Authors: Dan Tong
Categories: Article, Atrial fibrillation, atrial cardiomyopathy
Source: Physiology (Bethesda, Md.)
Authors: Dan Tong
Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant morbidity, mortality and health care expenditures. Increasing evidence has demonstrated that AF is a rather late-stage clinical manifestation of the underlying pathological remodeling of the atria, i.e., atrial cardiomyopathy (AtCM). The goal of this focused review is to highlight several emerging conceptual frameworks supported by contemporary basic and clinical studies, with an emphasis on the evolving definition of AtCM, the complex atrial micro-environment, the influence of both genetic and acquired risk factors and their synergistic effects in AF pathogenesis. Finally, I stressed the importance of assessing atrial and ventricular function as a synchronized unit to better appreciate the complicated interplay between AF and ventricular dysfunction. These conceptual frameworks will help to develop better strategies for personalized and mechanism-driven AF management.
The atria play a vital role in maintaining normal cardiac function, serving as dynamic chambers that modulate blood flow, facilitate ventricular filling, and maintain electrical stability. However, the atrial contribution to cardiovascular diseases has been historically underestimated due to a ventricular-centric approach in cardiovascular research, leading to a limited understanding of atrial pathophysiology.
The atria are a primary site for arrhythmia, particularly atrial fibrillation (AF), the most prevalent sustained arrhythmia^1,2^. In AF, chaotic electrical activities replace the rhythmic depolarization and contraction that is normally initiated from the sinoatrial (SA) node, resulting in uncoordinated and rapid atrial quiver or fibrillation, ineffective atrial blood flow, and dyssynchronization between the atria and ventricles^2,3^. The clinical presentation of AF can be subtle. Some patients may experience palpitations, dizziness, fatigue, or shortness of breath, due to rapid heartbeats and reduced cardiac output. In others, AF maybe be entirely asymptomatic, manifesting itself through more serious complications^1^. Patients with AF have an approximately five-fold increased risk of stroke, a 1.4-fold increased risk of dementia, a two-fold increased risk of heart failure, and a two- to four-fold increased risk of death^2,3^.
AF is a heterogeneous clinical syndrome. Common risk factors of AF include aging, heart failure, valvular heart diseases, and metabolic syndrome including obesity, hypertension and type 2 diabetes^1,2^. Driven by the aging population and rapidly rising obesity rates, the global prevalence of AF has risen markedly from 33.5 million in 2010 to 59 million in 2019^4,5^, with a lifetime risk of 1 in 3–5 individuals after age 45^5^. In the United States, AF cases are projected to reach 12 million by 2030, with incidence climbing to 2.6 million new diagnosis annually^5^.
Despite the significant morbidity, mortality and health care expenditures associated with AF, current AF therapies, which are largely focused on symptom control and complication prevention, are far from optimal with variable efficacy and significant side effects^1,2^. Therefore, there is a clear unmet need for a better mechanistic understanding of the molecular mechanisms of AF, in order to foster the development of novel, targeted, and mechanism-driven therapeutic approaches.
The mechanisms of AF are complex and have been comprehensively reviewed by numerous excellent papers. The goal of this focused review is to highlight several emerging conceptual frameworks supported by contemporary basic and clinical studies, with an emphasis on the evolving definition of atrial cardiomyopathy, the complex atrial micro-environment, the influence of both genetic and acquired risk factors and their synergistic effects in AF pathogenesis. Finally, given the intimate relationship between the atria and ventricles, I also emphasize the importance of assessing ventricular status in AF studies.
Increasing evidence has demonstrated that AF is a rather late-stage clinical manifestation of the underlying pathological remodeling of the atria, i.e., atrial cardiomyopathy (AtCM), which is broadly defined as “any complex of structural, architectural, contractile, or electrophysiological changes affecting the atria with the potential to produce clinically relevant manifestations”^6,7^. AtCM, by its broad definition, is far more than just a rhythm disturbance and is a progressive pathological process.
Most AF patients manifest additional atrial abnormalities, including atrial enlargement, contractile dysfunction, impaired sinoatrial node function, and thrombosis formation^6^. Many of which appear much earlier than the clinical diagnosis of AF^8^. To highlight the progressive nature of AtCM and facilitate a stage-specific understanding and characterization of AtCM, multiple consensuses have recommended the following AtCM staging^6,9^ (Figure 1):
Stage A – having risk of developing AtCM
Stage B – clinically detectable AtCM but asymptomatic
Stage C – clinically diagnosed AF and/or associated complications
Stage D – advanced-stage AtCM with significant atrial remodeling and dysfunction
Current clinical practice is mainly focused on patients with stage C and D diseases, managing symptoms and preventing complications. Arguably, early detection and management of AtCM at stage A and B would offer the most benefits to prevent AF and its complications. While primordial prevention at stage A is of paramount importance, how to identify and manage stage B AtCM is highly clinically relevant. However, clinically applicable and widely accepted diagnostic criteria for AtCM are still lacking, mainly due to our limited understanding of the natural course of AtCM and its mechanisms.
