The cardiac autonomic nervous system: an introduction.

In recent decades, numerous anatomical and physiological studies of the cardiac autonomic nervous system (ANS) have investigated the complex relationships between the brain and the heart. Autonomic activation not only alters heart rate, conduction, and hemodynamics, but also cellular and subcellular properties of individual myocytes. Moreover, the cardiac ANS plays an essential role in cardiac arrhythmogenesis. There is mounting evidence that neural modulation either by ablation or stimulation can effectively control a wide spectrum of cardiac arrhythmias. This article discusses anatomic aspects of the cardiac ANS, focusing on how autonomic activities influence cardiac electrophysiology. Specific autonomic triggers of various cardiac arrhythmias, in particular atrial fibrillation (AF) and ventricular arrhythmias, are also briefly discussed. Studies with heart-rate variability analysis indicate that, rather than being triggered by either vagal or sympathetic activity, the onset of AF can be associated with simultaneous discharge of both limbs, leading to an imbalance between these two arms of the cardiac ANS. At the same time, sudden cardiac death resulting from ventricular arrhythmias continues to be a significant health and societal burden. These nerve activities of the cardiac ANS can be targeted for the treatment for cardiac arrhythmias, in particular AF and ventricular tachyarrhythmias.

Improvement in renal function following cryoballoon ablation for atrial fibrillation.

PURPOSE: Patients with chronic kidney disease are predisposed to heart rhythm disorders including atrial fibrillation (AF). Several studies have suggested that radiofrequency catheter ablation of AF improves renal function. However, little data exists for pulmonary vein isolation with cryoballoon ablation (CBA). The purpose of this study is to assess change in renal function following CBA for AF. METHOD: This is a single-center retrospective study that included patients who underwent CBA for AF between 2011 and 2016. Patients were grouped by baseline-estimated glomerular filtration rate (eGFR): ≥ 90 (Stage G1), 60-89.9 (Stage G2), and 30-59.9 mL/min/1.73 m2 (Stage G3). Change in eGFR was assessed > 3 months post-ablation. RESULTS: A total of 306 patients with both pre- and post-ablation serum creatinine measurements available were included. Baseline eGFRs for Stages G1, G2, and G3 patients were 103.5 ± 12.9 (n = 82), 74.7 ± 8.2 (n = 184), and 52.6 ± 6.6 mL/min/1.73 m2 (n = 40), respectively. Renal function was assessed 310.8 ± 104.2 days post-ablation. Average intra-procedural contrast use was 58.4 ± 23.8 mL. There was no significant change in eGFR following CBA in Stage G1 patients (p = 0.10). For those with Stages G2 and G3 renal function, eGFR improved by 6.1% (4.2 mL/min/1.73 m2, p < 0.01) and 13.8% (7.2 mL/min/1.73 m2, p < 0.01), respectively. This improvement was seen regardless of the presence or absence of recurrent atrial arrhythmias. CONCLUSIONS: CBA for AF may be associated with an improvement in renal function, particularly among those with a reduced baseline eGFR despite recurrence of atrial arrhythmias and intra-procedural contrast use.

A novel risk model for very late return of atrial fibrillation beyond 1 year after cryoballoon ablation: the SCALE-CryoAF score.

