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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 VO 2Peak 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 VO 2Peak , 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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

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 VO 2peak (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)., Competing Interests: Funding Support and Author Disclosures Drs Ariyaratnam, Mishima, Kadhim, Emami, Malik, and Fitzgerald are supported by Postgraduate Scholarships from the University of Adelaide. Dr Elliott is supported by a Future Leader Fellowship from the National Heart Foundation of Australia. Dr Gallagher is supported by a Postdoctoral Fellowship from the University of Adelaide. Dr Lau is supported by a Mid-career fellowship from The Hospital Research Foundation. Dr Sanders is supported by a Practitioner Fellowship from the National Health and Medical Research Council of Australia. Dr Lau reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Abbott Medical, Bayer, Biotronik, BMS Pfizer, Boehringer Ingelheim, Medtronic, and MicroPort CRM. Dr Sanders has served on the advisory board of Medtronic, Abbott Medical, Boston-Scientific, Pacemate, and CathRx. Dr Sanders reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic, Boston-Scientific, and Abbott Medical; and reports that the University of Adelaide has received on his behalf research funding from Medtronic, Abbott Medical, Boston Scientific, and Microport CRM. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

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.

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)., Competing Interests: Funding Support and Author Disclosures This study was supported by funding from the National Heart Foundation of Australia through a postdoctoral fellowship to Dr Elliott. Dr Mahajan is supported by a mid-career fellowship from The Hospital Research Foundation. Drs Middeldorp and Gallagher are supported by postdoctoral fellowships from the University of Adelaide. Dr Hendriks is supported by a Future Leader Fellowship from the Australian Heart Foundation. Dr Sanders is supported by a Practitioner Fellowship from the National Health and Medical Research Council of Australia. The University of Adelaide has received on behalf of Dr Mahajan lecture and/or consulting fees from Medtronic, Abbott, Pfizer, and Bayer; and the University of Adelaide has also received on behalf of Dr Mahajan research funding from Medtronic, Abbott, and Bayer. Flinders University has received on behalf of Dr Hendriks lecture and/or consulting fees from Biotronik. The University of Adelaide has received on behalf of Dr Lau lecture and/or consulting fees from Abbott Medical, Boehringer Ingelheim, Bayer, and Pfizer. Dr Sanders has served on the advisory board of Boston Scientific, CathRx, Medtronic, Abbott Medical, and PaceMate. The University of Adelaide has received on behalf of Dr Sanders lecture and/or consulting fees from Medtronic, Boston Scientific, Abbott Medical, PaceMate, and CathRx; the University of Adelaide has also received on behalf of Dr Sanders research funding from Medtronic, Abbott Medical, Boston Scientific, PaceMate, and MicroPort. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Aims: There is a paucity of epidemiological evidence on alcohol and the risk of bradyarrhythmias. We thus characterized associations of total and beverage-specific alcohol consumption with incident bradyarrhythmias using data from the UK Biobank., Methods and Results: Alcohol consumption reported at baseline was calculated as UK standard drinks (8 g alcohol)/week. Bradyarrhythmia events were defined as sinus node dysfunction (SND), high-level atrioventricular block (AVB), and permanent pacemaker implantations. Outcomes were assessed through hospitalization and death records, and dose-response associations were characterized using Cox regression models with correction for regression dilution bias. We studied 407 948 middle-aged individuals (52.4% female). Over a median follow-up time of 11.5 years, a total of 8 344 incident bradyarrhythmia events occurred. Increasing total alcohol consumption was not associated with an increased risk of bradyarrhythmias. Beer and cider intake were associated with increased bradyarrhythmia risk up to 12 drinks/week; however, no significant associations were observed with red wine, white wine, or spirit intake. When bradyarrhythmia outcomes were analysed separately, a negative curvilinear was observed for total alcohol consumption and risk of SND, but no clear association with AVB was observed., Conclusion: In this predominantly White British cohort, increasing total alcohol consumption was not associated with an increased risk of bradyarrhythmias. Associations appeared to vary according to the type of alcoholic beverage and between different types of bradyarrhythmias. Further epidemiological and experimental studies are required to clarify these findings., Competing Interests: Conflict of interest: J.M.L.H. reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic and Pfizer/BMS. D.H.L. reports the University of Adelaide has received on his behalf lecture and/or consulting fees from Abbott Medical, Bayer, Biotronik, Boehringer Ingelheim, Medtronic, Microport, and Pfizer/BMS. P.S. reports having served on the advisory board of Medtronic, Abbott Medical, Boston Scientific, CathRx, and PaceMate. P.S. reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic, Abbott Medical, and Boston Scientific. P.S. reports that the University of Adelaide has received on his behalf research funding from Medtronic, Abbott Medical, Boston Scientific, and Microport. C.X.W. reports that the University of Adelaide has received on his behalf lecture, travel, and/or research funding from Abbott Medical, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Servier, St Jude Medical, and Vifor Pharma. The other authors have nothing to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To systematic review and meta-analyse the association and mechanistic links between atrial fibrillation (AF) and cognitive impairment., Methods and Results: PubMed, EMBASE, and Cochrane Library were searched up to 27 March 2021 and yielded 4534 citations. After exclusions, 61 were analysed; 15 and 6 studies reported on the association of AF and cognitive impairment in the general population and post-stroke cohorts, respectively. Thirty-six studies reported on the neuro-pathological changes in patients with AF; of those, 13 reported on silent cerebral infarction (SCI) and 11 reported on cerebral microbleeds (CMB). Atrial fibrillation was associated with 39% increased risk of cognitive impairment in the general population [n = 15: 2 822 974 patients; hazard ratio = 1.39; 95% confidence interval (CI) 1.25-1.53, I2 = 90.3%; follow-up 3.8-25 years]. In the post-stroke cohort, AF was associated with a 2.70-fold increased risk of cognitive impairment [adjusted odds ratio (OR) 2.70; 95% CI 1.66-3.74, I2 = 0.0%; follow-up 0.25-3.78 years]. Atrial fibrillation was associated with cerebral small vessel disease, such as white matter hyperintensities and CMB (n = 8: 3698 patients; OR = 1.38; 95% CI 1.11-1.73, I2 = 0.0%), SCI (n = 13: 6188 patients; OR = 2.11; 95% CI 1.58-2.64, I2 = 0%), and decreased cerebral perfusion and cerebral volume even in the absence of clinical stroke., Conclusion: Atrial fibrillation is associated with increased risk of cognitive impairment. The association with cerebral small vessel disease and cerebral atrophy secondary to cardioembolism and cerebral hypoperfusion may suggest a plausible link in the absence of clinical stroke. PROSPERO CRD42018109185., Competing Interests: Conflict of interest: D.L. reports having served on the advisory board of Liva Nova and Medtronic. The University of Adelaide reports receiving on behalf of Dr Linz reports lecture and/or consulting fees from LivaNova, Medtronic, Pfizer, and ResMed. The University of Adelaide reports receiving on behalf of Dr Linz research funding from Sanofi, ResMed, and Medtronic. The University of Adelaide reports receiving on behalf of Dr Lau lecture and/or consulting fees from Abbott, Bayer, Boehringer Ingelheim, Biotronik, and Pfizer. The University of Adelaide reports receiving on behalf of Dr Mahajan lecture and/or consulting fees from Abbott, Medtronic, Bayer, and Pfizer. The University of Adelaide reports receiving on behalf of Dr Mahajan research funding from Abbott and Medtronic. All the remaining authors have declared no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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 (β = 1.3, 95% CI 0.1-2.3, p = 0.02), reservoir (β = 1.5, 95% CI 0.9-2.1, p < 0.001), booster (β = 0.8, 95% CI 0.4-1.2, p < 0.001) and conduit strain (β = 0.7, 95% CI 0.3-1.1, p = 0.001). We observed an inverse association between CRF and both LA stiffness index (β = -0.02, 95% CI (-0.03)-(-0.01), p < 0.001) and LA to LV ratio (β = -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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Atrial fibrillation (AF) is the most common cardiac tachyarrhythmia and has a rising global prevalence. Given the increasing burden of AF-related symptoms and complications, new approaches to management are required. Anemia and iron deficiency are common conditions in patients with AF. Furthermore, emerging evidence suggests that the presence of anemia may be associated with worse outcome in these patients. The role of anemia and iron deficiency has been extensively explored in other cardiovascular states, such as heart failure and ischemic heart disease. In particular, the role of iron repletion amongst patients with heart failure is now an established treatment modality. However, despite the strong bidirectional inter-relationship between AF and heart failure, the implications of anemia and iron-deficiency in AF have been scarcely studied. This area is of mechanistic and clinical relevance given the potential that treatment of these conditions may improve symptoms and prognosis in the increasing number of individuals with AF. In this review, we summarise the current published literature on anemia and iron deficiency in patients with AF. We discuss AF complications such as stroke, bleeding, and heart failure, in addition to AF-related symptoms such as exercise intolerance, and the potential impact of anemia and iron deficiency on these. Finally, we summarize current research gaps on anemia, iron deficiency, and AF, and underscore potential research directions., (© 2022. The Author(s).)

