Effect of dronedarone vs. placebo on atrial fibrillation progression: a post hoc analysis from ATHENA trial.

AIMS: This post hoc analysis of the ATHENA trial (NCT00174785) assessed the effect of dronedarone on the estimated burden of atrial fibrillation (AF)/atrial flutter (AFL) progression to presumed permanent AF/AFL, and regression to sinus rhythm (SR), compared with placebo. METHODS AND RESULTS: The burden of AF/AFL was estimated by a modified Rosendaal method using available electrocardiograms (ECG). Cumulative incidence of permanent AF/AFL (defined as ≥6 months of AF/AFL until end of study) or permanent SR (defined as ≥6 months of SR until end of study) were calculated using Kaplan-Meier estimates. A log-rank test was used to assess statistical significance. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were estimated using a Cox model, adjusted for treatment group. Of the 4439 patients included in this analysis, 2208 received dronedarone, and 2231 placebo. Baseline and clinical characteristics were well balanced between groups. Overall, 304 (13.8%) dronedarone-treated patients progressed to permanent AF/AFL compared with 455 (20.4%) treated with placebo (P < 0.0001). Compared with those receiving placebo, patients receiving dronedarone had a lower cumulative incidence of permanent AF/AFL (log-rank P < 0.001; HR: 0.65; 95% CI: 0.56-0.75), a higher cumulative incidence of permanent SR (log-rank P < 0.001; HR: 1.19; 95% CI: 1.09-1.29), and a lower estimated AF/AFL burden over time (P < 0.01 from Day 14 to Month 21). CONCLUSION: These results suggest that dronedarone could be a useful antiarrhythmic drug for early rhythm control due to less AF/AFL progression and more regression to SR vs. placebo, potentially reflecting reverse remodeling. CLINICAL TRIAL REGISTRATION: NCT00174785.

Women and atrial fibrillation.

Atrial fibrillation (AF) remains a growing problem in the United States and worldwide, imposing a high individual and health system burden, including increased resource consumption due to repeated hospitalizations, stroke, dementia, heart failure, and death. This comprehensive review summarizes the most recent data on sex-related differences in risks associated with AF. Women with AF have increased risk of stroke and death compared to men, and possible reasons for this disparity are explored. Women also continue to have worse symptoms and quality of life, and poorer outcomes with stroke prevention, as well as with rate and rhythm control management strategies. Many current rhythm control treatment strategies for AF, including cardioversion and ablation, are used less frequently in women as compared to men, whereas women are more likely to be treated with rate control strategies or antiarrhythmic drugs. Sex differences should be considered in treating women with AF to improve outcomes and women and men should be offered the same interventions for AF. We need to improve the evidence base to understand if variation in utilization of rate and rhythm control management between men and women represents health inequities or appropriate clinical judgement.

Abnormal P-wave terminal force in lead V1 is associated with low left atrial appendage ejection velocity.

BACKGROUND: Sinus P-wave abnormalities have been associated stroke in people with atrial fibrillation (AF). The majority of AF-related strokes occur from left atrial appendage (LAA) thromboembolism. Dysfunction of the left atrium (LA) and left atrial appendage (LAA) can increase rates of thromboembolic stroke. We studied whether abnormal P wave terminal force in V1 (aPTFV1) is associated with decreased LAA ejection velocity (LAAV) on transesophageal echocardiography (TEE). METHODS: We conducted a retrospective cross-sectional study reviewing patients at a tertiary care medical center who underwent TEE in sinus rhythm and had an interpretable sinus ECG within 12 months of TEE. Participants were excluded for complex congenital heart disease, age <18, cardiac transplantation, and chronic atrial pacing. Logistic regression analysis was used to estimate the odds ratios of LAAV<40 cm/s for aPTFV1. RESULTS: In our final cohort of 169 patients (28% of which had LAAV <40), the multivariate odds ratio of aPTFV1 for LAAV<40 cm/s after adjustment for CHA2DS2VASc variables, heart rate during TEE, history of atrial arrhythmias, and left atrial volume index was 2.24 (95% CI of 1.13-6.00). CONCLUSION: Abnromal P-wave terminal force in lead V1 is associated with low LAAV after adjustment for potential confounders. Future research is needed for validation of our findings and determination of clinical utility.