PURPOSE: Cryoballoon ablation (CBA) is an effective technique for pulmonary vein isolation (PVI). To date, there are no risk models to predict very late recurrence of atrial fibrillation (VLRAF) after CBA. METHODS: Retrospective analysis of a single-center database was performed. Inclusion criteria included PVI using CBA for atrial fibrillation (AF) without additional ablation targets, follow-up > 365 days, and no recurrent AF between 90 and 365 days after procedure. The primary endpoint was recurrent AF > 30 s > 12 months post-CBA. A risk model was created using clinical variables. RESULTS: Of 674 CBA performed from 2011 to 2016, 300 patients (200 male, 62.0 ± 9.9 years) met inclusion criteria. Of these, 159 (53.0%) patients had paroxysmal AF. Patients had an average of 9.5 ± 2.7 cryoballoon freezes, and no patients required additional radiofrequency ablation lesion sets. Over a follow-up of 995 ± 490 days, 77/300 (25.7%) patients exhibited VLRAF. Univariate and multivariate analyses demonstrated that Structural heart disease (1 point), Coronary artery disease (3 points), left Atrial diameter > 43 mm (1 point), Left bundle branch block (3 points), Early return of AF (4 points), and non-paroxysmal AF (3 points) were risk factors for VLRAF. Combining these variables into a risk model, SCALE-CryoAF, (min 0; max 15) predicted VLRAF with an area under the curve of 0.73. CONCLUSION: SCALE-CryoAF is the first risk model to specifically predict first recurrence of AF beyond 1 year, VLRAF, after CBA. Model discrimination demonstrates that SCALE-CryoAF predicts VLRAF after CBA significantly better than other risk models for AF recurrence.

Atrial Myopathy.

This paper discusses the evolving concept of atrial myopathy by presenting how it develops and how it affects the properties of the atria. It also reviews the complex relationships among atrial myopathy, atrial fibrillation (AF), and stroke. Finally, it discusses how to apply the concept of atrial myopathy in the clinical setting-to identify patients with atrial myopathy and to be more selective in anticoagulation in a subset of patients with AF. An apparent lack of a temporal relationship between episodes of paroxysmal AF and stroke in patients with cardiac implantable electronic devices has led investigators to search for additional factors that are responsible for AF-related strokes. Multiple animal models and human studies have revealed a close interplay of atrial myopathy, AF, and stroke via various mechanisms (e.g., aging, inflammation, oxidative stress, and stretch), which, in turn, lead to fibrosis, electrical and autonomic remodeling, and a pro-thrombotic state. The complex interplay among these mechanisms creates a vicious cycle of ever-worsening atrial myopathy and a higher risk of more sustained AF and strokes. By highlighting the importance of atrial myopathy and the risk of strokes independent of AF, this paper reviews the methods to identify patients with atrial myopathy and proposes a way to incorporate the concept of atrial myopathy to guide anticoagulation in patients with AF.

Patient characteristics as predictors of recurrence of atrial fibrillation following cryoballoon ablation.

BACKGROUND: While several studies have evaluated predictors for atrial fibrillation (AF) recurrence following catheter ablation, there are limited data specific to cryoballoon ablation (CBA). METHODS: We analyzed a prospective registry of patients at a single institution who underwent CBA. Recurrence of AF (RAF) was defined as recurrence of AF by 12-month follow-up, excluding the 3-month blanking period. Univariate analysis was performed to evaluate predictors of RAF. Receiver operating characteristic analysis was used to compare and evaluate the performance of various risk scores for discriminating risk of RAF. RESULTS: There were 542 patients included in the analysis with mean age 61.3 ± 10.6 years, 67.9% male, and 51.6% paroxysmal AF (PAF). Overall, only left atrial diameter (LAD) > 40 mm and ERAF (early recurrence of AF within 0-3 month blanking period) were significant predictors of RAF. In the PAF specific subgroup, LAD > 40 mm, AF duration > 12 months, prior stroke or transient ischemic attack, ERAF, and having previously failed an antiarrhythmic drug were significant predictors of RAF. In persistent AF (PeAF) subgroup, obstructive sleep apnea (OSA) and ERAF were significant predictors of RAF. Out of clinical risk scores tested, BASEAF2 had the highest performance with area under the curve of 0.646 (95% confidence interval [0.548, 0.708]; P < .01). CONCLUSIONS: In this single-center retrospective study of CBA, we found only LAD > 40 mm and ERAF to be predictors of RAF. We identified OSA as a potential targetable risk factor in PeAF patients undergoing CBA. Out of risk scores tested for discriminating risk of RAF, BASEAF2 had the best performance.

Value of high-density mapping in the electrophysiology laboratory.

