Structural, Functional, and Electrical Remodeling of the Atria With Reduced Cardiorespiratory Fitness: Implications for AF.

BACKGROUND: Reduced cardiorespiratory fitness (CRF) is an independent risk factor for the progression of atrial fibrillation (AF). We hypothesized that reduced CRF is associated with structural, functional, and electrical remodeling of the left atrium. OBJECTIVES: This study sought to correlate objectively assessed CRF with functional and electrical left atrial (LA) parameters using invasive and noninvasive assessments. METHODS: Consecutive patients with symptomatic AF undergoing catheter ablation were recruited. CRF was objectively quantified pre-ablation by using cardiopulmonary exercise testing. Using peak oxygen consumption, participants were classified as preserved CRF (>20 mL/kg/min) or reduced CRF (<20 mL/kg/min). LA stiffness was assessed invasively with hemodynamic monitoring and imaging during high-volume LA saline infusion. LA stiffness was calculated as ΔLA diameter/ΔLA pressure over the course of the infusion. LA function was assessed with echocardiographic measures of LA emptying fraction and LA strain. Electrical remodeling was assessed by using high-density electroanatomical maps for LA voltage and conduction. RESULTS: In total, 100 participants were recruited; 43 had reduced CRF and 57 had preserved CRF. Patients with reduced CRF displayed elevated LA stiffness (P = 0.004), reduced LA emptying fraction (P = 0.006), and reduced LA reservoir strain (P < 0.001). Reduced CRF was also associated with reduced LA voltage (P = 0.039) with greater heterogeneity (P = 0.027) and conduction slowing (P = 0.04) with greater conduction heterogeneity (P = 0.02). On multivariable analysis, peak oxygen consumption was independently associated with LA stiffness (P = 0.003) and LA conduction velocities (P = 0.04). CONCLUSIONS: Reduced CRF in patients with AF is independently associated with worse LA disease involving functional and electrical changes. Improving CRF may be a target for restoring LA function in AF.

Utility and Validity of the HFA-PEFF and H2FPEF Scores in Patients With Symptomatic Atrial Fibrillation.

BACKGROUND: Diagnosis of heart failure with preserved ejection fraction (HFpEF) in patients with atrial fibrillation (AF) represents a significant clinical challenge. Two diagnostic scoring tools have been developed to aid the noninvasive diagnosis of HFpEF: the HFA-PEFF (Heart Failure Association Pre-test assessment, Echocardiography and natriuretic peptide, Functional testing, Final etiology) and the H2FPEF scoring systems. OBJECTIVES: The purpose of this study was to evaluate the performance of these 2 scoring tools for the diagnosis of HFpEF against a gold standard of invasive evaluation in a cohort of patients with AF. METHODS: The authors recruited consecutive patients with symptomatic AF and preserved ejection fraction who were scheduled for an AF ablation procedure. Gold-standard invasive diagnosis of HFpEF was performed at the AF ablation procedure using mean left atrial pressure at rest and following infusion of 500 mL fluid. Each participant was scored according to the noninvasive HFA-PEFF and H2FPEF scoring systems. Sensitivity and specificity analyses were performed to assess the accuracy of these scoring systems in diagnosing HFpEF. RESULTS: In total, 120 participants were recruited. HFpEF was diagnosed invasively in 88 (73.3%) participants, whereas 32 (26.7%) had no HFpEF. Using the HFA-PEFF score, 38 (31.7%) participants had a high probability of HFpEF and 82 (68.3%) had low/intermediate probability of HFpEF. Using the H2FPEF tool, 72 (60%) participants had a high probability of HFpEF and 48 (40%) had intermediate probability. A high HFA-PEFF (≥5 points) score could diagnose HFpEF with a sensitivity of 40% and a specificity of 91%, and a high H2FPEF score (≥6 points) could diagnose HFpEF with a sensitivity of 69% and specificity of 66%. Overall diagnostic accuracy was similar using both tools (AUC: 0.663 vs 0.707, respectively; P = 0.636). CONCLUSIONS: Against a gold standard of invasively diagnosed HFpEF, the HFA-PEFF and H2FPEF scores demonstrate only moderate accuracy in patients with AF and should be utilized with caution in this cohort of patients. (Characterising Left Atrial Function and Compliance in Atrial Fibrillation; ACTRN12620000639921).

Exercise echocardiography to assess left atrial function in patients with symptomatic AF.

