Atrial fibrillation and thromboembolic risk in hypertrophic cardiomyopathy

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with hypertrophic cardiomyopathy (HCM), conferring a markedly increased risk of thromboembolic events. Conventional risk stratification tools such as the CHA₂DS₂-VASc (congestive heart failure, hypertension, age ≥ 75 years [doubled], diabetes mellitus, prior stroke or transient ischemic attack [doubled], vascular disease, age 65–74 years, female sex) score are often insufficient to predict thromboembolic events in patients with HCM and AF, as thromboembolic risk in HCM is driven by disease-specific structural, functional, and prothrombotic substrates. This review synthesizes current evidence on the epidemiology, pathophysiological mechanisms, and clinical impact of AF and thromboembolism in HCM. We discuss variable imaging modalities—including strain echocardiography, cardiac magnetic resonance, and cardiac computed tomography—that offer enhanced characterization of atrial remodeling and thromboembolic risk in patients with HCM. Furthermore, we outline current guideline-based anticoagulation strategies, the evolving role of direct oral anticoagulants, and adjunctive therapies such as left atrial appendage occlusion and catheter ablation. A comprehensive, multidisciplinary approach that incorporates advanced imaging, molecular profiling, and individualized management is ideal to optimize outcomes and reduce stroke burden in patients with HCM and AF.

Background

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, characterized by unexplained left ventricular (LV) hypertrophy in the absence of loading conditions, such as hypertension or aortic stenosis. Its hallmark histopathologic features include myocyte disarray, interstitial fibrosis, and small vessel disease [1–3]. The prevalence of HCM in the general population is estimated to be approximately 1 in 200 to 1 in 500 individuals [4, 5]. The clinical presentation of HCM is highly variable, ranging from asymptomatic disease to progressive heart failure and sudden cardiac death. While HCM has been associated with adverse outcomes, including sudden cardiac death, heart failure, and arrhythmic complications, recent advances in early detection, longitudinal surveillance, and risk-guided management have significantly improved prognosis [6–8].

Atrial fibrillation (AF) represents the most common sustained arrhythmia in HCM, with a prevalence significantly higher than observed in the general population [9, 10]. This carries significant clinical implications, as the presence of AF in HCM is associated with a markedly increased risk of thromboembolism—often exceeding predictions from conventional risk stratification tools [9–15]. The heightened thromboembolic risk is attributed to the complex interplay among structural abnormalities, electrical remodeling, and the hypercoagulable state of HCM [16–19]. Current clinical guidelines recommend anticoagulation for all patients with HCM and AF, regardless of traditional stroke risk factors, unless contraindicated [20, 21].

This review provides a comprehensive overview of the epidemiology, underlying pathophysiologic mechanisms, and evolving strategies for risk stratification and management of AF and thromboembolism in HCM, with particular emphasis on the crucial role of multimodality imaging in clinical decision-making.

Epidemiology of AF and thromboembolism in HCM

AF is the most prevalent sustained arrhythmia in patients with HCM, occurring at a substantially higher rate than in the general population. The reported prevalence of AF in HCM ranges from 20 to 30% [9–11, 13, 14], with longitudinal studies estimating an annual incidence of new-onset AF of approximately 2%to 4% [9, 12, 22]. In patients with HCM over the age of 70 years, the lifetime prevalence of AF may approach 40% to 50% [10]. Overall, nearly one-third of individuals with HCM experience at least one episode of AF [12]. Among these, about two-thirds of AF episodes are paroxysmal, terminating spontaneously or with intervention within 7 days, while one-third are persistent and may progress to permanent AF [10, 23].

AF in HCM is associated with disproportionately high risk of thromboembolic events, even in patients with low CHA₂DS₂-VASc (congestive heart failure, hypertension, age ≥ 75 years [doubled], diabetes mellitus, prior stroke or transient ischemic attack [doubled], vascular disease, age 65–74 years, female sex) scores. The annual incidence of thromboembolic events in patients with both HCM and AF ranges from 3.8% to 7.6%, substantially exceeding the 1% to 2% yearly risk observed in the non-HCM AF population with similar CHA₂DS₂-VASc scores [9, 13]. In particular, cohort studies have reported annual stroke rates exceeding 3% in anticoagulation-naive patients with HCM and AF, underscoring the inadequacy of conventional risk stratification tools in this population [15]. Notably, even a single isolated paroxysmal episode of AF in HCM is associated with a significant risk of thromboembolism, in contrast to the general AF population, where sustained or permanent AF more strongly predicts adverse events [10, 14].