PURPOSE OF REVIEW: This article uses three commonly encountered clinical scenarios to highlight the value of high-density mapping in the electrophysiology laboratory for the identification of the circuits and substrates during catheter ablation of complex arrhythmias. RECENT FINDINGS: High-density mapping gathered with a multielectrode catheter, with its smaller individual electrode size and closer interelectrode spacing, helps during ablation procedures in a number of ways. When high-density mapping is performed during tachycardia, the characterization of macro-reentrant circuits is better. When there is suspicion of a change in tachycardia during mapping or ablation, the threshold of remapping is significantly lower because of the speed of remapping. When mapping is done during sinus rhythm (substrate mapping), the identification of true scar is more accurate. Lastly, when extensive ablation of a critical isthmus fails to terminate a tachycardia, high-density mapping may reveal the gap(s) along the ablation line and may provide an alternative approach for ablation. SUMMARY: High-density mapping shows promises of improving procedural outcomes with shorter procedural times.

Outcomes With Novel Oral Anticoagulants in Obese Patients who Underwent Electrical Cardioversion for Atrial Tachyarrhythmias.

The efficacy of novel oral anticoagulants (NOACs) in severely obese patients is uncertain as volume of distribution is related to weight, and few such patients were enrolled in the pivotal trials. As the month after direct-current cardioversion (DCCV) for atrial fibrillation and atrial flutter is a high-risk period for stroke, we sought to evaluate the safety of performing DCCV in obese patients on NOAC. All patients who underwent DCCV after ≥3 weeks of NOAC or therapeutic warfarin treatment without a previous transesophageal echocardiogram over a 3-year period at a single center were included. Obesity groups were defined as normal (body mass index [BMI] < 25), overweight (BMI 25 to <30), class 1 obesity (BMI 30 to <35), class 2 obesity (BMI 35 to <40), and class 3 or severe obesity (BMI ≥ 40). The primary end point was stroke at 30days. Of 761 patients, 73 were severely obese, 78 class 2 obese, 197 class 1 obese, 254 overweight, and 159 in the normal weight group. Average age 66.4 ± 10.3years and 32.5% women. Mean CHA2DS2-VASc score was 2.6 ± 1.6, and 78.9% were on NOACs with no differences in groups. There were no strokes in the severely obese group, and 1 each in class 2 obesity and normal weight (p = 0.3). In conclusion, there was a low rate of stroke in all weight classes after DCCV in patients taking NOACs and warfarin. NOAC use in severely obese patients who underwent DCCV appears safe even in the absence of transesophageal echocardiogram.

Simultaneous recordings of intrinsic cardiac nerve activity and skin sympathetic nerve activity from human patients during the postoperative period.

BACKGROUND: Intrinsic cardiac nerve activity (ICNA) and skin nerve activity (SKNA) are both associated with cardiac arrhythmias in dogs. OBJECTIVE: The purpose of this study was to test the hypothesis that ICNA and SKNA correlate with postoperative cardiac arrhythmias in humans. METHODS: Eleven patients (mean age 60 ± 13 years; 4 women) were enrolled in this study. Electrical signals were simultaneously recorded from electrocardiogram (ECG) patch electrodes on the chest wall and from 2 temporary pacing wires placed during open heart surgery on the left atrial epicardial fat pad. The signals were filtered to display SKNA and ICNA. Premature atrial contractions (PACs) and premature ventricular contractions were determined manually. The SKNA and ICNA of the first 300 minutes of each patient were calculated minute by minute to determine baseline average amplitudes of nerve activities and to determine their correlation with arrhythmia burden. RESULTS: We processed 1365 ± 973 minutes of recording per patient. Low-amplitude SKNA and ICNA were present at all time, while the burst discharges were observed much less frequently. Both SKNA and burst ICNA were significantly associated with the onset of PACs and premature ventricular contractions. Baseline average ICNA (aICNA), but not average SKNA, had a significant association with PAC burden. The correlation coefficient (r) between aICNA and PAC burden was 0.78 (P < .01). A patient with the greatest aICNA developed postoperative atrial fibrillation. CONCLUSION: ICNA and SKNA can be recorded from human patients in the postoperative period. The baseline magnitude of ICNA correlates with PAC burden and development of postoperative atrial fibrillation.