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)., Competing Interests: Funding Support and Author Disclosures This study was funded by the Centre for Heart Rhythm Disorders at the University of Adelaide. Drs Malik and Fitzgerald are supported by an Australian Postgraduate Award Scholarship from the University of Adelaide. Dr Elliott is supported by a Future Leader Fellowship from the National Heart Foundation of Australia. Dr Mishima is supported by the Robert J. Craig Postgraduate Scholarship from the University of Adelaide. Dr Middeldorp is supported by Postdoctoral Fellowships from the University of Adelaide. Dr Lau is supported by a Mid-Career Fellowship from the Hospital Research Foundation; and has received lecture and/or consulting fees directed to the University of Adelaide from Abbott Medical, Bayer, Biotronik, BMS Pfizer, Boehringer Ingelheim, Medtronic, and Microport CRM. Dr Sanders is supported by a Practitioner Fellowship from the National Health and Medical Research Council of Australia; has served on the advisory board of Biosense Webster, Medtronic, Abbott, Boston Scientific, Pacemate, and CathRx; has received lecture and/or consulting fees directed to the University of Adelaide from Medtronic, Abbott, and Boston Scientific; and has received research funding directed to the University of Adelaide from Medtronic, Abbott, Boston Scientific, and Microport. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

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., (Crown Copyright © 2021 Published by Elsevier Inc. on behalf of Heart Rhythm Society.)

