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.

Reduced Ejection Fraction in Elite Endurance Athletes: Clinical and Genetic Overlap With Dilated Cardiomyopathy.

BACKGROUND: Exercise-induced cardiac remodeling can be profound, resulting in clinical overlap with dilated cardiomyopathy, yet the significance of reduced ejection fraction (EF) in athletes is unclear. The aim is to assess the prevalence, clinical consequences, and genetic predisposition of reduced EF in athletes. METHODS: Young endurance athletes were recruited from elite training programs and underwent comprehensive cardiac phenotyping and genetic testing. Those with reduced EF using cardiac magnetic resonance imaging (defined as left ventricular EF <50%, or right ventricular EF <45%, or both) were compared with athletes with normal EF. A validated polygenic risk score for indexed left ventricular end-systolic volume (LVESVi-PRS), previously associated with dilated cardiomyopathy, was assessed. Clinical events were recorded over a mean of 4.4 years. RESULTS: Of the 281 elite endurance athletes (22±8 years, 79.7% male) undergoing comprehensive assessment, 44 of 281 (15.7%) had reduced left ventricular EF (N=12; 4.3%), right ventricular EF (N=14; 5.0%), or both (N=18; 6.4%). Reduced EF was associated with a higher burden of ventricular premature beats (13.6% versus 3.8% with >100 ventricular premature beats/24 h; P=0.008) and lower left ventricular global longitudinal strain (-17%±2% versus -19%±2%; P<0.001). Athletes with reduced EF had a higher mean LVESVi-PRS (0.57±0.13 versus 0.51±0.14; P=0.009) with athletes in the top decile of LVESVi-PRS having an 11-fold increase in the likelihood of reduced EF compared with those in the bottom decile (P=0.034). Male sex and higher LVESVi-PRS were the only significant predictors of reduced EF in a multivariate analysis that included age and fitness. During follow-up, no athletes developed symptomatic heart failure or arrhythmias. Two athletes died, 1 from trauma and 1 from sudden cardiac death, the latter having a reduced right ventricular EF and a LVESVi-PRS >95%. CONCLUSIONS: Reduced EF occurs in approximately 1 in 6 elite endurance athletes and is related to genetic predisposition in addition to exercise training. Genetic and imaging markers may help identify endurance athletes in whom scrutiny about long-term clinical outcomes may be appropriate. REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374976&isReview=true; Unique identifier: ACTRN12618000716268.

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).

Associations between postrace atrial fibrillation and measures of performance, racing history and airway disease in horses.

BACKGROUND: Atrial fibrillation (AF) is the most common performance limiting arrhythmia in racehorses. High dose exercise and airway disease promote AF in humans. Few studies have investigated epidemiological factors associated with AF in horses. OBJECTIVES: Explore variables relating to performance, exercise volume and postrace endoscopic findings in horses with AF. ANIMALS: A total of 164 horses with poor race performance and postrace AF were compared to 321 horses with poor performance without AF (PP) and 314 horses performing to expectation (TE). METHODS: Horse-level and race-level variables for horses racing in Australia and Hong Kong from 2009 to 2021 were compared using univariable and multivariable logistic regression. Postrace endoscopic exercise-induced pulmonary hemorrhage (EIPH) and tracheal mucus accumulation (TMA) grades for AF and PP horses were compared using chi-squared analysis. RESULTS: Variables that were significant in the multivariable model of AF compared to TE were distance (lengths) behind the winner, (odds ratio [OR]; 95% confidence interval [95% CI], 1.41 [1.32-1.51], P < .0001), cumulative prize money per start before the event (OR [95% CI] 1.02 [1.01-1.03], P = .01) and age (OR [95% CI] 0.72 [0.55-0.92], P = .01). More AF horses had EIPH grade ≥ 3 (23/109; 21.1%) than PP horses (7/213; 3.3%; OR [95%CI] 7.9 [3.3-20.2], P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Acute race performance was substantially impaired by AF but career earnings before the event were not inferior. Exercise volume did not promote AF. Higher grades of EIPH found in AF horses suggests a mechanistic relationship between these conditions.

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.

Influence of exercise training on the left atrium: implications for atrial fibrillation, heart failure, and stroke.

The left atrium (LA) plays a critical role in receiving pulmonary venous return and modulating left ventricular (LV) filling. With the onset of exercise, LA function contributes to the augmentation in stroke volume. Due to the growing focus on atrial imaging, there is now evidence that structural remodeling and dysfunction of the LA is associated with adverse outcomes including incident cardiovascular disease. In patients with established disease, pathological changes in atrial structure and function are associated with exercise intolerance, increased hospital admissions and mortality, independent of left ventricular function. Exercise training is widely recommended in patients with cardiovascular disease to improve patient outcomes and maintain functional capacity. There are widely documented changes in LV function with exercise, yet less attention has been given to the LA. In this review, we first describe LA physiology at rest and during exercise, before exploring its association with cardiac disease outcomes including atrial fibrillation, heart failure, and stroke. The adaptation of the LA to short- and longer-term exercise training is evaluated through review of longitudinal studies of exercise training in healthy participants free of cardiovascular disease and athletes. We then consider the changes in LA structure and function among patients with established disease, where adverse atrial remodeling may be implicated in the disease process. Finally, we consider important future directions for assessment of atrial structure and function using novel imaging modalities, in response to acute and chronic exercise.

Associations of dietary patterns, ultra-processed food and nutrient intake with incident atrial fibrillation.