Intermittent left cervical vagal nerve stimulation damages the stellate ganglia and reduces the ventricular rate during sustained atrial fibrillation in ambulatory dogs.

BACKGROUND: The effects of intermittent open-loop vagal nerve stimulation (VNS) on the ventricular rate (VR) during atrial fibrillation (AF) remain unclear. OBJECTIVE: The purpose of this study was to test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF. METHODS: We performed left cervical VNS in ambulatory dogs while recording the left SG nerve activity (SGNA) and vagal nerve activity. Tyrosine hydroxylase (TH) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess neuronal cell death in the SG. RESULTS: We induced persistent AF by atrial pacing in 6 dogs, followed by intermittent VNS with short ON-time (14 seconds) and long OFF-time (66 seconds). The integrated SGNA and VR during AF were 4.84 mV·s (95% confidence interval [CI] 3.08-6.60 mV·s) and 142 beats/min (95% CI 116-168 beats/min), respectively. During AF, VNS reduced the integrated SGNA and VR, respectively, to 3.74 mV·s (95% CI 2.27-5.20 mV·s; P = .021) and 115 beats/min (95% CI 96-134 beats/min; P = .016) during 66-second OFF-time and to 4.07 mV·s (95% CI 2.42-5.72 mV·s; P = .037) and 114 beats/min (95% CI 83-146 beats/min; P = .039) during 3-minute OFF-time. VNS increased the frequencies of prolonged (>3 seconds) pauses during AF. TH staining showed large confluent areas of damage in the left SG, characterized by pyknotic nuclei, reduced TH staining, increased percentage of TH-negative ganglion cells, and positive TUNEL staining. Occasional TUNEL-positive ganglion cells were also observed in the right SG. CONCLUSION: VNS damaged the SG, leading to reduced SGNA and better rate control during persistent AF.

Interventional and device-based autonomic modulation in heart failure.

"Heart failure is an increasingly prevalent disease with high mortality and public health burden. It is associated with autonomic imbalance characterized by sympathetic hyperactivity and parasympathetic hypoactivity. Evolving novel interventional and device-based therapies have sought to restore autonomic balance by neuromodulation. Results of preclinical animal studies and early clinical trials have demonstrated the safety and efficacy of these therapies in heart failure. This article discusses specific neuromodulatory treatment modalities individually-spinal cord stimulation, vagus nerve stimulation, baroreceptor activation therapy, and renal sympathetic nerve denervation."

Role of the autonomic nervous system in modulating cardiac arrhythmias.

The autonomic nervous system plays an important role in the modulation of cardiac electrophysiology and arrhythmogenesis. Decades of research has contributed to a better understanding of the anatomy and physiology of cardiac autonomic nervous system and provided evidence supporting the relationship of autonomic tone to clinically significant arrhythmias. The mechanisms by which autonomic activation is arrhythmogenic or antiarrhythmic are complex and different for specific arrhythmias. In atrial fibrillation, simultaneous sympathetic and parasympathetic activations are the most common trigger. In contrast, in ventricular fibrillation in the setting of cardiac ischemia, sympathetic activation is proarrhythmic, whereas parasympathetic activation is antiarrhythmic. In inherited arrhythmia syndromes, sympathetic stimulation precipitates ventricular tachyarrhythmias and sudden cardiac death except in Brugada and J-wave syndromes where it can prevent them. The identification of specific autonomic triggers in different arrhythmias has brought the idea of modulating autonomic activities for both preventing and treating these arrhythmias. This has been achieved by either neural ablation or stimulation. Neural modulation as a treatment for arrhythmias has been well established in certain diseases, such as long QT syndrome. However, in most other arrhythmia diseases, it is still an emerging modality and under investigation. Recent preliminary trials have yielded encouraging results. Further larger-scale clinical studies are necessary before widespread application can be recommended.

Hypokalemia promotes late phase 3 early afterdepolarization and recurrent ventricular fibrillation during isoproterenol infusion in Langendorff perfused rabbit ventricles.

