Cells of the adult human heart.

Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.

Autonomic modulation impacts conduction velocity dynamics and wavefront propagation in the left atrium.

AIMS: Atrial fibrosis and autonomic remodelling are proposed pathophysiological mechanisms in atrial fibrillation (AF). Their impact on conduction velocity (CV) dynamics and wavefront propagation was evaluated. METHODS AND RESULTS: Local activation times (LATs), voltage, and geometry data were obtained from patients undergoing ablation for persistent AF. LATs were obtained at three pacing intervals (PIs) in sinus rhythm (SR). LATs were used to determine CV dynamics and their relationship to local voltage amplitude. The impact of autonomic modulation- pharmacologically and with ganglionated plexi (GP) stimulation, on CV dynamics, wavefront propagation, and pivot points (change in wavefront propagation of ≥90°) was determined in SR. Fifty-four patients were included. Voltage impacted CV dynamics whereby at non-low voltage zones (LVZs) (≥0.5 mV) the CV restitution curves are steeper [0.03 ± 0.03 m/s ΔCV PI 600-400 ms (PI1), 0.54 ± 0.09 m/s ΔCV PI 400-250 ms (PI2)], broader at LVZ (0.2-0.49 mV) (0.17 ± 0.09 m/s ΔCV PI1, 0.25 ± 0.11 m/s ΔCV PI2), and flat at very LVZ (<0.2 mV) (0.03 ± 0.01 m/s ΔCV PI1, 0.04 ± 0.02 m/s ΔCV PI2). Atropine did not change CV dynamics, while isoprenaline and GP stimulation resulted in greater CV slowing with rate. Isoprenaline (2.7 ± 1.1 increase/patient) and GP stimulation (2.8 ± 1.3 increase/patient) promoted CV heterogeneity, i.e. rate-dependent CV (RDCV) slowing sites. Most pivot points co-located to RDCV slowing sites (80.2%). Isoprenaline (1.3 ± 1.1 pivot increase/patient) and GP stimulation (1.5 ± 1.1 increase/patient) also enhanced the number of pivot points identified. CONCLUSION: Atrial CV dynamics is affected by fibrosis burden and influenced by autonomic modulation which enhances CV heterogeneity and distribution of pivot points. This study provides further insight into the impact of autonomic remodelling in AF.

Innervation and Neuronal Control of the Mammalian Sinoatrial Node a Comprehensive Atlas.

[Figure: see text].

The Role of α7nAChR-Mediated Cholinergic Anti-Inflammatory Pathway in Vagal Nerve Regulated Atrial Fibrillation.

The aim was to investigate the role of the α7nAChR-mediated cholinergic anti-inflammatory pathway in vagal nerve regulated atrial fibrillation (AF).18 beagles (standard dogs for testing) were used in this study, and the effective refractory period (ERP) of atrium and pulmonary veins and AF inducibility were measured hourly during rapid atrial pacing at 800 beats/minute for 6 hours in all beagles. After cessation of 3 hours of RAP, the low-level vagal nerve stimulation (LL-VNS) group (n = 6) was given LL-VNS and injection of salinne (0.5 mL/GP) into four GPs, the methyllycaconitine (MLA, the antagonist of α7nAChR) group (n = 6) was given LL-VNS and injection of MLA into four GPs, and the Control group (n = 6) was given saline into four GPs and the right cervical vagal nerve was exposed without stimulation. Then, the levels of the tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), acetylcholine (ACh), STAT3, and NF-κB proteins were measured. During the first 3 hours of RAP, the ERPs gradually decreased while the dispersion of ERPs (dERPs) and AF inducibility gradually increased in all three groups. During the last 3 hours of 6 hours' RAP in this study, the ERPs in the LL-VNS group were higher, while the dERPs and AF inducibility were significantly lower when compared with the Control and MLA groups at the same time points. The levels of ACh in the serum and atrium in the LL-VNS and MLA groups were higher than in the Control group, and the levels of TNF-α and IL-6 were higher in the Control and MLA groups than in the LL-VNS group. The concentrations of STAT3 in RA and LA tissues were higher in the LL-VNS group while those of NF-κB were lower.In conclusion, the cholinergic anti-inflammatory pathway mediated by α7nACh plays an important role in low-level vagal nerve-regulated AF.

Sympathetic responses induced by radiofrequency catheter ablation of atrial fibrillation.

