Effect of physical exercise on metabolism in patients with atrial fibrillation

Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, is closely linked to metabolic dysfunctions, including obesity, diabetes, and dyslipidemia. These lead to pathological changes in myocardial metabolism and mitochondrial energy metabolism, thereby aggravating AF's incidence and severity. This review introduces the role of metabolic dysfunctions in exacerbating AF, assesses the therapeutic potential of physical exercise and investigates it as a non-pharmacological intervention to alleviate these metabolic disturbances. Evidence suggests that regular physical activity not only enhances metabolic profiles but also reduces the frequency of AF episodes and improves overall cardiovascular health. At the same time, the review emphasizes the need for individualized exercise regimens, individualized to the metabolic and cardiac conditions of each patient to optimize benefits and minimize risks. Additionally, it calls for more basic studies and large-scale clinical trials to establish and refine evidence-based exercise guidelines specific to AF management.

1 Introduction

Atrial fibrillation (AF) is a prevalent arrhythmia affecting 1% of individuals over the age of 60. The estimated global prevalence was 50 million in 2020. The main risk factors for AF include obesity, physical inactivity, diabetes and high blood pressure. As these factors are exacerbated with age, their incidence gradually increases with age. The 2023 ACC/AHA Guideline for the Management of AF shows that the increasing burden of AF is multifactorial, including the aging of the population, and a rising tide of obesity. The latest ESC guidelines for the management of atrial fibrillation in 2024 show that the prevalence of AF is expected to double in the coming decades due to an aging population, increasing comorbidities, and other reasons (1). To achieve optimal treatment of patients with AF, it is now widely recognized that early and dynamic management of these comorbidities and risk factors is necessary.

Metabolism refers to the organized series of chemical reactions essential for sustaining life, divided into material metabolism and energy metabolism. Material metabolism, encompassing anabolism and catabolism, is primarily the process by which the three major nutrients, sugar, lipids, and proteins, are digested, absorbed, operated on, and broken down in the body. Material metabolism is often accompanied by energy transformations, and catabolism often releases energy. The heart needs large amounts of energy to support its pumping, and the main form of energy, ATP, is obtained mainly from glucose, fatty acids and amino acids in the blood. Therefore, a sophisticated and efficient energy metabolism that works in tandem with material metabolism to maintain myocardial function. Metabolic disorders affecting the production of energy required to maintain systolic function and cardiac output may underlie disease entities.

Atrial fibrillation is marked by the rapid excitation and contraction of atrial myocytes, often associated with ischemia and hypoxia in tissues and organs. In this context, alterations in metabolites can serve as a compensatory mechanism (2). Research indicates that myocardial metabolism plays a crucial role in the pathophysiology of atrial fibrillation (3), and metabolic disorders directly influence the development of atrial fibrillation substrates (4). Thus, the onset and progression of atrial fibrillation are intimately linked to human metabolism and mitochondrial function.

Metabolic disorders including obesity, hyperlipidemia, metabolic syndrome, and diabetes are recognized risk factors for cardiometabolic diseases such as atrial fibrillation and heart failure. Additionally, the age of patients and their medications often contribute to a complex in vivo metabolic state, further disrupting metabolic equilibrium (5). A national study focusing on Asian populations revealed that individuals with metabolic health issues face a significantly increased risk of atrial fibrillation compared to those who are metabolically healthy (6).

As health awareness increases, particularly in developing countries, greater emphasis is being placed on physical activity. This not only aids in heart function and mood regulation but also appears to slow the progression of atrial fibrillation in patients. Although the specific benefits, such as improvements in blood metabolites, cardiac remodeling, and electrophysiological function, are not fully understood, the evidence underscores the need for further, individualized research to target physical activity recommendations effectively.

This review explores the altered metabolic status in patients with atrial fibrillation, with a focus on energy and substance metabolism. It aims to assess how exercise can improve symptoms and enhance the quality of life, analyzing the underlying mechanisms through which physical activity impacts patients with atrial fibrillation.

2 Metabolic characteristics of patients with atrial fibrillation

2.1 Lipid metabolism and atrial fibrillation

Under normal conditions, the heart generates ATP primarily from glucose, fatty acids, and amino acids, which it must derive from the bloodstream due to its limited storage capacity. Notably, over 50% of the ATP produced in the mitochondria is derived from fatty acid oxidation (7). Within cardiomyocytes, ingested fatty acids are converted into fatty acyl-coenzyme A (CoA), which is then subjected to β-oxidation to produce acetyl-CoA. This acetyl-CoA enters the tricarboxylic acid (TCA) cycle, essential for substance metabolism. Concurrently, this process generates FADH2 and NADH, which are crucial for the electron transport chain in the mitochondrial membrane, facilitating ATP production. Changes in the metabolites associated with the TCA cycle indicate cardiac metabolic dysregulation, often due to altered hemodynamics, hypoxia, and insufficient energy substrates. Obesity is a known risk predictor for atrial fibrillation, as the accumulation of fat enhances neurohormonal activation, oxidative stress, and cardiac remodeling (8). Obesity, a pro-inflammatory state, heightens the risk of insulin resistance, hypertension, and hyperlipidemia due to adipose tissue enlargement. The location of this enlargement varies in risk. Ectopic adipose tissue, such as myocardial adipose near coronary arteries, epicardial adipose tissue (EAT), and pericardial adipose tissue (PAT), significantly increases cardiovascular risk. This is particularly critical in patients with type 2 diabetes, where it contributes to structural and energetic abnormalities in the heart (9). EAT releases pro-inflammatory and pro-fibrotic cytokines such as IL-1β and IL-6 via paracrine or vascular secretion, with deleterious effects such as accelerated vascular sclerosis, a condition that can be mitigated through medication and physical activity (10). In addition, EAT and PAT play a role in the pathogenesis of cardiovascular diseases such as AF through complex mechanisms that include gene expression profiles, neuromodulation, and glucose and lipid metabolism (11). Specifically, EAT and PAT have become a risk factor and independent predictors of AF occurrence and recurrence after ablation (12, 13). The infiltration of EAT into the atrial myocardium plays a crucial role in forming the substrate for atrial fibrillation. The pathogenic role of EAT in AF may begin during embryogenesis and development, affecting the differentiation of cardiac fibroblasts and smooth muscle cells. Fatty acid infiltration and fibrosis then lead to cardiac conduction abnormalities and affect the local electrophysiological properties of the atria (11, 14). An Australian clinical study demonstrated that obesity leads to increased EAT infiltration, which in turn promotes atrial fibrosis and disrupts normal cardiac electrophysiological conduction (15). Patients with fatty liver exhibit thicker epicardial adipose tissue and more severe fibrosis compared to healthy individuals (16). Studies have established a connection between nonalcoholic fatty liver disease (NAFLD) and atrial fibrillation, noting significant changes in heart structure and function, including diastolic dysfunction. Furthermore, cardiometabolic risk factors often interact, exacerbating the adverse effects of fat accumulation, particularly in hypertensive patients (17).

In obese patients, those with metabolic disorders—such as hypertension, hypercholesterolemia, or diabetes—are more prone to the progression of atrial fibrillation (18). These metabolic disorders contribute to impaired vascular function, cellular inflammation, fibrosis, and remodeling of the atrial and arterial walls. This indicates that metabolic conditions are interconnected, with one abnormality potentially exacerbating others, leading to more severe health consequences.

Lipidomic and metabolomic analyses of obese mouse models on prolonged high-fat diets reveal that obesity disrupts atrial energy metabolism, primarily through the accumulation of long-chain lipids and the activation of β-oxidation. The excessive influx of fatty acids into the atria modifies the oxidative profile of the atrial myocardium, resulting in fatty, inflamed tissue and altered electrical properties, thereby increasing susceptibility to atrial fibrillation (19).

2.2 Glucose metabolism and atrial fibrillation

Poor glycemic control exacerbates oxidative stress, chronic inflammation, and leads to cardiac hypertrophy, as well as increased vascular and interstitial collagen deposition. It also contributes to abnormal intracellular calcium levels, endothelial and mitochondrial dysfunction, and increased apoptosis. Consequently, individuals with diabetes, particularly those with poor glycemic control and albuminuria, face a significantly higher risk of atrial fibrillation compared to the general population (20). Fibrosis development in the myocardial interstitium impairs cardiac electrophysiological conduction, a condition notably exacerbated in diabetic patients.

Hyperglycemia, a state of metabolic dysregulation, can induce stress in the endoplasmic reticulum, an organelle crucial for protein synthesis, folding, and transport. Under stress, it releases calcium into the cell, which then enters the mitochondria through calcium channels, inducing oxidative stress and impacting energy metabolism. Inhibiting this calcium transfer between the endoplasmic reticulum and mitochondria can mitigate calcium overload and oxidative stress, reduce the generation of reactive oxygen species (ROS) in mitochondria, and decrease apoptosis (21).