BACKGROUND: Hypokalemia and sympathetic activation are commonly associated with electrical storm (ES) in normal and diseased hearts. The mechanisms remain unclear. OBJECTIVE: The purpose of this study was to test the hypothesis that late phase 3 early afterdepolarization (EAD) induced by IKATP activation underlies the mechanisms of ES during isoproterenol infusion and hypokalemia. METHODS: Intracellular calcium (Cai) and membrane voltage were optically mapped in 32 Langendorff-perfused normal rabbit hearts. RESULTS: Repeated episodes of electrically induced ventricular fibrillation (VF) at baseline did not result in spontaneous VF (SVF). During isoproterenol infusion, SVF occurred in 1 of 15 hearts (7%) studied in normal extracellular potassium ([K(+)]o, 4.5 mmol/L), 3 of 8 hearts (38%) in 2.0 mmol/L [K(+)]o, 9 of 10 hearts (90%) in 1.5 mmol/L [K(+)]o, and 7 of 7 hearts (100%) in 1.0 mmol/L [K(+)]o (P <.001). Optical mapping showed that isoproterenol and hypokalemia enhanced Cai transient duration (CaiTD) and heterogeneously shortened action potential duration (APD) after defibrillation, leading to late phase 3 EAD and SVF. IKATP blocker (glibenclamide, 5 µmol/L) reversed the post-defibrillation APD shortening and suppressed recurrent SVF in all hearts studied despite no evidence of ischemia. Nifedipine reliably prevented recurrent VF when given before, but not after, the development of VF. IKr blocker (E-4031) and small-conductance calcium-activated potassium channel blocker (apamin) failed to prevent recurrent SVF. CONCLUSION: Beta-adrenergic stimulation and concomitant hypokalemia could cause nonischemic activation of IKATP, heterogeneous APD shortening, and prolongation of CaiTD to provoke late phase 3 EAD, triggered activity, and recurrent SVF. IKATP inhibition may be useful in managing ES during resistant hypokalemia.

Effects of carvedilol on cardiac autonomic nerve activities during sinus rhythm and atrial fibrillation in ambulatory dogs.

AIMS: We hypothesized that carvedilol can effectively suppress autonomic nerve activity (ANA) in ambulatory dogs during sinus rhythm and atrial fibrillation (AF), and that carvedilol withdrawal can lead to rebound elevation of ANA. Carvedilol is known to block pre-junctional ß2-adrenoceptor responsible for norepinephrine release. METHODS AND RESULTS: We implanted radiotransmitters to record stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA), and superior left ganglionated plexi nerve activity (SLGPNA) in 12 ambulatory dogs. Carvedilol (12.5 mg orally twice a day) was given for 7 days during sinus rhythm (n = 8). Four of the eight dogs and an additional four dogs were paced into persistent AF. Carvedilol reduced heart rate [from 103 b.p.m. (95% confidence interval (CI), 100-105) to 100 b.p.m. (95% CI, 98-102), P = 0.044], suppressed integrated nerve activities (Int-NAs, SGNA by 17%, VNA by 19%, and SLGPNA by 12%; all P < 0.05 vs. the baseline), and significantly reduced the incidence (from 8 ± 6 to 3 ± 3 episodes/day, P < 0.05) and total duration (from 68 ± 64 to 16 ± 21 s/day, P < 0.05) of paroxysmal atrial tachycardia (PAT). Following the development of persistent AF, carvedilol loading was associated with AF termination in three dogs. In the remaining five dogs, Int-NAs were not significantly suppressed by carvedilol, but SGNA significantly increased by 16% after carvedilol withdrawal (P < 0.001). CONCLUSION: Carvedilol suppresses ANA and PAT in ambulatory dogs during sinus rhythm.

Low-level vagus nerve stimulation upregulates small conductance calcium-activated potassium channels in the stellate ganglion.