Background: Left atrial (LA) function contributes to the augmentation of cardiac output during exercise. However, LA response to exercise in patients with atrial fibrillation (AF) is unknown. We explored the LA mechanical response to exercise and the association between LA dysfunction and exercise intolerance. Methods: We recruited consecutive patients with symptomatic AF and preserved left ventricular ejection fraction (LVEF). Participants underwent exercise echocardiography and cardiopulmonary exercise testing (CPET). Two-dimensional and speckle-tracking echocardiography were performed to assess LA function at rest and during exercise. Participants were grouped according to presenting rhythm (AF vs sinus rhythm). The relationship between LA function and cardiorespiratory fitness in patients maintaining SR was assessed using linear regression. Results: Of 177 consecutive symptomatic AF patients awaiting AF ablation, 105 met inclusion criteria; 31 (29.5 %) presented in AF whilst 74 (70.5 %) presented in SR. Patients in SR augmented LA function from rest to exercise, increasing LA emptying fraction (LAEF) and LA reservoir strain. In contrast, patients in AF demonstrated reduced LAEF and reservoir strain at rest, with failure to augment either parameter during exercise. This was associated with reduced VO2Peak compared to those in SR (18.4 ± 5.6 vs 22.5 ± 7.7 ml/kg/min, p = 0.003). In patients maintaining SR, LAEF and reservoir strain at rest and during exercise were associated with VO2Peak, independent of LV function. Conclusion: The maintenance of SR in patients with AF is associated with greater LA reservoir function at rest and greater augmentation with exercise compared to patients in AF. In patients in SR, reduced LA function is associated with reduced exercise tolerance, independent of LV function.

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).

Influence of sex on efficacy of exercise training for patients with symptomatic atrial fibrillation: insights from the ACTIVE-AF randomized controlled trial.

AIMS: Exercise training reduces recurrence of arrhythmia and symptom severity amongst patients with symptomatic, non-permanent atrial fibrillation (AF). However, there is little evidence on whether this effect is modified by patient sex. In a sub-analysis from the ACTIVE-AF (A Lifestyle-based, PhysiCal AcTIVity IntErvention for Patients With Symptomatic Atrial Fibrillation) randomized controlled trial, we compared the effects of exercise training on AF recurrence and symptom severity between men and women. METHODS AND RESULTS: The ACTIVE-AF study randomized 120 patients (69 men, 51 women) with paroxysmal or persistent AF to receive an exercise intervention combining supervised and home-based aerobic exercise over 6 months or to continue standard medical care. Patients were followed over a 12-month period. The co-primary outcomes were recurrence of AF, off anti-arrhythmic medications and without catheter ablation, and AF symptom severity scores. By 12 months, recurrence of AF was observed in 50 (73%) men and 34 (67%) women. In an intention-to-treat analysis, there was a between-group difference in favour of the exercise group for both men [hazard ratio (HR) 0.52, 95% confidence interval (CI): 0.29-0.91, P = 0.022] and women (HR 0.47, 95% CI: 0.23-0.95, P = 0.035). At 12 months, symptom severity scores were lower in the exercise group compared with controls amongst women but not for men. CONCLUSION: An exercise-based intervention reduced arrhythmia recurrence for both men and women with symptomatic AF. Symptom severity was reduced with exercise in women at 12 months. No difference was observed in symptom severity for men. REGISTRATION: Australia and New Zealand Clinical Trials Registry: ACTRN12615000734561.

This analysis examined the potential benefit of exercise training on arrhythmia recurrence and symptom severity amongst men and women with symptomatic atrial fibrillation enrolled in a randomized controlled trial of exercise and physical activity intervention compared with standard medical care. Previous studies have not provided evidence on whether men and women might benefit from exercise training to a similar degree. Our findings highlight the following key points: Both men and women in our study experienced fewer arrhythmia recurrences with exercise training compared with men and women in standard medical care.Exercise reduced arrhythmia symptoms in women, but we did not find any evidence of a reduction in symptoms amongst men.

An Exercise and Physical Activity Program in Patients With Atrial Fibrillation: The ACTIVE-AF Randomized Controlled Trial.