In addition to thromboembolic risk, AF has important prognostic implications in patients with HCM. AF is independently associated with increased mortality, with annual HCM-related mortality rates two to three times higher in patients with AF compared to those in sinus rhythm [12, 22, 24]. This excess mortality is largely attributed to both progressive heart failure and thromboembolic events. Importantly, the onset and progression of AF is not a simple phenomenon, but an important inflection point in the trajectory of the disease, often accompanied by acute decompensated heart failure, increased hospitalization, and increased risk of death [25–28].

Pathophysiological mechanism of AF and thromboembolism in HCM

Structural and functional substrate for AF

Left atrial (LA) remodeling stands as the central pathophysiological mechanism underlying AF in patients with HCM [29]. This remodeling process arises in response to the chronic pressure and volume overload, characteristics of HCM, resulting primarily from impaired myocardial relaxation and increased chamber stiffness. These hemodynamic abnormalities lead to sustained elevation in LV filling pressure, resulting in progressive LA dilation, increased wall stress, and the development of interstitial fibrosis [30–32].

Consistent with this remodeling, histopathological analyses of atrial tissue from patients with HCM have revealed extensive interstitial fibrosis and myocyte disarray, which collectively establish a vulnerable arrhythmogenic substrate capable of sustaining reentry circuits and ectopic foci that can initiate and maintain AF [30, 33]. Cardiac magnetic resonance imaging (MRI) also frequently demonstrates late gadolinium enhancement (LGE), a noninvasive marker of myocardial fibrosis, in both ventricles and atrial myocardium. The presence and extent of LGE in both LA and LV have been shown to correlate strongly with the risk of AF burden and recurrence risk, reflecting the underlying fibrotic remodeling [34–36]. In parallel, electrical remodeling occurs alongside these structural alterations, characterized by shortened atrial action potential duration, altered ion channel expression, and reduced conduction velocity [37–39]. Taken together, these structural and functional alterations create a permissive substrate for both the initiation and maintenance of AF in the setting of HCM.

Among the hemodynamic abnormalities in HCM, LV outflow tract (LVOT) obstruction is particularly influential in promoting LA remodeling and AF [40]. Present in approximately 40% to 60% of patients with HCM, either at rest or with provocation, LVOT obstruction is a major contributor to impairing LA mechanics [41, 42]. A key mechanism linking LVOT obstruction to LA remodeling is mitral regurgitation (MR), which occurs in 60% to 70% of patients with HCM, and is often secondary to systolic anterior motion of the mitral valve or intrinsic valve abnormalities [43–45]. The severity of MR has been positively correlated with both LA structural and functional impairment, as well as increased risk of AF in patients with HCM [43, 46].

Myocardial ischemia, which can occur in HCM due to microvascular dysfunction and supply–demand mismatch, may further contribute to atrial electrical instability, thereby serving as an additional trigger for AF in predisposed individuals through multiple mechanisms [47–49]. These mechanisms include worsening LV diastolic function, elevated LV filling pressure, increased LA stretch, atrial ischemia resulting from microcirculatory dysfunction, atrial fibrosis, and enhanced arrhythmogenicity. However, these proposed pathways remain largely speculative to date.

Once AF develops, it initiates a vicious cycle by eliminating coordinated atrial contraction, increasing atrial pressure, and promoting further atrial dilation and dysfunction [50]. This perpetuates the arrhythmogenic substrate and contributes to persistent arrhythmia maintenance [31]. Notably, AF also promotes blood stasis, particularly within the LA appendage (LAA), which is the most common site of thrombus formation. Even in sinus rhythm, LAA dysfunction is not uncommon in HCM and is markedly worsened by AF, thereby increasing the risk of thromboembolism [10, 19, 51].

