Neuromodulation of Cardiovascular Risks Associated With Cardiotoxic Chemotherapy: A First-in-Human Randomized Pilot Study. Neuromodulation in Cancer Study (NCAN).

OBJECTIVES: Cardiotoxic chemotherapy is used to treat malignancies such as breast cancer and lymphoma. These treatments predispose patients to cardiotoxicity that can lead to cancer treatment-related cardiac dysfunction (CTRCD). The use of high doses of anthracyclines or in combination with human epidermal growth factor receptor 2 antagonists is associated with a progressively higher risk of CTRCD. CTRCD is preceded by increased activation of the sympathetic nervous system and abnormal left ventricular mechanical deformation as measured by abnormal global longitudinal strain (GLS). Low-level tragus stimulation (LLTS) is a new, safe, noninvasive technique that offers great potential to reduce increased sympathetic activation and improve GLS. Here, we describe a study method to examine the effects of LLTS on autonomic balance and cardiac function in breast cancer or lymphoma patients treated with anthracyclines. METHODS: A first-in-human pilot, randomized, double-blind feasibility study will evaluate 104 patients (age >50 y) with breast cancer or lymphoma who receive anthracyclines with one additional CTRCD risk factor. Patients undergo 2 weeks of LLTS daily (1 h/d). Autonomic balance will be measured using heart rate variability metrics. Strain imaging using GLS will be performed pre and post-LLTS. Endothelial inflammation and oxidative stress measures will be performed using in vitro assays at baseline and after 2 weeks. CONCLUSION: We hypothesize that LLTS stabilizes sympathovagal imbalance and improves cardiac performance in anthracycline-treated patients with breast cancer or lymphoma.

Robust Artificial Intelligence Tool for Atrial Fibrillation Diagnosis: Novel Development Approach Incorporating Both Atrial Electrograms and Surface ECG and Evaluation by Head-to-Head Comparison With Hospital-Based Physician ECG Readers.

BACKGROUND: Atrial fibrillation (AF) increases risk of embolic stroke, and in postoperative patients, increases cost of care. Consequently, ECG screening for AF in high-risk patients is important but labor-intensive. Artificial intelligence (AI) may reduce AF detection workload, but AI development presents challenges. METHODS AND RESULTS: We used a novel approach to AI development for AF detection using both surface ECG recordings and atrial epicardial electrograms obtained in postoperative cardiac patients. Atrial electrograms were used only to facilitate establishing true AF for AI development; this permitted the establishment of an AI-based tool for subsequent AF detection using ECG records alone. A total of 5 million 30-second epochs from 329 patients were annotated as AF or non-AF by expert ECG readers for AI training and validation, while 5 million 30-second epochs from 330 different patients were used for AI testing. AI performance was assessed at the epoch level as well as AF burden at the patient level. AI achieved an area under the receiver operating characteristic curve of 0.932 on validation and 0.953 on testing. At the epoch level, testing results showed means of AF detection sensitivity, specificity, negative predictive value, positive predictive value, and F1 (harmonic mean of positive predictive value and sensitivity) as 0.970, 0.814, 0.976, 0.776, and 0.862, respectively, while the intraclass correlation coefficient for AF burden detection was 0.952. At the patient level, AF burden sensitivity and positive predictivity were 96.2% and 94.5%, respectively. CONCLUSIONS: Use of both atrial electrograms and surface ECG permitted development of a robust AI-based approach to postoperative AF recognition and AF burden assessment. This novel tool may enhance detection and management of AF, particularly in patients following operative cardiac surgery.

Potential consequences of cardioneuroablation for vasovagal syncope: A call for appropriately designed, sham-controlled clinical trials.

