comparison, group 2 dogs had no paroxysmal atrial fibrillation (P=0.046) or paroxysmal atrial tachycardia (P<0.001) episodes. Nerve sprouting, sympathetic hyperinnervation, and a massive elevation of transcardiac norepinephrine levels occurred in both groups. Conclusions— Intermittent rapid left atrial pacing results in sympathetic hyperinnervation, paroxysmal atrial fibrillation, and paroxysmal atrial tachycardia. Simultaneous sympathovagal discharges are common triggers of these arrhythmias. Cryoablation of extrinsic sympathovagal nerves eliminated paroxysmal atrial fibrillation and paroxysmal atrial tachycardia, which suggests that simultaneous sympathovagal discharges and these arrhythmias are causally related. Because cryoablation only delayed but did not prevent sustained atrial fibrillation, autonomic nerve activity is not the only factor that determines atrial fibrillation maintenance.

Neural mechanisms of atrial arrhythmias

The past 5 years have seen great advances in the knowledge of neural mechanisms of atrial arrhythmogenesis. Direct autonomic nerve recordings demonstrate that simultaneous sympathovagal discharges and intrinsic cardiac nerve activities are common triggers of paroxysmal atrial tachycardia and atrial fibrillation. While activity of the autonomous nervous system (ANS) is crucial in triggering paroxysmal atrial fibrillation, a high incidence of sympathovagal co-activation at baseline is associated with a high vulnerability to pacing-induced sustained atrial fibrillation, suggesting that ANS has a role in the development of persistent atrial fibrillation. Modulation of ANS activity may constitute an important therapeutic strategy for the management of atrial tachyarrhythmias. Specifically, continuous, low-level stimulation of the left cervical vagus nerve effectively suppresses atrial tachyarrhythmias by reducing the nerve activity of the stellate ganglion. Clinically, compared with pulmonary vein isolation alone, the addition of ablation of intrinsic cardiac ganglia may confer better outcomes for patients with paroxysmal atrial fibrillation. These findings suggest that further investigation of the neural mechanisms of atrial arrhythmias might lead to better management of patients with atrial arrhythmias. In this article, we review the role of the ANS in the induction and maintenance of atrial arrhythmias and the role of neural modulation as a treatment strategy for atrial arrhythmias.

Heart rate, autonomic markers, and cardiac mortality

Heart rate is a precisely regulated variable, which plays a critical role in health and disease. Numerous epidemiologic studies and large post-myocardial infarction trials have provided evidence that elevated resting heart rate is an independent risk factor for cardiac mortality. This body of knowledge has prompted the development and evaluation of negative chronotropic agents, prototypically the I(f) inhibitor Ivabradine. The present review addresses several fundamental questions: (1) How is heart rate regulated at the integrative, cellular, and molecular levels? (2) How are autonomic tone and reflexes measured clinically, and what is the prognostic utility of these parameters? (3) What mechanisms are responsible for the cardiovascular pathology associated with elevated heart rates? (4) Does reducing heart rate independent of effects on other factors protect against cardiovascular events?

Intracellular calcium dynamics and acetylcholine-induced triggered activity in the pulmonary veins of dogs with pacing-induced heart failure

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 micromol/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.

Intracellular Calcium and Vulnerability to Fibrillation and Defibrillation in Langendorff-Perfused Rabbit Ventricles

Background— The role of intracellular calcium (Cai) in defibrillation and vulnerability is unclear. Methods and Results— We simultaneously mapped epicardial membrane potential and Cai during shock on T-wave episodes (n=104) and attempted defibrillation episodes (n=173) in 17 Langendorff-perfused rabbit ventricles. Unsuccessful and type B successful defibrillation shocks were followed by heterogeneous distribution of Cai, including regions of low Cai surrounded by elevated Cai (“Cai sinkholes”) 31±12 ms after shock. The first postshock activation then originated from the Cai sinkhole 53±14 ms after the shock. No sinkholes were present in type A successful defibrillation. A Cai sinkhole also was present 39±32 ms after a shock on T that induced ventricular fibrillation, followed 22±15 ms later by propagated wave fronts that arose from the same site. This wave propagated to form a spiral wave and initiated ventricular fibrillation. Thapsigargin and ryanodine significantly decreased the upper limit of vulnerability and defibrillation threshold. We studied an additional 7 rabbits after left ventricular endocardial cryoablation, resulting in a thin layer of surviving epicardium. Cai sinkholes occurred 31±12 ms after the shock, followed in 19±7 ms by first postshock activation in 63 episodes of unsuccessful defibrillation. At the Cai sinkhole, the rise of Cai preceded the rise of epicardial membrane potential in 5 episodes. Conclusions— There is a heterogeneous postshock distribution of Cai. The first postshock activation always occurs from a Cai sinkhole. The Cai prefluorescence at the first postshock early site suggests that reverse excitation-contraction coupling might be responsible for the initiation of postshock activations that lead to ventricular fibrillation.