Objectives: This study sought to characterize associations of total and beverage-specific alcohol consumption with incident atrial fibrillation (AF)., Background: Although binge drinking and moderate to high consumption of alcohol are both established risk factors for AF, comparatively less is known about the effect of low alcohol consumption and whether associations differ by specific alcoholic beverages., Methods: Using data from the UK Biobank, total and beverage-specific alcohol consumption was calculated as UK standard drinks (8 g alcohol) per week. Past drinkers and those with a history of AF were excluded. Incident AF events were assessed through hospitalization and death records, and dose-response associations were characterized using Cox regression models with correction for regression dilution bias., Results: We studied 403,281 middle-aged individuals (52.4% female). Over a median follow-up time of 11.4 years (IQR: 10.7-12.3 years), a total of 21,312 incident AF events occurred. A J-shaped association of total alcohol consumption was observed, with lowest risk of AF with fewer than 7 drinks/week. Beverage-specific analyses demonstrated harmful associations of beer/cider consumption with any consumption. In contrast, consumption of red wine, white wine, and spirits up to 10, 8, and 3 drinks/week, respectively, was not associated with increased risk., Conclusions: In this predominantly White population, low levels of alcohol consumption (<7 U.K. standard drinks [56 g alcohol]/week) were associated with lowest AF risk. Low consumption of red and white wine and very low consumption of spirits may not be associated with increased AF risk, whereas any consumption of beer/cider may be associated with harm. These findings may have important implications for the primary prevention of AF that should be explored in future studies., Competing Interests: Funding Support and Author Disclosures Dr Gallagher is supported by a Postdoctoral Fellowship from the University of Adelaide. Dr Elliott is supported by an Early Career Fellowship from the National Heart Foundation of Australia. Dr Linz is supported by the Beacon Research Fellowship from the University of Adelaide. Mr Pitman is supported by a Postgraduate Scholarship from the Hospital Research Foundation. Dr Hendriks is supported by an Early Career Fellowship from the National Heart Foundation of Australia and the Derek Frewin Lectureship from the University of Adelaide. Dr Lau is supported by the Robert J. Craig Lectureship from the University of Adelaide. Dr Sanders is supported by a Practitioner Fellowship from the National Health and Medical Research Council of Australia and by the National Heart Foundation of Australia. Dr Wong is supported by a Mid-Career Fellowship from the Hospital Research Foundation and a Postdoctoral Fellowship from the National Heart Foundation of Australia. Dr Hendriks reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic and Pfizer/Bristol Myers Squibb. Dr Lau reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Abbott Medical, Bayer, Biotronik, Boehringer Ingelheim, Medtronic, Microport, and Pfizer/Bristol Myers Squibb. Dr Sanders has served on the Advisory Boards of Medtronic, Abbott Medical, Boston Scientific, CathRx, and PaceMate; reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic, Abbott Medical, and Boston Scientific; and reports that the University of Adelaide has received on his behalf research funding from Medtronic, Abbott Medical, Boston Scientific, and Microport. Dr Wong reports that the University of Adelaide has received on his behalf lecture, travel, and/or research funding from Abbott Medical, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Servier, St Jude Medical, and Vifor Pharma. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. All rights reserved.)

Aims: The aim of this study is to determine the association between the coronavirus disease 2019 (COVID-19) pandemic and atrial fibrillation (AF) occurrence in individuals with cardiac implantable electronic devices (CIEDs)., Method and Results: Multi-centre, observational, cohort study over a 100-day period during the COVID-19 pandemic (COVID-19) in the USA. Remote monitoring was used to assess AF episodes in patients with a CIED (pacemaker or defibrillator; 20 centres, 13 states). For comparison, the identical 100-day period in 2019 was used (Control). The primary outcomes were the AF burden during the COVID-19 pandemic, and the association of the pandemic with AF occurrence, as compared with 1 year prior. The secondary outcome was the association of AF occurrence with per-state COVID-19 prevalence. During COVID-19, 10 346 CIEDs with an atrial lead were monitored. There were 16 570 AF episodes of ≥6 min transmitted (16 events per 1000 patient days) with a significant increase in proportion of patients with AF episodes in high COVID-19 prevalence states compared with low prevalence states [odds ratio 1.34, 95% confidence interval (CI) 1.21-1.48, P < 0.001]. There were significantly more AF episodes during COVID-19 compared with Control [incident rate ratio (IRR) 1.33, 95% CI 1.25-1.40, P < 0.001]. This relationship persisted for AF episodes ≥1 h (IRR 1.65, 95% CI 1.53-1.79, P < 0.001) and ≥6 h (IRR 1.54, 95% CI 1.38-1.73, P < 0.001)., Conclusion: During the first 100 days of COVID-19, a 33% increase in AF episodes occurred with a 34% increase in the proportion of patients with AF episodes observed in states with higher COVID-19 prevalence. These findings suggest a possible association between pandemic-associated social disruptions and AF in patients with CIEDs., Clinical Trial Registration: Australian New Zealand Clinical Trial Registry: ACTRN12620000692932., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

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)., Competing Interests: Competing interests: DL reports the University of Adelaide has received on his behalf lecture and/or consulting fees from Abbott Medical, Bayer, Biotronik, Boehringer Ingelheim, Medtronic, Microport and Pfizer/BMS. PS reports having served on the advisory board of Medtronic, Abbott Medical, Boston Scientific, CathRx and PaceMate. PS reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic, Abbott Medical and Boston Scientific. PS reports that the University of Adelaide has received on his behalf research funding from Medtronic, Abbott Medical, Boston Scientific and Microport. CXW reports that the University of Adelaide has received on his behalf lecture, travel and/or research funding from Abbott Medical, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Servier, St Jude Medical and Vifor Pharma., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Identifying neural substrates of behavior requires defining actions in terms that map onto brain activity. Brain and muscle activity naturally correlate via the output of motor neurons, but apart from simple movements it has been difficult to define behavior in terms of muscle contractions. By mapping the musculature of the pupal fruit fly and comprehensively imaging muscle activation at single-cell resolution, we here describe a multiphasic behavioral sequence in Drosophila . Our characterization identifies a previously undescribed behavioral phase and permits extraction of major movements by a convolutional neural network. We deconstruct movements into a syllabary of co-active muscles and identify specific syllables that are sensitive to neuromodulatory manipulations. We find that muscle activity shows considerable variability, with sequential increases in stereotypy dependent upon neuromodulation. Our work provides a platform for studying whole-animal behavior, quantifying its variability across multiple spatiotemporal scales, and analyzing its neuromodulatory regulation at cellular resolution., Competing Interests: AE, AB, MH, SR, RS, CC, HS, BW No competing interests declared