Radiofrequency catheter ablation (RFCA) is a frequently performed procedure in patients with atrial fibrillation. Prior studies have shown that the RFCA may directly stimulate vagal afferents during the procedure, whereas the vagal tone assessed by heart rate variability (HRV) is lowered weeks after the RFCA procedure. The effects of RFCA performed in the left atrium on sympathetic nerve activity have not been assessed. In the present study, we hypothesized that RFCA would lower muscle sympathetic nerve activity (MSNA) during ablation and would raise MSNA 1 day postablation. A total of 18 patients were studied. In protocol 1 ( n = 10), electrocardiogram, blood pressure, and MSNA in the peroneal nerve were recorded through the RFCA procedure performed in the electrophysiology laboratory. In protocol 2, eight patients were studied before the procedure and 1 day postablation. RFCA led to a decrease in MSNA immediately after the procedure (25.4 ± 3.2 to 17.2 ± 3.8 bursts/min, P < 0.05). Cardiac parasympathetic activity was determined using indexes of HRV and increased during the procedure. One day postablation, MSNA was above baseline values (21.3 ± 3.7 to 35.7 ± 2.6 bursts/min, P < 0.05). HRV indexes of cardiac parasympathetic activity fell, and the HRV index of sympathovagal balance was not significantly altered. The results show that RFCA raised cardiac parasympathetic activity and decreased MSNA during the procedure. One day postablation, MSNA rose and cardiac parasympathetic activity fell. In addition, RFCA evokes differentiated sympathetic responses directed to the heart and skeletal muscles. NEW & NOTEWORTHY The effects of radiofrequency catheter ablation performed in the left atrium on muscle sympathetic nerve activity (MSNA) have not been assessed. The results of this study show that radiofrequency catheter ablation raised cardiac parasympathetic activity and decreased MSNA during the procedure. One day postablation, MSNA rose and cardiac parasympathetic activity fell. We speculate that the partial autonomic afferent denervation induces these effects on autonomic activity.

Preeminent role of the cardiorenal axis in the antihypertensive response to an arteriovenous fistula: an in silico analysis.

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and/or 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After a small fistula was stimulated, there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 wk, BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Furthermore, when chronic resetting of atrial mechanoreceptors was prevented during the fistula, RSNA decreased 7%, and along with the same threefold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared with the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after the creation of an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete.NEW & NOTEWORTHY The mechanisms that contribute to the antihypertensive effects of a small arteriovenous (AV) fistula comparable to the size used by the ROX coupler currently in clinical trials are unclear and not readily testable in clinical or experimental studies. The integrative mathematical model of human physiology used in the current study provides a tool for understanding key causal relationships that account for blood pressure (BP) lowering and for testing competing hypotheses. The findings from the simulations suggest that after creation of a small AV fistula increased ANP secretion plays a critical role in mediating long-term reductions in BP. Measurement of natriuretic peptide levels in hypertensive patients implanted with the ROX coupler would provide one critical test of this hypothesis.

Intrinsic Adaptation of SHR Right Atrium Reduces Heart Rate.

Hypertension represents an autonomic dysfunction, characterized by increased sympathetic and decreased parasympathetic cardiovascular tone leading to resting tachycardia. Therefore, studies assessing hypertension-associated changes in isolated cardiac tissues were conducted under electric field stimulation to stimulate the neurons. Herein, we characterize the influence of the autonomic neurotransmitter on the baseline atrial chronotropism of unpaced isolated right atria of normotensive Wistar rats (NWR) and spontaneously hypertensive rats (SHR). Our results revealed a resting bradycardia in tissues from SHR in comparison to NWR. The release of autonomic neurotransmitters, acetylcholine or norepinephrine, still occurs in the electrically unstimulated right atrium, after excision of the sympathetic nerve, which could explain differences in basal heart rate between NWR and SHR. Nicotine and the acetylcholinesterase inhibitor physostigmine reduced the chronotropism of right atria from either NWR or SHR. Conversely, the muscarinic receptor antagonist atropine did not affect the basal chronotropism of tissues from both strains. Furthermore, tyramine increased the chronotropism of NWR and SHR atria indicating availability of the neuronal stocks of noradrenaline. Although the monoamine uptake inhibitor cocaine increased right atrium chronotropism in both strains, the basal heart rate was not affected by the ß-adrenoceptor antagonist propranolol. In summary, after acute section of the sympathetic nerve, autonomic neurotransmitters are still released either in resting conditions or upon pharmacological stimulation of right atria from both strains. Nevertheless, autonomic neurotransmission does not affect resting chronotropism, nor is the responsible for reduced basal heart rate of the isolated right atrium of hypertensive rats.