Patterns of amiodarone use and outcomes in clinical practice for atrial fibrillation.

BACKGROUND: Amiodarone is the most effective antiarrhythmic drug (AAD) for atrial fibrillation (AF), but it has a high incidence of adverse effects. METHODS: Using the ORBIT AF registry, patients with AF on amiodarone at enrollment, prescribed amiodarone during follow-up, or never on amiodarone were analyzed for the proportion treated with a guideline-based indication for amiodarone, the variability in amiodarone use across sites, and the outcomes (mortality, hospitalization, and stroke) among patients treated with amiodarone. Hierarchical logistic regression modeling with site-specific random intercepts compared rates of amiodarone use across 170 sites. A logistic regression model for propensity to receive amiodarone created a propensity-matched cohort. Cox proportional hazards modeling, stratified by matched pairs evaluated the association between amiodarone and outcomes. RESULTS: Among 6,987 AF patients, 867 (12%) were on amiodarone at baseline and 451 (6%) started on incident amiodarone during the 3-year follow-up. Use of amiodarone varied among sites from 3% in the lowest tertile to 21% in the highest (p<0.0001). Among those treated, 32% had documented contraindications to other AADs or had failed another AAD in the past. Mortality, cardiovascular hospitalization, and stroke were similar among matched patients on and not on amiodarone at baseline, while incident amiodarone use in matched patients was associated with higher all-cause mortality (adjusted HR 2.06, 95% CI 1.35-3.16). CONCLUSIONS: Use of amiodarone among AF patients in community practice is highly variable. More than 2 out of 3 patients treated with amiodarone appeared to be eligible for a different AAD.

Guideline-directed therapies for comorbidities and clinical outcomes among individuals with atrial fibrillation.

BACKGROUND: Comorbidities are common in patients with atrial fibrillation (AF) and affect prognosis, yet are often undertreated. However, contemporary rates of use of guideline-directed therapies (GDT) for non-AF comorbidities and their association with outcomes are not well described. METHODS: We used the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) to test the association between GDT for non-AF comorbidities and major adverse cardiac or neurovascular events (MACNE; cardiovascular death, myocardial infarction, stroke/thromboembolism, or new-onset heart failure), all-cause mortality, new-onset heart failure, and AF progression. Adjustment was performed using Cox proportional hazards models and logistic regression. RESULTS: Only 6,782 (33%) of the 20,434 patients eligible for 1 or more GDT for non-AF comorbidities received all indicated therapies. Use of all comorbidity-specific GDT was highest for patients with hyperlipidemia (75.6%) and lowest for those with diabetes mellitus (43.1%). Use of "all eligible" GDT was associated with a nonsignificant trend toward lower rates of MACNE (HR 0.90 [0.79-1.02]) and all-cause mortality (HR 0.90 [0.80-1.01]). Use of GDT for heart failure was associated with a lower risk of all-cause mortality (HR 0.77 [0.67-0.89]), and treatment of obstructive sleep apnea was associated with a lower risk of AF progression (OR 0.75 [0.62-0.90]). CONCLUSIONS: In AF patients, there is underuse of GDT for non-AF comorbidities. The association between GDT use and outcomes was strongest in heart failure and obstructive sleep apnea patients where use of GDT was associated with lower mortality and less AF progression.

Dronedarone treatment following cardioversion in patients with atrial fibrillation/flutter: A post hoc analysis of the EURIDIS and ADONIS trials.