Molecular and genetic considerations

Several sarcomeric gene variants—most frequently in MYH7, which encodes β-myosin heavy chain, and MYBPC3, which encodes myosin-binding protein C—are well-established genetic drivers of HCM. These pathogenic variants are frequently associated with more pronounced myocardial disarray, an earlier onset of disease, and a greater degree of interstitial fibrosis, compared to noncarriers [17, 52]. Recent advances in genotype–phenotype correlating studies have begun to illuminate how specific variants may predispose individuals to a more arrhythmogenic atrial substrate [53]. For example, pathogenic MYH7 variants have been linked to a higher incidence of new-onset AF in patients with HCM, with a hazard ratio of 1.72 (95% confidence interval, 1.27–2.33) compared to MYBPC3 variants, based on data from the multinational registry of 1,040 genotype-positive, AF-free adult HCM patients followed for a mean of 7.2 years [54]. Patients with MYH7 variants were more likely to present at a younger age and exhibit phenotypic features such as LA hypertrophy, dilatation, and extensive fibrosis—structural substrates that facilitate arrhythmia initiation and maintenance [54, 55]. In contrast, patients with MYBPC3 variants tended to be older at diagnosis, were less frequently probands, and more often underwent septal reduction therapy before developing AF, with a relatively attenuated association with atrial arrhythmias [54]. These observations underscore the importance of integrating genetic information into clinical risk stratification frameworks, as it may offer valuable insights into individualized arrhythmia risk and thromboembolic potential.

Beyond sarcomeric mutation, nonsarcomeric genetic factors have also been implicated in modulating AF susceptibility in patients with HCM. Genome-wide association studies have identified common susceptibility loci for AF, most notably PITX2 and ZFHX3, and KCNN3, which appear to overlap with loci implicated in familial AF [56]. These nonsarcomeric loci may contribute to a heritable predisposition for atrial arrhythmias and thromboembolic events in patients with HCM, independent of the degree of structural remodeling.

Mechanisms underlying thromboembolic risk in HCM

The development of AF in patients with HCM is associated with a markedly increased risk of thromboembolic events, often disproportionate to conventional risk stratification metrics such as CHA₂DS₂-VASc scores [12, 14, 57, 58]. This heightened thrombotic risk in HCM reflects a distinct pathophysiologic profile.

A major contributor to thromboembolism in HCM is LA stasis, driven by a combination of atrial enlargement, impaired contractile function, and altered geometry that creates regions of blood stagnation, particularly in the LAA [19, 51]. Transesophageal echocardiography (TEE) has revealed that patients with HCM often exhibit reduced LAA emptying velocities and more complex morphologies, both independently associated with thrombus formation [51].

In addition to structural abnormalities, endocardial dysfunction plays a key role in thrombogenesis in HCM. Patients with HCM exhibit systemic evidence of endothelial dysfunction, as reflected by upregulated circulating levels of soluble thrombomodulin and tissue factor pathway inhibitor, including thrombomodulin and endothelial protein C [59]. Notably, these abnormalities were more pronounced in patients with LVOT obstruction [59]. Even in the absence of AF, LVOT obstruction is independently associated with enhanced thrombin generation and platelet activity in patients with HCM [60]. These alterations create endothelial activation and disruption of anticoagulant balance, potentially contributing to a prothrombotic state.

Furthermore, patients with HCM demonstrate elevated markers of thrombin generation, including plasma levels of fibrinopeptide A and thrombin-antithrombin III complex, compared to healthy controls, indicating activation of the coagulation system [18]. Importantly, these markers showed a positive correlation with LA diameter, implicating LA dilation as a key driver of coagulation activation in HCM.