Atrial arrhythmias and autonomic dysfunction in rats exposed to chronic intermittent hypoxia.

Obstructive sleep apnea, which involves chronic intermittent hypoxia (CIH), is a major risk factor for developing atrial fibrillation (AF). Whether or not CIH alone alters cardiac mechanisms to support AF is unknown. This study investigated the effects of CIH on atrial electrophysiology and arrhythmia vulnerability and evaluated the role of autonomics in CIH promotion of AF. Adult male Sprague-Dawley rats were exposed to 8 h/day of CIH or normoxia for 7 days. After exposure, rats were anesthetized for intracardiac electrophysiological experiments. Atrial effective refractory periods (AERPs) and AF inducibility were determined using programmed electrical stimulation and burst pacing in the absence and presence of autonomic receptor agonists and antagonists. Western blot analysis measured atrial protein expression of muscarinic M2, M3, and ß1-adrenergic receptors. Compared with normoxia-exposed control rats, CIH-exposed rats had enhanced AF vulnerability using both programmed electrical stimulation and burst pacing, accompanied by greater AERP responses to carbachol and propranolol, lesser responses to isoproterenol, and higher atrial M2 receptor protein levels. Enhanced atrial vulnerability was accentuated by carbachol and abolished by atropine, indicating that the AF-promoting effects of CIH depended principally on parasympathetic activation. Enhancement of atrial vulnerability and AERP shortening with cholinergic agonists in CIH-exposed rats is consistent with sensitivity to parasympathetic activation. Higher responses to adrenergic receptor blockade in CIH-exposed rats is consistent with sympathetic potentiation. These findings implicate CIH as an important mediator of enhanced AF susceptibility in obstructive sleep apnea and provide novel insights into the underlying mechanisms. NEW & NOTEWORTHY Our study demonstrates, for the first time, that chronic intermittent hypoxia alone enhances vulnerability to atrial arrhythmia induction, which depends principally on parasympathetic activation. Enhanced atrial vulnerability was accompanied by heightened electrophysiological responses of the atrial myocardium to carbachol and isoproterenol, dampened responses to propranolol, and increased atrial M2 receptor protein levels.

Determinants of new wavefront locations in cholinergic atrial fibrillation.

AIMS: Atrial fibrillation (AF) wavefront dynamics are complex and difficult to interpret, contributing to uncertainty about the mechanisms that maintain AF. We aimed to investigate the interplay between rotors, wavelets, and focal sources during fibrillation. METHODS AND RESULTS: Arrhythmia wavefront dynamics were analysed for four optically mapped canine cholinergic AF preparations. A bilayer computer model was tuned to experimental preparations, and varied to have (i) fibrosis in both layers or the epicardium only, (ii) different spatial acetylcholine distributions, (iii) different intrinsic action potential duration between layers, and (iv) varied interlayer connectivity. Phase singularities (PSs) were identified and tracked over time to identify rotational drivers. New focal wavefronts were identified using phase contours. Phase singularity density and new wavefront locations were calculated during AF. There was a single dominant mechanism for sustaining AF in each of the preparations, either a rotational driver or repetitive new focal wavefronts. High-density PS sites existed preferentially around the pulmonary vein junctions. Three of the four preparations exhibited stable preferential sites of new wavefronts. Computational simulations predict that only a small number of connections are functionally important in sustaining AF, with new wavefront locations determined by the interplay between fibrosis distribution, acetylcholine concentration, and heterogeneity in repolarization within layers. CONCLUSION: We were able to identify preferential sites of new wavefront initiation and rotational activity, in order to determine the mechanisms sustaining AF. Electrical measurements should be interpreted differently according to whether they are endocardial or epicardial recordings.

Median nerve stimulation prevents atrial electrical remodelling and inflammation in a canine model with rapid atrial pacing.