BACKGROUND: Small conductance calcium-activated potassium (SK) channels are responsible for afterhyperpolarization that suppresses nerve discharges. OBJECTIVES: To test the hypothesis that low-level vagus nerve stimulation (LL-VNS) leads to the upregulation of SK2 proteins in the left stellate ganglion. METHODS: Six dogs (group 1) underwent 1-week LL-VNS of the left cervical vagus nerve. Five normal dogs (group 2) were used as controls. SK2 protein levels were examined by using Western blotting. The ratio between SK2 and glyceraldehydes-3-phosphate-dehydrogenase levels was used as an arbitrary unit (AU). RESULTS: We found higher SK2 expression in group 1 (0.124 ± 0.049 AU) than in group 2 (0.085 ± 0.031 AU; P<.05). Immunostaining showed that the density of nerve structures stained with SK2 antibody was also higher in group 1 (11,546 ± 7,271 µm(2)/mm(2)) than in group 2 (5321 ± 3164 µm(2)/mm(2); P<.05). There were significantly more ganglion cells without immunoreactivity to tyrosine hydroxylase (TH) in group 1 (11.4%±2.3%) than in group 2 (4.9% ± 0.7%; P<.05). The TH-negative ganglion cells mostly stained positive for choline acetyltransferase (95.9% ± 2.8% in group 1 and 86.1% ± 4.4% in group 2; P = .10). Immunofluorescence confocal microscopy revealed a significant decrease in the SK2 staining in the cytosol but an increase in the SK2 staining on the membrane of the ganglion cells in group 1 compared to group 2. CONCLUSIONS: Left LL-VNS results in the upregulation of SK2 proteins, increased SK2 protein expression in the cell membrane, and increased TH-negative (mostly choline acetyltransferase-positive) ganglion cells in the left stellate ganglion. These changes may underlie the antiarrhythmic efficacy of LL-VNS in ambulatory dogs.

Neural control of ventricular rate in ambulatory dogs with pacing-induced sustained atrial fibrillation.

BACKGROUND: We hypothesize that inferior vena cava-inferior atrial ganglionated plexus nerve activity (IVC-IAGPNA) is responsible for ventricular rate (VR) control during atrial fibrillation (AF) in ambulatory dogs. METHODS AND RESULTS: We recorded bilateral cervical vagal nerve activity (VNA) and IVC-IAGPNA during baseline sinus rhythm and during pacing-induced sustained AF in 6 ambulatory dogs. Integrated nerve activities and average VR were measured every 10 seconds over 24 hours. Left VNA was associated with VR reduction during AF in 5 dogs (from 211 bpm [95% CI, 186-233] to 178 bpm [95% CI, 145-210]; P<0.001) and right VNA in 1 dog (from 208 bpm [95% CI, 197-223] to 181 bpm [95% CI, 163-200]; P<0.01). There were good correlations between IVC-IAGPNA and left VNA in the former 5 dogs and between IVC-IAGPNA and right VNA in the last dog. IVC-IAGPNA was associated with VR reduction in all dogs studied. Right VNA was associated with baseline sinus rate reduction from 105 bpm (95% CI, 95-116) to 77 bpm (95% CI, 64-91; P<0.01) in 4 dogs, whereas left VNA was associated with sinus rate reduction from 111 bpm (95% CI, 90-1250) to 81 bpm (95% CI, 67-103; P<0.01) in 2 dogs. CONCLUSIONS: IVC-IAGPNA is invariably associated with VR reduction during AF. In comparison, right or left VNA was associated with VR reduction only when it coactivates with the IVC-IAGPNA. The vagal nerve that controls VR during AF may be different from that which controls sinus rhythm.

Neural mechanisms of atrial fibrillation.

