Acceleration Of Sinus Rate Research Articles

Cardioneuroablation for asystolic reflex syncope with or without the use of extra cardiac vagal stimulation-one year follow-up results

Abstract Background Extra-Cardiac Vagal Stimulation (ECVS) during cardioneuroablation (CNA) has been introduced to confirm total vagal denervation – a clear intra-procedural end-point. However, whether the use of ECVS is associated with better outcome than simple intra-procedural assessment of CNA-induced changes in basic ECG parameters, has not been established. Purpose To compare one-year efficacy of CNA performed with versus without ECVS. Methods This retrospective analysis included 90 patients (age: 37±12 years, 39 males) divided into 2 groups: ECVS(+) (n=41, general anesthesia and total muscle relaxation, settings: 50 Hz, 0.05 ms, 1 V/kg (<70V) for 5 s) and ECVS(-) group (n=49, light sedation). CNA strategy was the same in all patients and was based on presumed anatomical localization of ganglionated plexi, combined with identification of ablation targets at sites with fragmented bipolar atrial electrograms. The end-point in the ECVS (+) group was complete vagal denervation, confirmed by ECVS, whereas in the ECVS (-) group - significant (>30%) acceleration of sinus rate. The primary endpoint was syncope recurrence during one-year follow-up. Results Both groups were comparable concerning clinical and demographic parameters. Primary endpoint occurred in 4 (10%) patients in the ECVS(+) group and in 7 (14%) patients in the ECVS(-) group (p=0.7481) (Figure). No complications were reported. Conclusions These preliminary results suggest that the use of ECVS only slightly improves the one-year CNA efficacy, however, prospective larger studies and longer follow-up are needed to confirm these initial findings.

Cardioneuroablation for symptomatic bradyarrhythmia: for whom it fails?

Abstract Background Cardioneuroablation (CNA) has been proposed as a new therapeutic approach in selected patients with symptomatic functional bradyarrhythmia including recurrent neurally-mediated syncope. Purpose In patients after CNA, we investigated the potential predictors of the recurrence of clinically significant bradyarrhythmia. Methods A retrospective study included 187 consecutive patients (age: 40±12 years; 57 % of males; predominant AV nodal phenotype of the disorder in 37 % of patients; post-atropine sinus rate acceleration by 72±31 %) who underwent their first CNA at our centre from 2014 to 2022 and were followed for the minimum of 3 months. Biatrial radiofrequency ablation was performed under general anaesthesia by irrigated-tip catheter at empirical sites of ganglionated plexi (GP) with the navigation by 3D electroanatomic mapping system and intracardiac echocardiography. Anterior right GP and posteromedial left GP were always targeted to modulate the innervation of both sinoatrial and atrioventricular nodes, irrespective of the clinical manifestation of the disease. The loss of responsiveness of both nodes to extracardiac vagus nerve stimulation (frequently bilateral) was the procedural endpoint. The association of baseline, procedural, and early follow-up characteristics with the recurrence of clinically significant bradyarrhythmia was analyzed. Results CNA with the procedural duration of 154±32 min and radiofrequency time of 14±7 min resulted acutely in sinus rate acceleration by 27±13 bpm, shortening of AH interval by 16±28 ms, an increase of Wenckebach point by 26±28 bpm, shortening of AV node effective refractory period by 114±128 ms, and sinus node recovery time by 462±867 ms. At the 3-month visit, the sinus rate was still significantly higher (83±14 bpm) than at baseline (61±13 bpm); with acceleration by 23±14 bpm. During a median follow up of 33 months (IQR: 18-48 months), recurrence of clinically significant bradyarrhythmia was documented in 18 (10 %) patients. Re-CNA was performed in 11 patients and was scheduled in 3 patients. In 6 (3 %) patients, a pacemaker was finally implanted. Compared to the rest of the population, patients with bradyarrhythmia recurrence were non-significantly younger (36±12 vs. 40±12 years, P=0.16) and had non-significantly less acceleration of sinus rate at the 3-month post-CNA visit (by 18±11 vs. 23±13 bpm, P=0.10) suggesting a trend to more pronounced reinnervation of the sinus node. Conclusion Long-term clinical efficacy of CNA is reasonably high. We did not identify practically useful predictors of CNA failure. This investigation was significantly limited by the low rate of clinical events.