BACKGROUND: There are limited data on the effect of exercise interventions on atrial fibrillation (AF) recurrence and symptoms. OBJECTIVES: The aim of this study was to determine the efficacy of an exercise and physical activity intervention on AF burden and symptoms among patients with symptomatic AF. METHODS: This prospective, randomized controlled trial included 120 patients with paroxysmal or persistent, symptomatic AF, randomized 1:1 to receive an exercise intervention, combining home and supervised aerobic exercise over 6 months, or to receive usual care. The coprimary outcomes were: 1) AF recurrence, off antiarrhythmic medications and without catheter ablation; and 2) symptom severity assessed by using a validated questionnaire. RESULTS: By 12 months, freedom from AF was achieved in 24 (40%) of 60 patients in the exercise group and 12 (20%) of 60 patients in the control group (HR: 0.50: 95% CI: 0.33 to 0.78). At 6 months, AF symptom severity was lower in the exercise group compared with the control group (mean difference -2.3; 95% CI: -4.3 to -0.2; P = 0.033). This difference persisted at 12 months (-2.3; 95% CI: -4.5 to -0.1; P = 0.041). Total symptom burden was lower at 6 months in the exercise group but not at 12 months. Peak oxygen consumption was increased in the exercise group at both 6 and 12 months. There were no between-group differences in cardiac structure or function, body mass index, or blood pressure. CONCLUSIONS: Participation in an exercise-based intervention over 6 months reduced arrhythmia recurrence and improved symptom severity among patients with AF. (A Lifestyle-based, PhysiCal AcTIVity IntErvention for Patients With Symptomatic Atrial Fibrillation [the ACTIVE-AF Study]; ACTRN12615000734561).

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.

Should We Check It? Assessing Interrogation of Cardiac Implantable Electronic Devices in the Emergency Department-The CHECK-ED Study: Implications for Service Planning and Care Delivery.

BACKGROUND: Requests from the emergency department (ED) for cardiac implantable electronic device (CIED) checks constitute a large workload for cardiac electrophysiology services. We sought to determine the yield of, and clinical characteristics associated with, clinically relevant (remarkable) issues from ED CIED checks. METHODS: Consecutive CIED checks from our ED over a 12-month period were studied. A remarkable issue (RI) was defined as arrhythmia relating to the presentation or device/lead issue requiring reprogramming or intervention. The association between the presenting complaint and an RI was assessed using regression analysis. Multivariable regression model was used to identify pre-specified patient-level characteristics that were predictive of a RI. RESULTS: A RI was found in 28% (n=98) of 354 ED CIED checks for 306 patients (76±16 yrs, 59% male). Most patients had no RI (n=224, 73%). One third of checks occurred after-hours and these had a higher yield of RIs than those during routine clinic hours (35% vs 23%, p=0.018). Presenting with a perceived ICD shock was predictive of a RI (odds ratio [OR] 6.0, 95% CI=1.8-20.0). Syncope/presyncope was five-fold less likely to be predictive of a RI (OR 0.19, 95% CI=0.13-0.28) despite being the most common indication for CIED check (51%, n=180 checks). Only history of AF was predictive of RI while advancing age was predictive of not finding a RI. CONCLUSION: Almost three-quarters of ED CIED checks did not yield any RI. Patient-reported ICD shock and history of AF were predictive of RI, while syncope/presyncope was not. New models of care especially during after-hours, may help to reduce the burden on cardiac electrophysiology services and health care costs.

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).

Rationale and design of the IRON-AF study: a double-blind, randomised, placebo-controlled study to assess the effect of intravenous ferric carboxymaltose in patients with atrial fibrillation and iron deficiency.

INTRODUCTION: Atrial fibrillation (AF) is associated with significantly impaired quality-of-life. Iron deficiency (ID) is prevalent in patients with AF. Correction of ID in other patient populations with intravenous iron supplementation has been shown to be a safe, convenient and effective way of improving exercise tolerance, fatigue and quality-of-life. The IRON-AF (Effect of Iron Repletion in Atrial Fibrillation) study is designed to assess the effect of iron repletion with intravenous ferric carboxymaltose in patients with AF and ID. METHODS AND ANALYSIS: The IRON-AF study is a double-blind, randomised controlled trial that will recruit at least 84 patients with AF and ID. Patients will be randomised to receive infusions of either ferric carboxymaltose or placebo, given in repletion and then maintenance doses. The study will have follow-up visits at weeks 4, 8 and 12. The primary endpoint is change in peak oxygen uptake from baseline to week 12, as measured by cardiopulmonary exercise testing (CPET) on a cycle ergometer. Secondary endpoints include changes in quality-of-life and AF disease burden scores, blood parameters, other CPET parameters, transthoracic echocardiogram parameters, 6-minute walk test distance, 7-day Holter/Event monitor burden of AF, health resource utilisation and mortality. ETHICS AND DISSEMINATION: The study protocol has been approved by the Central Adelaide Local Health Network Human Research Ethics Committee, Australia. The results of this study will be disseminated through publications in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12620000285954).

Remote Monitoring Alert Burden: An Analysis of Transmission in >26,000 Patients.