Aims: Studies have shown that stellate ganglion nerve activity has association with atrial electrical remodelling and atrial fibrillation (AF) inducibility, while median nerve stimulation (MNS) decreases cardiac sympathetic drive. In this study, we tested the hypothesis that MNS suppresses atrial electrical remodelling and AF vulnerability. Methods and results: The atrial effective refractory period (AERP) and AF inducibility at baseline and after 3 h of rapid atrial pacing were determined in dogs undergoing MNS (n = 7), MNS+ application of methyllycaconitine (n = 7) or sham procedure (n = 6). Then, the levels of tumour necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and acetylcholine (Ach) in the plasma and atrial tissues were measured. The control dogs (n = 4) were assigned to measure atrial inflammation cytokines. Short-term rapid atrial pacing induced shortening of the AERP, an increase in AERP dispersion, and an increase AF vulnerability in the sham dogs, which were all suppressed by MNS. Levels of TNF-a and IL-6 were higher, and Ach levels were lower in the left and the right atrium in the sham dogs than in the MNS dogs. Methyllycaconitine blunted the effects of MNS on the AERP, AERP dispersion, the AF vulnerability, and TNF-a and IL-6 levels in the atrium, but had no impact on the levels of Ach. Conclusions: The effects of MNS on atrial electrical remodelling and AF inducibility might be associated with the cholinergic anti-inflammatory pathway.

Heart rate variability after radiofrequency ablation of epicardial ganglionated plexuses on the ovine left atrium.

BACKGROUND: Ganglionated plexuses (GP) are terminal parts of cardiac autonomous nervous system (ANS). Radiofrequency ablation (RFA) for atrial fibrillation (AF) possibly affects GP. Changes in heart rate variability (HRV) after RFA can reflect ANS modulation. METHODS: Epicardial RFA of GP on the left atrium (LA) was performed under the general anesthesia in 15 mature Romanov sheep. HRV was used to assess the alterations in autonomic regulation of the heart. A 24 - hour ECG monitoring was performed before the ablation, 2 days after it and at each of the 12 following months. Ablation sites were evaluated histologically. RESULTS: There was an instant change in HRV parameters after the ablation. A standard deviation of all intervals between normal QRS (SDNN), a square root of the mean of the squared differences between successive normal QRS intervals (RMSSD) along with HRV triangular index (TI), low frequency (LF) power and high frequency (HF) power decreased, while LF/HF ratio increased. Both the SDNN, LF power and the HF power changes persisted throughout the 12 - month follow - up. Significant decrease in RMSSD persisted only for 3 months, HRV TI for 6 months and increase in LF/HF ratio for 7 months of the follow - up. Afterwards these three parameters were not different from the preprocedural values. CONCLUSIONS: Epicardial RFA of GP's on the ovine left atrium has lasting effect on the main HRV parameters (SDNN, HF power and LF power). The normalization of RMSSD, HRV TI and LF/HF suggests that HRV after epicardial RFA of GPs on the left atrium might restore over time.

Concealed Accessory Pathways with a Single Ventricular and Two Discrete Atrial Insertion Sites.

BACKGROUND: Atrioventricular reciprocating tachycardia (AVRT) utilizing a concealed accessory pathway is common. It is well appreciated that some patients may have multiple accessory pathways with separate atrial and ventricular insertion sites. METHODS: We present three cases of AVRT utilizing concealed pathways with evidence that each utilizing a single ventricular insertion and two discrete atrial insertion sites. RESULTS: In case one, two discrete atrial insertion sites were mapped in two separate procedures, and only during the second ablation was the Kent potential identified. Ablation of the Kent potential at this site remote from the two atrial insertion sites resulted in the termination of the retrograde conduction in both pathways. Case two presented with supraventricular tachycardia (SVT) with alternating eccentric atrial activation patterns without alteration in the tachycardia cycle length. The two distinct atrial insertion sites during orthodromic AVRT and ventricular pacing were targeted and each of the two atrial insertion sites were successfully mapped and ablated. In case three, retrograde decremental conduction utilizing both atrial insertion sites was identified prior to ablation. After mapping and ablation of the first discrete atrial insertion site, tachycardia persisted utilizing the second atrial insertion site. Only after ablation of the second atrial insertion site was SVT noninducible, and VA conduction was no longer present. CONCLUSIONS: Concealed retrograde accessory pathways with discrete atrial insertion sites may have a common ventricular insertion site. Identification and ablation of the ventricular insertion site or the separate discrete atrial insertion sites result in successful treatment.

Vagal stimulation targets select populations of intrinsic cardiac neurons to control neurally induced atrial fibrillation.

Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)-sided VNS (15 Hz, 500 µs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P < 0.001). Convergent LCNs were preferentially activated by MNS. Preemptive RCV reduced MNS-induced changes in LCN activity (by 70%) while mitigating MNS-induced AF (by 75%). Preemptive LCV reduced LCN activity by 60% while mitigating AF potential by 40%. IC neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory.

Nerve-granular cell communication in the atrium of the snail Achatina achatina occurs via the cardioexcitatory transmitters serotonin and FMRFamide.