Risk assessment for AF and thromboembolism in HCM

Risk factors for AF in HCM

Multiple clinical and demographic factors have been identified that predict AF development in patients with HCM. Left atrial enlargement represents the most robust and consistently reported risk factor, with numerous studies demonstrating that LA diameter exceeding 40 to 45 mm is associated with a threefold to fourfold increased risk of new-onset AF [9, 12, 24, 61]. Reflecting this evidence, the European Society of Cardiology (ESC) guidelines recommend 48-h ambulatory electrocardiographic monitoring every 6 to 12 months for AF detection in patients with HCM who are in sinus rhythm and have an LA diameter > 45 mm (class IIa recommendation) [62]. Beyond simple diameter measurements, volumetric assessment of LA provides superior prognostic information. An LA volume index greater than 34 mL/m² has been reported to predict new-onset AF with a sensitivity of 82% and a specificity of 73% in patients with HCM [63]. In contrast, a lower LA volume of < 37 mL/m² appears to strongly predict the absence of AF, with a reported negative predicted value of 92% [61].

Age remains a significant risk factor, with each additional decade of life approximately doubling the risk for AF in patients with HCM [12, 31, 64]. Specifically, Olivotto et al. [12] reported that an age at diagnosis greater than 50 years was associated with a twofold increase in the risk of developing AF. Additionally, symptomatic status correlates with AF risk, with studies demonstrating that patients with HCM in New York Heart Association (NYHA) functional class III–IV have approximately threefold to fourfold higher risk of developing AF compared to those with mild or no symptoms [12, 31, 65].

Risk factors for thromboembolism in HCM

AF is a well-established risk factor for thromboembolic events in patients with HCM. Nevertheless, over half of thromboembolic events occur in the absence of previously documented AF, indicating the involvement of other contributing factors. This is particularly notable among patients aged 65 years of age or older and those with chronic heart failure, who exhibit a 2.7- and 1.8-fold higher risk, respectively [66, 67].

Morphological abnormalities also contribute significantly to thromboembolic risk in HCM. LA enlargement, which is routinely assessed via echocardiography in clinical practice, is not only associated with AF, but also an independent predictor of thromboembolic events in patients with HCM [24, 57]. Moreover, LV morphological features, including apical ballooning, have likewise been associated with a higher prevalence of thrombus formation in patients with HCM [68, 69].

Several clinical comorbidities have also been associated with increased thromboembolic risk. These include a prior history of thromboembolic event and atherosclerotic cardiovascular disease (e.g., myocardial infarction, complex aortic plaque, and peripheral arterial disease), and the presence of NYHA functional class symptoms has also been associated with an elevated risk of thromboembolic events in patients with HCM [57].

Additionally, structural and biochemical markers also contribute to thromboembolic risk in patients with HCM. These include echocardiographic parameters (e.g., LA diameter, maximal wall thickness, and LVOT gradient) [57], cardiac MRI-based assessment of myocardial fibrosis (e.g., LGE > 14.4%) [16], and circulating biomarkers of atrial remodeling (e.g., N-terminal pro–B-type natriuretic peptide and troponins) [70–74]. Among circulating biomarkers, elevated natriuretic peptides reflect elevated filling pressures and the neurohormonal activation that contributes to thrombogenesis. Similarly, high-sensitivity troponin elevation may indicate ongoing myocardial injury and greater hemodynamic compromise, identifying patients with more advanced disease and heightened stroke risk [74, 75].

Imaging modalities for risk assessment

Imaging modalities for risk assessment are summarized in Table 1.

Table 1.

Comparative summary of imaging modalities for risk stratification in patients with HCM and AF

Modality	Key feature	Identified risk marker	Clinical application
TTE	LA diameter and volume MR severity and LVOT obstruction LA strain by speckle-tracking echocardiography	LA diameter > 45 mm → ↑ AF risk (threefold–fourfold), indication for 48-h ambulatory ECG monitoring every 6–12 months LA volume index > 34 mL/m2 → predicts new-onset AF with sensitivity of 82% and specificity of 73% LA volume index < 37 mL/m2 → NPV 92% for absence of AF LA strain < 23% → new-onset AF LA strain < 17% → thromboembolism in AF	Initial screening and routine monitoring LA structural and functional remodeling
TEE	LAA morphology and thrombus LAA flow velocities	LAA emptying velocity < 20 cm/sec → ↑ thrombus, SEC, embolic risk	Preprocedural assessment for cardioversion/ablation or LAA occlusion Identification of LAA thrombus
Cardiac MRI	Gold-standard for myocardial fibrosis assessment (LGE) LA volume and function	LGE > 14.4% → ↑ thromboembolism 10% ↑ LGE → approximately 1.8-fold ↑ AF risk LA strain reduction → ↑ AF/thromboembolism risk Apical aneurysm detection → ↑ thromboembolic risk	Fibrosis-guided AF/thromboembolism risk stratification Evaluation of LA function and strain
Cardiac CT	High-resolution 3D visualization of LAA anatomy Delayed contrast-enhanced imaging for thrombus LAA emptying fraction (not yet widely adopted)	High diagnostic accuracy (> 99%) for LAA thrombus LAA ejection fraction < 40% → ↑ thromboembolism risk	Noninvasive thrombus and anatomical evaluation of LAA (alternative to TEE) Planning for LAA occlusion