Sympathetic toggled sinus rate acceleration as a mechanism of sustained sinus tachycardia in chronic orthostatic intolerance syndrome

The role of sympathetic nerve activity to maintain sinus rate acceleration remains unclear. The purpose of this study was to test the hypothesis that sustained (>30 seconds) sinus rate acceleration can be associated with either a sympathetic driven or a sympathetic toggled mechanism. We used a patch monitor to record skin sympathetic nerve activity (SKNA) and electrocardiogram over 24 hours. Study 1 included chronic orthostatic intolerance (OI) (n = 18), atrial fibrillation (n = 7), and asymptomatic normal control (n = 19) groups. Study 2 included 17 participants with chronic OI not treated with ivabradine, pyridostigmine, or β-blockers. While a majority of sinus rate acceleration was driven by persistent SKNA in study 1, some episodes were toggled on and off by SKNA bursts without persistent SKNA elevation. The sympathetic toggled sinus rate acceleration episodes were found in 7 of 18 participants with chronic OI (39%), 2 of 7 participants with atrial fibrillation (29%), and 6 of 19 normal control participants (32%) (P = .847) and were faster and longer in the chronic OI group than in other groups. In study 2, there were a total of 11 episodes of sinus rate acceleration that persisted for >200 seconds. Among these episodes, 6 (35%) were toggled on and off by SKNA bursts. Sustained sinus rate acceleration (may be toggled on or off) is associated with SKNA bursts in participants with chronic OI, participants with atrial fibrillation, and normal controls. Patients with OI had more frequent and longer episodes than did other groups.

Anatomically-guided cardioneuroablation for recurrent neurally mediated syncope

Abstract Funding Acknowledgements Type of funding sources: None. Background Cardioneuroablation (CNA) has been proposed as a new therapeutic approach in selected patients with recurrent neurally mediated syncope and documented cardioinhibitory component. Purpose We report on procedural data and clinical outcomes of consecutive patients who underwent anatomically-guided CNA at our center in the period of 2014 - 2021. Methods A study investigated 145 otherwise healthy patients (age: 40 ± 14 years, 56% males) with recurrent reflex syncope and the physiological result of the atropine test. Biatrial radiofrequency (RF) ablation was performed under general anesthesia by irrigated-tip catheter at empirical sites of ganglionated plexi (GP) with the navigation by CARTO-3 system and intracardiac echocardiography. Anterior right GP and posteromedial left GP were always targeted to modulate the innervation of both sinoatrial (SAN) and atrioventricular (AVN) nodes, irrespective of clinical manifestation of the disease. The loss of responsiveness of both nodes to extracardiac vagus nerve stimulation was the procedural endpoint. Right vagus or bilateral vagus nerve stimulation was used in 86% and 54% of procedures, respectively. Results Enrolled patients had documented cardioinhibitory disorder of SAN (59%), AVN (30%), or both nodes (11%). CNA (duration: 157 ± 31 min; RF time: 15 ± 6 min; radiation dose: 84 ± 135 µGy.m²) resulted in sinus rate acceleration by 28 ± 12 bpm, shortening of AH interval by 15 ± 31 ms, an increase of Wenckebach point by 28 ± 33 bpm, shortening of AVN effective refractory period by 110 ± 115 ms, and sinus node recovery time by 508 ± 666 ms. During a median follow up of 26 (IQR: 12-39) months, CNA was repeated in 9 patients and is scheduled in 3 other (total 8%). Pacemaker was implanted only in 4 (3%) patients after single (n = 2) or repeated CNA (n = 2). Corresponding Kaplan-Meier curves are provided in the Figure. Any-syncope-free survival is comparable to that reported in active arms of historical and recent pacemaker studies. Conclusions CNA is a reasonably effective treatment option for patients with functional cardioinhibitory syncope. CNA can be performed by anatomically-guided ablation at empirical GP sites. Our study corroborates the clinical utility of CNA as a viable alternative to pacemaker implant in selected patients.

