Introduction
Atrial fibrillation (AF), characterized by irregular and often rapid electrical activity in the atria, is a common heart arrhythmia. AF affects around 60 million people worldwide, resulting in more than 8 million disability-adjusted life years. According to patient-level characteristics such as age, sex, race, and the load of clinical risk factors, the lifetime risk of AF is approximately 33%. Lifetime AF risk is influenced by modifiable risk factors – such as physical inactivity, type 2 diabetes mellitus, and hypertension – but not by hereditary risk [1].
Bioactive substances called adipokines are released by adipose tissue and have a variety of effects on health and diseases. They have crucial roles in controlling immunological responses, inflammation, metabolism, cardiovascular health, and even the development of cancer. However, diseases associated with obesity may result from imbalanced regulation of adipokines [2]. An estimated one-fifth of all cases of AF and almost 60% of the recent increases in AF incidence in the community have been linked to obesity. Several concomitant conditions, including heart failure, obstructive sleep apnea, diabetes, hypertension, and coronary artery disease, are also associated with obesity and can lead to AF development [3, 4].
According to Rafaqat et al., the development and course of AF are substantially influenced by adipokines, which are involved in the underlying pathophysiological mechanisms. These adipokines influence cardiac hypertrophy; enhance cardiac contractility and action potential length; and are involved in atrial fibrosis, atrial tissue electrical and structural remodeling, and atrial fibrosis [5].
This article highlights the pathophysiological aspects of adipokines, such as Angiopoietin-like protein 2, Fibroblast growth factor 21, Lipocalin, Vaspin, Visfatin, and Nesfatin-1, in AF, which is not reported in summarized form. A summary of major adipokines involved in pathophysiological aspects of AF is provided in Table 1. The circulating levels of major adipokines in individuals with AF are shown in Figure 1.
Summary of Major Adipokines Involved in Pathophysiological Aspects of AF.
Angiopoietin-Like Protein 2 (Angptl2)
Atrial myocardial fibrosis and peri-left atrial epicardial adipose tissue (EAT) have been linked through an association between atrial myocardial fibrosis and the protein concentration of Angptl2 in EAT. An increase in the number of myofibroblasts is a hallmark of atrial fibrosis induced in organo-cultured rat atrium in the presence of EAT-conditioned media. The profibrotic effect of EAT was greater than that of subcutaneous adipose tissue (SAT). EAT in patients with AF induced a more significant atrial fibrosis than in those without [6].
Administration of human recombinant Angptl2 has been demonstrated to cause atrial fibrosis in organo-cultured rats, whereas simultaneous administration of antibody to Angptl2 decreases these fibrotic effects. The expression of many indicators – such as α-smooth muscle actin, transforming growth factor-β1, phosphorylated extracellular signal-regulated kinase, phosphorylated inhibitor of κBα, and phosphorylated p38 mitogen-activated protein kinase – is elevated in cultured fibroblasts exposed to Angptl2. These results emphasize Angptl2’s critical function in EAT-induced inflammatory atrial fibrosis. Targeting Angptl2 expression in EAT may also be a potential strategy for AF prevention [6].
Using excised human left atrial appendage samples, Kira et al. demonstrated that epicardial adipose tissue are highly associated with atrial myocardial fibrosis as a substrate of AF. It revealed a link between atrial fibrosis and Angptl2 in EAT, although the underlying mechanism remains unknown. Research has been conducted to clarify the processes through which EAT affects the atrial myocardium. Global fibrosis has been observed in atria organo-cultures incubated with conditioned media for 7 days. Compared with the SAT and control groups, the EAT group had a considerably larger fibrotic region on the epicardial side (P < 0.05) [7].
Rat atria were subsequently exposed to 500 ng/mL recombinant Angptl2. A substantially greater fibrotic area and a higher number of α-smooth muscle actin (α-SMA) positive cells were observed in the Angptl2 group than the control group. In addition, the Angptl2 group had considerably greater levels of transforming growth factor-β1 (TGF-β1) and Col3a1 mRNA than the control group. Cultivated fibroblasts had higher expression of p-ERK and α-SMA in the Angptl2 group than the control group, according to western blotting. Thus, atrial myocardial fibrosis appears to be caused by EAT rather than SAT. ANGPTL2 secreted by EAT might potentially act as a paracrine trigger of atrial fibrosis [7].