Background: Atrial fibrillation (AF) impacts performance and horse and jockey safety. Understanding the outcomes of AF identified postrace will better inform regulatory policy., Hypothesis/objectives: To investigate the outcomes after episodes of AF identified postrace and determine whether affected horses are at increased risk of additional episodes compared to the general racing population., Animals: Total of 4684 Thoroughbred racehorses., Methods: Race records for Thoroughbred horses racing in Hong Kong from 2007 to 2017 were reviewed. Horses that performed below expectation were examined by cardiac auscultation and ECG. Incidence and recurrence of AF were compared between horses with and without a history of AF and between horses with paroxysmal and persistent episodes using Fisher's exact test., Results: There were 96 135 race starts during the study. Atrial fibrillation was identified in 4.9% of horses, with an overall incidence of 2.7 episodes per 1000 starts. The incidence of AF in horses after any previous episode (12.8 per 1000 starts) was higher than for horses with no previous episode (2.4 per 1000 starts; odds ratio [OR], 5.3; 95% confidence interval [CI], 3.8-7.6). Recurrence was seen in 64% of horses previously treated for persistent AF, which was higher than recurrence in horses with paroxysmal AF (23%; OR, 5.9; 95% CI, 1.6-21.2). Median duration between episodes was 343 days (range, 34-1065)., Conclusions and Clinical Importance: Thoroughbreds are at increased risk of recurrent AF after both paroxysmal and persistent episodes, but the duration of time between episodes varies widely. These findings support a substantial burden of AF among individual Thoroughbred racehorses., (© 2021 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC. on behalf of the American College of Veterinary Internal Medicine.)

Aims: Our objective was to determine the ventricular arrhythmia burden in implantable cardioverter-defibrillator (ICD) patients during COVID-19., Methods and Results: In this multicentre, observational, cohort study over a 100-day period during the COVID-19 pandemic in the USA, we assessed ventricular arrhythmias in ICD patients from 20 centres in 13 states, via remote monitoring. Comparison was via a 100-day control period (late 2019) and seasonal control period (early 2019). The primary outcome was the impact of COVID-19 on ventricular arrhythmia burden. The secondary outcome was correlation with COVID-19 incidence. During the COVID-19 period, 5963 ICD patients underwent remote monitoring, with 16 942 episodes of treated ventricular arrhythmias (2.8 events per 100 patient-days). Ventricular arrhythmia burden progressively declined during COVID-19 (P < 0.001). The proportion of patients with ventricular arrhythmias amongst the high COVID-19 incidence states was significantly reduced compared with those in low incidence states [odds ratio 0.61, 95% confidence interval (CI) 0.54-0.69, P < 0.001]. Comparing patients remotely monitored during both COVID-19 and control periods (n = 2458), significantly fewer ventricular arrhythmias occurred during COVID-19 [incident rate ratio (IRR) 0.68, 95% CI 0.58-0.79, P < 0.001]. This difference persisted when comparing the 1719 patients monitored during both the COVID-19 and seasonal control periods (IRR 0.69, 95% CI 0.56-0.85, P < 0.001)., Conclusions: During COVID-19, there was a 32% reduction in ventricular arrhythmias needing device therapies, coinciding with measures of social isolation. There was a 39% reduction in the proportion of patients with ventricular arrhythmias in states with higher COVID-19 incidence. These findings highlight the potential role of real-life stressors in ventricular arrhythmia burden in individuals with ICDs., Trial Registration: Australian New Zealand Clinical Trial Registry; URL: https://www.anzctr.org.au/; Unique Identifier: ACTRN12620000641998., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

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.

Introduction: Amiodarone is a highly effective antiarrhythmic-drug with well recognized toxic side-effects. The effects of the drug late in patients with atrial fibrillation (AF) is not well described., Methods and Results: We present a single centre prospectively collected series of patients with thyrotoxicosis occurring late after the cessation of amiodarone. Between 2006 and 2018, 8 patients were identified with amiodarone induced thyrotoxicosis (AIT). Amiodarone was prescribed for AF in 7 patients and ventricular tachycardia in 1 patient. Mean duration of therapy was 329 [42-1092] days, mean dose of 200 ± 103.5 mg/day. Amiodarone use was short term (<140 days) in 4 of the 8 cases, with one treated for 42 days. Patients presented with symptoms including weight loss, tremors, palpitations, AF, sweats all indicative of AIT at a median of 347 [60-967] days post cessation. Thyroid function testing confirmed suppressed thyroid stimulating hormone and elevated T levels in all patients. Nuclear thyroid imaging in all cases demonstrated low uptake of iodine indicative of Type II AIT. All patients recovered following pharmaceutical treatment with Carbimazole and Prednisolone., Conclusions: We describe a series of patients with late thyrotoxicosis after exposure to amiodarone. Our findings highlight the need for a high-index of clinical suspicion for AIT regardless of treatment duration or time after cessation of amiodarone., Competing Interests: Declaration of competing interest Dr Hendriks reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic and Pfizer/BMS. Dr Mahajan reports that the University of Adelaide has received on his behalf lecture fees and research funding from Medtronic and Abbott Medical. Dr Lau reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Abbott Medical, Boehringer Ingelheim, Bayer and Pfizer. Dr Sanders reports having served on the advisory board of Biosense-Webster, Boston Scientific, CathRx, Medtronic, and Abbott Medical. Dr Sanders reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Biosense-Webster, Medtronic, Boston-Scientific, Pfizer and Abbott Medical. Dr Sanders reports that the University of Adelaide has received on his behalf research funding from Medtronic, Abbott Medical, Boston Scientific, Biotronik and Liva Nova. All other authors have no disclosures., (Crown Copyright © 2020. Production and hosting by Elsevier B.V. All rights reserved.)