Cardioneuroablation (CNA) is being increasingly used to treat patients with vasovagal syncope (VVS). Bradycardia, in the cardioinhibitory subtype of VVS, results from transient parasympathetic overactivity leading to sinus bradycardia and/or atrioventricular block. By mitigating parasympathetic overactivity, CNA has been shown to improve VVS symptoms in clinical studies with relatively small sample sizes and short follow-up periods (<5 years) at selected centers. However, CNA may potentially tip the autonomic balance to a state of sympathovagal imbalance with attenuation of cardiac parasympathetic activity. A higher heart rate is associated with adverse cardiovascular events and increased mortality in healthy populations without cardiovascular diseases. Chronic sympathovagal imbalance may also affect the pathophysiology of spectra of cardiovascular disorders including atrial and ventricular arrhythmias. This review addresses potential long-term pathophysiological consequences of CNA for VVS.

Protein kinase A: A potential marker of sympathovagal imbalance in heart failure.

Mitigation of cardiac autonomic dysregulation by neuromodulation technologies is emerging as a new therapeutic modality of heart failure (HF). This recent progress has necessitated the identification of a biomarker for the quantification of sympathovagal balance, the potential target of 'neuromodulation' strategies. The currently available autonomic nervous system assessment parameters do not truly reflect the sympathovagal balance of the ventricle. Protein kinase A (PKA) is an intracellular enzyme that plays a major role in the pathophysiology of functional and structural ventricular remodeling in HF. Interestingly, sympathetic and parasympathetic activations exert reciprocal influence on the activity of PKA. The current review attempts to evaluate the potential concept and feasibility of using in vitro assessment of PKA activity as a marker of sympathovagal balance in HF.

Impact of proinflammatory epicardial adipose tissue and differentially enhanced autonomic remodeling on human atrial fibrillation.

OBJECTIVES: The mechanisms underlying atrial fibrillation are yet to be elucidated. We sought to investigate the interactions among autonomic remodeling, epicardial adipose tissue, inflammation, and atrial fibrillation. METHODS: Myocardium and adjacent epicardial adipose tissue of the left atrial appendage, right atrial appendage, and pulmonary vein muscle sleeves were obtained from 61 consecutive patients (35 with atrial fibrillation, 26 with no atrial fibrillation) during mitral valve surgeries. Patients were divided into the atrial fibrillation group and no atrial fibrillation group according to the history and Holter monitoring before surgery. Sympathetic and parasympathetic innervation were evaluated by tyrosine hydroxylase and choline acetyltransferase staining, respectively. Atrial fibrosis as well as cytokines/adipokines and related inflammatory proteins and signaling pathways in the epicardial adipose tissue were examined. RESULTS: Immunohistochemical studies revealed significantly increased tyrosine hydroxylase (+) and choline acetyltransferase (+) neural elements in the left atrial appendage and pulmonary vein muscle sleeve myocardium, as well as adjacent epicardial adipose tissue in the atrial fibrillation group, particularly the pulmonary vein muscle sleeve sites. The receiver operating curve identified a threshold ratio (tyrosine hydroxylase/choline acetyltransferase) of 0.8986 in the epicardial adipose tissue (sensitivity = 82.86%; specificity = 80.77%; area under the curve = 0.85, 95% confidence interval = 0.76-0.95, P < .0001). More patients with a higher tyrosine hydroxylase/choline acetyltransferase ratio (≥0.8986) had atrial fibrillation. Expression levels of the genes and related proteins of the ß1 adrenergic, mitogen-activated protein kinase, and nuclear factor kappa B signaling pathways were higher in patients with a higher tyrosine hydroxylase/choline acetyltransferase ratio. The tyrosine hydroxylase/choline acetyltransferase ratio also correlated with fibrosis. CONCLUSIONS: Differentially enhanced autonomic remodeling and proinflammatory and profibrotic cytokines/adipokines in the epicardial adipose tissue adjacent to the pulmonary vein muscle sleeve site may work synergistically to promote atrial fibrillation.

Calcium-Induced Autonomic Denervation in Patients With Post-Operative Atrial Fibrillation.