Diabetes mellitus and cardiovascular diseases are linked by numerous pathogenic mechanisms. At the vascular level, diabetes-related complications often present as pan-vascular lesions, characterized by endothelial dysfunction, which frequently leads to cardiovascular events. Diabetes also disrupts cardiac metabolism through glucotoxicity and lipotoxicity, impairs mitochondrial function, and triggers inflammation. These factors contribute to endoplasmic reticulum stress and apoptosis, ultimately leading to ventricular remodeling (22). Individuals with elevated blood glucose levels are at an increased risk of developing atrial fibrillation, particularly its persistent and permanent forms. Diabetes is not merely an isolated condition but part of a complex systemic disorder. This complexity is heightened as hyperglycemic individuals frequently exhibit comorbidities such as hypertension, peripheral vascular disease, obesity, and thromboembolism, all of which significantly contribute to the onset of atrial fibrillation (23).

Antidiabetic drugs are not only beneficial in controlling blood sugar but also have a protective effect on the heart. Dipeptidyl peptidase-4 (DPP-4) inhibitors ameliorate glucose metabolism by enhancing glucagon-like peptide-1 (GLP-1) receptor signaling, inducing insulin secretion and inhibiting glucagon secretion (24). DPP-4 inhibitors as well as GLP-1 receptor agonists can reduce monocyte/macrophage accumulation by inhibiting the inflammatory response of monocytes/macrophages and also beneficial to the cardiovascular system (25–28). Alogliptin, a DPP-4 inhibitor commonly used in diabetes management, not only regulates blood glucose levels but also exhibits antioxidant, anti-inflammatory, and antifibrotic properties, offering cardioprotective benefits (29, 30). Sodium-dependent glucose transporters 2 inhibitors(SGLT2i), which inhibit glucose reabsorption by the kidneys, allowing excess glucose to be excreted in the urine and reducing blood glucose. As a new antidiabetic drug, it also shows positive cardioprotective properties and can reduce hospitalization for cardiovascular outcomes in patients (31). Patients with type 2 diabetes at high risk for cardiovascular events who were treated with empagliflozin had a reduced incidence of the major composite cardiovascular outcome and all-cause mortality (32). Large-scale clinical trial has shown a decrease in the incidence and recurrence of atrial fibrillation in people treated with dapagliflozin (33). The largest network meta-analysis published to date has shown that the use of gliflozins has a significant effect on the reduction of the incidence of atrial fibrillation in the overall population (34).

2.3 Mitochondrial function and atrial fibrillation

Mitochondria are central to several cellular functions, including energy production (ATP), ROS generation and scavenging, calcium homeostasis, and regulation of nuclear gene expression, as well as cell death and survival mechanisms. As the main site for ROS production, maintaining mitochondrial integrity is vital for cardiac health. Cardiac tissues generate ROS through mechanisms involving NADPH oxidase, xanthine oxidase, and uncoupled nitric oxide synthase. Damage to mitochondrial DNA or mitochondrial dysfunction can disrupt cardiac rhythms by impairing the energy supply essential for ion channels and transporters (35, 36). Elevated levels of reactive oxygen species (ROS) can damage proteins, lipids, and DNA, particularly mitochondrial DNA. Additionally, ROS promotes inflammation by enhancing cytokine production and activating inflammatory cells, which exacerbates tissue damage. Increased mitochondrial ROS production is also associated with the formation of arrhythmic substrates, contributing to both structural changes and electrocardiographic remodeling in the heart. The dynamic balance of mitochondrial fusion and fission, which regulates mitochondrial size and quantity, is crucial for maintaining mitochondrial function. Disruption in this balance can impair the energy supply required for cardiac activity, leading to abnormal cardiac function.

Evidence suggests that mitochondrial dysfunction in the atria plays a critical role in the development of atrial fibrillation. Atrial remodeling, which includes structural and functional changes such as alterations in electrical properties and contractility, along with changes in the extracellular matrix composition, promotes tissue heterogeneity. This heterogeneity can lead to slowed conduction and electrolytic uncoupling, further advancing atrial fibrillation. Key mechanisms driving atrial remodeling include impaired mitochondrial oxidative respiration and endoplasmic reticulum stress. Additionally, inflammation and oxidative stress are pivotal in the pathogenesis of atrial fibrillation, highlighting the potential effectiveness of antioxidant therapies in preventing atrial remodeling (37). Research has demonstrated that alogliptin reduces mitochondrial swelling in the atria of diabetic animal models, stabilizes mitochondrial membrane potential, and curbs ROS production. Additionally, it prevents mitochondrial respiratory dysfunction and electrical remodeling of the heart (38). Furthermore, alogliptin reduces insulin resistance and plasma stress, and it restores impaired mitochondrial function (39).

2.4 Alcohol, caffeine, and cardiac electrophysiology

Caffeine and alcohol are known to trigger acute episodes of atrial fibrillation. Smoking increases the risk of AF by more than twofold, while the incidence tends to decrease in those who quit smoking (40). These correlation may be influenced by blood metabolites and cardiac electrophysiological conduction (41).

2.5 Renal metabolism and atrial fibrillation

The kidneys are essential organs for metabolism, playing a crucial role in maintaining body fluid and electrolyte balance, as well as performing endocrine functions. The incidence of atrial fibrillation is notably high in patients with chronic kidney disease. Chronic kidney disease and elevated urinary albumin-to-creatinine ratios are associated with the development of atrial fibrillation (42). Additionally, an association has been observed between chronic kidney disease and the incidence of atrial fibrillation in participants with a mean age over 70 years (43). Therefore, it is especially important to focus on the relationship between kidney health and cardiovascular health in older adults.

2.6 Gut flora and atrial fibrillation

Intestinal flora, composed of the normal microorganisms in the human gut, play a critical role in metabolizing sugars and proteins, as well as absorbing trace elements. The metabolism of intestinal flora is linked to the development of cardiovascular disease. Regular physical activity not only affects the distribution and metabolites of intestinal flora but also enhances intestinal barrier function. Promoting a healthy gut flora phenotype reduces the risk of cardiovascular diseases. Although the specific mechanisms are not fully understood, they may involve processes such as cellular material exchange, energy production, endotoxemia, bacterial translocation, and metabolite accumulation (44, 45). Physical activity helps regulate the transition of gut flora to a healthy phenotype, producing inflammatory factors that may modulate intestinal permeability and influence cardiovascular physiology (46).

3 Mechanisms of the effect of physical activity on atrial fibrillation

Atrial fibrillation is characterized by cardiac electrophysiological dysregulation, with patients experiencing abnormalities in the expression and activity of ion channels in cardiomyocytes. These changes may be related to fibroblast-mediated stress and mechanical stimulation. Elevated blood levels of inflammatory factors, such as IL-6, may also serve as potential mechanical stimuli, influencing ion channel activity in atrial myocytes (47). During exercise, the release of catecholamines, specifically epinephrine and norepinephrine, increases heart rate and cardiac contractility. This is accompanied by skeletal muscle vasodilation, muscle congestion, and enlargement. In individuals who engage in long-term exercise training, the myocardium may become hypertrophied due to increased cardiac load, driven by sympathetic nerve activation and the release of growth factors. However, this type of hypertrophy differs from pathological hypertrophy, as it lacks pathological features like fibrosis (48).

Animal experiments have shown that regular exercise training inhibits the expression of potassium channels and prolongs the atrial operational period, which protects the myocardium in atrial fibrillation (AF). Conversely, enhanced parasympathetic activity from strenuous exercise activates acetylcholine-sensitive potassium channels, shortening the refractory period and increasing susceptibility to AF (49).

Study has demonstrated that exercise training improves exercise capacity, cardiac function, and quality of life in AF patients (50). Patients undergoing catheter ablation for AF often show improved exercise capacity due to better cardiac rhythm control. However, a lack of improvement in exercise capacity within 12 months post-ablation is an independent risk factor for AF recurrence (51). The UK Biobank study, involving nearly half a million people, found that physically active participants had a lower risk of AF and reduced risk of ventricular arrhythmias (52). A European cohort study on AF outcomes revealed a nearly 35% increase in the odds of AF progression in physically inactive patients, with a higher incidence of AF progression at 1-year follow-up compared to active patients (17.7% vs. 6.8%) (53). Additionally, exercise-based rehabilitation reduced rates of all-cause mortality, rehospitalization, and stroke, regardless of gender, age, or AF subtype (54). Baseline survey has shown that physical activity in AF patients is associated with lower mortality, independent of gender and age (55). The risk of AF is lower in the exercise maintenance group compared to the continuously inactive group. An exercise level of 1,500 MET-min/week (1 MET equals 1 kilocalorie of energy burned per kilogram of body weight per hour) is the threshold above which exercise reduces the risk of AF progression. Current guidelines recommend 150 to 300 min of moderate-intensity aerobic exercise, 150 min of higher-intensity aerobic exercise, or 75 min of vigorous exercise per week, equivalent to 450 METs of physical activity (56). A meta-analysis including 1,464,539 people showed that achieving guideline-recommended exercise levels effectively reduces the risk of AF (57). Regular-intensity training improves risk factors for AF such as sleep apnea syndrome, obesity, and hypertension, and also reduces the burden of AF (58). Another study of 10,000 people confirmed that completing cardiac rehabilitation alone had no significant effect on reducing AF risk, highlighting the importance of improving cardiorespiratory fitness (59). Moderate physical activity and enhanced cardiorespiratory fitness have been associated with a lower long-term risk of cardiovascular disease and all-cause mortality in AF patients. This finding, from cohort studies, supports the role of routine physical activity and improved cardiorespiratory fitness in reducing the elevated risk of mortality and morbidity in AF patients (60).