Atrial enlargement is commonly observed under multiple pathological conditions^10^. As a thin-walled structure, the atria are easily stretched out in response to volume and/or pressure overload^8,11^. In the early stages, atrial dilation can be partially or completely reversible once the underlying etiology is resolved. However, under persistent stress, atrial dilation may become permanent or less reversible^10,12^. It is well established that atrial enlargement is associated with multiple adverse clinical outcomes, including increased risk of AF, stroke and other adverse cardiovascular events^13^, poor response to AF treatment^14^, as well as mortality^10,15–17^.
Ex vivo studies using perfused hearts have shown that atrial stretch is directly arrhythmogenic, presumably through the activation of stretch-activated channels (SACs)^18^. This is supported by findings that SAC antagonist, such as Gd^3+^ and GsMTX4, can block stretch-associated arrhythmogenesis^19^. However, the molecular identity of the atrial SACs remains to be determined by vigorous genetic approaches. How SACs activation leads to downstream atrial pathological remodeling and whether blocking SACs could serve as an anti-arrhythmic strategy are also areas of active investigation.
On the tissue level, atrial cardiomyocyte hypertrophy, fibrosis, myolysis, infiltration of immune cells, patchy amyloidosis, and increased pericardial adipose tissue, have been observed in the atrial tissue of AF patients and preclinical models and are speculated to play active roles in AF pathology^6,12,20^.
Atrial fibrosis has been widely proposed as a major underlying mechanism of AF and is commonly observed in AF preclinical models and patients with clinical AF^21,22^. Atrial fibrosis creates a substrate for AF by disrupting electrical conduction and promoting re-entry. Although activated fibroblasts are the major cell types involved in collagen synthesis and deposition, other systems and cell types often participate in fibroblast activation and signaling via a wide variety of pathways. Activation of the renin-angiotensin-aldosterone system (RAAS), transforming growth factor β (TGFβ) signaling, inflammation, oxidative stress, and extracellular matrix (ECM) remodeling^21,22^ are major mechanisms contributing to atrial fibrosis. For example, activation of the NLRP3 inflammasome in atrial cardiomyocytes leads to the production of cytokines including IL-18 and IL-1β, which can directly activate fibroblast cells and promote fibrosis^23,24^. These pro-inflammatory cytokines also attract circulating immune cells which synergistically contribute to fibrosis and an inflammatory environment^24^.
On the other hand, downregulation of endogenous repressors could also contribute to atrial remodeling. For example, atrial-enriched CIB2 (calcium and integrin-binding family member 2) protects against atrial hypertrophy and fibrosis by suppressing the calcineurin-NFAT (nuclear factor of activated T cells) pathway. Downregulation of CIB2 is observed in both preclinical and clinical AF^25^. Similarly, downregulation of SMAD7 in atrial fibroblasts contributes to atrial fibrosis in AF models^26^. Therefore, strategies to restore atrial CIB2 or SMAD7 expression could potentially suppress or reverse the atrial remodeling that underlies AF.
As observed in other tissues, atrial fibrosis could be a common late-stage presentation of diverse early pathological processes, particularly inflammation. Whether atrial fibrosis is a prominent pathology in the early stages of AtCM remains unknown and could very likely be etiology specific. It remains to be determined whether anti-fibrosis strategies can effectively attenuate AtCM progression.
Recent single-cell and single-nuclear RNA sequencing analyses have revealed complex changes in the cell composition, gene profile, and inter-cellular communication in the atrial tissue from AF patients and preclinical models. For example, one study identified an expansion of recruited inflammatory monocytes and SPP1 (osteopontin)+ macrophages in the atria of AF patients and their causative role in AF pathogenesis was confirmed in a preclinical model^27^; another study found enhanced inter-cellular communication between AREG1 (amphiregulin1)+ monocytes and macrophages and fibroblasts via epidermal growth factor (EGF) signaling^28^, which may contribute to atrial fibrosis. Besides immune cells and fibroblasts, significant gene profile changes in other cell types including atrial cardiomyocytes and endothelial cells were also identified in AF tissues^29,30^.