BACKGROUND: Post-operative atrial fibrillation (POAF) is associated with worse long-term cardiovascular outcomes. OBJECTIVES: This study hypothesized that injecting calcium chloride (CaCl2) into the major atrial ganglionated plexi (GPs) during isolated coronary artery bypass grafting (CABG) can reduce the incidence of POAF by calcium-induced autonomic neurotoxicity. METHODS: This proof-of-concept study randomized 200 patients undergoing isolated, off-pump CABG to CaCl2 (n = 100) or sodium chloride (sham, n = 100) injection. Two milliliters of CaCl2 (5%) or sodium chloride (0.9%) was injected into the 4 major atrial GPs during CABG. All patients received 7-day continuous telemetry and Holter monitoring. The primary outcome was incidence of POAF (≥30 s) in 7 days. Secondary outcomes included length of hospitalization, POAF burden, average ventricular rate during AF, plasma level of inflammatory markers, and actionable antiarrhythmic therapy to treat POAF. RESULTS: The POAF incidence was reduced from 36% to 15% (hazard ratio: 0.366; 95% confidence interval: 0.211 to 0.635; p = 0.001). Length of hospitalization did not differ between the 2 groups. POAF burden (first 7 post-operative days), the use of amiodarone or esmolol, and the incidence of atrial couplets and nonsustained atrial tachyarrhythmias were significantly reduced in the CaCl2 group. Heart rate variability data showed a decrease in both high-frequency and low-frequency power in the CaCl2 group with a preserved low-frequency/high-frequency ratio, suggesting that the sympathetic/parasympathetic balance was not perturbed by CaCl2 injection. CONCLUSIONS: Injection of CaCl2 into the 4 major atrial GPs reduced the POAF hazard by 63%. Inhibition of GP function by Ca-mediated neurotoxicity may underlie the therapeutic effect. (Calcium Autonomic Denervation Prevents Postoperative Atrial Fibrillation; ChiCTR1800019276).

Effects of 60-Hertz notch filtering on local abnormal ventricular activities.

BACKGROUND: It is known that electrical signals can be affected by notch filtering. OBJECTIVE: We sought to investigate the effect of 60-Hz notch filtering on local abnormal ventricular activities (LAVA) in patients undergoing ventricular tachycardia ablation. METHODS: To ensure catheter stability, only patients undergoing ablation using Stereotaxis mapping catheters were enrolled. Catheter stability was judged by the display on the electroanatomic map and the morphology of the bipolar and unipolar electrograms of the ablation catheter. At sites recording stable LAVA, 60-Hz notch filtering was applied. The duration, amplitude, and morphology of LAVA were compared before and after filtering. The area under LAVA was used to analyze the amplitude of continuous LAVA. RESULTS: A total of 110 LAVA potentials recorded from 13 patients were analyzed. Notch filtering significantly affected the LAVA morphology and reduced their amplitude (the sum of the absolute value of the largest positive and negative voltages before filtering: 0.267 mV [0.191-0.395 mV]; after filtering: 0.172 mV [0.112-0.266 mV]; P < .001). At least 2 high-frequency components were introduced into the LAVA by filtering at 33 sites. The area under continuous LAVA was reduced by 28% from 24.64 cm2 (16.20-33.45 cm2) to 17.53 cm2 (10.52-23.82 cm2) (P < .001). The duration of continuous LAVA was reduced by 12% from 79.2 ms (55.0-93.0 ms) to 69.5 ms (53.0-88.5 ms) (P < .001). CONCLUSION: Notch filtering can distort LAVA by reducing their amplitude, changing their morphology, and shortening their duration, leading to potential false positives and negatives. Mitigating the 60-Hz noise should focus on eliminating the source of noise, not applying notch filtering.

Pulmonary Artery Denervation for Patients With Residual Pulmonary Hypertension After Pulmonary Endarterectomy.