However, it is important to note that greater exercise intensity does not always equate to greater benefits. Current consensus suggests that, within limits, more intense exercise improves cardiorespiratory fitness. Yet, strenuous high-intensity exercise can be harmful (61), as it increases the risk of sudden death, acute myocardial infarction, stroke, and ventricular arrhythmia (62). High-intensity physical activity can lead to inflammation, remodeling, and autonomic activation (63), and the inflammatory environment resulting from prolonged intense exercise may trigger harmful arrhythmic events (64). The aforementioned meta-analysis indicated that the risk reduction for atrial fibrillation ceases when exercise exceeds 1,900 MET minutes per week (57). Strenuous endurance exercise can induce adverse atrial remodeling and increase arrhythmic susceptibility. In animal experiments, the release of the proinflammatory cytokine tumor necrosis factor induced by strenuous exercise mediates adverse atrial remodeling and susceptibility to atrial fibrillation (65).

When considering various factors, it is crucial to make a comprehensive judgment. For athletes, despite the risks of high-intensity exercise causing arrhythmia, they tend to have a longer life expectancy than other AF patients due to a lower prevalence of metabolic diseases such as hyperlipidemia, diabetes, hypertension, and coronary heart disease (60). Meanwhile, the UK Biobank study also found that vigorous exercise in women reduces the risk of atrial fibrillation and fatal ventricular arrhythmias (52). This suggesting that the effects of exercise can vary among individuals, exercise intensity, frequency, and type should be adjusted according to a patient's unique metabolic and cardiovascular profile. According to the newest guideline of sports cardiology by ESC, although AF is more common among elite male athletes and those who engage in high-intensity endurance sports, it is reasonable to recommend moderate-intensity exercise to prevent AF because of the U-shaped curve between exercise and AF (66). Notably, metabolism-related assessments, such as thyroid function and drinking status, are essential prior to exercise. In patients combined with obesity, exercise intervention alone have little effect on fat mass, so the addition of resistance exercise to resistance exercise is recommended. This can improve the glucose tolerance, insulin sensitivity, lipid profile, and chronic inflammation (67–69). In patients combined with dyslipidemia, such as hypertriglyceridemia or hypercholesterolemia, more intense exercise is suitable because it can improve the lipid profile and reduce cardiovascular risk (70, 71). In patients combined with diabetes mellitus, both aerobic and resistance exercise enhance pancreatic function, with moderate- or high-intensity exercise having a more pronounced effect on reducing the risk of metabolic impairment. In addition, flexibility and balance exercises are beneficial, especially in patients with microvascular complications due to diabetes (72, 73).

High-Intensity Interval Training (HIIT) involves short, intense workouts that increase heart rate and burn more calories in a shorter period, creating a hypoxic state that boosts the body's oxygen demand. A study published in JAMA Network Open reports that twice-weekly, 23-minute HIIT sessions are as effective as twice-weekly, 60-minute moderate to high-intensity continuous training for improving functional capacity, resting heart rate, and quality of life in patients with atrial fibrillation (74). Here, HIIT is defined as two 8-minute interval training blocks of 30-second work periods at 80%-100% of peak power output interspersed with 30-second recovery. There can be many types of HIIT, as its no specific formula and there are no international guidelines, but an entire HIIT workout usually lasts between four and thirty minutes. HIIT is a cardiovascular exercise strategy that can have many types as its no specific formula and there are no universal international guidelines, but the entire HIIT workout usually lasts around thirty to forty minutes and is a combination of short repetitions of maximal-intensity exercise (anaerobic) followed by short bursts of lower-intensity activity (recovery) until fatigue, and both the number of repetitions and the length of each interval can vary even slight (75, 76). For example, there is also a typical 4 × 4 HIIT, which includes 4 min of exercise at 95% peak heart rate followed by 3 min of active recovery at 60%–75% peak heart rate, repeated four times (77, 78). HIIT patterns in existing studies vary due to the different fitness levels and tolerance of patients, which requires specific analysis by clinicians, rehabilitation therapists, and exercise and sport specialists (79). Importantly, this approach reduces the total amount of physical activity, lessening the patient's burden. Patients with atrial fibrillation often have dilated left atria and increased vagal tone, which decreases with age. Therefore, the effects of exercise vary based on age and should be recommended on a case-by-case basis (80). It is also crucial to acknowledge the differing impacts of exercise on men and women, requiring careful consideration by clinicians (81).

4 Effects of physical activity on cardiac metabolism

4.1 Physical activity and lipid metabolism

Considering the pathophysiologic mechanism of fat accumulation in the development of atrial fibrillation, regular exercise training, which is less intense than high-intensity training, may reduce the risk of cardiovascular incidents and is a safe and effective strategy (82). Physical activity improves physiological regulation in obese patients by enhancing blood flow and vascular function. Adopting a healthy lifestyle leads to reductions in plasma LDL, triglyceride, and cholesterol levels, which are significant contributors to cardiovascular disease susceptibility. During exercise, lipolysis and the level of free fatty acids increase. High fatty acid oxidation induces a protective phenotype that shields the myocardium from ischemia-reperfusion injury, providing cardioprotection during cardiac stress. However, psychosocial factors are also important. Obese individuals often exercise less due to psychological barriers and decreased respiratory muscle strength and ventilatory restrictions. Consequently, exercise not only reduces the risk of atrial fibrillation but also improves the quality of life for these patients. Metabolomics analyses have indicated that long-term exercise training significantly reduces lipid levels in animal models, suggesting a lipid response to exercise and pressure overload. Intensive lipidomic studies in cardiovascular disease have shown that lipid species in the heart, plasma, or serum can have potential prognostic value. In particular, changes in plasma phospholipids are strongly correlated with atrial disease (83).

4.2 Physical activity and glucose metabolism

Glucose oxidation can occur aerobically or anaerobically (glycolysis). Under conditions of relative hypoxia or certain pathological states, the body accelerates glycolysis. During exercise, the rate of aerobic glucose oxidation increases while the rate of glycolysis decreases. Aerobic glucose oxidation produces fewer protons, maintaining intracellular calcium ion balance, limiting calcium overload, preserving pH balance, and reducing energy expenditure. Thus, the metabolic phenotype generated during exercise is characterized by lower cardiotoxicity and enhanced cardioprotection (48). A study involving over 40,000 diabetes patients in South Korea demonstrated that individuals who had previously exercised but stopped and those who recently started exercising had a lower risk of developing atrial fibrillation compared to those who had not exercised for an extended period. The benefits of exercise for diabetics are potentially linked to improved vascular elasticity, offering protection against pathological atrial remodeling, oxidative stress, inflammation, and permanent damage (84, 85). However, the pressure and volume overload resulting from high metabolic demand during excessive exercise might adversely impact the atria (77, 86).

Although the exact pathophysiological mechanisms are not fully elucidated, structural and electrical remodeling are major contributors to AF. Potential mechanisms linking diabetes and atrial fibrillation include disturbances in energy metabolism, cellular calcium levels, ion channel function, and abnormal conduction, all of which depend on mitochondrial function.

4.3 Physical activity and secondary causes of atrial fibrillation

Secondary causes of AF can also impact on young adults or adolescent metabolism, such as hypertension, hyperthyroidism, lifestyle factors, alcohol consumption, smoking, cardiomyopathies and channelopathies. While exercise or physical activity has been shown to have many benefits, available data suggest an association between endurance exercise and atrial fibrillation and flutter (87), and some rare genetic diseases may also be triggered by exercise. For instance, AF is quite common in patients with hyperthyroidism (88), and men, aging, ischemic heart disease, congestive heart failure, and heart valve disease are associated with an increased risk of AF (89). Fortunately, study has shown a correlation between the amount of physical activity and changes in thyroid function in adults, including thyroid hormone levels and thyroid disorders (90). In addition, some rare arrhythmogenic diseases can cause AF and are closely related to physical exercise. For example, patients with long QT Syndrome, especially LQT3, are at increased risk for early AF (91). European guideline recommend that exercise should be avoided until the cause is effectively corrected (66). Similarly, athletes with catecholaminergic polymorphic ventricular tachycardia should undergo strict risk stratification, while maintaining a healthy lifestyle (92). Recent studies have shown that a generalized ban on exercise for all patients with hypertrophic cardiomyopathy is not justified, and that patients should undergo careful risk stratification and expert advice before choosing an implantable-cardioverter-defibrillator for treatment or exercise (66, 93). In conclusion, some secondary and genetic factors should also be taken into account when considering the effect of physical exercise on AF.

4.4 Physical activity and mitochondrial function

Maintaining normal mitochondrial function is crucial for muscle performance, and its deterioration is a hallmark of cardiovascular diseases. Long-term sustained aerobic exercise effectively preserves mitochondrial health, significantly contributing to long-term cardiovascular well-being. Enhancing the number and function of mitochondria in cardiomyocytes improves electron transfer and oxidative phosphorylation, reduces oxidative stress, promotes mitochondrial autophagy, increases muscle mass, and decreases apoptosis in cardiomyocytes. Regular exercise is a powerful countermeasure against mitochondrial depletion due to aging (94).

