Cardioneuroablation for the treatment of reflex syncope and functional bradyarrhythmias: A Scientific Statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS) and the Latin American Heart Rhythm Society (LAHRS).

Cardioneuroablation has emerged as a potential alternative to cardiac pacing in selected cases with vasovagal reflex syncope, extrinsic vagally induced sinus bradycardia-arrest or atrioventricular block. The technique was first introduced decades ago, and its use has risen over the past decade. However, as with any intervention, proper patient selection and technique are a prerequisite for a safe and effective use of cardioneuroablation therapy. This document aims to review and interpret available scientific evidence and provide a summary position on the topic.

Is Atrial Fibrillation a Stroke Risk Factor or Risk Marker? An Appraisal Using the Bradford Hill Framework for Causality.

Atrial fibrillation (AF) is strongly associated with stroke risk but association on its own does not necessarily imply causality. Is AF a cause (risk factor) of stroke? Would treatment that reduces AF burden also reduce the burden of stroke? Or, perhaps, AF is a risk marker associated with a vascular syndrome in which there is co-existing atrial structural and electrical remodelling that results in the clinical manifestation of AF and the risk of stroke in parallel. A number of recent studies appear to detach AF as a direct cause of stroke. Studies in which cardiac implantable devices have been used to collect AF data preceding stroke appear to show no immediate temporal relationship. The Global Anticoagulant Registry in the Field - Atrial Fibrillation (GARFIELD-AF) a large worldwide registry of non-valvular AF, has shown that the risk of death exceeds the risk of stroke and that mortality, together with stroke and bleeding risk, is predicted by other vascular risk factors, defined by the CHA2DS2VASc score. Sir Bradford Hill proposed criteria to assess whether two associated factors are causal, more than 50 years ago. This method of analysing cause and effect in a complex scenario could be applied to AF and stroke. This paper aims to clinically appraise the evidence for each criterion outlined by Bradford Hill to single out whether the collective data supports one or the other.

The Role of the Autonomic Nervous System as Both "Trigger and "Substrate" in Atrial Fibrillation.

Several complex mechanisms, working alone, or together, initiate and maintain atrial fibrillation (AF). At disease onset, pulmonary vein-atrial triggers, producing ectopy, predominate. Then, as AF progresses, a shift toward substrate occurs, which AF also self-perpetuates. The autonomic nervous system (ANS) plays an important role as trigger and substrate. Although the efferent arm of the ANS as AF trigger is well-established, there is emerging evidence to show that (1) the ANS is a substrate for AF and (2) afferent or regulatory ANS dysfunction occurs in AF patients. These findings could represent a mechanism for the progression of AF.

Identification of Subclinical Heart Failure With Preserved Ejection Fraction in Patients With Symptomatic Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) commonly coexist. We hypothesize that patients with symptomatic AF but without overt clinical HF commonly exhibit subclinical HFpEF according to established hemodynamic criteria. OBJECTIVES: The authors sought to use invasive hemodynamics to investigate the prevalence and implications of subclinical HFpEF in AF ablation patients. METHODS: Consecutive symptomatic AF ablation patients were prospectively recruited. Diagnosis of subclinical HFpEF was undertaken by invasive assessment of left atrial pressure (LAP). Participants had HFpEF if the baseline mean LAP was >15 mm Hg and early HFpEF if the mean LAP was >15 mm Hg after a 500-mL fluid challenge. LA compliance was assessed invasively by monitoring the LAP and LA diameter during direct LA infusion of 15 mL/kg normal saline. LA compliance was calculated as Δ LA diameter/ΔLAP. LA cardiomyopathy was further studied with exercise echocardiography and electrophysiology study. Functional impact was evaluated using cardiopulmonary exercise testing and the AF Symptom Severity questionnaire. RESULTS: Of 120 participants, 57 (47.5%) had HFpEF, 31 (25.8%) had early HFpEF, and 32 (26.7%) had no HFpEF. Both HFpEF and early HFpEF were associated with lower LA compliance compared with those without HFpEF (P < 0.001). Participants with HFpEF and early HFpEF also displayed decreased LA emptying fraction (P = 0.004), decreased LA voltage (P = 0.001), decreased VO2peak (P < 0.001), and increased AF symptom burden (P = 0.002) compared with those without HFpEF. CONCLUSIONS: Subclinical HFpEF is common in AF ablation patients and is characterized by a LA cardiomyopathy, decreased cardiopulmonary reserve and increased symptom burden. The diagnosis of HFpEF may identify patients with AF with the potential to benefit from novel HFpEF therapies. (Characterising Left Atrial Function and Compliance in Atrial Fibrillation; ACTRN12620000639921).