The atria have diversified roles including mechanical, electrical, and endocrine functions. In response to stress, many of these functions are impaired and can be detected before the appearance of clinical AF. Impaired atrial contraction, both on the tissue level and cellular level, was observed in various preclinical AF models^6,20,31^. From perspective of electrical function, alterations in action potential duration (APD) and impaired conduction velocity are key features of atrial electrical remodeling, which are associated with the dysregulation of various ion channels^32,33^. The atrial-dominant two-pore domain K^+^ channels (K2P) and the small-conductance Ca^2+^-activated K^+^ channels (SK channels) have gained increasing attention given their roles in mediating atrial electrical remodeling. The K2P channels constitute the background K^+^ current in atrial cardiomyocytes, thus modulating APD and cell excitability^34^. The dysregulation of multiple K2P channels including TREK-1, TASK-1, TASK-2 and TASK-3 was observed in AF tissues, and their pharmacological modulators are considered as potential therapies for AF^34,35^. The preferentially atrial-expressed SK channels are unique as they are gated solely by intracellular Ca^2+^, therefore serving as a crucial link between calcium signaling and the electrical activity of the cells^36^. Upregulation of apamin-sensitive SK currents (ISK) was observed in atrial cardiomyocytes isolated from patients with chronic AF^37^ and various animal models^38^, and inhibiting SK channels terminated or prevented AF^38,39^. Therefore, SK channel inhibitors are emerging as a promising new therapeutic target for AF.
Thromboembolism is the most serious complication of AF^1^. Recent findings from long-term rhythm monitoring have revealed a weak temporal link between AF episodes and stroke, suggesting that additional mechanisms – beyond the rhythm disturbance itself^9,40^may contribute to AF-associated thrombosis and strokes. The determinants of the classic Virchow’s triad include stasis, endothelial damage and hypercoagulation. Blood stasis, as noted by the echocardiographic display of smoke or diminished left atrial (LA) appendage flow velocities, is associated with stroke in patients with AF^41^. Low flow velocity was also observed in AF patients even when they are in normal sinus rhythm^42^ suggesting that the underlying AtCM might be directly contributive. Stasis can be detected by the novel 4-dimensional flow MRI technique which might offer additional risk prediction value beyond the standard CHA2DS2-VASc clinical risk score^43,44^. There is also evidence for atrial endocardial/endothelial dysfunction with reduced nitric oxide production, and upregulation prothrombotic plasminogen activator inhibitor-1^33,45^. Elevated endothelial damage markers like von Willebrand factor and E-selection, have been detected in patients with AF and are associated with worse clinical outcomes^46–49^. However, the application of these biomarkers in AF or stroke risk prediction remains unclear^6^. These observations support the likelihood that the AtCM that underlying the development of AF may also directly affect the risk of thrombosis via impacts on atrial flow and the thrombotic profile, thereby increasing the risk for thromboembolism, even in the absence of AF^9^.
Together, these findings highlight that AtCM precedes AF and represents an upstream preventive target. However, there are still significant limitations in our capacity in detecting early-stage AtCM clinically.
Based on current evidence, major professional societies have published consensus documents that outline a framework for defining and diagnosing AtCM, with a focus on clinically-detectable structural and functional atrial remodeling^6^.
Common clinical imaging modalities including echocardiography, cardiac CT and MRI (CMR) can accurately measure atrial size, with established reference ranges provided by professional societies. CMR can detect atrial fibrosis through late gadolinium enhancement (LGE)^50^. However, this is limited by the spatial resolution of current CMR scanning in relation to the thin atrial wall. The acquisition and post-processing protocols are also need to standardized before widespread clinical use^6^.
Recently, atrial strain imaging has emerged as a sensitive and non-invasive tool for the early detection of AtCM^51^. Atrial strain measures the deformation of the atrial myocardium during the cardiac cycle, providing detailed information about atrial function beyond conventional parameters like the size and volume. Using speckle-tracking echocardiography, left atrial (LA) strain analysis has been introduced to assess the reservoir, conduit and booster function which reflects the atrial compliance and contractile function. One significant advantage of atrial strain analysis is its ability to detect subclinical atrial dysfunction in patients with risk factors such as hypertension, diabetes, or heart failure, even when atrial size appears normal^51,52^. Reduced atrial strain has been associated with the presence of atrial fibrosis, increased stiffness, and impaired atrial contractility^31,53^. Furthermore, atrial strain offers prognostic value by predicting the development of AF and thromboembolic events, supporting its role in risk stratification and early intervention^51,54^. Therefore, atrial strain imaging is a promising tool for the early detection of stage B AtCM.