AF atrial fibrillation, CT computed tomography, ECG electrocardiogram, HCM hypertrophic cardiomyopathy, LA left atrium, LAA, left atrial appendage, LGE late gadolinium enhancement, LVOT left ventricular outflow tract, MR mitral regurgitation, MRI magnetic resonance imaging, NPV negative predictive value, SEC spontaneous echo contrast, TEE transesophageal echocardiography, TTE, transthoracic echocardiography

Echocardiography

Multimodality imaging plays a pivotal role in the assessment of AF and thromboembolic risk in patients with HCM. Echocardiography remains the cornerstone imaging modality in routine clinical practice for diagnosis and risk stratification of HCM, providing critical insights on LA morphologies, LAA assessment, LVOT obstruction, MR severity, and diastolic dysfunction. Transthoracic echocardiography enables accurate measurement of LA diameter and volume, both of which are established predictors of AF and thromboembolism in HCM [24, 61, 63, 76].

Advanced echocardiographic techniques, such as speckle-tracking echocardiography, provide a functional assessment of LA mechanics. Although not yet widely adopted in all clinical settings, LA strain measurement has demonstrated predictive value for incident AF and thromboembolic risk [77, 78]. The reduction in LA reservoir strain is closely linked to LV diastolic dysfunction. Impaired LV relaxation and elevated LV filling pressures increase LA afterload and wall stress, which in turn promote LA fibrosis and impaired compliance. In a cohort of 414 patients with HCM, a novel LA strain-based classification effectively stratified LV diastolic dysfunction [79]. Thus, LA strain reflects both intrinsic atrial dysfunction and the downstream effects of LV diastolic impairment, underscoring its value as an early marker of AF and thromboembolic risk in HCM. Notably, in patients with established AF, reduced LA reservoir strain (< 23% in predicting new-onset AF and < 17% in predicting thromboembolic events) can identify atrial dysfunction even before atrial enlargement becomes apparent [61, 80]. In addition, reduced LA reservoir strain is the best predictor of reduced LAA emptying velocity and LAA thrombus [81].

TEE, though more invasive, is commonly used in practice to evaluate LAA morphology and thrombus [82], particularly in patients undergoing cardioversion or ablation [83]. Specifically, pulsed-wave Doppler–derived LAA emptying velocities < 20 cm/sec indicate an elevated risk of thrombus and spontaneous echocardiographic contrast [84].

Cardiac MRI

Cardiac MRI has emerged as a key tool for the comprehensive evaluation of patients with HCM, with its ability to characterize myocardial tissue being one of its most valuable strengths. Myocardial fibrosis detected by LGE has been shown to correlate independently with the risk of AF and thromboembolic events in patients with HCM [16, 64]. Notably, an increase in the extent of LGE by 10% has been associated with an approximately 1.8-fold rise in AF risk [64]. In addition, an LGE extent exceeding 14.4% has been identified as an independent predictor for thromboembolic events in patients with HCM [16]. While LGE assessment has traditionally focused on ventricular myocardium, recent studies have highlighted the utility of cardiac MRI in detecting atrial LGE, which correlates with atrial myopathy and AF susceptibility [36, 85]. However, LGE quantification may suffer from limited reproducibility across centers due to variability in image acquisition protocols and post-processing techniques [86]. This limits the generalizability of its prognostic value. Therefore, further efforts to standardize imaging protocols and quantification methods are necessary to improve consistency and facilitate broader clinical implementation.