Angiopoietin-2 has been examined as a novel putative biomarker for endothelial inflammation and vascular remodeling in individuals with AF. Elevated Angiopoietin-2 plasma levels have been independently associated with future hospitalization for heart failure in patients with AF [8].
Fibroblast Growth Factor 21 (FGF21)
Although the importance of FGF21 in cardiovascular disorders is acknowledged, its influence on atrial remodeling remains unknown. To evaluate the effects of FGF21 on atrial remodeling, a study has treated adult mice with Angiotensin II (Ang-II) and randomly administered FGF21 for 2 weeks. FGF21 administration attenuated the inducibility of AF/atrial tachycardia, improved epicardial conduction velocity in the mice atria. Mechanistically, FGF21 decreased oxidative stress in the atria and protected against atrial fibrosis. In vitro investigations further validated that FGF21 decreases tachypacing-induced oxidative stress markers in atrial myocytes – including reactive oxygen species, TGF-β, and ox-CaMKII – and blocks collagen upregulation by TGF-β in fibroblasts. That study has also demonstrated down-regulation of L-type calcium channels, upregulation of p-RyR2, and myofibril degradation induced by tachypacing, all of which indicate protective effects on structural and electrical atrial remodeling. Nuclear factor erythroid 2–related factor 2 (Nrf2) has been found to be is a downstream mediator of FGF21, thus contributing to the production of antioxidant genes expression in atrial myocytes activated by FGF21. FGF21 administration has been found to successfully inhibit atrial remodeling by decreasing oxidative stress, thus offering a unique treatment strategy for AF [9].
In one study, individuals with rather than without AF had significantly higher baseline FGF21 levels (median = 166.0 and 142.8 pg/mL, respectively, P < 0.001). However, elevated baseline FGF21 levels did not predict incident AF throughout the follow-up period after consideration of confounding variables, such as circulating inflammatory markers; conventional CVD risk factors; and demographic, socioeconomic, and lifestyle characteristics [10].
The levels of hs-CRP were also considerably higher in patients with AF than controls (2.36 ± 1.10 vs. 1.24 ± 0.82, P < 0.05), and the serum FGF-21 levels were significantly higher in patients with AF than controls (250.12 ± 78.48 vs. 144.15 ± 56.31 pg/mL, P < 0.001). In a subgroup study, individuals with permanent AF had higher serum FGF-21 levels than individuals with both persistent and paroxysmal AF. Serum FGF-21 levels were significantly associated (P < 0.01) with left atrial diameter after adjustment for age, sex, and body mass index. Moreover, AF was shown to be strongly associated (P < 0.05) with FGF-21, left atrial diameter, and hs-CRP. These results highlight the importance of elevated blood FGF-21 levels in atrial remodeling in patients with AF, regardless of the presence of recognized risk factors, such as C-reactive protein [11].
Compared with the sinus rhythm (SR) group, the AF group showed a much broader distribution of FGF-21. In addition, plasma and mRNA levels of FGF-21 in atrial tissue of AF showed the same trend as the result of immunohistochemistry. The degree of atrial fibrosis was positively correlated with FGF-21 expression in linear correlation analysis. In summary, FGF-21 may be involved in the onset and progression of atrial fibrosis in individuals with rheumatoid heart disease and AF. Moreover, FGF-21 may serve as a new biomarker in future assessment of cardiac fibrosis [12].
Lipocalin-2 (NGAL)
Patients with chronic heart failure with decreased ejection fraction (HFrEF) may have both AF and renal impairment. Argan et al. have sought to assess the effects of permanent AF on renal function in HFrEF, and to explore the relationships of AF with neutrophil gelatinase-associated lipocalin, neutrophil-to-lymphocyte ratio, and adverse clinical outcomes. In comparison to control patients, patients with HFrEF had considerably greater neutrophil-to-lymphocyte ratios and NGAL levels, and a significantly lower mean estimated glomerular filtration rate. Nevertheless, no statistically significant difference was observed between HFrEF with sinus rhythm (HFrEF-SR) and HFrEF-AF (NGAL: 95 ng/mL in HFrEF-SR, 113 ng/mL in HFrEF-AF, and 84 ng/mL in the control group; P < 0.001). The development of renal dysfunction or adverse clinical outcomes (such as all-cause mortality and re-hospitalization) have not been demonstrated to directly correlate with the existence of AF in patients with HFrEF [13].