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

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 (I 2 =37%; P=.11) for falls and moderate bias with low statistical heterogeneity (I 2 =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., (Copyright © 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

After myocardial infarction, remote ventricular remodeling and atrial cardiomyopathy progress despite successful revascularization. In a rat model of ventricular ischemia/reperfusion, pharmacological inhibition of the protease activity of cathepsin A initiated at the time point of reperfusion prevented extracellular matrix remodeling in the atrium and the ventricle remote from the infarcted area. This scenario was associated with preservation of more viable ventricular myocardium and the prevention of an arrhythmogenic and functional substrate for atrial fibrillation. Remote ventricular extracellular matrix remodeling and atrial cardiomyopathy may represent a promising target for pharmacological atrial fibrillation upstream therapy following myocardial infarction.

Objectives: This study sought to determine night-to-night variability in the severity of sleep-disordered breathing (SDB) and the dynamic intraindividual relationship to daily risk of incident atrial fibrillation (AF) by using simultaneous long-term day-by-day SDB and AF monitoring., Background: Night-to-night variability in SDB severity may result in a dynamic exposure to SDB related conditions impacting the timing and extent of cardiovascular responses., Methods: This study was an observational cohort study. Daily data for AF burden and average respiratory disturbance index (RDI) were extracted from pacemakers capable of monitoring nightly SDB and daily AF burden in 72 patients. Nightly RDI values were grouped into quartiles of severity within each patient. AF burdens of >5 min, >1 h, and >12 h were the outcome variables., Results: A total of 32% of patients had a mean RDI of ≥20/h, indicative of overall severe SDB. There was significant night-to-night variation in RDI reflected by an absolute SD of ±6.3 events/h (range 2 to 14 events/h) within any given patient. Within each patient, the nights with the highest RDI (in their highest quartile) conferred a 1.7-fold (1.2 to 2.2; p < 0.001), 2.3-fold (1.6 to 3.5; p < 0.001), and 10.2-fold (3.5 to 29.9; p < 0.001) increase risk of having at least 5 min, 1 h, and 12 h, respectively, of AF during the same day compared with the best sleep nights (in their lowest quartiles)., Conclusions: There is considerable night-to-night variability in SDB severity which cannot be detected by 1 single overnight sleep study. SDB burden may be a better metric with which to assess the extent of dynamic SDB related cardiovascular responses such as daily AF risk than the categorical diagnosis of SDB. (Night-to-Night Variability in Severity of Sleep Apnea and Daily Dynamic Atrial Fibrillation Risk [VARIOSA-AF]; ACTRN 12618000757213)., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Aims: Atrial fibrillation (AF) is a progressive disease. Obesity is associated with progression of AF. This study evaluates the impact of weight and risk factor management (RFM) on progression of the AF., Methods and Results: As described in the Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up (LEGACY) Study, of 1415 consecutive AF patients, 825 had body mass index ≥ 27 kg/m2 and were offered weight and RFM. After exclusion, 355 were included for analysis. Weight loss was categorized as: Group 1 (<3%), Group 2 (3-9%), and Group 3 (≥10%). Change in AF type was determined by clinical review and 7-day Holter yearly. Atrial fibrillation type was categorized as per the Heart Rhythm Society consensus. There were no differences in baseline characteristic or follow-up duration between groups (P = NS). In Group 1, 41% progressed from paroxysmal to persistent and 26% from persistent to paroxysmal or no AF. In Group 2, 32% progressed from paroxysmal to persistent and 49% reversed from persistent to paroxysmal or no AF. In Group 3, 3% progressed to persistent and 88% reversed from persistent to paroxysmal or no AF (P < 0.001). Increased weight loss was significantly associated with greater AF freedom: 45 (39%) in Group 1, 69 (67%) in Group 2, and 116 (86%) in Group 3 (P ≤ 0.001)., Conclusion: Obesity is associated with progression of the AF disease. This study demonstrates the dynamic relationship between weight/risk factors and AF. Weight-loss management and RFM reverses the type and natural progression of AF.

Aims: Several techniques have been utilized for the ablation of persistent (P) and long-standing persistent (LsP) atrial fibrillation (AF); however, the best approach of substrate ablation remains poorly defined. This study aims to examine the impact of ablation approach on outcomes associated with P or LsP AF ablation by conducting a meta-analysis and regression on contemporary literature., Methods and Results: A systematic literature review was conducted up to 29 July 2015 for scientific literature reporting on outcomes associated with P or LsP AF ablation. One hundred and thirteen studies reported outcomes in a total of 18 657 patients undergoing various ablation approaches for the treatment of P-LsP AF between 2001 and 2015. The point efficacy estimate of a single-AF ablation procedure without the use of anti-arrhythmic drugs was 43% (95% CI; 39-47%). Multiple procedures and/or the use of anti-arrhythmic drugs increase success to 69% (95% CI; 66-71%). Meta-regression revealed that ablation technique (P < 0.001) and left atrial size (P = 0.02) were predictive of single procedure, drug-free success. The addition of extra-pulmonary substrate approaches was associated with declining efficacy when compared to a pulmonary vein ablation alone., Conclusion: The efficacy of a single-AF ablation procedure for P or LsP AF is 43%; however, can be increased to 69% with the use of multiple procedures and/or anti-arrhythmic drugs. Current literature supports the finding that pulmonary vein antrum ablation/isolation is at least equivalently efficacious to other contemporary P-LsP ablation strategies.