In addition, cardiac MRI provides a gold-standard assessment of LA volumes and function [87], with feature-tracking techniques allowing detailed strain analysis that has shown strong associations with AF development and thromboembolic events in patients with HCM [29, 88]. Cardiac MRI may be additionally useful for identifying an apical thrombus in patients with HCM and apical aneurysm ballooning [89].

Cardiac computed tomography

Cardiac computed tomography (CT) is not routinely used for risk stratification in HCM but may provide clinically useful information in selected cases, particularly when echocardiographic images are suboptimal or when planning LAA occlusion procedures. Although evidence in HCM is limited, contrast-enhanced cardiac CT has demonstrated excellent sensitivity and specificity (> 99%) for LAA thrombus detection in broader AF populations, in a recent meta-analysis [90]. In addition, CT offers detailed 3D characterization of LAA anatomy, including volume, number of lobes, and orifice dimensions, which is particularly valuable when planning LAA occlusion procedures [91]. In research and specialized settings, CT-derived LAA emptying fraction (< 40%) [92] and LA strain measurement have shown potential for thromboembolic risk assessment, though their use remains investigational in HCM [93].

Prevention and management strategies

Anticoagulation approaches

Given the high incidence of stroke in patients with HCM and AF, current guidelines from major cardiovascular societies warrant a lower threshold for anticoagulation than in the general AF population. The 2024 American Heart Association/American College of Cardiology (AHA/ACC) guidelines for HCM recommend anticoagulation for all patients with HCM and persistent/paroxysmal AF, irrespective of CHA₂DS₂-VASc score (class I recommendation) [21]. Similarly, the ESC guidelines provide a class IIa recommendation, supporting anticoagulation for all patients with paroxysmal, persistent, or permanent AF [62]. Importantly, lifelong therapy with oral anticoagulants is advised, even after restoration of sinus rhythm, due to the persistent risk of thromboembolism in the high-risk population.

Historically, vitamin K antagonists (e.g., warfarin) were the mainstay of anticoagulation. However, accumulating observational evidence supports the use of direct oral anticoagulants (DOACs), including factor Xa inhibitors and direct thrombin inhibitors, demonstrating—or in some outcomes, superior—safety profiles regarding intracranial bleeding, hemorrhagic stroke, and major bleeding in patients with HCM and AF [94–97]. There are practical benefits to using DOACs, such as fixed dosing, fewer dietary and drug interactions, and no requirement for routine international normalized ratio monitoring, thereby enhancing convenience and adherence. Standard dosing regimens are appropriate for most patients, with adjustments guided by existing AF criteria based on renal function, age, and body weight. However, in patients with HCM, there are currently no head-to-head randomized controlled trials (RCTs) or guideline-endorsed recommendations favoring one DOAC over another, such as apixaban, rivaroxaban, or edoxaban, leaving the optimal agent undefined. In this context, shared decision-making remains essential, considering individual patient characteristics, comorbidities, bleeding risk, and clinical experience.

Rhythm control strategies

Restoration and maintenance of sinus rhythm in patients with HCM and AF reduce thromboembolic risk by improving atrial mechanical function and reducing blood stasis [98], as supported by strain imaging studies demonstrating LA reverse remodeling with a concomitant improvement in LA strain after rhythm control [99].

Pharmacological rhythm control in patients with HCM is challenging. Amiodarone is most effective for maintaining sinus rhythm in this population [100, 101], but its long-term toxicity limits its use, especially in younger patients [102]. Sotalol offers moderate efficacy and a more favorable safety profile [103, 104]. In a retrospective study of 98 patients (130 drug treatments) with HCM and symptomatic AF, the probability of remaining on sotalol was 74% at 1 year and 50% at 3 years, with only 2% discontinuing due to side effects and no serious adverse events reported; however, clinical experience in HCM remains limited [104]. Disopyramide is particularly useful in obstructive HCM for symptom relief and, in select cases, rhythm control due to its negative inotropic effects. While randomized trials are lacking, observational data support its medium-term efficacy and safety. In a study of 92 patients, 67% of patients remained on therapy after 7.2 years, with 46% showing resolution of LVOT obstruction [105]. Serious adverse events were rare. However, use remains limited by anticholinergic side effects, the need for inpatient initiation in some cases, and limited availability [106]. Class IC drugs (e.g., flecainide, propafenone) are generally avoided due to their proarrhythmic potential in the presence of structural heart disease. Thus, in the context of HCM, their use should be approached with caution and is typically reserved for selected patients, preferably those with an implantable cardioverter-defibrillator [107].