At the microscopic level, regulating mitochondrial fusion-associated proteins (Mfn2 and OPA1) and fission-associated proteins (DRP1) is a key target for cardiac therapy. Research indicates that inhibiting excessive mitochondrial fission benefits the heart, and exercise modulates changes in proteins related to mitochondrial fusion and fission (95, 96). Animal study has shown that aerobic training enhances impaired mitochondrial respiratory function and inhibits excessive fission while promoting fusion (97). During exercise, oxygen consumption and muscle ATP usage increase, leading to intensified ATP synthesis. Exercise training promotes endothelial nitric oxide synthase (eNOS)-dependent mitochondrial biogenesis in the heart, crucial for cardiac glucose transport. Coenzyme Q10, a component of the electron transport chain found in high-energy organs like the heart, increases in myocardial levels post-exercise. Elevated coenzyme Q10 levels are beneficial in conditions such as heart failure and diabetic cardiomyopathy (98). Thus, physical exercise positively impacts cardiac energy metabolism by influencing mitochondrial function (99).

4.5 Physical activity and the immune system

The relationship between physical activity and immunity, although not fully understood, exhibits significant heterogeneity based on the type, duration, and intensity of exercise. Physical activity rejuvenates the immune system and reduces inflammatory immune cells by regulating the circulation of immune progenitor cells (100, 101). While moderate exercise strengthens the immune system, strenuous exercise can be counterproductive (102). After vigorous exercise, a rise followed by a fall in peripheral blood lymphocytes is observed (103). The increase in lymphocytes is linked to the influx of natural killer cells and CD8+ T cells into the bloodstream, though the mechanism behind the post-exercise decrease in lymphocytes, potentially involving immune cell redistribution, remains unclear (104). Physical activity modulates macrophage function and regulates the expression of anti-inflammatory factors, possibly through the mTOR pathway or the NLRP3 inflammasome pathway (58). Beyond influencing cytokine synthesis and distribution, the type of muscle used in exercise and an individual's cardiorespiratory fitness level impact the entire immune system (105). Understanding how exercise influences immune cells both acutely and chronically is essential to complement current guidelines and optimize the therapeutic effects of exercise in preventing and reducing inflammation.

5 Discussion

With an increased focus on public health, preventive care, including physical activity and exercise, is gaining more attention. In cardiology, physical activity is linked to various beneficial effects, such as lowering blood pressure, improving hyperlipidemia, and increasing insulin sensitivity (106–109). Regular physical activity has been shown to reduce the risk of stroke and myocardial infarction, as well as decrease overall mortality risk (110). Additionally, regular exercise enhances atrial viability by increasing capillary density, preventing ischemia-reperfusion injury, and promoting the expression of antioxidant genes (111, 112). However, research findings can be contrasting. For example, a study on individuals with metabolic syndrome revealed that lifestyle changes, including diet and exercise, did not impact the occurrence of atrial fibrillation or alter the structure and function of the atria (113). Therefore, this review incorporates various studies to summarize and evaluate the actual effects of physical activity. Generally, the cardiovascular protective benefits of moderate exercise are well-established, partly due to improvements in the body's metabolic status.

A genome-wide association study involving 300,000 people indicated that a healthy lifestyle, including exercise, reduces the risk of developing cardiovascular disease, even in those with a genetic predisposition (114). This finding is significant, especially for individuals with high genetic susceptibility, as it underscores the potential for lifestyle improvements to confer substantial benefits.

This article first discusses the metabolic characteristics of patients with atrial fibrillation, including aspects such as glucose metabolism, lipid metabolism, energy metabolism, and inflammatory status. Understanding these specific metabolic characteristics is crucial for comprehending how exercise impacts these patients and exploring modifiable underlying mechanisms. Following this, the article reviews several clinical cohort studies to summarize the effects of different exercise patterns and intensities. It's important to recognize that more exercise is not always more beneficial, and individual differences must be considered.

During physical activity, the body's metabolic state undergoes changes in anabolism, catabolism, and energy metabolism. Physical activity helps maintain lower blood lipid and glucose levels, reducing the risk of cardiovascular disease, which is particularly crucial for individuals with atrial fibrillation. Exercise induces a protective phenotype through metabolic profile alterations and improves patients' lipid profiles. It also boosts energy metabolism, enhancing physical endurance and reducing frailty. Since glucose and fatty acids are substrates for ATP production, there is a mutual influence between energy metabolism and material metabolism.

Additionally, physical activity positively influences the heart's structure and function in patients with atrial fibrillation. Moderate exercise can enhance heart rhythm and decrease the frequency of atrial fibrillation episodes. Establishing proper exercise habits can improve heart structure and function, reducing the risk of cardiac hypertrophy and, consequently, the incidence of atrial fibrillation. Furthermore, the social and psychological aspects are equally important. Exercise not only benefits physical health but also alleviates psychological issues like anxiety and depression, enhancing the quality of life. Engaging in sports activities increases social interaction and bolsters patients' social support, fostering a supportive community environment for patients.

This review also offers suggestions for future research and clinical practice. There is a growing consensus among clinicians and researchers to employ physical activity as a preventive and therapeutic approach for various heart diseases, including heart failure and atrial fibrillation. These interventions are straightforward, typically without notable side effects, and can reduce healthcare costs while enhancing overall population health. Importantly, a tailored exercise prescription should be provided, considering the individual's condition and characteristics, aligning with the direction of precision medicine.

In conclusion, physical activity benefits not only patients with atrial fibrillation but also those with other cardiovascular diseases, largely through metabolic improvement. Efforts are needed to alter patients' misconceptions and physical limitations regarding exercise, promoting its benefits while ensuring safety and personalization. However, this review acknowledges its limitations, as sports cardiology is an evolving field. The relevant foundational research is not yet extensive, and more detailed findings are required to substantiate the arguments presented.

Author contributions

YW: Conceptualization, Writing – original draft. SW: Writing – review & editing. CX: Writing – original draft. TX: Methodology, Resources, Writing – review & editing. XS: Methodology, Resources, Writing – review & editing. FW: Funding acquisition, Writing – review & editing.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by grants from the National High Level Hospital Clinical Research Funding (BJ-2022-117), CAMS Innovation Fund for Medical Sciences (CIFMS) 2023-I2M-C&T-B-117, 2024 General Program of National Natural Science Foundation of China (No. 82470363) and National High Level Hospital Clinical Research Funding (BJ-2024-150).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Van Gelder IC, Rienstra M, Bunting KV, Casado-Arroyo R, Caso V, Crijns H, et al. 2024 Esc guidelines for the management of atrial fibrillation developed in collaboration with the European association for cardio-thoracic surgery (eacts). Eur Heart J. (2024) 45(36):3314–414. doi: 10.1093/eurheartj/ehae176

PubMed Abstract | Crossref Full Text | Google Scholar

2. Bulló M, Papandreou C, García-Gavilán J, Ruiz-Canela M, Li J, Guasch-Ferré M, et al. Tricarboxylic acid cycle related-metabolites and risk of atrial fibrillation and heart failure. Metab Clin Exp. (2021) 125:154915. doi: 10.1016/j.metabol.2021.154915

PubMed Abstract | Crossref Full Text | Google Scholar

3. Dublin S, Glazer NL, Smith NL, Psaty BM, Lumley T, Wiggins KL, et al. Diabetes mellitus, glycemic control, and risk of atrial fibrillation. J Gen Intern Med. (2010) 25(8):853–8. doi: 10.1007/s11606-010-1340-y

PubMed Abstract | Crossref Full Text | Google Scholar

4. Fossier L, Panel M, Butruille L, Colombani S, Azria L, Woitrain E, et al. Enhanced mitochondrial calcium uptake suppresses atrial fibrillation associated with metabolic syndrome. J Am Coll Cardiol. (2022) 80(23):2205–19. doi: 10.1016/j.jacc.2022.09.041

PubMed Abstract | Crossref Full Text | Google Scholar

5. Volgman AS, Nair G, Lyubarova R, Merchant FM, Mason P, Curtis AB, et al. Management of atrial fibrillation in patients 75 years and older: jacc state-of-the-art review. J Am Coll Cardiol. (2022) 79(2):166–79. doi: 10.1016/j.jacc.2021.10.037

PubMed Abstract | Crossref Full Text | Google Scholar

6. Lee SY, Lee SR, Choi EK, Kwon S, Yang S, Park J, et al. Association between change in metabolic syndrome status and risk of incident atrial fibrillation: a nationwide population-based study. J Am Heart Assoc. (2021) 10(16):e020901. doi: 10.1161/JAHA.121.020901

PubMed Abstract | Crossref Full Text | Google Scholar

7. Lopaschuk GD, Karwi QG, Tian R, Wende AR, Abel ED. Cardiac energy metabolism in heart failure. Circ Res. (2021) 128(10):1487–513. doi: 10.1161/CIRCRESAHA.121.318241

PubMed Abstract | Crossref Full Text | Google Scholar

8. Kornej J, Borschel CS, Benjamin EJ, Schnabel RB. Epidemiology of atrial fibrillation in the 21st century: novel methods and new insights. Circ Res. (2020) 127(1):4–20. doi: 10.1161/CIRCRESAHA.120.316340