Other functional assessments, including detailed P wave analysis on a traditional electrocardiogram (EKG), and atrial contractility measurements by standard echocardiography or MRI, or measuring biomarkers including brain natriuretic peptide (BNP) or atrial brain natriuretic peptide (ANP) levels, have shown inconsistent values in terms of their sensitivity and specificity for the early detection of AtCM, clinical prediction of AF and associated complications^6^. However, with the emergence of artificial intelligence (AI) - assisted tools, a comprehensive application of existing clinical parameters for the diagnosis of AtCMs is an area of active research and holds great promise^55^.
Epidemiology studies have demonstrated that age-adjusted AF incidence and prevalence are higher in men as compared with women^56^. However, women with AF tend to have more atypical symptoms, report lower quality of life, and may have higher mortality than men with AF, although the results have been inconsistent^56^. Female sex has also been shown to be a risk factor for AF-associated stroke or thromboembolism^57,58^. On the structure level, female patients demonstrate more advanced atrial remodeling on high density electroanatomic mapping^59^ and potentially more fibrosis on MRI studies^60^. However, many studies have limited sample size and did not formally test for effect modification by sex.
Significant gaps exist in our understanding of AtCM, hindering its accurate diagnosis and effective management. AtCM arises from diverse etiologies, but whether its progression is driven by shared mechanisms or distinct, etiology-specific pathways remains to be determined. Longitudinal studies in humans and preclinical models are required to understand the natural course of AtCM. Additionally, our molecular understanding of the AtCM is in its very early stages. Therefore, etiology-specific, longitudinal, mechanistic studies are urgently needed to better understand AtCM, so that better diagnostic tools and management strategies can be developed. While atrial strain analysis has shown great promise in detecting early atrial dysfunction, additional biomarkers and imaging modalities to detect other aspects of atrial remodeling are urgently needed. Further, whether the early detection of AtCM improves clinical outcomes also needs to be tested in clinical studies. Finally, substantial gaps also exist in our knowledge of sex-specific difference in atrial remodeling and AF features.
Although the pathophysiological basis of AF is complex and incompletely understood, it is widely accepted that for the initiation and maintenance of AF activities, two key components are required. First, increased ectopic firings from the atria, particularly around the pulmonary vein (PV) area, is a key component of AF initiation. For the maintenance and progression of AF activities, a vulnerable substrate, the structural and electrophysiological milieu that creates a pro-arrhythmic environment, is also required^33,61^.
Here, I propose a “seed and soil” concept, originally developed in cancer biology^62^, for a better understanding of AF mechanisms. In this context, the “seed” refers to ectopic firing – abnormal electrical triggers that initiate AF. The “soil” represents substrate changes that sustains AF (Figure 2).
The “seed” of AF consists of ectopic beats – spontaneous electrical impulses originating outside the sinoatrial node, most commonly from around the PVs. This forms the basis for pulmonary vein isolation (PVI), the major AF therapy in current clinical practice^63^. Focal ectopic activities can result from delayed afterdepolarizations (DADs), early afterdepolarizations (EADs), or enhanced or abnormal atrial automaticity^61^. These mechanisms have been extensively reviewed previously^61,64,65^.
DADs and associated triggered activities are believed to be the primary mechanism for ectopic atrial firing. The central event causing DADs is calcium mishandling, particularly abnormal spontaneous Ca^2+^ release from the sarcoplasmic reticulum (SR) during diastole. The released Ca^2+^ is exchanged for extracellular Na^+^ in a 3 ratio by the Na^+^-Ca^2+^ exchanger (NCX), resulting in a net inward flow that depolarizes the cell. If the depolarization reaches a sufficient magnitude, the resulting DAD can cause spontaneous firing^61,65^.
One of the key mechanisms for spontaneous SR Ca^2+^ release is the dysfunction of ryanodine receptor 2 (RyR2). RyR2 hyperphosphorylation by kinases like calcium-calmodulin-dependent kinase II (CaMKII) or protein kinase A (PKA), along with RyR2 oxidation, promote RyR2 dysfunction and Ca^2+^ leak from the SR, leading to spontaneous Ca^2+^ release that triggers arrhythmogenesis. Mice carrying a gain-of-function RyR2 mutation, or the loss of FKBP12.6, a RyR2-stabilizing protein, have increased SR Ca^2+^ leak and are predisposed to atrial arrhythmias^66,67^. Consistent with this, mice carrying a non-phosphorylatable RyR2 mutation (S2814A) are protected from AF induction^68^. Selective modulators that stabilize RyR2 have also demonstrated therapeutic effects in animal models^69^.