In the present study, the anatomical association and functional interaction between nerve fibres and granular cells in the atrium of the snail Achatina achatina are investigated using a combination of scanning electron microscopy (SEM), pharmacological and immunofluorescence techniques. The SEM studies support a close anatomical association of axons with granular cells and new features of surface morphology are revealed. Pharmacological experiments showed that both serotonin and FMRFamide were able to induce degranulation of granular cells and the release of cysteine-rich atrial secretory protein. Serotonin- and FMRFamide-immunoreactive nerve fibres were observed at variable distances from granular cells, ranging from close contact to distances as far as the diameter of a muscle bundle. These results suggest that serotonin and FMRFamide play a role as paracrine excitatory transmitters in nerve-to-granular cell communication.

Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy.

Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia and atrial fibrillation (AF). The importance of the autonomic nervous system in atrial arrhythmogenesis is also supported by circadian variation in the incidence of symptomatic AF in humans. Methods that reduce autonomic innervation or outflow have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. In this review, we focus on the relationship between the autonomic nervous system and the pathophysiology of AF and the potential benefit and limitations of neuromodulation in the management of this arrhythmia. We conclude that autonomic nerve activity plays an important role in the initiation and maintenance of AF, and modulating autonomic nerve function may contribute to AF control. Potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, cervical vagal nerve stimulation, baroreflex stimulation, cutaneous stimulation, novel drug approaches, and biological therapies. Although the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future.

Selective atrial vagal denervation guided by spectral mapping to treat advanced atrioventricular block.

AIMS: Asymptomatic nocturnal long ventricular pauses are usually detected accidentally and it has been suggested that they may lead to sudden death. Identification of predisposing factors could prevent cardiovascular events. METHODS AND RESULTS: We report the case of a patient with frequent asymptomatic nocturnal ventricular pauses of 3-11 s, characteristic of a vagally mediated atrioventricular (AV) block. Echocardiography, treadmill test, thyroid function test levels, and polysomnogram were normal. In an attempt to reduce the risk, it was decided that an atrial vagal denervation induced by radiofrequency (RF) ablation (cardioneuroablation) could be useful. Spectral mapping was used to localize endocardial vagal innervation in the right and left aspects of the inter-atrial septum, responsible for the sinus node and AV node modulation, and RF pulses were applied in those sites only. After finishing the procedure, significant changes were observed in the heart rate (66-90 b.p.m.), atrial-His interval (115-74 ms), Wenckebach cycle length (820-570 ms), and sinus node recovery time (1100-760 ms). Follow-up Holter recording demonstrated that the number of ventricular pauses had reduced from 438 to 0. Heart rate and time domain characteristics were compatible with vagal denervation. CONCLUSION: Ablation of the endocardial vagal innervation sites seems to be safe and efficient in reducing the frequency and the length of the ventricular pauses. It was possible by identifying certain spectral components of the atrial electrogram, resulting in a conservative approach.

Interconnections between Left Atrial Ganglionic Plexi: Insights from Minimally Invasive Maze Procedures and Their Outcomes.

BACKGROUND: Ganglionic plexi (GPs) have been implicated as triggers of atrial fibrillation (AF) and are known to have functional interconnections. Understanding these connections could result in a more effective ablation. The objective of this study is to assess relationships between right- and left-sided GPs in patients undergoing mini-maze (MM) surgery. We also analyzed the impact of these findings on AF recurrence. METHODS: The GPs were accessed thoracoscopically right side first (group 1) or left side first (group 2). GPs were identified by high-frequency stimulation at 20 predetermined sites and ablation of GPs was performed using a selective or an empiric anatomic approach. Ganglionic plexus (GP) activity was then assessed on the contralateral side and ablated. RESULTS: Sixty-seven patients underwent MM (45 patients in group 1 and 22 in group 2). Fewer patients with active left GPs (LGP) were noted in group 1 (13, 29%) as compared to group 2 (18, 82%). The number of active LGP was also lower (0.6 ± 1.2) in group 1 compared to group 2 (4.7 ± 2.7); P < 0.0001. No significant differences were noted in the frequency of identifiable right GPs (RGP) between groups 1 and 2 (P > 0.05). There were no differences in atrial tachyarrhythmia (AT)/AF recurrence rates between groups 1 and 2 (P = 0.21). However, group 1 patients who underwent selective GP ablation alone had higher recurrence rates (P = 0.016). CONCLUSION: Mapping and ablation of RGPs first decreased identifiable LGP activity. With selective GP ablation, patients who underwent RGP ablation first had higher AT/AF recurrence.