INTRODUCTION: The phase 3 EURIDIS and ADONIS studies evaluated dronedarone for atrial fibrillation (AF)/atrial flutter (AFL) recurrence in patients with nonpermanent AF. Here we assessed whether patient characteristics and/or treatment outcomes in these studies differed based on the need for cardioversion before randomization. METHODS: Time to adjudicated first AF/AFL recurrence, symptomatic recurrence, cardiovascular hospitalization/death, and AF hospitalization, and safety were assessed by cardioversion status. RESULTS: Of 1237 patients randomized (2:1 dronedarone:placebo), 364 required baseline cardioversion (dronedarone 243, placebo 121). Patients requiring cardioversion had a greater prevalence of cardiovascular comorbidities and shorter times to first AF/AFL recurrence compared with those not requiring cardioversion. Dronedarone was associated with longer median time to first AF/AFL recurrence vs placebo regardless of cardioversion status (cardioversion: 50 vs 15 days, hazard ratio [HR] 0.76; 95% confidence interval [CI], 0.59-0.97; P = .02; non-cardioversion: 150 vs 77 days, HR 0.76; 95% CI, 0.64-0.90; P < .01). Dronedarone was similarly associated with prolonged median time to symptomatic recurrence vs placebo in the cardioversion (347 vs 87 days, HR 0.65; 95% CI, 0.49-0.87) and non-cardioversion (288 vs 120 days, HR 0.74; 95% CI, 0.62-0.90) populations. Risk of cardiovascular hospitalization/death and first AF hospitalization was lower with dronedarone vs placebo regardless of cardioversion status, but differences were not statistically significant. The safety of dronedarone was similar in both groups. CONCLUSION: Patients requiring baseline cardioversion represent a distinct population, having more underlying cardiovascular disease and experiencing a shorter time to AF/AFL recurrences. Dronedarone was associated with improved efficacy vs placebo regardless of cardioversion status.

Rhythm Control of Atrial Fibrillation in Heart Failure with Reduced Ejection Fraction.

PURPOSE OF REVIEW: Atrial fibrillation and heart failure frequently co-exist with an increasing prevalence of atrial fibrillation as ejection fraction decreases. Atrial fibrillation is associated with increased mortality in patients with heart failure. This article will review rhythm and rate control options, ultimately supporting rhythm control via endocardial ablation. RECENT FINDINGS: Randomized trials of a rhythm control strategy in patients with reduced ejection fraction heart failure have shown significant improvements in ejection fraction, oxygen consumption and also a significant reduction in mortality. The treatment of atrial fibrillation in patients with reduced ejection fraction heart failure should include an early rhythm control strategy via endocardial ablation.

Prognostic Significance of Nuisance Bleeding in Anticoagulated Patients With Atrial Fibrillation.

BACKGROUND: Bleeding is commonly cited as a reason for stopping oral anticoagulants (OACs). Whether minor bleeding events (nuisance bleeding, NB) in patients with atrial fibrillation on OACs are associated with OAC discontinuation, major bleeding, and stroke/systemic embolism (SSE) is unknown. METHODS: Within the ORBIT-AF prospective, outpatient registry (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation), we identified 6771 patients ≥18 years of age at 172 sites with atrial fibrillation and eligible follow-up visits. NB was ascertained from the medical record and was defined as minor bleeding that did not require medical attention (eg, bruising, hemorrhoidal bleeding). We used multivariable pooled logistic regression modeling to evaluate the associations between NB and major bleeding and SSE in the 180 days after documentation of NB. Our unit of analysis was the patient visit, occurring at ≈6-month intervals for a median of 1.5 years following enrollment. Changes in anticoagulation treatment satisfaction after NB were examined descriptively in a subset of patients. RESULTS: The median age of the overall population was 75.0 (interquartile range, 67.0-81.0); 90.0% were white and 42.5% were female. Among 6771 patients (18 560 visits), n=1357 (20.0%) had documented NB, for an incidence rate of 14.8 events per 100 person-years. Over 96.4% of patients remained on OAC therapy after the NB event. Overall, 287 (4.3%) patients experienced major bleeding and 64 (0.96%) had a SSE event during follow-up. NB was not associated with a significant increased risk of major bleeding over 6 months in models adjusting for the ATRIA bleeding score (Anticoagulation and Risk Factors in Atrial Fibrillation) (odds ratio, 1.04; 95% confidence interval, 0.68-1.60; P=0.86). NB was also not associated with increased SSE risk over 6 months in models adjusting for the CHA2DS2-VASc risk score (odds ratio, 1.24; 95% confidence interval, 0.53-2.91; P=0.62). CONCLUSIONS: NB is common among patients with atrial fibrillation on OACs. However, NB was not associated with a higher risk of major bleeding or SSE over the next 6 months, suggesting its occurrence should not lead to changes in anticoagulation treatment strategies in OAC-treated patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01165710.