BACKGROUND: Pulmonary artery denervation (PADN) procedure has not been applied to patients with residual chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy (PEA). OBJECTIVES: This study sought to assess the safety and efficacy of PADN using remote magnetic navigation in patients with residual CTEPH after PEA. METHODS: Fifty patients with residual CTEPH despite medical therapy at least 6 months after PEA, who had mean pulmonary artery pressure ≥25 mm Hg or pulmonary vascular resistance (PVR) > 400 dyn‧s‧cm-5 based on right heart catheterization were randomized to treatment with PADN (PADN group; n = 25) using remote magnetic navigation for ablation or medical therapy with riociguat (MED group; n = 25). In the MED group, a sham procedure with mapping but no ablation was performed. The primary endpoint was PVR at 12 months after randomization. Key secondary endpoint included 6-min walk test. RESULTS: After PADN procedure, 2 patients (1 in each group) developed groin hematoma that resolved without any consequences. At 12 months, mean PVR reduction was 258 ± 135 dyn‧s‧cm-5 in the PADN group versus 149 ± 73 dyn‧s‧cm-5 in the MED group, mean between-group difference was 109 dyn‧s‧cm-5 (95% confidence interval: 45 to 171; p = 0.001). The 6-min walk test distance was significantly increased in the PADN group as compared to distance in the MED group (470 ± 84 m vs. 399 ± 116 m, respectively; p = 0.03). CONCLUSIONS: PADN in patients with residual CTEPH resulted in substantial reduction of PVR at 12 months of follow-up, accompanied by improved 6-min walk test.

Metformin regulates adiponectin signalling in epicardial adipose tissue and reduces atrial fibrillation vulnerability.

Epicardial adipose tissue (EAT) remodelling is closely related to the pathogenesis of atrial fibrillation (AF). We investigated whether metformin (MET) prevents AF-dependent EAT remodelling and AF vulnerability in dogs. A canine AF model was developed by 6-week rapid atrial pacing (RAP), and electrophysiological parameters were measured. Effective refractory periods (ERP) were decreased in the left and right atrial appendages as well as in the left atrium (LA) and right atrium (RA). MET attenuated the RAP-induced increase in ERP dispersion, cumulative window of vulnerability, AF inducibility and AF duration. RAP increased reactive oxygen species (ROS) production and nuclear factor kappa-B (NF-κB) phosphorylation; up-regulated interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and transforming growth factor-ß1 (TGF-ß1) levels in LA and EAT; decreased peroxisome proliferator-activated receptor gamma (PPARγ) and adiponectin (APN) expression in EAT and was accompanied by atrial fibrosis and adipose infiltration. MET reversed these alterations. In vitro, lipopolysaccharide (LPS) exposure increased IL-6, TNF-α and TGF-ß1 expression and decreased PPARγ/APN expression in 3T3-L1 adipocytes, which were all reversed after MET administration. Indirect coculture of HL-1 cells with LPS-stimulated 3T3-L1 conditioned medium (CM) significantly increased IL-6, TNF-α and TGF-ß1 expression and decreased SERCA2a and p-PLN expression, while LPS + MET CM and APN treatment alleviated the inflammatory response and sarcoplasmic reticulum Ca2+ handling dysfunction. MET attenuated the RAP-induced increase in AF vulnerability, remodelling of atria and EAT adipokines production profiles. APN may play a key role in the prevention of AF-dependent EAT remodelling and AF vulnerability by MET.

TREAT AF (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation): A Randomized Clinical Trial.