OBJECTIVES: This study sought to determine the remote monitoring (RM) alert burden in a multicenter cohort of patients with a cardiac implantable electronic device (CIED). BACKGROUND: RM of CIEDs allows timely recognition of patient and device events requiring intervention. Most RM involves burdensome manual workflow occurring exclusively on weekdays during office hours. Automated software may reduce such a burden, streamlining real-time alert responses. METHODS: We retrospectively analyzed 26,713 consecutive patients with a CIED undergoing managed RM utilizing PaceMate software between November 2018 and November 2019. Alerts were analyzed according to type, acuity (red indicates urgent, and yellow indicates nonurgent) and CIED category. RESULTS: In total, 12,473 (46.7%) patients had a permanent pacemaker (PPM), 9,208 (34.5%) had an implantable cardioverter-defibrillator (ICD), and 5,032 (18.8%) had an implantable loop recorder (ILR). Overall, 82,797 of the 205,804 RM transmissions were alerts, with the remainder being scheduled transmissions. A total of 14,638 (54.8%) patients transmitted at least 1 alert. Permanent pacemakers were responsible for 25,700 (31.0%) alerts, ICDs for 15,643 (18.9%) alerts, and ILRs for 41,454 (50.1%) alerts, with 3,935 (4.8%) red alerts and 78,862 (95.2%) yellow alerts. ICDs transmitted 2,073 (52.7%) red alerts; 5,024 (32.1%) ICD alerts were for ventricular tachyarrhythmias and antitachycardia pacing/shock delivery. CONCLUSIONS: In an RM cohort of 26,713 patients with CIEDs, 54.8% of patients transmitted at least 1 alert during a 12-month period, totaling over 82,000 alerts. ILRs were overrepresented, and ICDs were underrepresented, in these alerts. The enormity of the number of transmissions and the growing ILR alert burden highlight the need for new management pathways for RM.

Factors Contributing to Exercise Intolerance in Patients With Atrial Fibrillation.

BACKGROUND: Reduced exercise capacity and exercise intolerance are commonly reported by individuals with atrial fibrillation (AF). Our objectives were to evaluate the contributing factors to reduced exercise capacity and describe the association between subjective measures of exercise intolerance versus objective measures of exercise capacity. METHODS: Two hundred and three (203) patients with non-permanent AF and preserved ejection fraction undergoing cardiopulmonary exercise testing (CPET) were recruited. Clinical characteristics, AF-symptom evaluation, and transthoracic echocardiography measures were collected. Peak oxygen consumption (VO2peak) was calculated during CPET as an objective measure of exercise capacity. We assessed the impact of 16 pre-defined clinical features, comorbidities and cardiac functional parameters on VO2peak. RESULTS: Across this cohort (Age 66±11 years, 40.4% female and 32% in AF), the mean VO2peak was 20.3±6.3 mL/kg/min. 24.9% of patients had a VO2peak considered low (<16 mL/kg/min). In multivariable analysis, echocardiography-derived estimates of elevated left ventricular (LV) filling pressure (E/E') and reduced chronotropic index were significantly associated with lower VO2peak. The presence of AF at the time of testing was not significantly associated with VO2peak but was associated with elevated minute ventilation to carbon dioxide production indicating impaired ventilatory efficiency. There was a poor association between VO2peak and subjectively reported exercise intolerance and exertional dyspnoea. CONCLUSION: Reduced exercise capacity in AF patients is associated with elevated LV filling pressure and reduced chronotropic response rather than rhythm status. Subjectively reported exercise intolerance is not a sensitive assessment of reduced exercise capacity. These findings have important implications for understanding reduced exercise capacity amongst AF patients and the approach to management in this cohort. (ACTRN12619001343190).

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.

Heart failure with preserved ejection fraction: An alternative paradigm to explain the clinical implications of atrial fibrillation.

Atrial fibrillation (AF) is associated with exercise intolerance, stroke, and all-cause mortality. However, whether this can be solely attributable to the arrhythmia itself or alternative mechanisms remains controversial. Heart failure with preserved ejection (HFpEF) commonly coexists with AF and may contribute to the poor outcomes associated with AF. Indeed, several invasive hemodynamic studies have confirmed that patients with AF are at increased risk of underlying HFpEF and that the presence of HFpEF may have important prognostic implications in these patients. Mechanistically, AF and HFpEF are closely linked. Both conditions are driven by the presence of common cardiovascular risk factors and are associated with left atrial (LA) myopathy, characterized by mechanical and electrical dysfunction. Progressive worsening of this left atrial (LA) myopathy is associated with both increased AF burden and worsening HFpEF. In addition, there is growing evidence to suggest that worsening LA myopathy is associated with poorer outcomes in both conditions and that reversal of the LA myopathy could improve outcomes. In this review article, we will present the epidemiologic and mechanistic evidence underlying the common coexistence of AF and HFpEF, discuss the importance of a progressive LA myopathy in the pathogenesis of both conditions, and review the evidence from important invasive hemodynamic studies. Finally, we will review the prognostic implications of HFpEF in patients with AF and discuss the relative merits of AF burden reduction vs HFpEF reduction in improving outcomes of patients with AF and HFpEF.