PubMed Abstract | Crossref Full Text | Google Scholar

9. Neeland IJ, Ross R, Despres JP, Matsuzawa Y, Yamashita S, Shai I, et al. Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement. Lancet Diabetes Endocrinol. (2019) 7(9):715–25. doi: 10.1016/S2213-8587(19)30084-1

PubMed Abstract | Crossref Full Text | Google Scholar

10. Muzurović EM, Vujošević S, Mikhailidis DP. Can we decrease epicardial and pericardial fat in patients with diabetes? J Cardiovasc Pharmacol Ther. (2021) 26(5):415–36. doi: 10.1177/10742484211006997

PubMed Abstract | Crossref Full Text | Google Scholar

11. Iacobellis G. Epicardial adipose tissue in contemporary cardiology. Nat Rev Cardiol. (2022) 19(9):593–606. doi: 10.1038/s41569-022-00679-9

PubMed Abstract | Crossref Full Text | Google Scholar

12. Wong CX, Ganesan AN, Selvanayagam JB. Epicardial fat and atrial fibrillation: current evidence, potential mechanisms, clinical implications, and future directions. Eur Heart J. (2017) 38(17):1294–302. doi: 10.1093/eurheartj/ehw045

PubMed Abstract | Crossref Full Text | Google Scholar

13. Thanassoulis G, Massaro JM, O'Donnell CJ, Hoffmann U, Levy D, Ellinor PT, et al. Pericardial fat is associated with prevalent atrial fibrillation: the framingham heart study. Circ Arrhythm Electrophysiol. (2010) 3(4):345–50. doi: 10.1161/CIRCEP.109.912055

PubMed Abstract | Crossref Full Text | Google Scholar

14. Munger TM, Dong YX, Masaki M, Oh JK, Mankad SV, Borlaug BA, et al. Electrophysiological and hemodynamic characteristics associated with obesity in patients with atrial fibrillation. J Am Coll Cardiol. (2012) 60(9):851–60. doi: 10.1016/j.jacc.2012.03.042

PubMed Abstract | Crossref Full Text | Google Scholar

15. Mahajan R, Nelson A, Pathak RK, Middeldorp ME, Wong CX, Twomey DJ, et al. Electroanatomical remodeling of the atria in obesity: impact of adjacent epicardial fat. JACC Clin Electrophysiol. (2018) 4(12):1529–40. doi: 10.1016/j.jacep.2018.08.014

PubMed Abstract | Crossref Full Text | Google Scholar

16. Polyzos SA, Kechagias S, Tsochatzis EA. Review article: non-alcoholic fatty liver disease and cardiovascular diseases: associations and treatment considerations. Aliment Pharmacol Ther. (2021) 54(8):1013–25. doi: 10.1111/apt.16575

PubMed Abstract | Crossref Full Text | Google Scholar

17. Aker A, Saliba W, Zafrir B. The interplay among body weight, blood pressure, and cardiorespiratory fitness in predicting atrial fibrillation. Hellenic J Cardiol. (2023) 71:1–7. doi: 10.1016/j.hjc.2022.12.005

PubMed Abstract | Crossref Full Text | Google Scholar

18. Wang R, Olier I, Ortega-Martorell S, Liu Y, Ye Z, Lip GY, et al. Association between metabolically healthy obesity and risk of atrial fibrillation: taking physical activity into consideration. Cardiovasc Diabetol. (2022) 21(1):208. doi: 10.1186/s12933-022-01644-z

PubMed Abstract | Crossref Full Text | Google Scholar

19. Suffee N, Baptista E, Piquereau J, Ponnaiah M, Doisne N, Ichou F, et al. Impacts of a high-fat diet on the metabolic profile and the phenotype of atrial myocardium in mice. Cardiovasc Res. (2022) 118(15):3126–39. doi: 10.1093/cvr/cvab367

PubMed Abstract | Crossref Full Text | Google Scholar

20. Seyed Ahmadi S, Svensson AM, Pivodic A, Rosengren A, Lind M. Risk of atrial fibrillation in persons with type 2 diabetes and the excess risk in relation to glycaemic control and renal function: a Swedish cohort study. Cardiovasc Diabetol. (2020) 19(1):9. doi: 10.1186/s12933-019-0983-1

PubMed Abstract | Crossref Full Text | Google Scholar

21. Yuan M, Gong M, He J, Xie B, Zhang Z, Meng L, et al. Ip3r1/Grp75/Vdac1 Complex mediates endoplasmic Reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling. Redox Biol. (2022) 52:102289. doi: 10.1016/j.redox.2022.102289

PubMed Abstract | Crossref Full Text | Google Scholar

22. Luo Q, Zhuang B, Li G, Jiang Y, Wang Q, Yuan J, et al. Consistency evaluation of exercise target heart rate determined by resting heart rate and anaerobic threshold in chronic heart failure patients. Int J Cardiol. (2023) 381:52–6. doi: 10.1016/j.ijcard.2023.03.056

PubMed Abstract | Crossref Full Text | Google Scholar

23. Gumprecht J, Lip GYH, Sokal A, Średniawa B, Mitręga K, Stokwiszewski J, et al. Relationship between diabetes mellitus and atrial fibrillation prevalence in the Polish population: a report from the non-invasive monitoring for early detection of atrial fibrillation (nomed-af) prospective cross-sectional observational study. Cardiovasc Diabetol. (2021) 20(1):128. doi: 10.1186/s12933-021-01318-2

PubMed Abstract | Crossref Full Text | Google Scholar

24. Satoh-Asahara N, Sasaki Y, Wada H, Tochiya M, Iguchi A, Nakagawachi R, et al. A dipeptidyl peptidase-4 inhibitor, sitagliptin, exerts anti-inflammatory effects in type 2 diabetic patients. Metab Clin Exp. (2013) 62(3):347–51. doi: 10.1016/j.metabol.2012.09.004

PubMed Abstract | Crossref Full Text | Google Scholar

25. Matsubara J, Sugiyama S, Sugamura K, Nakamura T, Fujiwara Y, Akiyama E, et al. A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. J Am Coll Cardiol. (2012) 59(3):265–76. doi: 10.1016/j.jacc.2011.07.053

PubMed Abstract | Crossref Full Text | Google Scholar

26. Arakawa M, Mita T, Azuma K, Ebato C, Goto H, Nomiyama T, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes. (2010) 59(4):1030–7. doi: 10.2337/db09-1694

PubMed Abstract | Crossref Full Text | Google Scholar

27. Shah Z, Kampfrath T, Deiuliis JA, Zhong J, Pineda C, Ying Z, et al. Long-Term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation. (2011) 124(21):2338–49. doi: 10.1161/CIRCULATIONAHA.111.041418

PubMed Abstract | Crossref Full Text | Google Scholar

28. Terasaki M, Nagashima M, Watanabe T, Nohtomi K, Mori Y, Miyazaki A, et al. Effects of Pkf275-055, a dipeptidyl peptidase-4 inhibitor, on the development of atherosclerotic lesions in apolipoprotein E-null mice. Metab Clin Exp. (2012) 61(7):974–7. doi: 10.1016/j.metabol.2011.11.011

PubMed Abstract | Crossref Full Text | Google Scholar

29. Tremblay AJ, Lamarche B, Deacon CF, Weisnagel SJ, Couture P. Effects of sitagliptin therapy on markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. Metab Clin Exp. (2014) 63(9):1141–8. doi: 10.1016/j.metabol.2014.06.004

PubMed Abstract | Crossref Full Text | Google Scholar

30. Ravassa S, Beaumont J, Huerta A, Barba J, Coma-Canella I, Gonzalez A, et al. Association of low glp-1 with oxidative stress is related to cardiac disease and outcome in patients with type 2 diabetes Mellitus: a pilot study. Free Radic Biol Med. (2015) 81:1–12. doi: 10.1016/j.freeradbiomed.2015.01.002

PubMed Abstract | Crossref Full Text | Google Scholar

31. Leslie BR, Gerwin LE. Gliflozins in the management of cardiovascular disease. N Engl J Med. (2022) 387(5):478. doi: 10.1056/NEJMc2207597

PubMed Abstract | Crossref Full Text | Google Scholar

32. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. (2015) 373(22):2117–28. doi: 10.1056/NEJMoa1504720

PubMed Abstract | Crossref Full Text | Google Scholar

33. Zelniker TA, Bonaca MP, Furtado RHM, Mosenzon O, Kuder JF, Murphy SA, et al. Effect of dapagliflozin on atrial fibrillation in patients with type 2 diabetes Mellitus: insights from the declare-timi 58 trial. Circulation. (2020) 141(15):1227–34. doi: 10.1161/CIRCULATIONAHA.119.044183

PubMed Abstract | Crossref Full Text | Google Scholar

34. Mariani MV, Manzi G, Pierucci N, Laviola D, Piro A, D'Amato A, et al. Sglt2i effect on atrial fibrillation: a network meta-analysis of randomized controlled trials. J Cardiovasc Electrophysiol. (2024) 35(9):1754–65. doi: 10.1111/jce.16344

PubMed Abstract | Crossref Full Text | Google Scholar

35. Opacic D, van Bragt KA, Nasrallah HM, Schotten U, Verheule S. Atrial metabolism and tissue perfusion as determinants of electrical and structural remodelling in atrial fibrillation. Cardiovasc Res. (2016) 109(4):527–41. doi: 10.1093/cvr/cvw007

