Exercising immune cells: The immunomodulatory role of exercise on atrial fibrillation
Introduction
The benefits of regular physical activity (PA) have been vastly documented by clinical and basic science evidence, demonstrating attenuation of cardiovascular (CV) disease (CVD) risk factors and, consequently, reducing the chance of developing CVD.1,2 Taking into consideration that multiple modifiable CVD risk factors raise the occurrence of atrial fibrillation (AF), a planned and structured exercise intervention to improve or maintain cardiorespiratory fitness (CRF) is recommended as a feasible and non-pharmacology therapy for AF patients.3, 4, 5, 6 Although the CV benefits of exercise are undeniable, there is increasing evidence suggesting an increased risk of AF in individuals participating in decades of vigorous endurance programs and in high-performance endurance athletes.7, 8, 9, 10 In this sense, studies have proposed that long-term vigorous exercise may lead to harmful arrhythmic events associated with inflammation.11,12 However, the pathophysiological and molecular mechanisms underlying the exercise-induced AF are not fully understood.
Exercise intensity has been suggested as the determining factor for the increased risk of AF in highly trained individuals.13, 14, 15 Nevertheless, other variables of exercise training and the presence of genetic or acquired CV abnormalities are also decisive to either lead to a prevention/management of AF or to trigger AF substrates. To the best of our knowledge, this is the first review to debate the implication of exercise-induced immunomodulation on AF. Additionally, here we discuss the conjecture that excessive endurance exercise over many years may induce AF by triggering atrial inflammation.
Section snippets
High-intensity exercise: too much of a good thing?
AF is the most common clinical arrhythmia with a significant impact on the healthcare system, particularly because it is associated with a 5-fold increase in the risk of stroke.16 While the therapeutic effects of exercise training have been largely reported in patients with heart failure and AF,3,17, 18, 19 opposite CVD outcomes have also been observed.20,21 Since the pioneering study by Karjalainen et al.22 reporting that endurance athletes have a higher incidence of AF than sedentary
Mechanisms of AF in athletes: a lone event?
The mechanisms by which exercise affects the development of AF are unclear. Atrial remodeling (atrial dilatation and fibrosis) is a potential factor contributing to exercise-induced proarrhythmogenic risk and a critical substrate for AF-promoting reentry and self-perpetuation.50,51 LA enlargement is commonly observed in larger cohorts of competitive athletes with AF,37,38,52, 53, 54 as well as LA function reduction.54
However, it is not clear whether atrial remodeling observed in athletes is
Exercise-induced changes in innate immunity
The concept that exercise modulates the immune system emerged from the observation of increased peripheral blood lymphocyte during vigorous exertion, which is suppressed in the following hours after exercise.63 Lymphocyte mobilization observed during acute vigorous exercise is associated with enhanced influx of natural killer and CD8+ T cells into the bloodstream.64 Upon exercise cessation, the transient lymphocyte reduction remains poorly understood, whether it represents a suppression of
What does the evidence from animal research tell Us?
Despite the compelling progress in the identification of factors related to the pathogenesis of exercise-induced AF, this area is still an emerging research topic. Multiple mechanisms, such as enhanced vagal tone, electrophysiological changes, and tissue remodeling, are viewed as critical for AF pathogenesis.50 However, genetic variants are also decisive components and facilitators of arrhythmias.79 In this context, exercise training might be deleterious or lethal in some particular cases, like
Conclusion
Given the high complexity involving interactions between stimuli generated by endurance exercise and the responses of the innate immune system, the final response might be different in healthy versus diseased individuals. Thus, linear, exponential, or J-shaped projections establishing the relationship between endurance training and the development of AF misrepresent the inherent molecular fingerprint and its interaction with the variables of exercise training. Despite the great progress both in
Disclosures
None.
Funding
None.
Declaration of Competing Interest
None.
Acknowledgement
This work was carried out with the support of the Coordination for the Improvement of Higher Education Personnel - Brazil (Capes).
References (143)
- et al.
Resistance exercise mediates remote ischemic preconditioning by limiting cardiac eNOS uncoupling
J Mol Cell Cardiol
(2018) - et al.
Sudden death in young adults: an autopsy-based series of a population undergoing active surveillance
J Am Coll Cardiol
(2011) - et al.
Atrial fibrillation in athletes: a lesson in the virtue of moderation
JACC Clin Electrophysiol
(2017) - et al.
Atrial fibrillation promotion by endurance exercise: demonstration and mechanistic exploration in an animal model
J Am Coll Cardiol
(2013) - et al.
Running away from cardiovascular disease at the right speed: the impact of aerobic physical activity and cardiorespiratory fitness on cardiovascular disease risk and associated subclinical phenotypes
Prog Cardiovasc Dis
(2020) - et al.