OBJECTIVES: This study was a sham-controlled, double-blind, randomized clinical trial to examine the effect of chronic low level tragus stimulation (LLTS) in patients with paroxysmal AF. BACKGROUND: Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve at the tragus (LLTS) acutely suppresses atrial fibrillation (AF) in humans, but the chronic effect remains unknown. METHODS: LLTS (20 Hz, 1 mA below the discomfort threshold) was delivered using an ear clip attached to the tragus (active arm) (n = 26) or the ear lobe (sham control arm) (n = 27) for 1 h daily over 6 months. AF burden over 2-week periods was assessed by noninvasive continuous electrocardiogram monitoring at baseline, 3 months, and 6 months. Five-minute electrocardiography and serum were obtained at each visit to measure heart rate variability and inflammatory cytokines, respectively. RESULTS: Baseline characteristics were balanced between the 2 groups. Adherence to the stimulation protocol (≤4 sessions lost per month) was 75% in the active arm and 83% in the control arm (p > 0.05). At 6 months, the median AF burden was 85% lower in the active arm compared with the control arm (ratio of medians: 0.15; 95% confidence interval: 0.03 to 0.65; p = 0.011). Tumor necrosis factor-alpha was significantly decreased by 23% in the active group relative to the control group (ratio of medians: 0.77; 95% confidence interval: 0.63 to 0.94; p = 0.0093). Frequency domain indices of heart rate variability were significantly altered with active versus control stimulation (p < 0.01). No device-related side effects were observed. CONCLUSIONS: Chronic, intermittent LLTS resulted in lower AF burden than did sham control stimulation, supporting its use to treat paroxysmal AF in selected patients. (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation [TREAT-AF]; NCT02548754).

Low-level transcutaneous vagus nerve stimulation attenuates cardiac remodelling in a rat model of heart failure with preserved ejection fraction.

NEW FINDINGS: What is the central question of this study? What is the effect of chronic intermittent low-level transcutaneous vagus nerve stimulation on cardiac inflammation, fibrosis and diastolic dysfunction in a rat model of heart failure with preserved ejection fraction? What is the main finding and its importance? In salt-sensitive rats fed with high salt diet, low-level transcutaneous vagus nerve stimulation significantly attenuated blood pressure elevation, ameliorated diastolic function, and attenuated left ventricular inflammation and fibrosis compared to the sham group. Further studies to examine the efficacy of this novel treatment in humans are warranted. ABSTRACT: Inflammation and fibrosis play a central role in the development of heart failure with preserved ejection fraction (HFpEF). We previously showed that low-level, transcutaneous stimulation of the vagus nerve at the tragus (LLTS) is anti-inflammatory. We investigated the effect of chronic intermittent LLTS on cardiac inflammation, fibrosis and diastolic dysfunction in a rat model of HFpEF. Dahl salt-sensitive (DS) rats were randomized in three groups: low salt (LS, 0.3% NaCl; n = 12; control group without stimulation) and high salt (HS, 4% NaCl) with either active (n = 18) or sham (n = 18) LLTS at 7 weeks of age. After 6 weeks of diet (baseline), sham or active LLTS (20 Hz, 2 mA, 0.2 ms) was implemented for 30 min daily for 4 weeks. Echocardiography was performed at baseline and 4 weeks after treatment (endpoint). At endpoint, left ventricle (LV) histology and gene expression were examined. After 6 weeks of diets, HS rats developed hypertension and LV hypertrophy compared to LS rats. At endpoint, LLTS significantly attenuated blood pressure elevation, prevented the deterioration of diastolic function and improved LV circumferential strain, compared to the HS sham group. LV inflammatory cell infiltration and fibrosis were attenuated in the HS active compared to the HS sham group. Pro-inflammatory and pro-fibrotic genes (tumour necrosis factor, osteopontin, interleukin (IL)-11, IL-18 and IL-23A) were differentially altered in the two groups. Chronic intermittent LLTS ameliorates diastolic dysfunction, and attenuates cardiac inflammation and fibrosis in a rat model of HFpEF, suggesting that LLTS may be used clinically as a novel non-invasive neuromodulation therapy in HFpEF.

Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients undergoing cardiac surgery: Three-year follow-up of a randomized study.