235Anatomic guided ablation of the right ganglionated plexus is enough for cardiac autonomic denervation in patients with significant bradyarrhythmias

Abstract Background In patients with significant bradyarrhytmias, cardiac denervation is an alternative therapeutic approach. Previous reports proposed different methods (as high frequency ednocardial stimulation of ganglionated plexus and specific atrial electrogram identification) and targets (right and left atrial ganglionated plexus) for adequate denervation. There is no consensus on the best way to perform these procedures, in spite the right atrial ganglia plexus (GP) ablation seeming to be the most contributive to its success. Purpose To assess the results of a purely anatomic approach for ablation of just the right atrial plexus in patients with severe vagal bradyarrhytmias. Methods We enrolled patients referred for ablation of cardiac parasympathetic ganglia, with or without atrial fibrillation ablation. We performed eletroanatomic mapping of the right and left atria and used an irrigated tip catheter for ablation, aiming at the anterior right GP at the right pulmonary veins antrum along with ablation at the superior vena cava junction and the inferior right GP at the posterior aspect of the right inferior pulmonary vein along with ablation of the right aspect of the interatrial septum, between the posterior wall and coronary sinus ostium (Figure 1). We assessed the PW and Wenckenback cycle lengths (CL) pre and post procedure in patients with sinus arrest or AV block, respectively, and the patients had new 24h holter readings at least 30 days from the index procedure. Results We enrolled 12 patients: 9 males (75%), median age of 49,5 years (IQR 36-61,75). All patients had structurally normal hearts. 7 patients had only ablation of the parasympathetic ganglia and 5 patients had simultaneous pulmonary vein isolation for previously documented atrial fibrillation. 7 patients (58,3%) had sinus bradycardia (2 patients had sinus arrest with pauses of 8 and 13 seconds), 2 patients with cardioinhibitory syncope (with pauses of 23 and 28 seconds) and 3 patients had transient high degree AV block. The ablation procedure led to a median sinus rate acceleration of 15 bpm (IQR 3-29), a median decrease of 320 ms in PW (IQR 23,75-609,5) in patients with sinus arrest and a decrease of 80 ms in wenckenback CL (IQR 60-200) in patients with AV block. With a median follow up of 133,50 days (IQR 36-61,75), no patient had recurrence of symptoms or conduction disturbances. Conclusions In selected patients with severe functional paroxysmal bradyarrhytmias, cardiac denervation using an ablation strategy purely based on anatomic aspects and targeting only the right GP, seems to be an effective therapeutic approach. Abstract Figure 1: Abl of right ganglionated plex

P3752Ablation of the superior left ganglionic plexus is not necessary for effective denervation of the sinoatrial and atrioventricular nodes