Catheter ablation is a reasonable option for patients with symptomatic AF who are refractory to medical therapy or prefer a rhythm control strategy [108–110]. However, compared to individuals without structural heart disease, patients with HCM exhibit significantly higher recurrence rates and tend to show greater fibrotic remodeling of the LA and less favorable LA reverse remodeling following catheter ablation [17, 111–113]. Although procedure-related complications are uncommon, patients with HCM tend to have longer hospital stays and higher readmission rates, often due to AF-related symptoms or heart failure [112, 114].

On the other hand, in patients with HCM undergoing cardiac surgery (e.g., myectomy), concomitant surgical AF ablation (Cox-Maze or modified procedures) along with LAA exclusion should be considered. In experienced centers, these combined approaches have achieved freedom from recurrent AF in over 70% at 5 years [115]. Notably, 1-year freedom from AF recurrence is reported to be approximately 44% after catheter ablation, compared to 75% following surgical Maze procedures [10]. In addition, advanced ablation technologies such as pulse field ablation have demonstrated improved safety and efficacy profiles compared to conventional thermal ablation [116].

LAA occlusion

LAA occlusion represents an alternative strategy for stroke prevention in selected patients with HCM and AF [117, 118]. However, since no RCTs have specifically evaluated LAA occlusion in the HCM population, decisions should therefore be individualized based on a comprehensive assessment of stroke and bleeding risk. Real-world data involving 364 patients with HCM and AF treated with LAA occlusion do not support its use as the primary stroke prevention strategy in patients eligible for long-term oral anticoagulation [118]. In this cohort, patients with HCM and AF undergoing LAA occlusion experienced a higher rate of ischemic stroke (13% vs 8%) and systemic embolism (14% vs 9%) compared with propensity-matched patients receiving oral anticoagulation. In contrast, another large real-world study including 71,980 patients with HCM and AF demonstrated that both surgical and transcatheter LAA occlusion were associated with a lower risk of hemorrhagic stroke and major bleeding compared to those without LAA occlusion, although no significant difference was observed in ischemic stroke [119]. These findings suggest that while LAA occlusion may offer bleeding-related benefits, its role in ischemic stroke prevention, particularly among patients with HCM, remains uncertain.

The 2020 European Heart Rhythm Association/European Association of Percutaneous Cardiovascular Interventions Expert Consensus Statement supports percutaneous LAA occlusion in patients with a high thromboembolic risk who have contraindications to long-term anticoagulation [120]. Similarly, the 2019 AHA/ACC Focused Update assigns a class IIb indication for LAA occlusion in such populations [121]. Although large, prospective RCTs have demonstrated the efficacy of LAA occlusion for stroke prevention, as well as reductions in bleeding risk and cardiovascular mortality in patients with nonvalvular AF, these trials have not included individuals with HCM [122, 123]. Consequently, LAA occlusion may be considered in patients with HCM and AF, who have absolute contraindications to anticoagulation, experience recurrent bleeding despite optimized anticoagulation, or have poor anticoagulation control.

Emerging role of myosin inhibitor

Recently, mavacamten, a selective cardiac myosin inhibitor, has emerged as a novel therapeutic option for patients with obstructive HCM [124]. In addition to its established benefits in reducing LVOT gradients, improving symptoms, and enhancing exercise capacity, preliminary data suggest that mavacamten may also exert favorable effects on LA hemodynamics [125, 126]. By reducing LV diastolic pressure and improving LA compliance, mavacamten may indirectly mitigate AF burden and support LA reverse remodeling. Ongoing studies are exploring its potential role in modulating atrial arrhythmia susceptibility and long-term stroke risk reduction.