Calcium-handling abnormalities are also a common finding in atrial cardiomyocytes obtained from patients with AF (including chronic AF^70^, paroxysmal AF^71^, and post-operative AF POAF^72^), as well as in those with AF risk factors such as HF^73–75^. In patients with chronic AF, enhanced SR Ca^2+^ leak through the CaMKII-hyperphosphorylated RyR2, in combination with a larger NCX current synergistically contribute to DADs^70^. RyR2 dysregulation and enhanced sarco-endoplasmic reticulum Ca^2+^ ATPase 2a (SERCA2a) activity were observed in atrial cardiomyocytes of patients with paroxysmal AF, promoting increased SR Ca^2+^ leak and DADs^71^. Preexisting Ca^2+^-handling abnormalities, altered cytosolic calcium handling^76^, and activation of NLRP3-inflammasome/CaMKII signaling are also evident in atrial cardiomyocytes obtained from patients who subsequently develop POAF^72^. Additionally, integrating clinical predictors with cellular Ca^2+^-handling signatures improves the prediction of POAF^77^.
As CaMKII activation appears to play a central role in this process via its pleiotropic effects and multiple regulatory mechanisms^78^, selective CaMKII inhibition is being actively pursued as a promising therapeutic strategy for AF^78,79^. In addition to CaMKII, the stress-activated protein kinase JNK2 has also been found to play a key role in several AF-promoting conditions, such as aging and binge drinking^80,81^, likely via its interaction with CaMKII^82^.
The “soil” of AF refers to the altered atrial substrate – the structural and electrophysiological environment that promotes heterogeneity of conduction and/or focal conduction block thus enabling sustained re-entrant circuits or wavelets^61^. Substrate changes create a fertile ground where ectopic seeds can take root and perpetuate AF.
Reentry substrates can be structural, due to fixed anatomical changes, such as fibrosis or atrial enlargement. They can also be functional, elicited by altered electrical properties within or between atrial cardiomyocytes.^83,84^ For example, in a classical AF model induced by rapid atrial pacing, altered L-type calcium current (ICa,L) along with an increased repolarizing K^+^ current culminate in APD shortening, thus promoting AF.^85^ In the same model, a combination of atrial dilation and fibrosis creates longer pathways for electrical conduction, promoting reentry; this, coupled with conduction slowing favors initiation and maintenance of multiple, irregular reentrant circuits that sustain AF.^86^ In addition to altered muscle bundle architecture, a reduced excitatory sodium current (INa/Nav1.5) and impaired gap junction (GJ)-dependent intercellular coupling also contribute to slow conduction, thereby facilitating the development and maintenance of AF.^84^ Connexin40 (Cx40) is the major gap junction protein that participates in electrical coupling between atrial myocytes.^87^ Mice lacking Cx40 manifest conduction abnormalities and atrial arrhythmias.^88,89^ Missense mutations of Cx40 have been identified in patients with idiopathic AF.^90,91^ Connexin43 (Cx43) is predominantly expressed in the ventricles but also contributes to intra-atrial electrical communication.^91,92^Consistently with this, shortened APD, impaired GJ communication, and reduced INa have been observed in human atrial tissue or preclinical models of AF.
Besides the structural and functional alterations of atrial cardiomyocytes, other atrial cell types also contribute to the local micro-environment that promotes AF. As introduced earlier, recruited pro-inflammatory CCR2+ SPP1+ macrophages are expanded in AF and are pathogenic in preclinical AF models likely via promoting cardiomyocyte dysfunction and tissue fibrosis^27^. Additionally, endothelial dysfunction may also contribute to atrial structural and functional remodeling and thrombogenesis^93,94^. Analysis of inter-cellular communication revealed dynamic changes between different cell types, which synergistically contribute to the diseased atrial micro-environment.
In the “seed and soil” framework, ectopic firing (the seed) initiates AF through calcium mishandling, autonomic dysregulation, and increased automaticity, while substrate changes (the soil) – driven by structural and electrophysiological abnormalities – sustain it. The interplay between these mechanisms, amplified by shared pathways like inflammation and oxidative stress, creates a self-perpetuating cycle of AF^61,65^. Therefore, therapies targeting both are critical for effective management.
Without an abnormal substrate, ectopic triggers may not sustain the arrhythmia. Conduction heterogeneity and/or delay provide the necessary conditions for re-entry.