PubMed Abstract | Crossref Full Text | Google Scholar

36. Liu GZ, Hou TT, Yuan Y, Hang PZ, Zhao JJ, Sun L, et al. Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through ppar-alpha/sirtuin 1/pgc-1alpha pathway. Br J Pharmacol. (2016) 173(6):1095–109. doi: 10.1111/bph.13438

PubMed Abstract | Crossref Full Text | Google Scholar

37. Qiu J, Zhao J, Li J, Liang X, Yang Y, Zhang Z, et al. Nadph oxidase inhibitor apocynin prevents atrial remodeling in alloxan-induced diabetic rabbits. Int J Cardiol. (2016) 221:812–9. doi: 10.1016/j.ijcard.2016.07.132

PubMed Abstract | Crossref Full Text | Google Scholar

38. Shao Q, Meng L, Lee S, Tse G, Gong M, Zhang Z, et al. Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet/streptozotocin-induced diabetic rats. Cardiovasc Diabetol. (2019) 18(1):165. doi: 10.1186/s12933-019-0964-4

PubMed Abstract | Crossref Full Text | Google Scholar

39. Zhu B, Li Y, Xiang L, Zhang J, Wang L, Guo B, et al. Alogliptin improves survival and health of mice on a high-fat diet. Aging Cell. (2019) 18(2):e12883. doi: 10.1111/acel.12883

PubMed Abstract | Crossref Full Text | Google Scholar

40. Chamberlain AM, Agarwal SK, Folsom AR, Duval S, Soliman EZ, Ambrose M, et al. Smoking and incidence of atrial fibrillation: results from the atherosclerosis risk in communities (aric) study. Heart Rhythm. (2011) 8(8):1160–6. doi: 10.1016/j.hrthm.2011.03.038

PubMed Abstract | Crossref Full Text | Google Scholar

41. Marcus GM, Modrow MF, Schmid CH, Sigona K, Nah G, Yang J, et al. Individualized studies of triggers of paroxysmal atrial fibrillation: the I-stop-afib randomized clinical trial. JAMA Cardiol. (2022) 7(2):167–74. doi: 10.1001/jamacardio.2021.5010

PubMed Abstract | Crossref Full Text | Google Scholar

42. Ding WY, Gupta D, Wong CF, Lip GYH. Pathophysiology of atrial fibrillation and chronic kidney disease. Cardiovasc Res. (2021) 117(4):1046–59. doi: 10.1093/cvr/cvaa258

PubMed Abstract | Crossref Full Text | Google Scholar

43. Bansal N, Zelnick LR, Alonso A, Benjamin EJ, de Boer IH, Deo R, et al. Egfr and albuminuria in relation to risk of incident atrial fibrillation: a meta-analysis of the Jackson heart study, the multi-ethnic study of atherosclerosis, and the cardiovascular health study. Clin J Am Soc Nephrol. (2017) 12(9):1386–98. doi: 10.2215/CJN.01860217

PubMed Abstract | Crossref Full Text | Google Scholar

44. Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, et al. Non-Lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell. (2015) 163(7):1585–95. doi: 10.1016/j.cell.2015.11.055

PubMed Abstract | Crossref Full Text | Google Scholar

45. Chen J, Guo Y, Gui Y, Xu D. Physical exercise, gut, gut Microbiota, and atherosclerotic cardiovascular diseases. Lipids Health Dis. (2018) 17(1):17. doi: 10.1186/s12944-017-0653-9

PubMed Abstract | Crossref Full Text | Google Scholar

46. Yan Q, Zhai W, Yang C, Li Z, Mao L, Zhao M, et al. The relationship among physical activity, intestinal Flora, and cardiovascular disease. Cardiovasc Ther. (2021) 2021:3364418. doi: 10.1155/2021/3364418

PubMed Abstract | Crossref Full Text | Google Scholar

47. Jakob D, Klesen A, Allegrini B, Darkow E, Aria D, Emig R, et al. Piezo1 and bk(ca) channels in human atrial fibroblasts: interplay and remodelling in atrial fibrillation. J Mol Cell Cardiol. (2021) 158:49–62. doi: 10.1016/j.yjmcc.2021.05.002

PubMed Abstract | Crossref Full Text | Google Scholar

48. Bernardo BC, Ooi JYY, Weeks KL, Patterson NL, McMullen JR. Understanding key mechanisms of exercise-induced cardiac protection to mitigate disease: current knowledge and emerging concepts. Physiol Rev. (2018) 98(1):419–75. doi: 10.1152/physrev.00043.2016

PubMed Abstract | Crossref Full Text | Google Scholar

49. Goette A, Kalman JM, Aguinaga L, Akar J, Cabrera JA, Chen SA, et al. Ehra/hrs/aphrs/solaece expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication. Europace. (2016) 18(10):1455–90. doi: 10.1093/europace/euw161

PubMed Abstract | Crossref Full Text | Google Scholar

50. Alves LS, Bocchi EA, Chizzola PR, Castro RE, Salemi VMC, de Melo MDT, et al. Exercise training in heart failure with reduced ejection fraction and permanent atrial fibrillation: a randomized clinical trial. Heart Rhythm. (2022) 19(7):1058–66. doi: 10.1016/j.hrthm.2022.03.1217

PubMed Abstract | Crossref Full Text | Google Scholar

51. Mujovic NM, Marinkovic MM, Nedeljkovic I, Markovic N, Banovic M, Vucicevic V, et al. Improvement of maximal exercise performance after catheter-ablation of atrial fibrillation and its prognostic significance for long-term rhythm outcome. J Am Heart Assoc. (2021) 10(3):e017445. doi: 10.1161/JAHA.120.017445

PubMed Abstract | Crossref Full Text | Google Scholar

52. Elliott AD, Linz D, Mishima R, Kadhim K, Gallagher C, Middeldorp ME, et al. Association between physical activity and risk of incident arrhythmias in 402 406 individuals: evidence from the UK biobank cohort. Eur Heart J. (2020) 41(15):1479–86. doi: 10.1093/eurheartj/ehz897

PubMed Abstract | Crossref Full Text | Google Scholar

53. Vitolo M, Proietti M, Imberti JF, Bonini N, Romiti GF, Mei DA, et al. Factors associated with progression of atrial fibrillation and impact on all-cause mortality in a cohort of European patients. J Clin Med. (2023) 12(3):768. doi: 10.3390/jcm12030768

PubMed Abstract | Crossref Full Text | Google Scholar

54. Buckley BJR, Harrison SL, Fazio-Eynullayeva E, Underhill P, Lane DA, Thijssen DHJ, et al. Exercise-Based cardiac rehabilitation and all-cause mortality among patients with atrial fibrillation. J Am Heart Assoc. (2021) 10(12):e020804. doi: 10.1161/JAHA.121.020804

PubMed Abstract | Crossref Full Text | Google Scholar

55. Mozaffarian D, Furberg CD, Psaty BM, Siscovick D. Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study. Circulation. (2008) 118(8):800–7. doi: 10.1161/CIRCULATIONAHA.108.785626

PubMed Abstract | Crossref Full Text | Google Scholar

56. Piercy KL, Troiano RP, Ballard RM, Carlson SA, Fulton JE, Galuska DA, et al. The physical activity guidelines for Americans. JAMA. (2018) 320(19):2020–8. doi: 10.1001/jama.2018.14854

PubMed Abstract | Crossref Full Text | Google Scholar

57. Mishima RS, Verdicchio CV, Noubiap JJ, Ariyaratnam JP, Gallagher C, Jones D, et al. Self-Reported physical activity and atrial fibrillation risk: a systematic review and meta-analysis. Heart Rhythm. (2021) 18(4):520–8. doi: 10.1016/j.hrthm.2020.12.017

PubMed Abstract | Crossref Full Text | Google Scholar

58. Miguel-Dos-Santos R, Moreira JBN, Loennechen JP, Wisloff U, Mesquita T. Exercising immune cells: the immunomodulatory role of exercise on atrial fibrillation. Prog Cardiovasc Dis. (2021) 68:52–9. doi: 10.1016/j.pcad.2021.07.008

PubMed Abstract | Crossref Full Text | Google Scholar

59. Liu H, Southern DA, Arena R, Sajobi T, Aggarwal S, James MT, et al. Cardiac rehabilitation and risk of incident atrial fibrillation in patients with coronary artery disease. Can J Cardiol. (2022) 38(10):1621–8. doi: 10.1016/j.cjca.2022.06.006

PubMed Abstract | Crossref Full Text | Google Scholar

60. Garnvik LE, Malmo V, Janszky I, Ellekjær H, Wisløff U, Loennechen JP, et al. Physical activity, cardiorespiratory fitness, and cardiovascular outcomes in individuals with atrial fibrillation: the hunt study. Eur Heart J. (2020) 41(15):1467–75. doi: 10.1093/eurheartj/ehaa032

PubMed Abstract | Crossref Full Text | Google Scholar

61. Franklin BA, Quindry J. High level physical activity in cardiac rehabilitation: implications for exercise training and leisure-time pursuits. Prog Cardiovasc Dis. (2022) 70:22–32. doi: 10.1016/j.pcad.2021.12.005