The matrix metalloproteinase neutrophil gelatinase-associated lipocalin (MMP-NGAL) complex is poorly understood in AF. Recurrence of AF is significantly associated with a left atrial diameter ≥4.5 cm at follow-up (P = 0.009). In a sample of 39 obese individuals, the MMP-NGAL complex was correlated with AF recurrence (P = 0.03). The likelihood of AF recurrence increased 4% with each 1 ng/mL rise in MMP-NGAL complex concentration (OR 1.04; CI: 1.00–1.08; P = 0.03). Nonetheless, among individuals undergoing their first episode of AF, those over 65 years of age, those with an left atrial diameter ≥4.5 cm, or those with chronic renal disease, the MMP-NGAL complex has not been associated with recurrent AF. In obese individuals, the MMP-NGAL complex may be a predictor of AF recurrence after successful cardioversion [14].
Vaspin
Individuals with AF have been shown to have significantly lower plasma vaspin levels than those without AF. Moreover, a higher incidence of AF in obese individuals has been associated with lower plasma vaspin levels. Vaspin therapy in vitro has moderating effects on mitochondrial damage, atrial myocyte apoptosis, cardiomyocyte injury, and atrial fibrosis in atrial myocytes under Ang-II stress. Crucially, vaspin promotes mitophagy and consequently protects against atrial myocyte dysfunction caused by angiotensin. In addition, vaspin administration leads to phosphorylation of Fun14 domain-containing protein 1 (FUNDC1) at Ser17 via unc-51-like autophagy activating kinase 1 (ULK1), thereby inducing mitophagy. Notably, suppression of ULK1 in Ang-II-stimulated HL-1 cells has been shown to reverse the positive effects of vaspin. Therefore, vaspin may be a new therapeutic target for AF and is essential in AF pathophysiology through ULK1/FUNDC1-regulated mitophagy [15].
Visfatin
A potential correlation between baseline visfatin levels and the likelihood of arrhythmia recurrence after AF ablation has been examined by Platek et al. Individuals with higher visfatin levels are more likely to experience arrhythmia recurrence after AF ablation. Consequently, visfatin may serve as a useful marker for risk categorization in patients with AF [16].
Angiogenesis, endothelial dysfunction, and the weakness of atherosclerotic plaques have all been associated with visfatin levels. Visfatin and apelin levels are higher in individuals with rather than without AF and therefore might potentially serve as independent prognostic markers [17].
A study has investigated the relationships between AF prevalence after percutaneous coronary intervention and cardiovascular risk factors and the severity of acute myocardial infarction in patients with peripheral blood visfatin levels. In that study, the degree of AF after percutaneous coronary intervention was strongly correlated with cardiovascular risk factors and visfatin levels in the peripheral blood in patients with acute myocardial infarction [18].
Nesfatin-1
The relationship between serum nesfatin-1 concentration and AF has been examined by Duan et al. It observed lower blood levels of nesfatin-1 in patients with AF than control individuals. The occurrence of AF is inversely correlated with serum nesfatin-1 concentrations. Individuals with permanent AF were found to have lower blood nesfatin-1 concentrations among the AF patient categories than individuals with paroxysmal and persistent AF. In addition, individuals with paroxysmal AF had higher blood nesfatin-1 concentrations than those with chronic AF. Furthermore, a negative connection has been observed between left atrial diameter and serum nesfatin-1 concentration. In conclusion, serum nesfatin-1 concentrations are inversely connected with the development of AF [19].
Conclusion
Angiopoietin-like protein 2, Fibroblast growth factor 21, Lipocalin, Vaspin, Visfatin, and Nesfatin-1 play major roles in AF pathogenesis, as explained in Figure 1 and Table 1. Additionally, lifestyle interventions, including weight loss and improved physical activity, have been shown to decrease AF risk in obese individuals. Management strategies for AF in individuals with obesity may involve addressing these underlying mechanisms through a combination of lifestyle modifications and medical interventions.