Patterns of baseline autonomic nerve activity and the development of pacing-induced sustained atrial fibrillation

BACKGROUND Whether autonomic nerve activity is important in the development of pacing-induced sustained atrial fibrillation (AF) is unclear. OBJECTIVE The purpose of this study was to test the hypothesis that patterns of baseline autonomic nerve activity are important in the development of pacing-induced sustained AF. METHODS Radiotransmitters were implanted in 12 ambulatory dogs to record left stellate ganglion nerve activity (SGNA) and vagal nerve activity (VNA). Sustained (>48 hours) AF was induced with intermittent rapid atrial pacing. RESULTS At baseline (before pacing), 1-minute integrated nerve activity between SGNA and VNA demonstrated either a single linear relationship with excellent correlation (group 1, N = 3, r = 0.816 ± 0.105) or nonlinear relationships with poor correlation (group 2, N = 9, r = 0.316 ± 0.162, P <.05 vs group 1). Group 1 dogs had higher VNA (97.0 ± 11.5 mV-s) compared to group 2 (33.4 ± 21.7 mV-s, P <.001). Group 1 dogs had more frequent sympathovagal co-activation episodes than did group 2 (50 ± 19 per day vs 15 ± 6 per day, P <.05) and more paroxysmal atrial tachycardia (PAT; 5 ± 1 per day vs 2 ± 1 per day, P <.05) at baseline. Sustained AF occurred after 16 ± 4 days (range 13-20 days) of pacing in group 1 and after 46 ± 18 days (range 23-72 days) of pacing in group 2 (P <.05). In the week before development of sustained AF, VNA of group 2 dogs was significantly increased compared to baseline (P <.05). CONCLUSION Ambulatory dogs with good linear sympathovagal correlation and higher vagal tone at baseline have more PAT episodes at baseline and faster induction of sustained AF by rapid pacing. Rapid atrial pacing increased the VNA of the remaining dogs before induction of sustained AF.

Cryoablation of stellate ganglia and atrial arrhythmia in ambulatory dogs with pacing-induced heart failure

BACKGROUND There is an association between autonomic nerve discharges and atrial arrhythmias (including bradycardia and tachycardia) in ambulatory dogs with pacing-induced heart failure (HF). OBJECTIVE The purpose of this study was to test the hypothesis that stellate ganglia ablation can reduce the incidence of atrial arrhythmias in a canine model of pacing-induced HF. METHODS Cryoablation of the caudal half of the left and right stellate ganglia and T2-T4 thoracic sympathetic ganglia was performed in six dogs (experimental group). Left upper stellate ganglia nerve activity, vagal nerve activity, and electrocardiogram were continuously recorded using an implanted radiotransmitter. RESULTS After 2 weeks of baseline recording, rapid right ventricular pacing (28 +/- 4 days) was used to induce HF. The control group (N = 6) underwent the same procedures except for cryoablation. The experimental group had no episodes of paroxysmal atrial tachycardia (P <.0001 vs control). Cryoablation significantly (P = .0097) reduced prolonged (>3 seconds) sinus pause episodes from 5 +/- 6 to 0 on day 1, from 250 +/- 424 to 11 +/- 11 on day 7, and from 123 +/- 206 to 30 +/- 33 on day 14 after induction of HF. In the experimental group only, vagal nerve activity may occur alone without concomitant stellate ganglia nerve activity. However, these isolated vagal nerve activity episodes did not result in prolonged sinus pause. Histologic studies confirmed successful cryoablation of the caudal half of the stellate ganglia. CONCLUSION Cryoablation of bilateral stellate and T2-T4 thoracic ganglia significantly reduced paroxysmal atrial tachycardia and prolonged sinus pause episodes induced by sympathetic discharges in dogs with pacing-induced HF.