Prediction models for AF and thromboembolism in HCM

While sudden cardiac death risk stratification has first been the focus of HCM management, increasing attention is now directed toward predicting AF and thromboembolic events, which significantly impact quality of life and long-term outcomes.

The HCM-AF score is an externally validated risk prediction model in a cohort of 1,900 patients with HCM to estimate 2-and 5-year risk of new-onset AF [65]. It incorporates age (+ 3 points per decade), LA dimension (+ 2 points per 6-mm increase), age at HCM diagnosis (–2 points per decade), and heart failure symptoms (+ 3 points if present), stratifying patients into risk categories of low (< 1.0% per year), intermediate (1.0%–2.0% per year), and high (> 2.0% per year). In external validation in a separate cohort, high-risk patients had a 2.7% per year AF incidence versus 0.2% per year in low-risk patients. The model demonstrated good discrimination (C-statistic, 0.70 in the development cohort and 0.68 in the validation cohorts) and outperformed LA dimension alone and non-HCM-specific risk models.

More recently, machine learning models integrating multiple clinical, imaging, genetic, and biomarker data have shown superior predictive accuracy [127]. In a prospective multicenter cohort of 1,069 HCM patients without prior AF, a machine learning model achieved an area under the curve of 0.84, with a sensitivity of 82% and specificity of 76%, respectively, significantly outperforming the HCM-AF score [127].

For thromboembolic events, the R-CHA₂DS₂-VASc score modifies the traditional CHA₂DS₂-VASc score by integrating HCM-specific variables [128]. In a study of 446 patients with HCM, it demonstrated strong discrimination (C-statistic, 0.77), with thromboembolism rates rising from 0.84 per 100 person-years in the low-risk group (score ≤ 2) to 17.54 per 100 person-years in the high-risk group (score ≥ 8). The HCM Risk-CVA score, though incorporating important clinical variables such as LA size, AF status, and vascular disease, is limited by its complexity [57]. Alternatively, the French HCM score, derived from a large national cohort (n = 32,206), offers a simplified approach based on age, heart failure, AF, prior stroke, smoking, and nutrition status, achieving comparable performance (C-statistic, 0.65–0.70) without imaging data [13].

Conclusions

AF represents a pivotal complication in HCM, associated with increased morbidity and mortality, primarily driven by heightened thromboembolic risk. Its pathophysiology in HCM is distinct, involving structural remodeling, atrial dysfunction, and prothrombotic states, necessitating tailored risk stratification and management strategies. DOACs are preferred for stroke prevention in patients with HCM and AF, and rhythm control strategies such as advanced catheter ablation and surgical Maze procedures may be effective in selected patients. LAA occlusion may offer an alternative in those with contraindications to anticoagulation, though further validation is needed. Recent advances, including HCM-specific prediction models, machine learning approaches, and multimodality imaging, have improved risk assessment for AF and thromboembolism. Future research should prioritize prospective studies focused on HCM-specific anticoagulation and rhythm control strategies, with the goal of enabling individualized, evidence-based care to improve long-term outcomes.

Abbreviations

ACC

American College of Cardiology

AHA

American Heart Association

AF

Atrial fibrillation

CHA₂DS₂-VASc

Congestive heart failure, hypertension, age ≥ 75 years (doubled), diabetes mellitus, prior stroke or transient ischemic attack (doubled), vascular disease, age 65–74 years, female sex

CT

Computed tomography

DOAC

Direct oral anticoagulant

ESC

European Society of Cardiology

HCM

Hypertrophic cardiomyopathy

LA

Left atrial

LAA

Left atrial appendage

LGE

Late gadolinium enhancement

LV

Left ventricular

LVOT

Left ventricular outflow tract

MR

Mitral regurgitation

MRI

Magnetic resonance imaging

NYHA

New York Heart Association

RCT

Randomized controlled trials

TEE

Transesophageal echocardiography

Authors’ contributions

You-Jung Choi conceptualized the review, performed the literature search, drafted the manuscript, and coordinated the overall structure and revisions. She also served as the corresponding author and supervised all aspects of manuscript preparation and submission. Neal K. Lakdawala provided critical expertise in hypertrophic cardiomyopathy and atrial fibrillation, and revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.