BACKGROUND: Botulinum toxin (BTX) injections into epicardial fat pads in patients undergoing coronary artery bypass grafting (CABG) has resulted in suppression of atrial fibrillation (AF) during the early postoperative period through 1-year of follow-up in a pilot program. OBJECTIVE: The purpose of this study was to report 3-year AF patterns by the use of implantable cardiac monitors (ICMs). METHODS: Sixty patients with a history of paroxysmal AF and indications for CABG were randomized 1:1 to either BTX or placebo injections into 4 posterior epicardial fat pads. All patients received an ICM with regular follow-up for 3 years after surgery. The primary end point of the extended follow-up period was incidence of any atrial tachyarrhythmia after 30 days of procedure until 36 months on no antiarrhythmic drugs. The secondary end points included clinical events and AF burden. RESULTS: At the end of 36 months, the incidence of any atrial tachyarrhythmia was 23.3% in the BTX group vs 50% in the placebo group (hazard ratio 0.36; 95% confidence interval 0.14-0.88; P = .02). AF burden at 12, 24, and 36 months was significantly lower in the BTX group than in the placebo group: 0.22% vs 1.88% (P = .003), 1.6% vs 9.5% (P < .001), and 1.3% vs 6.9% (P = .007), respectively. In the BTX group, 2 patients (7%) were hospitalized during follow-up compared with 10 (33%) in the placebo group (P = .02). CONCLUSION: Injection of BTX into epicardial fat pads in patients undergoing CABG resulted in a sustained and substantial reduction in atrial tachyarrhythmia incidence and burden during 3-year follow-up, accompanied by reduction in hospitalizations.

Optogenetic Modulation of Cardiac Sympathetic Nerve Activity to Prevent Ventricular Arrhythmias.

BACKGROUND: Studies have shown that left stellate ganglion (LSG) suppression protects against ventricular arrhythmias (VAs). Optogenetics is a novel technique to reversibly regulate the activity of the targeted neurons. OBJECTIVES: This study aimed to investigate whether an optogenetically silenced LSG could protect against VAs induced by myocardial ischemia. METHODS: Adeno-associated virus (AAV) was used as the vector to deliver ArchT, an inhibitory light-sensitive opsin, to the LSG neurons. Twenty male beagles were randomized into the optogenetics group (n = 10, AAV2/9-CAG-ArchT-GFP microinjected into LSG) and control group (n = 10, AAV2/9-CAG-GFP microinjected into LSG). After 4 weeks, the LSG function and neural activity, heart rate variability, ventricular action potential duration, and effective refractory period were measured in the absence or presence of a light-emitting diode illumination (565 nm). Myocardial ischemia was induced by left anterior coronary artery ligation and 1 h of electrocardiography was recorded for VAs analysis. RESULTS: ArchT was successfully expressed in all dogs. Transient light-emitting diode illumination significantly suppressed the LSG function, LSG neural activity, and sympathetic nerve indices of heart rate variability as well as prolonged left ventricular effective refractory period and APD90 only in the optogenetics group. Thirty-minute illumination further enhanced these changes in the optogenetics group. Importantly, all of these changes returned to baseline within 2 h after illumination was turned off. Moreover, the ischemia-induced VAs were significantly suppressed by illumination only in the optogenetics group. CONCLUSIONS: Optogenetic modulation could reversibly inhibit the neural activity of LSG, thereby increasing electrophysiological stability and protecting against myocardial ischemia-induced VAs.

Low-Level Vagus Nerve Stimulation Suppresses Post-Operative Atrial Fibrillation and Inflammation: A Randomized Study.