An abnormal substrate could enhance ectopic firing by altering the interaction between cardiomyocytes and immune cells or fibroblasts, therefore impacting calcium handling and electrical activities^27,95^. Local inflammation and oxidative stress associated with an abnormal substrate can amplify calcium sparks and DADs^33,61^.
“AF begets AF”, AF itself promotes further remodeling, is a widely observed clinical phenomenon^96,97^. Rapid atrial firings enhance electrical and structural remodeling, which in turn facilitate more ectopic activities^61^.
Common mechanisms, including inflammation, oxidative stress, autonomic nervous system remodeling, as well as metabolic and energetic changes, may contribute to both ectopic firing (the seed) and substrate remodeling (the soil)^6,61^.
Current AF therapies, including catheter ablation and anti-arrhythmic medications, mainly focus on eliminating or suppressing ectopic firing, which are associated with limited efficacy and high recurrence rate^63^. Strategies targeting both the seed and the soil may provide great synergistic benefits.
Studies investigating sex-related differences in the pathophysiology underlying AF are quite limited, and the mechanisms remain elusive. Increased spontaneous SR calcium release linked with higher RyR2 phosphorylation was observed in atrial cardiomyocytes obtained from female patients with chronic AF as compared with the males^98^, suggesting that difference in calcium handling might contribute to the discrepancy between sexes.
Notable knowledge gaps exist in our understanding of the underlying AF mechanisms. Developing non-invasive strategies to selectively suppress the “seeds” is an area of active investigation. A more detailed molecular understanding of the “soil”, particularly in specific subtypes of AF, could inform targeted strategies to improve the “soil”. Likewise, uncovering the mechanisms that govern the interplay between the “seed” and the “soil” may enable a more comprehensive approach to address both contributors to AF. Further research is also needed to elucidate sex-specific mechanisms of AF.
The structural and functional remodeling of the atria described above are shaped by the intimate interplay between genetic predisposition and acquired stressors (Figure 3).
Genetic factors play a significant role in AF susceptibility^99^. Individuals with a first-degree relative diagnosed with early-onset AF (before age 60) have approximately a fivefold increased risk of developing AF, with heritability estimated around 22%^3,100^. Genetic contributions can be divided into 2 major common variants with smaller effect sizes, and rare variants with stronger effects^3,101^.
Rare variants causing AF are often discovered in AF pedigree studies. They typically occur in protein-coding regions and predominantly affect genes encoding ion channels and structure proteins. Common AF-associated variants (which are most often single nucleotide polymorphisms, SNPs) have been identified by genome-wide association studies (GWAS)^99^. The first published GWAS of AF reported SNPs on chromosome 4q25 near the PITX2 gene^102^. With an increasing number of large-scale population studies, more than 300 AF risk loci have now been identified in various GWAS^99^. The majority of AF-associated variants are found in the non-coding genome regions. The prevailing hypothesis is that these variants alter the transcriptional regulation of their target genes which could be distant from the loci. As a result, experimental validation of these predictions remains a major rate-limiting step for AF genetic studies^99^.
Studies have shown that common genetic variants contribute to over 20 times more to AF risk than the rare variants^99,103^. Thus, GWAS have identified loci that account for the majority of the population-level genetic susceptibility to AF. Polygenic risk scores (PRS) aggregate the effects of hundreds to thousands of common variants to estimate an individual’s genetic predisposition to AF^99^. Despite consistent independent associations between PRS and AF risk^104,105^, the clinical value of PRS as a stand-alone tool for AF prediction remains unclear with many studies reporting a limited effect^106^. One study found that the PRS only explains 4.7% of the variance of AF risk in the general population^107^. More promising results were reported when PRS was combined with other traditional AF risk factors^106,108^. Additional studies have suggested that PRS may have a better predictive value in certain populations including those with a high risk of developing AF such as individuals with heart failure and those that undergo cardiovascular surgery^109,110^.
Although genetic factors undoubtedly contribute to AF pathogenesis, many prevalent AF risk factors are acquired conditions including aging, obesity, hypertension, diabetes, and binge drinking. These factors may interact with genetic susceptibility to drive atrial remodeling and contribute to the development, progression, and exacerbation of AF^111,112^.
