This systematic review comprehensively evaluates the current evidence on the association between VEGF and AF. The results highlight VEGF as a potentially critical player in the pathogenesis of AF, particularly through its effects on atrial remodelling, fibrosis, angiogenesis, and inflammation. While the findings indicate a consistent pattern of elevated VEGF levels in patients with AF, certain inconsistencies and variability among studies necessitate a cautious interpretation and underscore the need for further research.

The majority of included studies observed significantly higher VEGF levels in AF patients compared to controls. For example, A.Y. Chung et al. [13] and Freestone et al. [16] demonstrated marked elevations in VEGF concentrations in AF groups, with mean values of 560 pg/mL (range: 120–1400 pg/mL) and 110 pg/mL (range: 40–540 pg/mL), respectively. These findings provide strong evidence supporting the role of VEGF in AF pathophysiology. VEGF’s role in angiogenesis, endothelial cell proliferation, and vascular permeability may explain its elevated levels in the context of AF, as these processes are integral to atrial remodeling and arrhythmogenesis. In contrast, Tan et al. [19] reported lower VEGF levels in AF patients compared to controls, raising questions about the factors contributing to this divergence. Differences in population characteristics, comorbidities, or study methodologies may account for these discrepancies. For example, Tan et al. focused on a cohort of patients with permanent AF, a population that may differ biologically from those with paroxysmal or persistent AF. Factors such as older patient populations, small sample sizes, and the choice of control groups can significantly influence findings. Additionally, the lack of standardized detection methods for VEGF and varying statistical analyses, including adjustments for confounders, can complicate comparisons across studies.

VEGF subtypes show varying degrees of association with atrial fibrillation (AF), highlighting the need to differentiate their roles in AF pathogenesis. VEGF-A levels were significantly elevated in AF patients, with Wang et al. [20] reporting mean levels of 188.81 pg/mL compared to 88.90 pg/mL in controls, and Han et al. identifying VEGF-A as a risk factor for AF with an odds ratio (OR) of 1.025 (95% CI: 1.004–1.047). These findings underscore VEGF-A’s potent angiogenic effects and its role in promoting inflammation and fibrosis. Similarly, VEGF-D demonstrated significant associations with AF risk, with Han et al. reporting an OR of 1.080 (95% CI: 1.039–1.123) and VEGF-D levels being elevated in AF patients (HR = 1.10, 95% CI: 1.01–1.20). VEGF-D’s involvement in lymph angiogenesis and inflammation likely contributes to atrial remodeling and fibrosis. In contrast, VEGF-C showed no significant association with AF in most studies, as exemplified by Wang et al.’s findings of negligible differences between AF patients (1,051.91 pg/mL) and controls (1,040.20 pg/mL), and Han et al.’s OR of 0.977 (95% CI: 0.938–1.019). The inconsistencies in VEGF-C findings highlight the need for further investigation into its specific role in AF. VEGF-C primarily regulates lymphangiogenesis, which may have a limited impact on the vascular remodeling, angiogenesis, and fibrosis central to AF pathogenesis [9]. Its weak association with AF could be context-dependent, influenced by disease stage, comorbidities, or AF subtype. Methodological differences, such as variations in VEGF assay sensitivity and population characteristics, may also contribute to these discrepancies. Future research should explore VEGF-C’s interactions with other VEGF subtypes and inflammatory cytokines, particularly its role in lymphatic remodeling and immune cell recruitment in the atria. These findings emphasize the importance of subtype-specific analyses in future research to clarify their distinct contributions and therapeutic potential in AF.