Cardiorespiratory fitness, obesity and left atrial function in patients with atrial fibrillation.

Background: Low cardiorespiratory fitness (CRF) and obesity are related to the development and maintenance of atrial fibrillation (AF). The aim of this study was to determine the association between CRF, obesity and left atrial (LA) mechanical parameters in patients with AF. Methods: A cohort of 154 consecutive paroxysmal and persistent AF patients (Age: 62 ± 10, 26% female) referred for exercise stress testing and transthoracic echocardiography were included. We included patients in sinus rhythm with preserved left ventricular ejection fraction who were able to complete a maximal exercise test. Left atrial strain in the reservoir (LASr), booster (LASb) and conduit (LASc) phases were assessed using dedicated software. LA stiffness, emptying fraction (LAEF) and LA to LV ratio were calculated using previously described formulas. Results: CRF was positively associated with LAEF (ß = 1.3, 95% CI 0.1-2.3, p = 0.02), reservoir (ß = 1.5, 95% CI 0.9-2.1, p < 0.001), booster (ß = 0.8, 95% CI 0.4-1.2, p < 0.001) and conduit strain (ß = 0.7, 95% CI 0.3-1.1, p = 0.001). We observed an inverse association between CRF and both LA stiffness index (ß = -0.02, 95% CI (-0.03)-(-0.01), p < 0.001) and LA to LV ratio (ß = -0.03, 95% CI (-0.04)-(-0.01), p < 0.001). Obese patients had significantly higher indexed LA volumes compared to overweight and normal BMI patients. The association between obesity and measures of LA function and stiffness did not reach statistical significance. Conclusion: Among AF patients, higher CRF was independently associated with greater LA function and compliance. Obesity was associated with higher LA volumes yet preserved mechanical function.

Autonomic Afferent Dysregulation in Atrial Fibrillation.

OBJECTIVES: This study sought to evaluate the role of cardiac afferent reflexes in atrial fibrillation (AF). BACKGROUND: Efferent autonomic tone is not associated with atrial remodeling and AF persistence. However, the role of cardiac afferents is unknown. METHODS: Individuals with nonpermanent AF (n = 48) were prospectively studied (23 in the in-AF group and 25 in sinus rhythm [SR]) with 12 matched control subjects. We performed: 1) low-level lower body negative pressure (LBNP), which decreases cardiac volume, offloading predominantly cardiac afferent (volume-sensitive) low-pressure baroreceptors; 2) Valsalva reflex (predominantly arterial high-pressure baroreceptors); and 3) isometric handgrip reflex (both baroreceptors). We measured beat-to-beat mean arterial pressure (MAP) and heart rate (HR). LBNP elicits reflex vasoconstriction, estimated using venous occlusion plethysmography-derived forearm blood flow (∝1/vascular resistance), maintaining MAP. To assess reversibility, we repeated LBNP (same day) after 1-hour low-level tragus stimulation (in n = 5 in the in-AF group and n = 10 in the in-SR group) and >6 weeks post-cardioversion (n = 7). RESULTS: The 3 groups were well matched for age (59 ± 12 years, 83% male), body mass index, and risk factors (P = NS). The in-AF group had higher left atrial volume (P < 0.001) and resting HR (P = 0.01) but similar MAP (P = 0.7). The normal LBNP vasoconstriction (-49 ± 5%) maintaining MAP (control subjects) was attenuated in the in-SR group (-12 ± 9%; P = 0.005) and dysfunctional in the in-AF group (+11 ± 6%; P < 0.001), in which MAP decreased and HR was unchanged. Valsalva was normal throughout. Handgrip MAP response was lowest in the in-AF group (P = 0.01). Interestingly, low-level tragus stimulation and cardioversion improved LBNP vasoconstriction (-48 ± 15%; P = 0.04; and -32 ± 9%; P = 0.02, respectively). CONCLUSIONS: Cardiac afferent (volume-sensitive) reflexes are abnormal in AF patients during SR and dysfunctional during AF. This could contribute to AF progression, thus explaining "AF begets AF." (Characterisation of Autonomic function in Atrial Fibrillation [AF-AF Study]; ACTRN12619000186156).