Objective: To identify the evidence base and evaluate the efficacy of each treatment for postural tachycardia syndrome (POTS) in light of a recent consensus statement highlighting the lack of treatment options with clear benefit to risk ratios for this debilitating condition., Methods: The CENTRAL (Cochrane Central Register of Controlled Trials), PubMed, and Embase databases from inception to May 2017 were searched using the terms postural AND tachycardia AND syndrome. A total of 135 full-text publications were screened after excluding duplicates (n=681), conference abstracts (n=467), and records that did not relate to POTS therapy (n=876). We included 28 studies with at least 4 patients with POTS in which symptomatic response was reported after more than 4 weeks of therapy. This review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Two investigators independently performed the data extraction and evaluated the quality of evidence., Results: This study comprised 25 case series and 3 small randomized controlled trials that evaluated 755 and 103 patients with POTS, respectively. Interventions directed at increasing intravascular volume, increasing peripheral or splanchnic vascular tone, controlling heart rate, and increasing exercise tolerance demonstrate moderate efficacy (range, 51%-72%). Few data exist on their comparative effectiveness. Significant heterogeneities were seen in terms of patient age, symptom severity, and the measures used to evaluate treatment efficacy., Conclusion: The current evidence base to guide optimal management of patients with POTS is extremely limited. More high-quality collaborative research with standardized reporting of symptom response and treatment tolerability is urgently needed., (Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Atrial remodeling, vagal tone, and atrial ectopic triggers are suggested to contribute to increased incidence of atrial fibrillation (AF) in endurance athletes. How these parameters change with increased lifetime training hours is debated., Hypothesis: Atrial remodeling occurs in proportion to total training history, thus contributing to elevated risk of AF., Methods: We recruited 99 recreational endurance athletes, subsequently grouped according to lifetime training hours, to undergo evaluation of atrial size, autonomic modulation, and atrial ectopy. Athletes were grouped by self-reported lifetime training hours: low (<3000 h), medium (3000-6000 h), and high (>6000 h). Left atrial (LA) volume, left ventricular (LV) dimensions, and LV systolic and diastolic function were assessed by echocardiography. We used 48-hour ambulatory electrocardiographic monitoring to determine heart rate, heart rate variability, premature atrial contractions, and premature ventricular contractions., Results: LA volume was significantly greater in the high (+5.1 mL/m 2 , 95% CI: 1.3-8.9) and medium (+4.2 mL/m 2 , 95% CI: 0.2-8.1) groups, compared with the low group. LA dilation was observed in 19.4%, 12.9%, and 0% of the high, medium, and low groups, respectively (P = 0.05). No differences were observed between groups for measures of LV dimensions or function. Minimum heart rate, parasympathetic tone expressed using heart rate variability indices, and premature atrial contraction and premature ventricular contraction frequencies did not differ between groups., Conclusions: In recreational endurance athletes, increased lifetime training is associated with LA dilation in the absence of increased vagal parameters or atrial ectopy, which may promote incidence of AF in this cohort., (© 2018 Wiley Periodicals, Inc.)

Aims: To determine stroke risk in subclinical atrial fibrillation (AF) and temporal association between subclinical AF and stroke., Methods and Results: Pubmed/Embase was searched for studies reporting stroke in subclinical AF in patients with cardiac implantable electronic devices (CIEDs). After exclusions, 11 studies were analysed. Of these seven studies reported prevalence of subclinical AF, two studies reported association between subclinical and clinical AF, seven studies reported stroke risk in subclinical AF, and five studies reported temporal relationship between subclinical AF and stroke. Subclinical AF was noted after CIEDs implant in 35% [interquartile range (IQR) 34-42] of unselected patients with pacing indication over 1-2.5 years. The definition and cut-off duration (for stroke risk) of subclinical AF varied across studies. Subclinical AF was strongly associated with clinical AF (OR 5.7, 95% CI 4.0-8.0, P < 0.001, I2 = 0%). The annual stroke rate in patients with subclinical AF > defined cut-off duration was 1.89/100 person-year (95% CI 1.02-3.52) with 2.4-fold (95% CI 1.8-3.3, P < 0.001, I2 = 0%) increased risk of stroke as compared to patients with subclinical AF < cut-off duration (absolute risk was 0.93/100 person-year). Three studies provided mean CHADS2 score. In these studies, with mean CHADS2 score of 2.1 ± 0.1, subclinical AF was associated with annual stroke rate of 2.76/100 person-years (95% CI 1.46-5.23). After excluding patients without AF, only 17% strokes occurred in presence of ongoing AF. Subclinical AF was noted in 29% [IQR 8-57] within 30 days preceding stroke., Conclusion: Subclinical AF strongly predicts clinical AF and is associated with elevated absolute stroke risk albeit lower than risk described for clinical AF.