2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation
Heart Rhythm
(2017) - et al.
Relation of physical activity and incident atrial fibrillation (from the multi-ethnic study of atherosclerosis)
Am J Cardiol
(2015) - et al.
Relation of vigorous exercise to risk of atrial fibrillation
Am J Cardiol
(2009) - et al.
High-intensity interval exercise effectively improves cardiac function in patients with type 2 diabetes mellitus and diastolic dysfunction: a randomized controlled trial
J Am Coll Cardiol
(2014) - et al.
Impact of CARDIOrespiratory FITness on arrhythmia recurrence in obese individuals with atrial fibrillation: the CARDIO-FIT study
J Am Coll Cardiol
(2015)
High-intensity endurance training is associated with left atrial fibrosis
Am Heart J
State of the art review: atrial fibrillation in athletes
Heart Lung Circ
Acute exercise mobilises CD8+ T lymphocytes exhibiting an effector-memory phenotype
Brain Behav Immun
Exercise-induced redistribution of T lymphocytes is regulated by adrenergic mechanisms
Brain Behav Immun
Exercise, sleep and cytokines: is there a relation?
Sleep Med Rev
FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death
Cell.
Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation
Heart Rhythm
Accentuated vagal antagonism paradoxically increases ryanodine receptor calcium leak in long-term exercised Calsequestrin2 knockout mice
Heart Rhythm
Atrial fibrillation in inherited cardiac channelopathies: from mechanisms to management
Heart Rhythm
Inhibition of soluble TNFα prevents adverse atrial remodeling and atrial arrhythmia susceptibility induced in mice by endurance exercise
J Mol Cell Cardiol
Downregulation of connexin 43 gene expression in rat heart during inflammation. The role of tumour necrosis factor
Cytokine.
Cross-talk between macrophages and atrial myocytes in atrial fibrillation
Basic Res Cardiol
Exercise-related acute cardiovascular events and potential deleterious adaptations following Long-term exercise training: placing the risks into perspective-an update: a scientific statement from the American Heart Association
Circulation.
Lifestyle and risk factor modification for reduction of atrial fibrillation: a scientific statement from the American Heart Association
Circulation
Physical activity, cardiorespiratory fitness, and cardiovascular outcomes in individuals with atrial fibrillation: the HUNT study
Eur Heart J
ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS)
Eur Heart J
ESC guidelines on sports cardiology and exercise in patients with cardiovascular disease
Eur Heart J
Incidence of sudden cardiac death in National Collegiate Athletic Association athletes
Circulation.
Long-term endurance sport practice increases the incidence of lone atrial fibrillation in men: a follow-up study
Europace.
Is atrial fibrillation an inflammatory disorder?
Eur Heart J
Differential association of exercise intensity with risk of atrial fibrillation in men and women: evidence from a meta-analysis
J Cardiovasc Electrophysiol
Diagnosis, pathophysiology, and management of exercise-induced arrhythmias
Nat Rev Cardiol
Atrial fibrillation as an independent risk factor for stroke: the Framingham study
Stroke.
Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study
Circulation.
Physical activity is associated with a reduced risk of atrial fibrillation in middle-aged and elderly women
Heart.
Excess of exercise increases the risk of atrial fibrillation
Scand J Med Sci Sports
Lone atrial fibrillation in vigorously exercising middle aged men: case-control study
BMJ.
Is the risk of atrial fibrillation higher in athletes than in the general population? A systematic review and meta-analysis
Europace.
Emerging risk factors and the dose-response relationship between physical activity and lone atrial fibrillation: a prospective case-control study
Europace.
Physical activity, height, and left atrial size are independent risk factors for lone atrial fibrillation in middle-aged healthy individuals
Europace.
Sinus node disease and arrhythmias in the long-term follow-up of former professional cyclists
Eur Heart J
Cardiorespiratory fitness and risk of incident atrial fibrillation: results from the Henry ford exercise testing (FIT) project
Circulation.
Physical activity and the risk of incident atrial fibrillation in women
Circ Cardiovasc Qual Outcomes
Physical activity modifies the risk of atrial fibrillation in obese individuals: the HUNT3 study
Eur J Prev Cardiol
The physical activity guidelines for Americans
JAMA.
Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study
Circulation.
Aerobic interval training reduces the burden of atrial fibrillation in the short term: a randomized trial
Circulation.
Effects of long-term exercise training on autonomic control in myocardial infarction patients
Hypertension.
Atrial fibrillation is associated with different levels of physical activity levels at different ages in men
Heart.
Exercise capacity and muscle strength and risk of vascular disease and arrhythmia in 1.1 million young Swedish men: cohort study
BMJ
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