Prevalence and Assessment of Sleep-Disordered Breathing in Patients With Atrial Fibrillation: A Systematic Review and Meta-analysis.

BACKGROUND: In this study, we sought to estimate the prevalence of concomitant sleep-disordered breathing (SDB) in patients with atrial fibrillation (AF) and to systematically evaluate how SDB is assessed in this population. METHODS: We searched Medline, Embase and Cinahl databases through August 2020 for studies reporting on SDB in a minimum 100 patients with AF. For quantitative analysis, studies were required to have systematically assessed for SDB in consecutive AF patients. Pooled prevalence estimates were calculated with the use of the random effects model. Weighted mean differences and odds ratios were calculated when possible to assess the strength of association between baseline characteristics and SDB. RESULTS: The search yielded 2758 records, of which 33 studies (n = 23,894 patients) met the inclusion criteria for qualitative synthesis and 13 studies (n = 2660 patients) met the meta-analysis criteria. The pooled SDB prevalence based on an SDB diagnosis cutoff of apnea-hypopnea index (AHI) ≥ 5/h was 78% (95% confidence interval [CI] 70%-86%; P < 0.001). For moderate-to-severe SDB (AHI ≥ 15/h), the pooled SDB prevalence was 40% (95% CI 32%-48%; P < 0.001). High degrees of heterogeneity were observed (I2 = 96% and 94%, respectively; P < 0.001). Sleep testing with the use of poly(somno)graphy or oximetry was the most common assessment tool used (in 22 studies, 66%) but inconsistent diagnostic thresholds were used. CONCLUSIONS: SDB is highly prevalent in patients with AF. Wide variation exists in the diagnostic tools and thresholds used to detect concomitant SDB in AF. Prospective systematic testing for SDB in unselected cohorts of AF patients may be required to define the true prevalence of SDB in this population.

Self-reported physical activity and atrial fibrillation risk: A systematic review and meta-analysis.

BACKGROUND: Although physical activity (PA) is an important component of cardiovascular disease prevention and treatment, its role in atrial fibrillation (AF) risk is less well established. OBJECTIVE: The purpose of this study was to systematically summarize the evidence pertaining to the relationship of PA and risk of AF. METHODS: We searched the PubMed and Embase databases for prospective cohort studies reporting the risk of AF associated with a specific PA volume through March 2020. From each study, we extracted the risk associated with a given PA level, in comparison with insufficiently active ("inactive") individuals. The reported risk was normalized to metabolic equivalent of task (MET)-minutes per week. A random-effects meta-analysis was used to compare AF risk between those who met and those who did not meet PA recommendations (450 MET-minutes per week), and a dose-response analysis between the level of PA and the risk of AF was performed. RESULTS: Fifteen studies reporting data from 1,464,539 individuals (median age 55.3 years; 51.7% female) were included. Individuals achieving guideline-recommended level of PA had a significantly lower risk of AF (hazard ratio 0.94; 95% confidence interval 0.90-0.97; P = .001). Dose-response analysis showed that PA levels up to 1900 MET-minutes per week were associated with a lower risk of AF, with less certainty beyond that level. CONCLUSION: PA at guideline-recommended levels and above are associated with a significantly lower AF risk. However, at 2000 MET-minutes per week and beyond, the benefit is less clear.

The "Road" to Atrial Fibrillation: The Role of the Cardiac Autonomic Nervous System.

At the population level, there is a parallel escalation in the healthcare burden of both, atrial fibrillation (AF) as well its risk factors. Compounding this relationship, AF is associated with escalating burden at an individual level, due its self-perpetuating and progressive nature. The mechanisms by which these risk factors interact to produce atrial remodelling and subsequent AF are unclear. This intersection is critical to the development of strategies to combat this disease at both the individual and population-level. It is well known that AF can manifest from disturbances in autonomic activity. At the population level, there is growing data to suggest a role of the autonomic nervous system in the future incidence of AF. Here, we provide an overview of the association of cardiac autonomic dysfunction with the incidence of AF, review the role of the autonomic nervous system (ANS) as an intermediary between risk factors and the development of AF and finally, we discuss the bidirectional relationship between AF and cardiac autonomic nervous system dysfunction; to determine whether this is implicated in the progression of AF.