OBJECTIVES: This study sought to examine the efficacy of low-level vagus nerve stimulation (LLVNS) in suppressing post-operative atrial fibrillation (POAF) and inflammatory cytokines in patients undergoing cardiac surgery. BACKGROUND: POAF often complicates cardiac surgery. METHODS: Patients undergoing cardiac surgery were randomized to active or sham LLVNS. In all patients, a bipolar wire was sutured to the vagus nerve pre-ganglionic fibers alongside the lateral aspect of the superior vena cava. High-frequency (20 Hz) stimulation, 50% below the threshold for slowing the heart rate, was delivered for 72 h in the LLVNS group. The development of POAF was monitored continuously during the entire hospital stay by use of telemetry. Blood was collected on arrival in the intensive care unit and at 24 and 72 h for measurement of inflammatory cytokines. Patients were followed up within 1 month after cardiac surgery. RESULTS: A total of 54 patients were randomized to either active LLVNS (n = 26) or sham control (n = 28). The baseline characteristics of the patients were balanced in the 2 groups. POAF occurred in 3 patients (12%) in the LLVNS group and 10 patients (36%) in the control group (hazard ratio: 0.28; 95% confidence interval: 0.10 to 0.85; p = 0.027). None of the patients developed any complications as a result of wire placement. At 72 h, serum tumor necrosis factor-α and interleukin-6 levels were significantly lower in the LLVNS group than in the control group. CONCLUSIONS: These data suggest that LLVNS suppresses POAF and attenuates inflammation in patients undergoing cardiac surgery. Further studies are warranted.

Long-Term Suppression of Atrial Fibrillation by Botulinum Toxin Injection Into Epicardial Fat Pads in Patients Undergoing Cardiac Surgery: One-Year Follow-Up of a Randomized Pilot Study.

BACKGROUND: Animal models suggest that the neurotransmitter inhibitor, botulinum toxin, when injected into the epicardial fat pads can suppress atrial fibrillation inducibility. The aim of this prospective randomized double-blind study was to compare the efficacy and safety of botulinum toxin injection into epicardial fat pads for preventing atrial tachyarrhythmias. METHODS AND RESULTS: Patients with history of paroxysmal atrial fibrillation and indication for coronary artery bypass graft surgery were randomized to botulinum toxin (Xeomin, Merz, Germany; 50 U/1 mL at each fat pad; n=30) or placebo (0.9% normal saline, 1 mL at each fat pad; n=30) injection into epicardial fat pads during surgery. Patients were followed for 1 year to assess maintenance of sinus rhythm using an implantable loop recorder. All patients in both groups had successful epicardial fat pad injections without complications. The incidence of early postoperative atrial fibrillation within 30 days after coronary artery bypass graft was 2 of 30 patients (7%) in the botulinum toxin group and 9 of 30 patients (30%) in the placebo group (P=0.024). Between 30 days and up to the 12-month follow-up examination, 7 of the 30 patients in the placebo group (27%) and none of the 30 patients in the botulinum toxin group (0%) had recurrent atrial fibrillation (P=0.002). There were no complications observed during the 1-year follow-up. CONCLUSIONS: Botulinum toxin injection into epicardial fat pads during coronary artery bypass graft provided substantial atrial tachyarrhythmia suppression both early as well as during 1-year follow-up, without any serious adverse events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01842529.

Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation.

BACKGROUND: Transcutaneous low-level tragus electrical stimulation (LLTS) suppresses atrial fibrillation (AF) in canines. OBJECTIVES: This study examined the antiarrhythmic and anti-inflammatory effects of LLTS in humans. METHODS: Patients with paroxysmal AF who presented for AF ablation were randomized to either 1 h of LLTS (n = 20) or sham control (n = 20). Attaching a flat metal clip onto the tragus produced LLTS (20 Hz) in the right ear (50% lower than the voltage slowing the sinus rate). Under general anesthesia, AF was induced by burst atrial pacing at baseline and after 1 h of LLTS or sham treatment. Blood samples from the coronary sinus and the femoral vein were collected at those time points and then analyzed for inflammatory cytokines, including tumor necrosis factor alpha and C-reactive protein, using a multiplex immunoassay. RESULTS: There were no differences in baseline characteristics between the 2 groups. Pacing-induced AF duration decreased significantly by 6.3 ± 1.9 min compared with baseline in the LLTS group, but not in the control subjects (p = 0.002 for comparison between groups). AF cycle length increased significantly from baseline by 28.8 ± 6.5 ms in the LLTS group, but not in control subjects (p = 0.0002 for comparison between groups). Systemic (femoral vein) but not coronary sinus tumor necrosis factor (TNF)-alpha and C-reactive protein levels decreased significantly only in the LLTS group. CONCLUSIONS: LLTS suppresses AF and decreases inflammatory cytokines in patients with paroxysmal AF. Our results support the emerging paradigm of neuromodulation to treat AF.