PubMed Abstract | Crossref Full Text | Google Scholar

62. Franklin BA, Eijsvogels TMH, Pandey A, Quindry J, Toth PP. Physical activity, cardiorespiratory fitness, and cardiovascular health: a clinical practice statement of the aspc part I: bioenergetics, contemporary physical activity recommendations, benefits, risks, extreme exercise regimens, potential maladaptations. Am J Prev Cardiol. (2022) 12:100424. doi: 10.1016/j.ajpc.2022.100424

PubMed Abstract | Crossref Full Text | Google Scholar

63. Drca N, Wolk A, Jensen-Urstad M, Larsson SC. Physical activity is associated with a reduced risk of atrial fibrillation in middle-aged and elderly women. Heart. (2015) 101(20):1627–30. doi: 10.1136/heartjnl-2014-307145

PubMed Abstract | Crossref Full Text | Google Scholar

64. Guasch E, Benito B, Qi X, Cifelli C, Naud P, Shi Y, et al. Atrial fibrillation promotion by endurance exercise: demonstration and mechanistic exploration in an animal model. J Am Coll Cardiol. (2013) 62(1):68–77. doi: 10.1016/j.jacc.2013.01.091

PubMed Abstract | Crossref Full Text | Google Scholar

65. Lakin R, Polidovitch N, Yang S, Parikh M, Liu X, Debi R, et al. Cardiomyocyte and endothelial cells play distinct roles in the tumour necrosis factor (tnf)-dependent atrial responses and increased atrial fibrillation vulnerability induced by endurance exercise training in mice. Cardiovasc Res. (2023) 119(16):2607–22. doi: 10.1093/cvr/cvad144

PubMed Abstract | Crossref Full Text | Google Scholar

66. Pelliccia A, Sharma S, Gati S, Back M, Borjesson M, Caselli S, et al. 2020 Esc guidelines on sports cardiology and exercise in patients with cardiovascular disease. Eur Heart J. (2021) 42(1):17–96. doi: 10.1093/eurheartj/ehaa605

PubMed Abstract | Crossref Full Text | Google Scholar

67. Yumuk V, Tsigos C, Fried M, Schindler K, Busetto L, Micic D, et al. European Guidelines for obesity management in adults. Obes Facts. (2015) 8(6):402–24. doi: 10.1159/000442721

PubMed Abstract | Crossref Full Text | Google Scholar

68. You T, Arsenis NC, Disanzo BL, Lamonte MJ. Effects of exercise training on chronic inflammation in obesity: current evidence and potential mechanisms. Sports Med. (2013) 43(4):243–56. doi: 10.1007/s40279-013-0023-3

PubMed Abstract | Crossref Full Text | Google Scholar

69. Keating SE, Johnson NA, Mielke GI, Coombes JS. A systematic review and meta-analysis of interval training versus moderate-intensity continuous training on body adiposity. Obes Rev. (2017) 18(8):943–64. doi: 10.1111/obr.12536

PubMed Abstract | Crossref Full Text | Google Scholar

70. Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma SM, et al. 2017 Focused update of the 2016 acc expert consensus decision pathway on the role of non-statin therapies for ldl-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol. (2017) 70(14):1785–822. doi: 10.1016/j.jacc.2017.07.745

PubMed Abstract | Crossref Full Text | Google Scholar

71. Kokkinos PF, Faselis C, Myers J, Panagiotakos D, Doumas M. Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study. Lancet. (2013) 381(9864):394–9. doi: 10.1016/S0140-6736(12)61426-3

PubMed Abstract | Crossref Full Text | Google Scholar

72. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 Esc guidelines on diabetes, Pre-diabetes, and cardiovascular diseases developed in collaboration with the easd. Eur Heart J. (2020) 41(2):255–323. doi: 10.1093/eurheartj/ehz486

PubMed Abstract | Crossref Full Text | Google Scholar

73. Diabetes Prevention Program Research G, Knowler WC, Fowler SE, Hamman RF, Christophi CA, et al. 10-year follow-up of diabetes incidence and weight loss in the diabetes prevention program outcomes study. Lancet. (2009) 374(9702):1677–86. doi: 10.1016/S0140-6736(09)61457-4

PubMed Abstract | Crossref Full Text | Google Scholar

74. Reed JL, Terada T, Vidal-Almela S, Tulloch HE, Mistura M, Birnie DH, et al. Effect of high-intensity interval training in patients with atrial fibrillation: a randomized clinical trial. JAMA Network Open. (2022) 5(10):e2239380. doi: 10.1001/jamanetworkopen.2022.39380

PubMed Abstract | Crossref Full Text | Google Scholar

75. Hood MS, Little JP, Tarnopolsky MA, Myslik F, Gibala MJ. Low-volume interval training improves muscle oxidative capacity in sedentary adults. Med Sci Sports Exercise. (2011) 43(10):1849–56. doi: 10.1249/MSS.0b013e3182199834

PubMed Abstract | Crossref Full Text | Google Scholar

76. Kiuchi MG, Chen S, Hoye NA. The effects of different physical activities on atrial fibrillation in patients with hypertension and chronic kidney disease. Kidney Res Clin Pract. (2017) 36(3):264–73. doi: 10.23876/j.krcp.2017.36.3.264

PubMed Abstract | Crossref Full Text | Google Scholar

77. Opondo MA, Aiad N, Cain MA, Sarma S, Howden E, Stoller DA, et al. Does high-intensity endurance training increase the risk of atrial fibrillation? A longitudinal study of left atrial structure and function. Circ Arrhythm Electrophysiol. (2018) 11(5):e005598. doi: 10.1161/CIRCEP.117.005598

PubMed Abstract | Crossref Full Text | Google Scholar

78. Malmo V, Nes BM, Amundsen BH, Tjonna AE, Stoylen A, Rossvoll O, et al. Aerobic interval training reduces the burden of atrial fibrillation in the short term: a randomized trial. Circulation. (2016) 133(5):466–73. doi: 10.1161/CIRCULATIONAHA.115.018220

PubMed Abstract | Crossref Full Text | Google Scholar

79. Wang Y, Wang Y, Xu D. Effects of different exercise methods and intensities on the incidence and prognosis of atrial fibrillation. Trends Cardiovasc Med. (2024) 34(8):510–5. doi: 10.1016/j.tcm.2024.01.002

PubMed Abstract | Crossref Full Text | Google Scholar

80. Swearingen S, du Fay de Lavallaz JM, Rana N, Abid QU, Wasserlauf J, Krishnan K, et al. Correlation between exercise metabolic equivalents and risk factors in nonathletes with atrial fibrillation. Am J Cardiol. (2021) 138:128–9. doi: 10.1016/j.amjcard.2020.10.028

PubMed Abstract | Crossref Full Text | Google Scholar

81. Anagnostopoulos I, Kousta M, Kossyvakis C, Lakka E, Vrachatis D, Deftereos S, et al. Weekly physical activity and incident atrial fibrillation in females—a dose-response meta-analysis. Int J Cardiol. (2023) 370:191–6. doi: 10.1016/j.ijcard.2022.11.007

PubMed Abstract | Crossref Full Text | Google Scholar

82. Buckley BJR, Lip GYH, Thijssen DHJ. The counterintuitive role of exercise in the prevention and cause of atrial fibrillation. Am J Physiol Heart Circ Physiol. (2020) 319(5):H1051–H8. doi: 10.1152/ajpheart.00509.2020

PubMed Abstract | Crossref Full Text | Google Scholar

83. Tham YK, Bernardo BC, Huynh K, Ooi JYY, Gao XM, Kiriazis H, et al. Lipidomic profiles of the heart and circulation in response to exercise versus cardiac pathology: a resource of potential biomarkers and drug targets. Cell Rep. (2018) 24(10):2757–72. doi: 10.1016/j.celrep.2018.08.017

PubMed Abstract | Crossref Full Text | Google Scholar

84. Nattel S, Guasch E, Savelieva I, Cosio FG, Valverde I, Halperin JL, et al. Early management of atrial fibrillation to prevent cardiovascular complications. Eur Heart J. (2014) 35(22):1448–56. doi: 10.1093/eurheartj/ehu028

PubMed Abstract | Crossref Full Text | Google Scholar

85. Gunawardene MA, Willems S. Atrial fibrillation progression and the importance of early treatment for improving clinical outcomes. Europace. (2022) 24(Suppl 2):ii22–ii8. doi: 10.1093/europace/euab257

PubMed Abstract | Crossref Full Text | Google Scholar

86. Benito B, Gay-Jordi G, Serrano-Mollar A, Guasch E, Shi Y, Tardif JC, et al. Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Circulation. (2011) 123(1):13–22. doi: 10.1161/CIRCULATIONAHA.110.938282

PubMed Abstract | Crossref Full Text | Google Scholar

87. Mont L, Elosua R, Brugada J. Endurance sport practice as a risk factor for atrial fibrillation and atrial flutter. Europace. (2009) 11(1):11–7. doi: 10.1093/europace/eun289

PubMed Abstract | Crossref Full Text | Google Scholar

88. Wiersinga WM, Poppe KG, Effraimidis G. Hyperthyroidism: aetiology, pathogenesis, diagnosis, management, complications, and prognosis. Lancet Diabetes Endocrinol. (2023) 11(4):282–98. doi: 10.1016/S2213-8587(23)00005-0