Cerebral Blood Flow and Cognitive Performance in Postural Tachycardia Syndrome: Insights from Sustained Cognitive Stress Test.

Background The physiology underlying "brain fog" in the absence of orthostatic stress in postural tachycardia syndrome (POTS) remains poorly understood. Methods and Results We evaluated cognitive and hemodynamic responses (cardiovascular and cerebral: heart rate, blood pressure, end-tidal carbon dioxide, and cerebral blood flow velocity (CBFv) in the middle cerebral artery at baseline, after initial cognitive testing, and after (30-minutes duration) prolonged cognitive stress test (PCST) whilst seated; as well as after 5-minute standing in consecutively enrolled participants with POTS (n=22) and healthy controls (n=18). Symptom severity was quantified with orthostatic hypotensive questionnaire at baseline and end of study. Subjects in POTS and control groups were frequency age- and sex-matched (29±11 versus 28±13 years; 86 versus 72% women, respectively; both P≥0.4). The CBFv decreased in both groups (condition, P=0.04) following PCST, but a greater reduction in CBFv was observed in the POTS versus control group (-7.8% versus -1.8%; interaction, P=0.038). Notably, the reduced CBFv following PCST in the POTS group was similar to that seen during orthostatic stress (60.0±14.9 versus 60.4±14.8 cm/s). Further, PCST resulted in greater slowing in psychomotor speed (6.1% versus 1.4%, interaction, P=0.027) and a greater increase in symptom scores at study completion (interaction, P<0.001) in the patients with POTS, including increased difficulty with concentration. All other physiologic responses (blood pressure and end-tidal carbon dioxide) did not differ between groups after PCST (all P>0.05). Conclusions Reduced CBFv and cognitive dysfunction were evident in patients with POTS following prolonged cognitive stress even in the absence of orthostatic stress.

Atrial Fibrillation Is Associated With Syncope and Falls in Older Adults: A Systematic Review and Meta-analysis.

OBJECTIVE: To examine the potential association of atrial fibrillation (AF) to syncope and falls, we undertook a systematic review and meta-analysis given the increasing prevalence of AF in older adults as well as emerging data that it is a risk factor for dementia. PATIENTS AND METHODS: CENTRAL, PubMed, and EMBASE databases were searched from inception to January 31, 2019, to retrieve relevant studies. Search terms consisted of MeSH, tree headings, and keywords relating patients with "AF," "falls," "syncope," and "postural hypotension." When possible; results were pooled using a random-effects model. RESULTS: A total of 10 studies were included, with 7 studies (36,444 patients; mean ± SD age, 72±10 years) reporting an association between AF and falls and 3 studies (6769 patients; mean ± SD age, 65±3 years) reporting an association between AF and syncope. Pooled analyses demonstrate that AF is independently associated with falls (odds ratio, 1.19; 95% CI, 1.07-1.33; P=.001) and syncope (odds ratio, 1.88; 95% CI, 1.20-2.94; P=.006). There was overall moderate bias and low-moderate heterogeneity (I2=37%; P=.11) for falls and moderate bias with low statistical heterogeneity (I2=0%; P=.44) for syncope. Persistent AF, but not paroxysmal AF, was associated with orthostatic intolerance in 1 study (4408 patients; mean ± SD age, 66±6 years). CONCLUSION: AF is independently associated with syncope and falls in older adults. Further studies are needed to delineate mechanistic links and to guide management to improve outcomes in these patients. TRIAL REGISTRATION: PROSPERO: trial identifier: CRD4201810721.

Clinical evidence of autonomic dysfunction due to atrial fibrillation: implications for rhythm control strategy.