Cellular mechanism of premature ventricular contraction–induced cardiomyopathy

BACKGROUND Frequent premature ventricular contractions (PVCs) are associated with increased risk of sudden cardiac death and can cause secondary cardiomyopathy. OBJECTIVE We sought to determine the mechanism(s) responsible for prolonged refractory period and left ventricular (LV) dysfunction demonstrated in our canine model of PVC-induced cardiomyopathy. METHODS Single myocytes were isolated from LV free wall of PVC and control canines and used for patch-clamp recording, intracellular Ca(2+) measurements, and immunocytochemistry/confocal microscopy. LV tissues adjacent to the area of myocyte isolation were used for the immunoblot quantification of protein expression. RESULTS In the PVC group, LV ejection fraction decreased from 57.6% ± 1.5% to 30.4% ± 3.1% after ≥4 months of ventricular bigeminy. Compared to control myocytes, PVC myocytes had decreased densities of both outward (transient outward current [Ito] and inward rectifier current [IK1]) and inward (L-type Ca current [ICaL]) currents, but no consistent changes in rapid or slow delayed rectifier currents. The reduction in Ito, IK1, and ICaL was accompanied by decreased protein levels of their channel subunits. The extent of reduction in Ito, IK1, and ICaL varied among PVC myocytes, creating marked heterogeneity in action potential configurations and durations. PVC myocytes showed impaired Ca-induced Ca release from the sarcoplasmic reticulum (SR), without increase in SR Ca leak or decrease in SR Ca store. This was accompanied by a decrease in dyad scaffolding protein, junctophilin-2, and loss of Cav1.2 registry with Ca-releasing channels (ryanodine receptor 2). CONCLUSION PVCs increase dispersion of action potential configuration/duration, a risk factor for sudden cardiac death, because of the heterogeneous reduction in Ito, IK1, and ICaL. The excitation-contraction coupling is impaired because of the decrease in ICaL and Cav1.2 misalignment with respect to ryanodine receptor 2.

Autonomic nerve activity and blood pressure in ambulatory dogs

BACKGROUND The relationship between cardiac autonomic nerve activity and blood pressure (BP) changes in ambulatory dogs is unclear. OBJECTIVE The purpose of this study was to test the hypotheses that simultaneous termination of stellate ganglion nerve activity (SGNA) and vagal nerve activity (VNA) predisposes to spontaneous orthostatic hypotension and that specific β₂-adrenoceptor blockade prevents the hypotensive episodes. METHODS We used a radiotransmitter to record SGNA, VNA, and BP in eight ambulatory dogs. Video imaging was used to document postural changes. RESULTS Of these eight dogs, five showed simultaneous sympathovagal discharges in which the minute-by-minute integrated SGNA correlated with integrated VNA in a linear pattern (group 1). In these dogs, abrupt termination of simultaneous SGNA-VNA at the time of postural changes (as documented by video imaging) was followed by abrupt (>20 mm Hg over four beats) drops in BP. Dogs without simultaneous on/off firing (group 2) did not have drastic drops in pressure. ICI-118,551 (ICI, a specific β₂-blocker) infused at 3 µg/kg/h for 7 days significantly increased BP from 126 mm Hg (95% confidence interval 118-133) to 133 mm Hg (95% confidence interval 125-141; P = .0001). The duration of hypotension (mean systolic BP <100 mm Hg) during baseline accounted for 7.1% of the recording. The percentage was reduced by ICI to 1.3% (P = .01). CONCLUSION Abrupt simultaneous termination of SGNA-VNA was observed at the time of orthostatic hypotension in ambulatory dogs. Selective β₂-adrenoceptor blockade increased BP and reduced the duration of hypotension in this model.

Circulating fibrosis biomarkers and risk of atrial fibrillation: The Cardiovascular Health Study (CHS)

BACKGROUND Cardiac fibrosis is thought to play a central role in the pathogenesis of atrial fibrillation (AF). Retrospective studies have suggested that circulating fibrosis biomarkers are associated with AF, but prospective studies are limited. METHODS We measured circulating levels of 2 fibrosis biomarkers, procollagen type III, N-terminal propeptide (PIIINP) and transforming growth factor β1 among participants of the CHS, a population-based study of older Americans. We used Cox proportional hazards and competing risks models to examine adjusted risk of incident AF over a median follow-up of 8.8 years. RESULTS Levels of PIIINP were assessed in 2,935 participants, of whom 767 developed AF. Compared with the median PIIINP level (4.45 μg/L), adjusted hazard ratios (95% CIs) were 0.85 (0.72-1.00) at the 10th percentile, 0.93 (0.88-0.99) at the 25th percentile, 1.04 (0.95-1.04) at the 75th percentile, and 1.07 (0.90-1.26) at the 90th. Transforming growth factor β1 levels, assessed in 1,538 participants with 408 cases of incident AF, were not associated with AF risk. CONCLUSION In older adults, PIIINP levels were associated with risk of incident AF in a complex manner, with an association that appeared to be positive up to median levels but with little relationship beyond that. Further studies are required to confirm and possibly delineate the mechanism for this relationship.