Abstract Background Cardioneuroablation by targeting of atrial ganglionic plexi (GP) has been proposed as a new therapeutic option in selected patients with reflex syncope. Contribution of individual GPs to cardiac autonomic regulations is not fully established. Purpose Because consistent vagal responses have been observed during left superior pulmonary vein isolation in patients undergoing ablation for atrial fibrillation, we investigated whether standalone ablation of the superior left GP modifies the vagal input into the sinoatrial (SAN) and atrioventricular node (AVN). Methods Study hypothesis was investigated in otherwise healthy patients undergoing cardioneuroablation for symptomatic bradyarrhythmias. All had preprocedural atropine test suggesting functional disorder. Anatomically-navigated (CARTO-3) radiofrequency (RF) ablation (25–30 W/30 s/20 ml/min) at empirical GP sites was performed in general anaesthesia. Extracardiac high-frequency vagal nerve stimulation (25–60 V/30–50 Hz/0.05–0.1 ms) via right jugular vein was performed at baseline, after initial superior left GP ablation, and after the ablation of remaining septal and inferior GPs. High-frequency vagal nerve stimulation was always done in both sinus rhythm and atrial pacing. The elimination of all stimulation-induced vagal responses was the endpoint of the procedure. Results A study included 8 patients (34±8 years; 5 males). Six of them had recurrent syncope with cardioinhibitory response at the SAN (n=4), AVN (n=1) or both nodes (n=1); and 2 patients had symptomatic sinus bradycardia. At baseline, high-frequency vagal nerve stimulation induced long episodes of sinus arrest and advanced AV block in all patients. Cluster ablation at the superior left GP (RF time: 192±28 s) did not change the sinus rate (59±14 vs 60±15, NS), PQ interval (174±37 vs 173±37, NS), and did not induce any tangible change in SAN/AVN response to high-frequency vagal nerve stimulation. Subsequently, anterior right GP was targeted from the aspect of right atrium (n=7), from the anterior antrum of right pulmonary veins (n=6), and inferior GPs were targeted from the aspect of left atrium (n=7). This lesion set finally resulted in complete non-responsiveness of SAN and AVN to high-frequency vagal nerve stimulation in all patients. Ablation procedure overall (duration: 172±15 min; RF time: 988±306 s; radiation dose: 70±34 μGy·m2) led to sinus rate acceleration by a median of 29 (IQR: 18–38) bpm, increase of Wenckebach point by 21 (IQR: 9–28) bpm, and shortening of AVN effective refractory period by 40 (IQR: 15–73) ms. Conclusions Cardioneuroablation guided by extracardiac high-frequency vagal nerve stimulation can achieve complete denervation of SAN and AVN by ablation of postero(para)septal and inferior GPs only. Ablation of the superior left GP appears unnecessary and can be eliminated from the lesion set design.

Selective Sinoatrial Node Optical Mapping and the Mechanism of Sinus Rate Acceleration

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. 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. 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.

Synergistic Dual Automaticity in Sinoatrial Node Cell and Tissue Models

The mechanism of sinoatrial node (SAN) automaticity is traditionally attributed to membrane ion currents. Recent evidence indicates spontaneous sarcoplasmic reticulum (SR) Ca(2+) cycling also plays an important role. A computer simulation on SAN cell and 1D tissue model was performed. In the SAN cells, SR Ca(2+) cycling broadly modulated the sinus rate from 1.74 Hz to 3.87 Hz. Shortening of the junctional SR refilling time and increase of SR Ca(2+) release were responsible for sinus rate acceleration. However, under the fast SR Ca(2+) cycling, decreased L-type Ca(2+) current (I(CaL)) resulted in irregular firing. When Ca(2+) cycling was suppressed, I(f) and I(CaT) both acted to stabilize the pacemaker rhythm, but I(CaT) had less effect than I(f). At the 1D level, the electrical coupling between neighboring cells had little effect on the earliest pacemaker location. The leading pacemaking site always colocalized with the site with the highest SR Ca(2+) cycling rate, but shifted to the site with less inhibited I(CaL). The rate of SR Ca(2+) cycling can effectively and broadly modulate the sinus rate. I(f), I(CaL) and I(CaT) play integral roles to guarantee SAN cell rhythmic firing. The leading pacemaker site is determined by intracellular Ca(2+) dynamics and membrane currents, indicating the synergistic dual automaticity not only exists in single SAN cells, but also at the tissue level.