OBJECTIVE: To examine the associations between specific dietary patterns and incident atrial fibrillation (AF). METHODS: Using data from the UK Biobank, dietary intakes were calculated from 24-hour diet recall questionnaires. Indices representing adherence to dietary patterns (Mediterranean-style, Dietary Approaches to Stop Hypertension (DASH) and plant-based diets) were scored, and ultra-processed food consumption was studied as a percentage of total food mass consumed. Incident AF hospitalisations were assessed in Cox regression models. RESULTS: A total of 121 300 individuals were included, with 4 579 incident AF cases over a median follow-up of 8.8 years. Adherence to Mediterranean-style or DASH diets was associated with a lower incidence of AF in minimally adjusted analyses (HR for highest vs lowest quintile 0.87 (95% CI 0.80-0.96) and HR 0.78 (95% CI 0.71-0.86), respectively). However, associations were no longer significant after accounting for lifestyle factors (HR 0.95 (95% CI 0.87-1.04) and 0.94 (95% CI 0.86-1.04) respectively), with adjustment for body mass index responsible for approximately three-quarters of the effect size attenuation. Plant-based diets were not associated with AF risk in any models. Greatest ultra-processed food consumption was associated with a significant increase in AF risk even in fully adjusted models (HR 1.13 (95% CI 1.02-1.24)), and a 10% increase in absolute intake of ultra-processed food was associated with a 5% increase in AF risk (HR 1.05 (95% CI 1.01-1.08)). CONCLUSION: With the possible exception of reducing ultra-processed food consumption, these findings suggest that attention to other modifiable risk factors, particularly obesity, may be more important than specific dietary patterns for the primary prevention of AF.

Incident Atrial Fibrillation in Relation to Ventilatory Parameters: A Prospective Cohort Study.

BACKGROUND: There is a paucity of data on the association between respiratory function and atrial fibrillation (AF). This study aimed to assess the relationship between forced expiratory volume (FEV1), forced vital capacity (FVC), and FEV1/FVC and incident AF. METHODS: We performed an analysis of prospectively collected data from the UK Biobank. We included all participants with available spirometry and excluded those with prior AF. Incident AF was ascertained through hospitalisation and death records, and dose-response associations were assessed by means of multivariable Cox regression analysis with adjustment for known AF risk factors. RESULTS: We studied 348,219 white individuals (54.1% female) with a median age of 58.1 years (interquartile range [IQR] 50.8-63.5 years). Over a median follow-up time of 11.5 years (IQR 11.0-12.6 years), a total of 18,188 incident AF events occurred. After standardisation to sex, age, and height, the risk of AF consistently increased with decreasing FEV1 percentage predicted, FEV1 z score, and FVC z score. The risk of AF linearly increased with decreasing FEV1/FVC ratio, and those that had airway obstruction as defined by FEV1/FVC ratio < 0.70 had a 23% greater risk of incident AF (adjusted hazard ratio [aHR] 1.23, 95% confidence interval [CI] 1.19-1.28) compared with those without airway obstruction. Patients with known chronic obstructive pulmonary disease and asthma were at 40% (aHR 1.40, 95% CI 1.29-1.51) and 17% (aHR 1.17, 95% CI 1.12-1.22) increased risk of incident AF respectively. CONCLUSIONS: These findings indicate that reduced ventilatory function is associated with increased risk of AF independently from age, sex, smoking, and other known AF risk factors.

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).

Epidemiology and modifiable risk factors for atrial fibrillation.

The global prevalence of atrial fibrillation (AF) has increased substantially over the past three decades and is currently approximately 60 million cases. Incident AF and its clinical consequences are largely the result of risk factors that can be modified by lifestyle changes. In this Review, we provide evidence that the lifetime risk of AF is modified not only by sex and race but also through the clinical risk factor and comorbidity burden of individual patients. We begin by summarizing the epidemiology of AF, focusing on non-modifiable and modifiable risk factors, as well as targets and strategies for the primary prevention of AF. Furthermore, we evaluate the role of modifiable risk factors in the secondary prevention of AF as well as the potential effects of risk factor interventions on the frequency and severity of subsequent AF episodes. We end the Review by proposing strategies that require evaluation as well as global policy changes that are needed for the prevention of incident AF and the management of recurrent episodes in patients already affected by AF.

Use of heart rate for guiding exercise training in patients with atrial fibrillation.

BACKGROUND: Heart rate reserve (HRR) is used to guide exercise training in patients with cardiovascular disease, primarily as a surrogate for oxygen uptake reserve (VO2R) as a marker of metabolic demand. However, the relationship between HRR and VO2R in patients with atrial fibrillation (AF) is not well described. We aimed to assess the validity of HRR as a surrogate for VO2R to guide exercise intensity in AF patients. METHODS: One hundred one patients with non-permanent AF undertaking a cardiopulmonary exercise test (CPET) were prospectively enrolled. HR and VO2 values were recorded throughout exercise to determine HRR and VO2R at each workload. Linear regression was used to calculate the slope and y-intercept for HRR versus VO2R with an equivalent slope defined as 1 and y-intercept of 0. The impact of rhythm during exercise, beta blockers and chronotropic incompetence (CI) on the HRR-VO2R relationship was also assessed. RESULTS: The slope of HRR-VO2R was 0.79±0.4, indicating a significant difference from an assumed slope of 1.0 (mean difference: -0.21, 95% CI: -0.30 to -0.12, P<0.001). The mean y-intercept slope was 20.1±41.6, differing significantly from 0 (mean difference: 20.1, 95% CI: 11.9-28.3, P<0.001). The presence of AF during CPET, beta-blockers or chronotropic incompetence did not independently alter the association between VO2R and HRR. CONCLUSIONS: HRR is not equivalent to VO2R in AF patients. There was no significant effect of rhythm status, chronotropic incompetence or beta-blockers on this relationship. These findings highlight that the HR prescription of exercise intensity in AF patients should be guided by an individualised HRR-VO2R relationship.

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.