Treatment of atrial fibrillation with concomitant coronary or peripheral artery disease: Results from the outcomes registry for better informed treatment of atrial fibrillation II.

BACKGROUND: Treatment patterns and outcomes of individuals with vascular disease who have new-onset atrial fibrillation (AF) are not well characterized. METHODS: Among patients with new-onset AF, we analyzed treatment and outcomes in those with or without vascular disease in the ORBIT-AF II registry. Vascular disease was defined as coronary disease with or without myocardial infarction (MI) or revascularization, or peripheral artery disease. The primary outcomes included major adverse cardiovascular or neurological events (MACNE) and major bleeding. Cox proportional hazard models were used to adjust the difference in patient characteristics. RESULTS: Overall 1920 of 6203 (31.0%) of new-onset AF had vascular disease. In patients with vascular disease, 62.2% of those were treated with direct oral anticoagulants (DOACs) and 23.4% with warfarin. Dual therapy and triple therapy were used in 36.9% and 4.9%, respectively. Vascular disease patients had increased risk of MACNE (adjusted hazard ratio [aHR] 1.83 [95%CIs 1.32-2.55]), but not major bleeding (aHR 1.24 [0.95-1.63]). Among patients with vascular disease, relative to those on warfarin, those treated with DOACs had similar risk for MACNE (aHR 1.20 [0.77-1.87]) but lower risks for bleeding, although it did not reach statistical significance (aHR 0.70 [0.43-1.15]). Concomitant antiplatelet therapy was associated with higher bleeding (aHR 2.27 [1.38-3.73]) with no apparent reduction in MACNE (aHR 1.50 [1.00-2.25]). CONCLUSIONS: Most patients with AF and vascular disease were managed with oral anticoagulation. About half of them were also treated with concomitant antiplatelet therapy, which was associated with increased risk of bleeding, without evidence of improved cardiovascular outcomes.

Association of sex, age and education level with patient reported outcomes in atrial fibrillation.

BACKGROUND: In atrial fibrillation (AF), there are known sex and sociodemographic disparities in clinical outcomes such as stroke. We investigate whether disparities also exist with respect to patient-reported outcomes. We explored the association of sex, age, and education level with patient-reported outcomes (AF-related quality of life, symptom severity, and emotional and functional status). METHODS: The PaTH AF cohort study recruited participants (N = 953) with an AF diagnosis and age ≥ 18 years across 4 academic medical centers. We performed longitudinal multiple regression with random effects to determine if individual characteristics were associated with patient-reported outcomes. RESULTS: Women reported poorer functional status (ß - 2.23, 95% CI: -3.52, - 0.94) and AF-related quality of life (ß - 4.12, 95% CI: -8.10, - 0.14), and higher symptoms of anxiety (ß 2.08, 95% CI: 0.76, 3.40), depression (ß 1.44, 95% CI: 0.25, 2.63), and AF (ß 0.29, 95% CI: 0.08, 0.50). Individuals < 60 years were significantly (p < 0.05) more likely to report higher symptoms of depression, anxiety, and AF, and poorer AF-related quality of life. Lack of college education was associated with reporting higher symptoms of AF (ß 0.42, 95% CI: 0.17, 0.68), anxiety (ß 1.86, 95% CI: 0.26, 3.45), and depression (ß 1.11, 95% CI: 0.15, 2.38), and lower AF-related quality of life (ß - 4.41, 95% CI: -8.25, - 0.57) and functional status. CONCLUSION: Women, younger adults, and individuals with lower levels of education reported comparatively poor patient-reported outcomes. These findings highlight the importance of understanding why individuals experience AF differently based on certain characteristics.

Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial.