The use of low-level electromagnetic fields to suppress atrial fibrillation.

BACKGROUND: Extremely low-level electromagnetic fields have been proposed to cause significant changes in neural networks. OBJECTIVE: We sought to investigate whether low-level electromagnetic fields can suppress atrial fibrillation (AF). METHODS: In 17 pentobarbital anesthetized dogs, bilateral thoracotomies allowed the placement of multielectrode catheters in both atria and at all pulmonary veins. AF was induced by rapid atrial pacing (RAP) or programmed atrial extrastimulation. At baseline and end of each hour of RAP, during sinus rhythm, atrial programmed stimulation gave both the effective refractory period (ERP) and the width of the window of vulnerability. The latter was a measure of AF inducibility. Microelectrodes inserted into the anterior right ganglionated plexi recorded neural firing. Helmholtz coils were powered by a function generator inducing an electromagnetic field (EMF; 0.034 µG, 0.952 Hz). The study sample was divided into 2 groups: group 1 (n = 7)-application of EMF to both cervical vagal trunks; group 2 (n = 10)-application of EMF across the chest so that the heart was located in the center of the coil. RESULTS: In group 1, EMF induced a progressive increase in AF threshold at all pulmonary vein and atrial sites (all P < .05). In group 2, the atrial ERP progressively shortened and ERP dispersion and window of vulnerability progressively increased (P < .05 compared to baseline values) during 3 hours of RAP and then returned to baseline values during 3 hours of combined application of RAP and EMF (P < .05 compared to the end of the third hour of RAP). The frequency and amplitude of the neural activity recorded from the anterior right ganglionated plexi were markedly suppressed by EMF in both groups. CONCLUSION: Pulsed EMF applied to the vagal trunks or noninvasively across the chest can significantly reverse AF inducibility.

Risk of coronary artery injury with radiofrequency ablation and cryoablation of epicardial posteroseptal accessory pathways within the coronary venous system.

BACKGROUND: Ablation of epicardial posteroseptal accessory pathways requires ablation within the coronary venous system. We assessed the risk of coronary artery (CA) injury with radiofrequency ablation (RFA) within the coronary venous system as a function of the distance between the CA and ablation site. We also examined the efficacy and safety of cryoablation close to a CA. METHODS AND RESULTS: Two-hundred forty patients underwent ablation for epicardial posteroseptal accessory pathways. Coronary angiography was performed before ablation in the last 169 patients and was repeated after ablation if performed in the coronary venous system within 5 mm of a significant CA. The distance between the ideal ablation site and closest CA was <2 mm in 100 (59%), 3 to 5 mm in 28 (16%), and >5 mm in 41 of 169 (25%) patients. CA injury was observed in 11 of 22 (50%) and 1 of 15 (7%) patients when RFA was performed within 2 and 3 to 5 mm of a CA, respectively. Cryoablation was performed in 26 patients with a significant CA located within 5 mm. Cryoablation alone eliminated epicardial posteroseptal accessory pathway conduction in 17 of 26 (65%) patients and in 8 patients with additional RFA without CA narrowing in any patient. During a follow-up period of 3 to 6 months, single procedure success rates were 90% and 77% for RFA and cryoablation at the ideal site, respectively. CONCLUSIONS: The risk of CA injury with RFA is correlated inversely with the distance from the ablation site. Cryoablation is a safe and reasonably effective alternative when a significant CA is located close to the ideal ablation site.