Atrial remodeling, particularly fibrosis, is a key pathological feature of AF. VEGF has been implicated in several mechanisms that contribute to structural remodeling. Elevated VEGF levels are thought to influence fibroblast activation and extracellular matrix turnover, processes critical to the development of atrial fibrosis [21, 22]. Studies included in this review, such as those by A.Y. Chung et al. (2002) and Freestone et al. (2005), support the role of VEGF in promoting structural changes that predispose the atria to arrhythmogenesis and Elevated VEGF levels contribute to endothelial dysfunction, inflammation, and fibrosis, forming a mechanistic link between VEGF dysregulation and AF pathophysiology. These findings highlight VEGF as a potential therapeutic target for mitigating atrial remodeling and preventing AF progression. Scridon et al. (2012) provided additional insight by analyzing VEGF levels across different AF subtypes. They found that VEGF levels were higher in persistent AF compared to paroxysmal AF, suggesting that VEGF may contribute to disease progression. Persistent AF is associated with more extensive atrial fibrosis and remodeling than paroxysmal AF, further linking VEGF to the structural changes underlying AF chronicity. While VEGF’s direct contribution to fibrosis was not definitively proven in this study, its role in the early stages of atrial remodeling in paroxysmal AF is strongly suggested. The transient nature of VEGF secretion and its reduction in persistent AF highlight its dynamic role in AF progression. Inflammation is a well-recognized driver of AF pathogenesis, and VEGF plays a central role in mediating vascular inflammation. VEGF enhances leukocyte recruitment, increases endothelial permeability, and amplifies pro-inflammatory signalling pathways [23]. These effects may create a pro-arrhythmic milieu by promoting atrial tissue injury and remodeling. Han et al. (2024) demonstrated that VEGF-A and VEGF-D are significantly associated with AF risk, supporting the hypothesis that these subtypes may act as mediators of inflammation. VEGF’s interaction with inflammatory cytokines, such as interleukin-6 and tumor.

necrosis factor-alpha, may exacerbate atrial fibrosis and remodeling [24]. Future research should explore these interactions to identify potential therapeutic targets for mitigating inflammation in AF.

The elevated VEGF levels observed in AF patients across most studies suggest that VEGF may serve as a biomarker for disease activity or progression [25]. VEGF-A, in particular, appears to have strong potential as a diagnostic or prognostic marker, given its consistent association with AF in both observational and genetic studies. However, the variability in VEGF levels across studies highlights the need for standardized measurement techniques and well-defined reference ranges. The potential utility of VEGF as a biomarker extends beyond diagnosis. Monitoring VEGF levels could provide insights into AF progression or treatment response, particularly in patients undergoing interventions such as catheter ablation or antiarrhythmic therapy. Future studies should aim to validate VEGF as a biomarker in larger, more diverse cohorts.

Information from a variety of study types, including as cross-sectional, genetic, and observational studies, supports the conclusions of this systematic review. This variety offers a thorough understanding of VEGF’s function in AF and improves the data’ generalizability. However, it is important to recognize a number of limitations like understanding the involvement of VEGF in AF is significantly hampered by demographic and research design heterogeneity. Inconsistent results are caused by variations in sample sizes, VEGF measuring methods, and patient population features, such as the inclusion of distinct AF subtypes (paroxysmal, persistent, and permanent). These variations are especially significant because VEGF levels can be influenced by the severity and duration of the condition. The comparability of outcomes is further complicated by methodological variations. The necessity for uniform measurement protocols is highlighted by the possibility that part of the variability shown among studies might be explained by differences in VEGF assay techniques, sample handling protocols, and research approaches. Furthermore, it is difficult to determine the temporal correlations between VEGF levels and the development of AF due to the paucity of longitudinal data. Since the majority of the studies in this review are cross-sectional, it is difficult to determine whether VEGF dysregulation causes or results from AF. Last but not least, whereas some studies looked at VEGF subtypes like VEGF-A and VEGF-D, others just reported overall VEGF levels, which limits the ability to draw firm conclusions regarding the precise contributions of different subtypes. Future studies must do more focused analysis in order to clarify these roles.