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.

Pharmacological inhibition of sodium-proton-exchanger subtype 3-mediated sodium absorption in the gut reduces atrial fibrillation susceptibility in obese spontaneously hypertensive rats.

BACKGROUND: Increased sodium uptake has been shown to contribute to hypertension and cardiac end-organ damage. The sodium-proton-exchanger subtype 3 (NHE3) is an important mediator of intestinal sodium absorption. Whether a reduction in intestinal sodium absorption can prevent the development of an atrial arrhythmogenic substrate in hypertension is unknown. METHODS: Eight-week-old obese spontaneously hypertensive rats (SHR-ob) were treated for six weeks with the gut-specific NHE3-inhibitor SAR (1-(ß-D-glucopyranosyl)-3-{3-[(4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroiso-chinolin-4-yl]phenyl}urea, 1 mg/kg/d in chow, SHR-ob SAR, n = 7) and compared to aged-matched placebo-treated SHR-ob (SHR-ob PLAC, n = 8). Cardiac magnetic resonance imaging was performed at the end of the treatment period to assess atrial emptying function. Afterwards, local conduction disturbances and inducible atrial fibrillation (AF) duration were determined and histological analysis to quantify atrial fibrosis amount were performed. RESULTS: Inhibition of intestinal NHE3 by SAR increased fecal sodium excretion, resulted in marked changes in feces electrolyte concentrations and water content, reduced blood pressure and preserved atrial emptying function (active total percent emptying: SHR-ob SAR: 0.47 ± 0.05% vs. SHR-ob PLAC: 0.38 ± 0.007, p < 0.0001). Atrial fibrosis content was lower (21.4 ± 2.5% vs. 36.7 ± 1.2%, p < 0.0001) and areas of slow conduction were smaller (2.5 ± 0.09% vs. 5.3 ± 0.2%, p < 0.0001) in SHR-ob SAR compared to SHR-ob PLAC. Left atrial burst stimulation resulted in shorter inducible AF-durations in SHR-ob SAR compared to SHR-ob PLAC. CONCLUSIONS: Reduction of intestinal sodium absorption and subsequent changes in feces milieu by pharmacological NHE3 inhibition in the gut preserved atrial emptying function and reduced AF susceptibility. Whether pharmacological NHE3 inhibition in the gut prevents AF in humans warrants further study.

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.

Association between physical activity and risk of incident arrhythmias in 402 406 individuals: evidence from the UK Biobank cohort.

AIMS: Physical activity reduces cardiovascular disease burden and mortality, although its relationship with cardiac arrhythmias is less certain. The aim of this study was to assess the association between self-reported physical activity and atrial fibrillation (AF), ventricular arrhythmias and bradyarrhythmias, across the UK Biobank cohort. METHODS AND RESULTS: We included 402 406 individuals (52.5% female), aged 40-69 years, with over 2.8 million person-years of follow-up who underwent self-reported physical activity assessment computed in metabolic equivalent-minutes per week (MET-min/wk) at baseline, detailed physical assessment and medical history evaluation. Arrhythmia episodes were diagnosed through hospital admissions and death reports. Incident AF risk was lower amongst physically active participants, with a more pronounced reduction amongst female participants [hazard ratio (HR) for 1500 vs. 0 MET-min/wk: 0.85, 95% confidence interval (CI) 0.74-0.98] than males (HR for 1500 vs. 0 MET-min/wk: 0.90, 95% CI 0.82-1.0). Similarly, we observed a significantly lower risk of ventricular arrhythmias amongst physically active participants (HR for 1500 MET-min/wk 0.78, 95% CI 0.64-0.96) that remained relatively stable over a broad range of physical activity levels between 0 and 2500 MET-min/wk. A lower AF risk amongst female participants who engaged in moderate levels of vigorous physical activity was observed (up to 2500 MET-min/wk). Vigorous physical activity was also associated with reduced ventricular arrhythmia risk. Total or vigorous physical activity was not associated with bradyarrhythmias. CONCLUSION: The risk of AF and ventricular arrhythmias is lower amongst physically active individuals. These findings provide observational support that physical activity is associated with reduced risk of atrial and ventricular arrhythmias.