Simultaneous conduction mapping and intracellular membrane potential recording in isolated atria.

We describe a novel approach for simultaneously determining regional differences in action potential (AP) morphology and tissue electrophysiological properties in isolated atria. The epicardial surface of rat atrial preparations was placed in contact with a multi-electrode array (9 × 10 silver chloride electrodes, 0.1 mm diameter and 0.1 mm pitch). A glass microelectrode (100 MΩ) was simultaneously inserted into the endocardial surface to record intracellular AP from either of 2 regions (A, B) during pacing from 2 opposite corners of the tissue. AP duration at 80% of repolarisation and its restitution curve was significantly different only in region A (p < 0.01) when AP was initiated at different stimulation sites. Alternans in AP duration and AP amplitude, and in conduction velocity were observed during 2 separate arrhythmic episodes. This approach of combining microelectrode array and intracellular membrane potential recording may provide new insights into arrhythmogenic mechanisms in animal models of cardiovascular disease.

Autonomic Remodeling: How Atrial Fibrillation Begets Atrial Fibrillation in the First 24 Hours.

BACKGROUND: The mechanism(s) of how atrial fibrillation (AF) sustains itself in the first 24 hours is not well understood. OBJECTIVE: We sought to investigate the role of autonomic remodeling in the first 24 hours of AF simulated by rapid atrial pacing (RAP). METHODS: Forty-eight rabbits were divided into 6 groups. One group (n = 8) was euthanized after baseline recordings. Another group (n = 8) did not receive RAP during the 24-hour period to serve as controls. In the other 4 groups, rabbits were euthanized after RAP for 4, 8, 12, or 24 hours (n = 8 for each). Before and after designated hours of RAP, atrial effective refractory period, heart rate variability, and left vagal and sympathetic nerve activity (VNA and SNA, respectively) were determined. The right and left atrial tissues were obtained for immunocytochemical analysis for growth-associated protein 43 (GAP43), tyrosine hydroxylase (TH), and choline acetyltransferase (ChAT). RESULTS: RAP resulted in progressively shortened atrial effective refractory period and slower heart rate. In the first 12 hours of RAP, both SNA and VNA progressively increased. Then, VNA remained stably elevated but SNA began to attenuate. The high-frequency component and low-frequency/high-frequency ratio of heart rate variability followed the trend of VNA and SNA, respectively. The density of GAP43-positive, ChAT-positive, and TH-positive neural elements in the right and left atria was progressively higher with RAP. CONCLUSIONS: AF resulted in progressive autonomic remodeling, manifesting as nerve sprouting, sympathetic and vagal hyperinnervation. Autonomic remodeling may play an important role in sustaining AF in the first 24 hours.

Long-Term Effects of Atrial Ganglionated Plexi Ablation on Function and Structure of Sinoatrial and Atrioventricular Node in Canine.

BACKGROUND: Long-term effects of ganglionated plexi (GP) ablation on sinoatrial node (SAN) and atrioventricular node (AVN) remain unclear. This study is to investigate the long-term effects of ablation of cardiac anterior right GP (ARGP) and inferior right GP (IRGP) on function and structure of SAN and AVN in canine. METHODS: Thirty-two dogs were randomly divided into an operated group (n = 24) and sham-operated group (n = 8). ARGP and IRGP were ablated in operated group which was randomly divided into three subgroups according to the period of evaluation after operation (1 month, 6 months, 12 months). The functional and histological characteristics of SAN and AVN, as well as the expression of connexin (Cx) 43 and Cx 45 in SAN and AVN, were evaluated before and after ablation. RESULTS: Resting heart rate was increased and AVN effective refractory period was prolonged and sinus node recovery time (SNRT) and corrected SNRT were shortened immediately after ablation. These changes were reverted to preablation level after 1 month. At 1 month, ventricular rate during atrial fibrillation was slowed, atria-His intervals were prolonged, and Cx43 and Cx45 expression in SAN and AVN were downregulated. At 6 months, all changes were reverted to preablation level. The histological characteristics of SAN and AVN did not change. CONCLUSION: Ablation of ARGP and IRGP has short-term effects on function and structure of SAN and AVN rather than long-term effects, which suggests that ablation of ARGP and IRGP is safe. Atrioventricular conduction dysfunction after ablation may be related to downregulated Cx43 and Cx45 expression in AVN.