Intracellular Calcium Dynamics and Acceleration of Sinus Rhythm by β-Adrenergic Stimulation

Recent evidence indicates that membrane voltage and Ca2+ clocks jointly regulate sinoatrial node (SAN) automaticity. Here we test the hypothesis that sinus rate acceleration by beta-adrenergic stimulation involves synergistic interactions between these clock mechanisms. We simultaneously mapped intracellular calcium (Ca(i)) and membrane potential in 25 isolated canine right atrium, using previously described criteria of the timing of late diastolic Ca(i) elevation (LDCAE) relative to the action potential upstroke to detect the Ca2+ clock. Before isoproterenol, the earliest pacemaking site occurred in the inferior SAN, and LDCAE was observed in only 4 of 25 preparations. Isoproterenol infusion (1 micromol/L) increased sinus rate and shifted pacemaking site to superior SAN, concomitant with the appearance of LDCAE preceding the action potential upstroke by 98+/-31 ms. Caffeine had similar effects, whereas sarcoplasmic reticulum Ca2+ depletion with ryanodine and thapsigargin prevented isoproterenol-induced LDCAE and blunted sinus rate acceleration. Ca(i) transient relaxation time during isoproterenol was shorter in superior SAN (124+/-34 ms) than inferior SAN (138+/-24 ms; P=0.01) or right atrium (164+/-33 ms; P=0.001) and was associated with a lower sarcoplasmic reticulum Ca2+ ATPase pump to phospholamban protein ratio in SAN than in right atrium. Hyperpolarization-activated pacemaker current (I(f)) blockade with ZD 7288 modestly blunted but did not prevent LDCAE or sinus rate acceleration by isoproterenol. Acceleration of the Ca2+ clock in the superior SAN plays an important role in sinus acceleration during beta-adrenergic stimulation, interacting synergistically with the voltage clock to increase sinus rate.

Antagonism between manganese and caffeine on the SA node of the dog heart in situ.

Direct perfusion of the sinus node artery under a constant pressure of 100mm Hg was arranged in eight canine hearts in situ. The administration of MnCl2, at doses from 10 μg to 10mg into the sinus node artery induced a longlasting negative chronotropic response. MnCl, blocked the effects of caffeine which induced double peaked positive chronotropic responses, i.e., initial rapid acceleration of sinus rate followed by slow and long-lasting acceleration. The initial acceleration was resistant to propranolol or tetrodotoxin, but completely blocked by MnCl2. Thus, the initial positive chronotropic response to caffeine may be probably ascribed to its essential effect of the movement of Ca ions on the SA nodal pacemaker cell.

Pharmacologic analysis of nicotine and dimethylphenylpiperazinium on pacemaker activity of the SA node in the dog.

It is well known that nicotine and l,l-dimethyl-4-phenylpiperazinium (DMPP) have biphasic chronotropic responses both by stimulating the intracardiac parasympathetic ganglia and by liberating catecholamines locally (1-4). In 1967, Nadeau and James reported effects of nicotine on heart rate using a direct perfusion technique of the SA node in dogs (5). They showed that the negative chronotropic response to nicotine was abolished by treatment with atropine and that of the positive by either propranolol or hexamethonium. Furthermore, Bhagat et al. reported that nicotine-induced acceleration of sinus rate was inhibited by hexamethonium but the DMPP-induced one was not suppressed by hexamethonium in isolated guineapig atria (6).

Pharmacologic Analysis of Nicotine and Dimethyl-Phenylpiperazinium on Pacemaker Activity of the SA Node in the Dog

It is well known that nicotine and l,l-dimethyl-4-phenylpiperazinium (DMPP) have biphasic chronotropic responses both by stimulating the intracardiac parasympathetic ganglia and by liberating catecholamines locally (1-4). In 1967, Nadeau and James reported effects of nicotine on heart rate using a direct perfusion technique of the SA node in dogs (5). They showed that the negative chronotropic response to nicotine was abolished by treatment with atropine and that of the positive by either propranolol or hexamethonium. Furthermore, Bhagat et al. reported that nicotine-induced acceleration of sinus rate was inhibited by hexamethonium but the DMPP-induced one was not suppressed by hexamethonium in isolated guineapig atria (6).