Aging is one of the most significant risk factors for AF^81^. The incidence of AF rises sharply with age. AF affects 1–2% of individuals under 65, but the rate increases to 10–15% in those over 80^5,113^. Aging is associated with structural and functional atrial remodeling including atrial dilation, fibrosis, a slower electrical conduction rate, and altered refractory period^113^. Impaired calcium handling is also observed in aged atria^114^. Older individuals often have co-morbidities including hypertension, diabetes, and coronary diseases, which are also major AF risk factors^113,114^. How aging contributes to AF pathogenesis remains incompletely understood. Inflammation and oxidative stress are commonly proposed as the underlying mechanisms^113,114^. Clonal hematopoiesis of Indeterminate Potential (CHIP) is an age-related condition where somatic mutations in hematopoietic stem cells lead to the clonal expansion of blood cells without causing overt hematologic malignancies^115^. Emerging studies revealed that CHIP is a novel independent risk factor for AF onset, progression, and adverse outcomes^116,117^. CHIP, particularly TET2-mutated CHIP clones produce exacerbated inflammatory signals including IL-1β and IL-6 via the activation of the NLRP3 inflammasome, leading to atrial fibrosis, calcium mishandling and electrical remodeling thus promoting arrhythmogenesis^118^.
Obesity and its associated metabolic syndrome (MetS) including hypertension, type 2 diabetes, hyperlipidemia, as well as obstructive sleep apnea (OSA), are some of the most significant risk factors for AF^119,120^. Numerous studies have consistently depicted a robust link between MetS and AF, even after adjusting for the coexistence of other major cardiovascular conditions such as coronary artery disease and heart failure^119–121^.
Studies have shown that elevated BMI at any stage of life can potentially serve as a risk factor for AF^122^. Obese individuals have a 50% increased risk of developing AF compared to their non-obese counterparts^123^. Amplified blood volume, increased cardiac output, cardiac remodeling, and an augmentation of epicardial fat, together with increased inflammation and oxidative stress, have been observed in obese individuals and proposed as the underlying mechanisms for obesity associated AF susceptibility^124^. Studies, such as the LEGACY trial, have shown that sustained weight loss (>10% body weight) reduces AF burden and recurrence, improves symptoms and reverses atrial remodeling^125^.
Other components of MetS, including hypertension, Type2 DM, and OSA, are all independent risk factors of AF, and are associated with significant atrial remodeling including atrial dilation and fibrosis^112,121,126^. Various electrophysiological changes including altered APD, slowed signal conduction, as well as calcium mishandling, are also frequently observed in both human atrial tissues and preclinical models^126–128^. Neurohormonal activation including activation of RAAS and sympathetic overaction also likely contribute to increased ectopic firing and atrial fibrosis^112,128^. These factors often co-exist and amplify AF risk by promoting AF onset and progression and increasing the risk of AF complications including stroke, heart failure and mortality. They are also associated with worse quality of life and increased symptom burden^121^.
Interestingly, despite the multi-dimensional benefits of exercise, studies have demonstrated that strenuous exercise, particularly endurance or high-intensity activities performed over prolonged periods, may increase the risk of AF, especially in male athletes^129,130^. Atrial dilation, inflammation, and autonomic imbalance are all possible contributors^129,131,132^. Increased atrial wall stress has been shown to trigger TNFα -mediated activation of local inflammation, eventually leading to atrial fibrosis in an animal model^133^ and blocking TNF-α prevents exercise-induced atrial fibrosis and AF inducibility^134^.
Active management of these modifiable risk factors, including weight loss, blood pressure control, and continuous positive airway pressure (CPAP) therapy, have shown benefits in reducing AF risk and recurrence and improving outcomes^125,135,136^. Given the many shared mechanisms including inflammation, oxidative stress, and autonomic imbalance among these etiologies, strategies targeting these common pathways hold great potential in reducing AF risk.
Most AF results from a complex interplay between genetic predispositions and acquired risk factors. They often converge on shared molecular pathways to amplify AF susceptibility. Studies have shown that AF rates increase with poorer lifestyle choices across all levels of genetic risk, as determined by PRS. This significant interaction suggests that lifestyle modification may offer disproportionately greater benefits for individuals with higher genetic risk^101^.
Functional validation of the genetic variants identified by GWAS remain one of the major bottleneck steps in AF genetic studies. Identifying specific gene(s) or gene regulatory elements that contribute to AF predisposition and pathogenesis may provide novel avenues for AF prevention and risk assessment and could provide targets for potential gene therapy. How genetic factors impact the disease course and response to therapies remains poorly understood. A better understanding of the common and specific molecular pathways associated with the acquired conditions will help to develop novel targeted therapies. Deciphering the complex interaction between the genetic and environmental factors will facilitate synergetic approaches for AF prevention and management.
