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).

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).

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).

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).

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.

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).

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).

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.

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.

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).

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.