Fluorescent protein (FP) biosensors based on Förster resonance energy transfer (FRET) are commonly used to study molecular processes in living cells. There are FP-FRET biosensors for many cellular molecules, but it remains difficult to perform simultaneous measurements of multiple biosensors. The overlapping emission spectra of the commonly used FPs, including CFP/YFP and GFP/RFP make dual FRET measurements challenging. In addition, a snapshot imaging modality is required for simultaneous imaging. The Image Mapping Spectrometer (IMS) is a snapshot hyperspectral imaging system that collects high resolution spectral data and can be used to overcome these challenges. We have previously demonstrated the IMS's capabilities for simultaneously imaging GFP and CFP/YFP-based biosensors in pancreatic β-cells. Here, we demonstrate a further capability of the IMS to image simultaneously two FRET biosensors with a single excitation band, one for cAMP and the other for Caspase-3. We use these measurements to measure simultaneously cAMP signaling and Caspase-3 activation in pancreatic β-cells during oxidative stress and hyperglycemia, which are essential components in the pathology of diabetes.

Neural networks are typically defined by their synaptic connectivity, yet synaptic wiring diagrams often provide limited insight into network function. This is due partly to the importance of non-synaptic communication by neuromodulators, which can dynamically reconfigure circuit activity to alter its output. Here, we systematically map the patterns of neuromodulatory connectivity in a network that governs a developmentally critical behavioral sequence in Drosophila . This sequence, which mediates pupal ecdysis, is governed by the serial release of several key factors, which act both somatically as hormones and within the brain as neuromodulators. By identifying and characterizing the functions of the neuronal targets of these factors, we find that they define hierarchically organized layers of the network controlling the pupal ecdysis sequence: a modular input layer, an intermediate central pattern generating layer, and a motor output layer. Mapping neuromodulatory connections in this system thus defines the functional architecture of the network.

Background: Besides hypertension, obesity and the metabolic syndrome have recently emerged as risk factors for atrial fibrillation. This study sought to delineate the development of an arrhythmogenic substrate for atrial fibrillation in hypertension with and without concomitant obesity and metabolic syndrome., Methods and Results: We compared obese spontaneously hypertensive rats (SHR-obese, n=7-10) with lean hypertensive controls (SHR-lean, n=7-10) and normotensive rats (n=7-10). Left atrial emptying function (MRI) and electrophysiological parameters were characterized before the hearts were harvested for histological and biochemical analyses. At the age of 38 weeks, SHR-obese, but not SHR-lean, showed increased body weight and impaired glucose tolerance together with dyslipidemia compared with normotensive rats. Mean blood pressure was similarly increased in SHR-lean and SHR-obese when compared with normotensive rats (178±9 and 180±8 mm Hg [not significant] versus 118±5 mm Hg, P <0.01 for both), but left ventricular end-diastolic pressure was more increased in SHR-obese than in SHR-lean. Impairment of left atrial emptying function, increase in total atrial activation time, and conduction heterogeneity, as well as prolongation of inducible atrial fibrillation durations, were more pronounced in SHR-obese as compared with SHR-lean. Histological and biochemical examinations revealed enhanced triglycerides and more pronounced fibrosis in the left atrium of SHR-obese. Besides increased expression of profibrotic markers in SHR-lean and SHR-obese, the profibrotic extracellular matrix protein osteopontin was highly upregulated only in SHR-obese., Conclusions: In addition to hypertension alone, concomitant obesity and metabolic syndrome add to the atrial arrhythmogenic phenotype by impaired left atrial emptying function, local conduction abnormalities, interstitial atrial fibrosis formation, and increased propensity for atrial fibrillation., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: There exists a high risk of post-operative complications with primary and revision total ankle replacement surgery. Delayed wound healing of the anterior incision is common. The reason for this is multi-factorial and, to date, most of the research has focused on predisposing factors involving the patients themselves. Only recently have researchers begun to look at the post-operative dressing as a possible consideration when trying to prevent incision wound healing complications. Currently, no standard post-operative dressing for primary or revision total ankle replacement exists. However, the principles of post-operative edema reduction to improve healing, as advocated by Sir Robert Jones and demonstrated in his compressive dressing, have been known for decades. We have been using a modified Sir Robert Jones compressive dressing for both primary and revision total ankle replacements. Recently, we have added an aperture pad made of cotton cast padding over the anterior incision in order to protect the area from pressure necrosis., Methods: This is a comparison study of the post-operative wound complications involving 35 patients that received the original dressing and 33 patients that received the addition of the aperture pad., Results: With no significant difference in the patient populations, the results demonstrate a 3-fold decrease in the number of anterior incision wound healing complications with the use of the aperture pad., Conclusion: This dressing represents a simple, reproducible, easy to apply and inexpensive way to prevent post-operative edema and anterior incision wound healing complications.