PubMed Abstract | Crossref Full Text | Google Scholar

89. Frost L, Vestergaard P, Mosekilde L. Hyperthyroidism and risk of atrial fibrillation or flutter: a population-based study. Arch Intern Med. (2004) 164(15):1675–8. doi: 10.1001/archinte.164.15.1675

PubMed Abstract | Crossref Full Text | Google Scholar

90. Tian L, Lu C, Teng W. Association between physical activity and thyroid function in American adults: a survey from the nhanes database. BMC Public Health. (2024) 24(1):1277. doi: 10.1186/s12889-024-18768-4

PubMed Abstract | Crossref Full Text | Google Scholar

91. Platonov PG, McNitt S, Polonsky B, Rosero SZ, Zareba W. Atrial fibrillation in long qt syndrome by genotype. Circ Arrhythm Electrophysiol. (2019) 12(10):e007213. doi: 10.1161/CIRCEP.119.007213

PubMed Abstract | Crossref Full Text | Google Scholar

92. Mascia G, Brugada J, Arbelo E, Porto I. Athletes and suspected catecholaminergic polymorphic ventricular tachycardia: awareness and current knowledge. J Cardiovasc Electrophysiol. (2023) 34(10):2095–101. doi: 10.1111/jce.16045

PubMed Abstract | Crossref Full Text | Google Scholar

93. Buongiorno AL, Blandino A, Bianchi F, Masi AS, Pierri A, Mabritto B, et al. Effectiveness of 2014 esc hcm-risk-scd score in prediction of appropriate implantable-cardioverter-defibrillator shocks. J Cardiovasc Med. (2023) 24(5):313–4. doi: 10.2459/JCM.0000000000001458

PubMed Abstract | Crossref Full Text | Google Scholar

94. Poznyak AV, Ivanova EA, Sobenin IA, Yet SF, Orekhov AN. The role of mitochondria in cardiovascular diseases. Biology (Basel). (2020) 9(6):137. doi: 10.3390/biology9060137

PubMed Abstract | Crossref Full Text | Google Scholar

95. Scandalis L, Kitzman DW, Nicklas BJ, Lyles M, Brubaker P, Nelson MB, et al. Skeletal muscle mitochondrial respiration and exercise intolerance in patients with heart failure with preserved ejection fraction. JAMA Cardiol. (2023) 8(6):575–84. doi: 10.1001/jamacardio.2023.0957

PubMed Abstract | Crossref Full Text | Google Scholar

96. Knudsen NH, Stanya KJ, Hyde AL, Chalom MM, Alexander RK, Liou YH, et al. Interleukin-13 drives metabolic conditioning of muscle to endurance exercise. Science. (2020) 368(6490):eaat3987. doi: 10.1126/science.aat3987

PubMed Abstract | Crossref Full Text | Google Scholar

97. Jin L, Geng L, Ying L, Shu L, Ye K, Yang R, et al. Fgf21-Sirtuin 3 axis confers the protective effects of exercise against diabetic cardiomyopathy by governing mitochondrial integrity. Circulation. (2022) 146(20):1537–57. doi: 10.1161/CIRCULATIONAHA.122.059631

PubMed Abstract | Crossref Full Text | Google Scholar

98. Zoladz JA, Koziel A, Woyda-Ploszczyca A, Celichowski J, Jarmuszkiewicz W. Endurance training increases the efficiency of rat skeletal muscle mitochondria. Pflugers Arch. (2016) 468(10):1709–24. doi: 10.1007/s00424-016-1867-9

PubMed Abstract | Crossref Full Text | Google Scholar

99. Vettor R, Valerio A, Ragni M, Trevellin E, Granzotto M, Olivieri M, et al. Exercise training boosts enos-dependent mitochondrial biogenesis in mouse heart: role in adaptation of glucose metabolism. Am J Physiol Endocrinol Metab. (2014) 306(5):E519–28. doi: 10.1152/ajpendo.00617.2013

PubMed Abstract | Crossref Full Text | Google Scholar

100. Frodermann V, Rohde D, Courties G, Severe N, Schloss MJ, Amatullah H, et al. Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells. Nat Med. (2019) 25(11):1761–71. doi: 10.1038/s41591-019-0633-x

PubMed Abstract | Crossref Full Text | Google Scholar

101. Mooren FC, Kruger K. Apoptotic lymphocytes induce progenitor cell mobilization after exercise. J Appl Physiol (1985). (2015) 119(2):135–9. doi: 10.1152/japplphysiol.00287.2015

PubMed Abstract | Crossref Full Text | Google Scholar

102. Gleeson M. Immune function in sport and exercise. J Appl Physiol (1985). (2007) 103(2):693–9. doi: 10.1152/japplphysiol.00008.2007

PubMed Abstract | Crossref Full Text | Google Scholar

103. Alack K, Kruger K, Weiss A, Schermuly R, Frech T, Eggert M, et al. Aerobic endurance training Status affects lymphocyte apoptosis sensitivity by induction of molecular genetic adaptations. Brain Behav Immun. (2019) 75:251–7. doi: 10.1016/j.bbi.2018.10.001

PubMed Abstract | Crossref Full Text | Google Scholar

104. Gustafson MP, Wheatley-Guy CM, Rosenthal AC, Gastineau DA, Katsanis E, Johnson BD, et al. Exercise and the immune system: taking steps to improve responses to cancer immunotherapy. J Immunother Cancer. (2021) 9(7):e001872. doi: 10.1136/jitc-2020-001872

PubMed Abstract | Crossref Full Text | Google Scholar

105. Fischer CP. Interleukin-6 in acute exercise and training: what is the biological relevance? Exerc Immunol Rev. (2006) 12:6–33.17201070

PubMed Abstract | Google Scholar

106. Lopes S, Mesquita-Bastos J, Garcia C, Bertoquini S, Ribau V, Teixeira M, et al. Effect of exercise training on ambulatory blood pressure among patients with resistant hypertension: a randomized clinical trial. JAMA Cardiol. (2021) 6(11):1317–23. doi: 10.1001/jamacardio.2021.2735

PubMed Abstract | Crossref Full Text | Google Scholar

107. Allard NAE, Janssen L, Aussieker T, Stoffels AAF, Rodenburg RJ, Assendelft WJJ, et al. Moderate intensity exercise training improves skeletal muscle performance in symptomatic and asymptomatic statin users. J Am Coll Cardiol. (2021) 78(21):2023–37. doi: 10.1016/j.jacc.2021.08.075

PubMed Abstract | Crossref Full Text | Google Scholar

108. Liu Y, Wang Y, Ni Y, Cheung CKY, Lam KSL, Wang Y, et al. Gut microbiome fermentation determines the efficacy of exercise for diabetes prevention. Cell Metab. (2020) 31(1):77–91 e5. doi: 10.1016/j.cmet.2019.11.001

PubMed Abstract | Crossref Full Text | Google Scholar

109. Kokkinos P, Myers J. Exercise and physical activity: clinical outcomes and applications. Circulation. (2010) 122(16):1637–48. doi: 10.1161/CIRCULATIONAHA.110.948349

PubMed Abstract | Crossref Full Text | Google Scholar

110. Lear SA, Hu W, Rangarajan S, Gasevic D, Leong D, Iqbal R, et al. The effect of physical activity on mortality and cardiovascular disease in 130 000 people from 17 high-income, middle-income, and low-income countries: the pure study. Lancet. (2017) 390(10113):2643–54. doi: 10.1016/S0140-6736(17)31634-3

PubMed Abstract | Crossref Full Text | Google Scholar

111. Olah A, Barta BA, Sayour AA, Ruppert M, Virag-Tulassay E, Novak J, et al. Balanced intense exercise training induces atrial oxidative stress counterbalanced by the antioxidant system and atrial hypertrophy that is not associated with pathological remodeling or arrhythmogenicity. Antioxidants (Basel). (2021) 10(3):452. doi: 10.3390/antiox10030452

PubMed Abstract | Crossref Full Text | Google Scholar

112. Leosco D, Rengo G, Iaccarino G, Golino L, Marchese M, Fortunato F, et al. Exercise promotes angiogenesis and improves beta-adrenergic receptor signalling in the post-ischaemic failing rat heart. Cardiovasc Res. (2008) 78(2):385–94. doi: 10.1093/cvr/cvm109

PubMed Abstract | Crossref Full Text | Google Scholar

113. Rossello X, Ramallal R, Romaguera D, Alonso-Gomez AM, Alonso A, Tojal-Sierra L, et al. Effect of an intensive lifestyle intervention on the structural and functional substrate for atrial fibrillation in people with metabolic syndrome. Eur J Prev Cardiol. (2024) 31(5):629–39. doi: 10.1093/eurjpc/zwad380

PubMed Abstract | Crossref Full Text | Google Scholar

114. Ye Y, Chen X, Han J, Jiang W, Natarajan P, Zhao H. Interactions between enhanced polygenic risk scores and lifestyle for cardiovascular disease, diabetes, and lipid levels. Circ Genom Precis Med. (2021) 14(1):e003128. doi: 10.1161/circgen.120.003128

PubMed Abstract | Crossref Full Text | Google Scholar