Importance: Catheter ablation is effective in restoring sinus rhythm in atrial fibrillation (AF), but its effects on long-term mortality and stroke risk are uncertain. Objective: To determine whether catheter ablation is more effective than conventional medical therapy for improving outcomes in AF. Design, Setting, and Participants: The Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation trial is an investigator-initiated, open-label, multicenter, randomized trial involving 126 centers in 10 countries. A total of 2204 symptomatic patients with AF aged 65 years and older or younger than 65 years with 1 or more risk factors for stroke were enrolled from November 2009 to April 2016, with follow-up through December 31, 2017. Interventions: The catheter ablation group (n = 1108) underwent pulmonary vein isolation, with additional ablative procedures at the discretion of site investigators. The drug therapy group (n = 1096) received standard rhythm and/or rate control drugs guided by contemporaneous guidelines. Main Outcomes and Measures: The primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Among 13 prespecified secondary end points, 3 are included in this report: all-cause mortality; total mortality or cardiovascular hospitalization; and AF recurrence. Results: Of the 2204 patients randomized (median age, 68 years; 37.2% female; 42.9% had paroxysmal AF and 57.1% had persistent AF), 89.3% completed the trial. Of the patients assigned to catheter ablation, 1006 (90.8%) underwent the procedure. Of the patients assigned to drug therapy, 301 (27.5%) ultimately received catheter ablation. In the intention-to-treat analysis, over a median follow-up of 48.5 months, the primary end point occurred in 8.0% (n = 89) of patients in the ablation group vs 9.2% (n = 101) of patients in the drug therapy group (hazard ratio [HR], 0.86 [95% CI, 0.65-1.15]; P = .30). Among the secondary end points, outcomes in the ablation group vs the drug therapy group, respectively, were 5.2% vs 6.1% for all-cause mortality (HR, 0.85 [95% CI, 0.60-1.21]; P = .38), 51.7% vs 58.1% for death or cardiovascular hospitalization (HR, 0.83 [95% CI, 0.74-0.93]; P = .001), and 49.9% vs 69.5% for AF recurrence (HR, 0.52 [95% CI, 0.45-0.60]; P < .001). Conclusions and Relevance: Among patients with AF, the strategy of catheter ablation, compared with medical therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest. However, the estimated treatment effect of catheter ablation was affected by lower-than-expected event rates and treatment crossovers, which should be considered in interpreting the results of the trial. Trial Registration: ClinicalTrials.gov Identifier: NCT00911508.

Patient factors associated with quality of life in atrial fibrillation.

BACKGROUND: As treatment options for atrial fibrillation (AF) increase, more attention is focused on patients' experiences and quality of life (QoL). However, little is known about the factors associated with these outcomes. METHODS: The Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) is a disease-specific QoL tool for AF, with domain and summary scores ranging from 0 (the worst QoL) to 100. Using multivariable linear regression, we evaluated factors associated with baseline AFEQT Summary and Subscale Scores in ORBIT AF, a large, community-based AF registry. Independent associations were reported as coefficient estimates in scores and 95% confidence intervals (CI). RESULTS: Overall, AFEQT was assessed in 2007 AF outpatients from 99 sites. Median age (IQR) was 76 years (67-82) and 43% were female. The median AFEQT summary score was 82 (67-94). Female sex, younger age, new onset AF, higher heart rate, obstructive sleep apnea, symptomatic heart failure (HF), chronic obstructive pulmonary disease and coronary artery disease were all independently associated with reduced QoL. Female sex [Estimate -7.03, 95% CI (-9.31, -4.75)] and new onset versus permanent AF [Estimate -7.44, 95% CI (-11.03, -3.84)] were independently associated with increased symptoms. NYHA Class III or IV HF [Estimate -14.44, 95% CI (-19.46, -8.76)] and female sex [Estimate -7.91, 95% CI (-9.95, -5.88)] were most independently associated with impaired daily activities. CONCLUSIONS: QoL in patients with AF varies widely and is associated with several patient factors. Understanding patient factors independently associated with worse QoL can be a foundation for tailoring treatment.

Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.