PURPOSE: The role of the autonomic nervous system in the genesis of atrial fibrillation (AF) has been well studied; however, the converse remains poorly understood. Pulmonary veins (PV) contain receptors important in cardiac reflexes. Here, we evaluated reflex responses in patients with paroxysmal AF (PAF) to lower body negative pressure (LBNP). METHODS: Thirty-four PAF patients (including 14 PAF patients post successful PV Isolation; PVI) were compared to 14 age and sex-matched controls. Mean arterial pressure (MAP), heart rate (HR), systemic vascular resistance index (SVRI), cardiac index (CI), and stroke volume index (SVI) were measured continuously during - 0, - 20, and - 40 mmHg LBNP. LBNP reduces venous return, deactivating atrial receptors, thereby eliciting a reflex increase in SVRI to maintain MAP. RESULTS: AF patients have higher BMI than the controls (p = 0.02). In control subjects, LBNP did not alter MAP as SVRI increased. In PAF patients, LBNP resulted in a reduction in MAP (- 4.8%) with attenuated SVRI response (+ 4.2%) compared to controls (p < 0.05). However, in the post-PVI group, SVRI increase was similar to controls (p = 0.12) although that was insufficient to maintain MAP. In all patients, both reduction in SVI and CI and increase in HR were similar in response to LBNP. CONCLUSIONS: This study provides novel clinical evidence of autonomic dysfunction in PAF patients. Successful PVI results in partial recovery of the cardiac reflex. Therefore, not only does autonomic disturbance predispose to AF but it is also a consequence of AF; potentially contributing to disease progression. This could help explain the dictum "AF begets AF."

Feasibility, Safety, and Efficacy of Posterior Wall Isolation During Atrial Fibrillation Ablation: A Systematic Review and Meta-Analysis.

BACKGROUND: The posterior left atrium is an arrhythmogenic substrate that contributes to the initiation and maintenance of atrial fibrillation (AF); however, the feasibility, safety, and efficacy of posterior wall isolation (PWI) as an AF ablation strategy has not been widely reported. METHODS: We undertook a systematic review and meta-analysis of studies performing PWI to assess (1) acute procedural success including the ability to achieve PWI and the number of procedure-related complications, (2) Long-term, clinical success including rates of arrhythmia recurrence and posterior wall reconnection, and (3) The efficacy of PWI compared with pulmonary vein isolation on preventing arrhythmia recurrence. MEDLINE, EMBASE, and Web of Science databases were searched in May 2018 to retrieve relevant studies. Results were pooled using a random effects model. RESULTS: Seventeen studies (13 box isolation, 3 single ring isolation, and 1 debulking ablation) comprising 1643 patients (31.3% paroxysmal AF, left atrial diameter 41±3.1 mm) were included in the final analysis. In studies focusing specifically on PWI, the acute procedural success rate for achieving PWI was 94.1% (95% CI, 87.2%-99.3%). Single-procedure 12-month freedom from atrial arrhythmia was 65.3% (95% CI, 57.7%-73.9%) overall and 61.9% (54.2%-70.8%) for persistent AF. Randomized control trials comparing PWI to pulmonary vein isolation (3 studies, 444 patients) yielded conflicting results and could not confirm an incremental benefit to PWI. Fifteen major complications (0.1%), including 2 atrio-esophageal fistulas, were reported. CONCLUSIONS: PWI as an end point of AF ablation can be achieved in a large proportion of cases with good rates of 12-month freedom from atrial arrhythmia. Although the procedure-related complication rate is low, it did not eliminate the risk of atrio-esophageal fistula. Registration: URL: http://www.crd.york.ac.uk/prospero. PROSPERO registration number: CRD42018107212.

Role of autonomic nervous system in atrial fibrillation.

Atrial fibrillation is the most common sustained arrhythmia and is associated with significant morbidity and mortality. The autonomic nervous system has a significant role in the milieu predisposing to the triggers, perpetuators and substrate for atrial fibrillation. It has direct electrophysiological effects and causes alterations in atrial structure. In a significant portion of patients with atrial fibrillation, the autonomic nervous system activity is likely a composite of reflex excitation due to atrial fibrillation itself and contribution of concomitant risk factors such as hypertension, obesity and sleep-disordered breathing. We review the role of autonomic nervous system activation, with focus on changes in reflex control during atrial fibrillation and the role of combined sympatho-vagal activation for atrial fibrillation initiation, maintenance and progression. Finally, we discuss the potential impact of combined aggressive risk factor management as a strategy to modify the autonomic nervous system in patients with atrial fibrillation and to reverse the arrhythmogenic substrate.