Background: Obesity and atrial fibrillation (AF) frequently coexist. Weight loss reduces the burden of AF, but whether this is sustained, has a dose effect, or is influenced by weight fluctuation is unknown., Objectives: This study sought to evaluate the long-term impact of weight loss and weight fluctuation on rhythm control in obese individuals with AF., Methods: Of 1,415 consecutive patients with AF, 825 had a body mass index ≥ 27 kg/m(2) and were offered weight management. After screening for exclusion criteria, 355 were included in this analysis. Weight loss was categorized as group 1 (≥ 10%), group 2 (3% to 9%), and group 3 (<3%). Weight trend and/or fluctuation was determined by yearly follow-up. We determined the impact on the AF severity scale and 7-day ambulatory monitoring., Results: There were no differences in baseline characteristics or follow-up among the groups. AF burden and symptom severity decreased more in group 1 compared with groups 2 and 3 (p < 0.001 for all). Arrhythmia-free survival with and without rhythm control strategies was greatest in group 1 compared with groups 2 and 3 (p < 0.001 for both). In multivariate analyses, weight loss and weight fluctuation were independent predictors of outcomes (p < 0.001 for both). Weight loss ≥ 10% resulted in a 6-fold (95% confidence interval: 3.4 to 10.3; p < 0.001) greater probability of arrhythmia-free survival compared with the other 2 groups. Weight fluctuation >5% partially offset this benefit, with a 2-fold (95% confidence interval: 1.0 to 4.3; p = 0.02) increased risk of arrhythmia recurrence., Conclusions: Long-term sustained weight loss is associated with significant reduction of AF burden and maintenance of sinus rhythm. (Long-Term Effect of Goal directed weight management on Atrial Fibrillation Cohort: A 5 Year follow-up study [LEGACY Study]; ACTRN12614001123639)., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The dysregulation of glucose-inhibited glucagon secretion from the pancreatic islet α-cell is a critical component of diabetes pathology and metabolic disease. We show a previously uncharacterized [Ca(2+)]i-independent mechanism of glucagon suppression in human and murine pancreatic islets whereby cAMP and PKA signaling are decreased. This decrease is driven by the combination of somatostatin, which inhibits adenylyl cyclase production of cAMP via the Gαi subunit of the SSTR2, and insulin, which acts via its receptor to activate phosphodiesterase 3B and degrade cytosolic cAMP. Our data indicate that both somatostatin and insulin signaling are required to suppress cAMP/PKA and glucagon secretion from both human and murine α-cells, and the combination of these two signaling mechanisms is sufficient to reduce glucagon secretion from isolated α-cells as well as islets. Thus, we conclude that somatostatin and insulin together are critical paracrine mediators of glucose-inhibited glucagon secretion and function by lowering cAMP/PKA signaling with increasing glucose., (Copyright © 2015 the American Physiological Society.)

Inappropriate glucagon secretion contributes to hyperglycemia in inflammatory disease. Previous work implicates the proinflammatory cytokine interleukin-6 (IL-6) in glucagon secretion. IL-6-KO mice have a blunted glucagon response to lipopolysaccharide (LPS) that is restored by intravenous replacement of IL-6. Given that IL-6 has previously been demonstrated to have a transcriptional (i.e., slow) effect on glucagon secretion from islets, we hypothesized that the rapid increase in glucagon following LPS occurred by a faster mechanism, such as by action within the brain. Using chronically catheterized conscious mice, we have demonstrated that central IL-6 stimulates glucagon secretion uniquely in the presence of an accompanying stressor (hypoglycemia or LPS). Contrary to our hypothesis, however, we found that IL-6 amplifies glucagon secretion in two ways; IL-6 not only stimulates glucagon secretion via the brain but also by direct action on islets. Interestingly, IL-6 augments glucagon secretion from both sites only in the presence of an accompanying stressor (such as epinephrine). Given that both adrenergic tone and plasma IL-6 are elevated in multiple inflammatory diseases, the interactions of the IL-6 and catecholaminergic signaling pathways in regulating GCG secretion may contribute to our present understanding of these diseases., (Copyright © 2014 the American Physiological Society.)

Androgen receptor (AR) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between AR and forkhead box (FOX) transcription factors, particularly FOXA1. We sought to identity additional FOXA1 binding partners that may mediate prostate-specific gene expression. Here we identify the nuclear factor I (NFI) family of transcription factors as novel FOXA1 binding proteins. All four family members (NFIA, NFIB, NFIC, and NFIX) can interact with FOXA1, and knockdown studies in androgen-dependent LNCaP cells determined that modulating expression of NFI family members results in changes in AR target gene expression. This effect is probably mediated by binding of NFI family members to AR target gene promoters, because chromatin immunoprecipitation (ChIP) studies found that NFIB bound to the prostate-specific antigen enhancer. Förster resonance energy transfer studies revealed that FOXA1 is capable of bringing AR and NFIX into proximity, indicating that FOXA1 facilitates the AR and NFI interaction by bridging the complex. To determine the extent to which NFI family members regulate AR/FOXA1 target genes, motif analysis of publicly available data for ChIP followed by sequencing was undertaken. This analysis revealed that 34.4% of peaks bound by AR and FOXA1 contain NFI binding sites. Validation of 8 of these peaks by ChIP revealed that NFI family members can bind 6 of these predicted genomic elements, and 4 of the 8 associated genes undergo gene expression changes as a result of individual NFI knockdown. These observations suggest that NFI regulation of FOXA1/AR action is a frequent event, with individual family members playing distinct roles in AR target gene expression.

The development of multi-colored fluorescent proteins, nanocrystals and organic fluorophores, along with the resulting engineered biosensors, has revolutionized the study of protein localization and dynamics in living cells. Hyperspectral imaging has proven to be a useful approach for such studies, but this technique is often limited by low signal and insufficient temporal resolution. Here, we present an implementation of a snapshot hyperspectral imaging device, the image mapping spectrometer (IMS), which acquires full spectral information simultaneously from each pixel in the field without scanning. The IMS is capable of real-time signal capture from multiple fluorophores with high collection efficiency (∼65%) and image acquisition rate (up to 7.2 fps). To demonstrate the capabilities of the IMS in cellular applications, we have combined fluorescent protein (FP)-FRET and [Ca(2+)](i) biosensors to measure simultaneously intracellular cAMP and [Ca(2+)](i) signaling in pancreatic β-cells. Additionally, we have compared quantitatively the IMS detection efficiency with a laser-scanning confocal microscope.