PURPOSE OF REVIEW: The autonomic nerve system is a potentially potent modulator of the initiation and perpetuation of atrial fibrillation. This review will briefly summarize the neural mechanisms of atrial fibrillation. RECENT FINDINGS: Complex interactions exist between the sympathetic and parasympathetic nervous system on the atrial electrophysiologic properties. Direct autonomic recordings in canine models demonstrated simultaneous sympathovagal discharges are the most common triggers of paroxysmal atrial tachycardia and paroxysmal atrial fibrillation. Also, intrinsic cardiac autonomic nerve can serve as a sole triggering factor for the initiation of atrial fibrillation. Modulation of autonomic nervous system (ANS) by electrical stimulation has been tried as a treatment strategy clinically and experimentally. Recent studies showed that autonomic nervous system modulation can suppress the stellate ganglion nerve activity and reduce the incidence of paroxysmal atrial tachyarrhythmias in ambulatory dogs. SUMMARY: The autonomic nerve system influences the initiation and perpetuation of atrial fibrillation. Scientific advances toward a better understanding of the complex interrelationships of the various components of the ANS will hopefully lead to improvement of treatments for this common arrhythmia.

Heart failure decreases nerve activity in the right atrial ganglionated plexus.

OBJECTIVE: We tested the hypothesis that heart failure (HF) results in right atrial ganglionated plexus (RAGP) denervation that contributes to sinoatrial node dysfunction. BACKGROUND: HF is associated with sinoatrial node dysfunction. However, the detailed mechanisms remain unclear. METHODS: We recorded nerve activity (NA) from the RAGP, right stellate ganglion (SG), and right vagal nerve in 7 ambulatory dogs at baseline and after pacing-induced HF. We also determined the effects of RAGP stimulation in isolated normal and HF canine RA. RESULTS: NAs in both the SG and vagal were significantly higher in HF than at baseline. The relationship between 1-minute integrated NAs of vagal and RAGP showed either a positive linear correlation (Group 1, n = 4) or an L-shaped correlation (Group 2, n = 3). In all dogs, a reduced heart rate was observed when vagal-NA was associated with simultaneously increased RAGP-NA. On the other hand, when vagal-NA was not associated with increased RAGP-NA, the heart rate was not reduced. The induction of HF significantly decreased RAGP-NA in all dogs (P < 0.05). Stimulating the superior RAGP in isolated RA significantly reduced the sinus rate in normal but not the HF hearts. Immunohistochemical staining revealed lower densities of tyrosine hydroxylase- and choline acetyltransferase-positive nerve tissues in HF RAGP than normal (P < 0.001 and P = 0.001, respectively). CONCLUSIONS: The RAGP-NA is essential for the vagal nerve to counterbalance the SG in sinus rate control. In HF, RAGP denervation and decreased RAGP-NA contribute to the sinus node dysfunction.

Selective sinoatrial node optical mapping and the mechanism of sinus rate acceleration.

BACKGROUND: Studies using isolated sinoatrial node (SAN) cells indicate that rhythmic spontaneous sarcoplasmic reticulum calcium release (Ca clock) plays an important role in SAN automaticity. In the intact SAN, cross-contamination of optical signals from the SAN and the right atrium (RA) prevent the definitive testing of Ca clock hypothesis. The aim of this study was to use a novel approach to selectively mapping the intact SAN to examine the Ca clock mechanism. METHODS AND RESULTS: We simultaneously mapped intracellular Ca (Ca(i)) and membrane potential (V(m)) in 10 isolated, Langendorff-perfused normal canine RAs. The excitability of the RA was suppressed with high-potassium Tyrode's solution, allowing selective optical mapping of V(m) and Ca(i) of the SAN. Isoproterenol (ISO, 0.03 µmol/L) decreased the cycle length of the sinus beats, and shifted the leading pacemaker site from the middle or inferior SAN to the superior SAN in all RAs. The Ca(i) upstroke preceded the V(m) in the leading pacemaker site by up to 18 ± 2 ms. ISO-induced changes to SAN were inhibited by ryanodine (3 µmol/L), but not ZD7288 (3 µmol/L), a selective I(f) blocker. CONCLUSIONS: We conclude that, in the isolated canine RA, a high extracellular potassium concentration can suppress atrial excitability thus leading to SAN-RA conduction block, allowing selective optical mapping of the intact SAN. Acceleration of Ca cycling in the superior SAN underlies the mechanism of sinus tachycardia during sympathetic stimulation.