The atria cannot be studied in isolation. The atria and ventricles are anatomically and functionally intertwined and operate as a synchronized unit. Through coordinated contraction, the atria receive blood and actively prime the ventricles to enhance ventricular filling. This interdependence means that atrial function directly influences ventricular performance, while ventricular dynamics, in turn, affect atrial workload^137^. Therefore, AF is common in heart failure as ventricular dysfunction imposes a mechanical burden on the atria, leading to increased pressure, remodeling, and arrhythmias. AF, in turn, exacerbates ventricular failure by causing irregular and rapid ventricular rates, reducing effective ventricular filling. These changes create a vicious cycle, worsening heart failure outcomes^138,139^. Additionally, many pathological stresses impact both the atria and ventricles causing dysfunction of both chambers^139^.
Although AF and heart failure (HF) frequently co-exist, this association is notably stronger in heart failure with preserved ejection fraction (HFpEF)^140^. AF is more prevalent in patients with HFpEF (about 60–70% of cases) than in those with heart failure with reduced ejection fraction (HFrEF) (around 30–40%). AF is poorly tolerated in patients with HFpEF and is associated with significantly worse clinical outcomes^141^. Consistent with this, studies have shown that atrial status, including size, stiffness, and contractile dysfunction, is more prognostic in HFpEF^142^ suggesting an intimate relationship between these two conditions. Although both HFpEF and AF are heterogeneous clinical syndromes, they share many common risk factors including advanced age, obesity and MetS, and pathological changes such as inflammation and oxidative stress. Therefore, it is proposed that HFpEF and AF are the ventricular and atrial manifestations of the same underlying cardiometabolic syndrome, respectively^143^. In short, they are two sides of the same coin (Figure 4).
This conceptual framework has multiple clinical and mechanistic implications. First, given that both AF and HFpEF can be clinically subtle and hard to diagnose, it is reasonable to search for the other condition when one is discovered. Specifically, screening for AF in patients with HFpEF, and vice versa^144^. A recent study revealed that in patients referred for AF ablation, about 73% of them may have had previously un-diagnosed HFpEF, as demonstrated by elevated intra-atrial filling pressure^145^. On the other hand, in patients with HFpEF, long-term rhythm monitoring revealed a significantly higher rate of sub-clinical AF as compared to those with comparable risk factors but without HFpEF^146^. Second, it indicates that common mechanisms might contribute to both pathologies. Indeed, features of AtCM and AF predisposition are prominent is a preclinical cardiometabolic HFpEF model^147^, providing an ideal tool to study whether common pathways are shared between the chambers. Last but not the least, this also suggests that therapies that target common pathways could be efficacious in both conditions. Consistently with this, a recent meta-analysis suggested that both sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonist (GLP1RA), which have shown clinical benefits in HFpEF, also reduce AF risk^148–151^. In preclinical models, both these medications led to attenuated atrial remodeling and reduced AF predisposition^152,153^. Mechanistically, this “whole heart” framework underscores the importance of assessing the status of both chambers when studying either AF and/or HFpEF.
Besides HFpEF, AF is also highly prevalent in other cardiac conditions including hypertrophic cardiomyopathy and dilated cardiomyopathy. Our understanding of the molecular mechanisms that collectively contribute to both atrial and ventricular dysfunction and the interplay between the two chambers remains incomplete. The chronological sequence of chamber-specific pathologies also needs to be further defined. Chamber-specific genetically modified mouse models will help to elucidate the interaction between these two closely connected partners.
AF is a complex clinical syndrome derived from underlying pathological atrial remodeling. Here, I introduced the evolving concept of atrial myopathy and described its progressive nature and relationship with AF. I proposed a novel “seed and soil” concept to better understand the interplay between ectopic firing and a vulnerable substrate, highlighting the importance of the atrial micro-environment in perpetuating and maintaining the arrhythmia. I also summarized the current understanding of the genetic and environmental risk factors that synergistically contribute to AF. Finally, I stressed the importance of assessing atrial and ventricular function as a synchronized unit to better appreciate the complicated interplay between AF and ventricular dysfunction. These conceptual frameworks will help to develop better strategies for personalized and mechanism-driven AF management. Future studies integrating spatial transcriptomics, AI-based atrial imaging and functional analysis, and proteomic profiling will enable stratification of AtCM subtypes and precision therapy development. Strategies targeting substrate reversal - including CaMKII inhibition, metabolic modulation, and anti-inflammatory interventions - may redefine AF treatment beyond rhythm control.