AIMS: VENTURE-AF is the first prospective randomized trial of uninterrupted rivaroxaban and vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF) undergoing catheter ablation (CA). METHODS AND RESULTS: Trial size was administratively set at 250, the protocol-specified target. Events were independently and blindly adjudicated. We randomly assigned 248 NVAF patients to uninterrupted rivaroxaban (20 mg once-daily) or to an uninterrupted VKA prior to CA and for 4 weeks afterwards. The primary endpoint was major bleeding events after CA. Secondary endpoints included thromboembolic events (composite of stroke, systemic embolism, myocardial infarction, and vascular death) and other bleeding or procedure-attributable events. Patients were 59.5 ± 10 years of age, 71% male, 74% paroxysmal AF, and had a CHA2DS2-VASc score of 1.6. The average total heparin dose used to manage activated clotting time (ACT) was slightly higher (13 871 vs. 10 964 units; P < 0.001) and the mean ACT level attained slightly lower (302 vs. 332 s; P < 0.001) in rivaroxaban and VKA arms, respectively. The incidence of major bleeding was low (0.4%; 1 major bleeding event). Similarly, thromboembolic events were low (0.8%; 1 ischemic stroke and 1 vascular death). All events occurred in the VKA arm and all after CA. The number of any adjudicated events (26 vs. 25), any bleeding events (21 vs. 18), and any other procedure-attributable events (5 vs. 5) were similar. CONCLUSION: In patients undergoing CA for AF, the use of uninterrupted oral rivaroxaban was feasible and event rates were similar to those for uninterrupted VKA therapy. NAME OF THE TRIAL REGISTRY: Clinicaltrials.gov trial registration number is NCT01729871.

Late onset of exercise induced focal ventricular tachycardia originating from the ventricular end of an A-V accessory pathway after elimination of conduction.

The authors report the unique case of remote onset of exercise induced focal ventricular tachycardia in a 40-year old male patient that originated from the ventricular end of an accessory atrioventricular pathway 18 months after a successful ablation. There was no residual conduction across the pathway after the first ablation. The ventricular tachycardia (VT) was mapped to and successfully ablated at the same site where the ventricular end of the pathway was previously ablated. The VT morphology was similar to that of the pre-excited QRS beats noted before. Thus far, in all reported cases of accessory pathway related automaticity there was intact conduction over the pathway or acute injury to it. To the best of our knowledge a case similar to our patient is not yet reported.

Surface 12 lead electrocardiogram recordings using smart phone technology.

IMPORTANCE: AliveCor ECG is an FDA approved ambulatory cardiac rhythm monitor that records a single channel (lead I) ECG rhythm strip using an iPhone. In the past few years, the use of smartphones and tablets with health related applications has significantly proliferated. OBJECTIVE: In this initial feasibility trial, we attempted to reproduce the 12 lead ECG using the bipolar arrangement of the AliveCor monitor coupled to smart phone technology. METHODS: We used the AliveCor heart monitor coupled with an iPhone cellular phone and the AliveECG application (APP) in 5 individuals. RESULTS: In our 5 individuals, recordings from both a standard 12 lead ECG and the AliveCor generated 12 lead ECG had the same interpretation. CONCLUSIONS: This study demonstrates the feasibility of creating a 12 lead ECG with a smart phone. The validity of the recordings would seem to suggest that this technology could become an important useful tool for clinical use. This new hand held smart phone 12 lead ECG recorder needs further development and validation.

Tricuspid valve incompetence following implantation of ventricular leads.

Most cardiovascular implantable electronic devices (CIEDs) require a ventricular lead to be placed across the tricuspid valve. Tricuspid regurgitation (TR) is an understudied clinical complication of right ventricular lead implantation and its clinical significance is unknown. We review the incidence, predictors, and current management of TR as a complication of ventricular lead implantation. Emerging technologies, including leadless pacing devices and subcutaneous systems, offer the benefit of little or none tricuspid valve disruption.

An atypical case of vagally mediated atrial fibrillation in an elderly woman: electrocardiographic caveats to diagnosis.

Vagally mediated paroxysmal atrial fibrillation is typically described to occur in otherwise healthy young-to-middle aged males during periods of high vagal tone. We report a case of cardioinhibitory type neurocardiogenic syncope associated with atrial fibrillation in an elderly female during episodes of nausea. This was replicated during tilt-table testing. The atrial fibrillation was part of a unique snap shot of the entire electrophysiological spectrum of the vagal response captured in detail in this index patient.