VEGF holds significant potential as both a biomarker and therapeutic target in the management of AF, offering opportunities for early diagnosis, risk stratification, and monitoring of disease progression [26]. Elevated VEGF levels, particularly VEGF-A and VEGF-D, may aid in identifying patients at risk of AF and distinguishing between disease subtypes [27]. Longitudinal assessments of VEGF could track the efficacy of interventions such as catheter ablation or antiarrhythmic therapy. Therapeutically, modulating VEGF pathways could address atrial fibrosis and inflammation, which are central to AF pathophysiology [28]. Strategies such as VEGF inhibitors, gene therapy, or angiogenesis-modulating treatments may complement existing approaches by reducing structural remodeling and improving cardiac stability. Incorporating VEGF into multimodal biomarker panels or using it to guide surgical and device-based interventions could enhance personalized treatment strategies. However, realizing these applications requires standardization of VEGF measurement techniques and large-scale validation studies to harness its full potential for improving AF management.

The relationship between VEGF and AF is further supported by studies exploring the role of angiogenesis in arrhythmogenesis [29, 30]. Angiogenesis, which is intricately regulated by VEGF, has been implicated in the development of ectopic foci and re-entrant circuits [31], critical components of AF pathophysiology. Experimental models have demonstrated that aberrant angiogenesis can lead to microvascular dysfunction, hypoxia, and inflammation in the atria, all of which contribute to an arrhythmogenic milieu [32]. Furthermore, clinical studies have observed elevated circulating VEGF levels in patients with AF [33], raising the question of whether VEGF serves as a biomarker for disease activity or progression. Inflammation is another key contributor to AF pathogenesis, with numerous studies highlighting the role of inflammatory cytokines and immune responses in atrial remodeling [34]. VEGF, as an important mediator of vascular inflammation, can enhance leukocyte recruitment, increase endothelial permeability, and amplify pro-inflammatory signalling pathways [35]. The interplay between VEGF-mediated inflammation and atrial remodeling underscores the complexity of AF pathophysiology and suggests that targeting VEGF signalling may offer dual benefits in mitigating both inflammation and fibrosis.

Addressing these challenges will require several key advancements in research. First, large-scale, longitudinal studies are needed to establish causal relationships between VEGF and AF while exploring temporal trends in VEGF levels throughout the disease’s progression. This will help determine whether VEGF dysregulation precedes or follows AF onset. Second, future studies should focus on investigating the roles of specific VEGF subtypes, particularly VEGF-A and VEGF-D, which show the strongest associations with AF pathophysiology. Understanding their individual contributions could unveil novel therapeutic targets. Third, developing and validating standardized protocols for VEGF measurement is crucial to improve the reliability and comparability of results across studies. Such protocols should address assay techniques, sample handling, and reporting practices. Finally, exploring the utility of VEGF as a biomarker for AF could revolutionize its clinical management. This includes evaluating its potential in diagnosing AF, stratifying patients based on risk, and monitoring treatment responses in diverse populations. Together, these directions aim to clarify VEGF’s role in AF and enhance its clinical and therapeutic implications.

Management of AF with the help of oral anticoagulation (OAC) and left atrial appendage (LAA) occlusion can be considered. Elevated VEGF levels, which enhance angiogenesis and vascular permeability, can increase inflammation and thrombosis, raising thromboembolic risk in AF patients [36]. Non-vitamin K antagonist oral anticoagulants (NOACs) and LAA occlusion, a mechanical intervention to prevent clot formation, are key strategies. This dual approach, combining pharmacological and mechanical methods, is crucial, particularly for patients who cannot tolerate long-term anticoagulation. The complexity of treating AF requires personalized strategies that consider each patient’s risk and comorbidities [36].The impact of AF on quality of life is profound, with symptoms like palpitations, fatigue, and dyspnea significantly affecting daily activities and well-being. Interventions targeting pathways involved in AF, such as VEGF signalling, could enhance patients’ quality of life by stabilizing cardiac function and reducing symptoms. Addressing the molecular underpinnings of AF offers potential not only for improved pathological outcomes but also for greater overall life quality by mitigating the symptoms and risks associated with this condition [37].