Cardiac Involvement in Emery-Dreifuss Muscular Dystrophy: From Arrhythmias to Heart Failure and Sudden Death: A Contemporary Review

1. Introduction

In 1966, the neurologists Alan E. Emery and Fritz E. Dreifuss first identified a clinical phenotype distinct from other progressive muscular dystrophies. In their original report, Emery and Dreifuss described a benign X-linked neuromuscular phenotype characterized by a distinctive clinical triad [1]:

• early contractures (particularly involving the elbows, Achilles tendons, and cervical spine), often preceding the onset of muscle weakness;
• slowly progressive myopathy with a scapulohumeral and peroneal distribution;
• cardiac involvement with conduction system disease, responsible for syncope and sudden cardiac death, already recognized as an integral component of the disorder

Since the 1960s, the term “Emery-Dreifuss syndrome” has been used to describe a group of rare inherited syndromes sharing muscular, joint, and cardiac manifestations and caused by different types of genetic mutations. They are considered neuromuscular degenerative disorders, similar to Duchenne and Becker muscular dystrophies (DMD and BMD), but belonging to the spectrum of nuclear envelope diseases and with a more favorable course [2]. From a gene-level perspective, according to the corresponding mutations, different types of Emery-Dreifuss muscular dystrophy (EDMD) can be distinguished [3,4]:

• EDMD1 (X-linked transmission), the most frequently diagnosed form, linked to mutations in the EMD gene, which encodes the protein “emerin”, a component of the inner nuclear membrane;
• EDMD2 (laminopathy, autosomical dominant transmission), caused by mutations in the lamin gene (LMNA);
• EDMD4 and EDMD5, caused by mutations in the SYNE1 or SYNE2 genes, respectively, encoding nesprin-1 or nesprin-2.

Figure 1. Classical clinical triad and major genetic determinants of Emery-Dreifuss muscular dystrophy. Emery-Dreifuss muscular dystrophy is classically defined by the association of early musculo-tendinous contractures, slowly progressive humeroperoneal muscle weakness, and cardiac involvement characterized by conduction disease, arrhythmias, and variable cardiomyopathy. The figure also highlights the principal genes implicated in EDMD, including EMD, LMNA, and other nuclear-envelope/LINC-complex–related genes, underscoring the genetic heterogeneity of the disorder and the close link between molecular substrate and clinical phenotype. Abbreviations: EDMD, Emery-Dreifuss muscular dystrophy; EMD, emerin gene; LMNA, lamin A/C gene; LINC, linker of nucleoskeleton and cytoskeleton.

A large-scale study conducted on cells from affected patients showed that myogenic, metabolic, and fibrotic signaling pathways are strongly implicated. It was demonstrated that alpha smooth muscle actin positive myofibroblasts are overrepresented and that the profibrotic miRNA-21 is upregulated. Consistent with this, correction of the sequence carrying the mutation was associated with reduced expression of fibrogenic molecules [4]. From a clinical standpoint, disease progression is often characterized by the so-called “triad,” with early development of contractures, followed by fatigue and muscle atrophy, and finally the development of cardiac abnormalities [5]. There is no absolute correlation between muscular manifestations and cardiac manifestations. Cardiac involvement in EDMD may follow an independent course and can even precede neuromuscular symptoms [6]. In some cases, cardiomyopathy may present with syncope or sudden death, which can be the first symptom in rare instances in certain forms [7]. Symptomatic treatments mitigate orthopedic and cardiac complications, but no curative therapy is currently available for these diseases [4]. This lack of association between cardiac and muscular symptoms was emphasized in a study by Ishikawa et al., which introduced the concept of “cardiac emerinopathy” to describe patients carrying the EDM mutation who exhibit an isolated cardiac phenotype, without clinically relevant neuromuscular manifestations [8]. The 2023 ESC Guidelines for the management of cardiomyopathies explicitly recognize laminopathies, including EDMD, as important causes of genetic cardiomyopathy and emphasize the need for an aetiology-driven, multidisciplinary diagnostic approach rather than a purely morphological classification [9].

Figure 1. summarizes the classical clinical triad of EDMD together with the main genes involved in its pathogenesis.

Figure 1. summarizes the classical clinical triad of EDMD together with the main genes involved in its pathogenesis.

The pathophysiological link between the underlying genetic defect and the major cardiovascular manifestations of Emery-Dreifuss muscular dystrophy is schematically illustrated in Figure 2.

2. Materials and Methods

A targeted literature search was conducted in PubMed, Embase, and Web of Science to identify original studies, case series, registries, guideline documents, and high-quality reviews addressing cardiovascular involvement in EDMD. Particular attention was given to genotype–phenotype correlations (e.g., EMD, LMNA), arrhythmic risk, conduction disease, cardiomyopathy progression, and device-based and pharmacological management strategies.

The retrieved evidence was selected and synthesized in a narrative manner, prioritizing clinical relevance, methodological rigor, and consistency with contemporary recommendations for inherited cardiomyopathies and neuromuscular disorders. Rare and under-recognized clinical presentations were also included to provide a comprehensive and practice-oriented perspective.

This review does not present new or unpublished data. The manuscript was prepared in accordance with the International Committee of Medical Journal Editors (ICMJE) recommendations for the conduct, reporting, editing, and publication of scholarly work in medical journals. Artificial intelligence tools were used exclusively for the generation of illustrative figures. All content was fully reviewed, verified, and curated by the authors, who take full responsibility for the accuracy and integrity of the work. No AI was used for data generation, analysis, or interpretation.

3. Results

3.1. Epidemiology, Diagnostic Criteria, and Neuromuscular Involvement

EDMD is a rare disorder whose real prevalence is uncertain and estimates vary widely across sources and subtypes, ranging from ~1:400,000 to ~1.3–2 per 100,000 (≈ 1:50,000–1:77,000). In the epidemiological literature, it has been estimated from ~0.39 per 100,000 (≈ 1:256,000) to 1:250.000 births, while X-linked EDMD has been reported at ~0.13 per 100,000 in a regional population study and commonly at ~1:100,000 male births [5,10,11,12,13,14]. Despite its classical description, the epidemiology remains imprecise, largely due to marked genetic heterogeneity, incomplete penetrance, and frequent under-recognition, particularly in patients presenting with an apparently isolated cardiac phenotype [9,15].

3.1.1. Age and Sex Distribution

Age at presentation and sex distribution are strongly dependent on the underlying gene and mode of inheritance. In X-linked EDMD (EDMD1) due to pathogenic variants, the full clinical phenotype is observed almost exclusively in males, whereas heterozygous females typically show a milder and later-onset presentation [13,16]. In a recent large multicentre cohort, males with EDMD1 had a mean age of 33.4 ± 13.3 years at clinical evaluation and exhibited a substantial risk of malignant ventricular arrhythmias and progression to end-stage heart failure. In contrast, female carriers were older (43.3 ± 16.8 years) and, although approximately 40-45% developed cardiac involvement during follow-up, this typically occurred later in life (median age ~58.6 years) and was associated with a markedly lower incidence of life-threatening ventricular arrhythmias [16]. Female carriers are often asymptomatic but may present cardiac symptoms after age 50, especially for the conduction anomalies [12]. These data have direct clinical implications, supporting lifelong cardiac surveillance even in apparently asymptomatic female carriers. In autosomal dominant EDMD (EDMD2) associated with LMNA variants, both sexes are affected, and clinical expression is considerably more heterogeneous [17,18]. In these patients, disease onset frequently occurs in adulthood and may be dominated by a cardiac-first phenotype, characterized by early conduction disease, atrial arrhythmias, or dilated cardiomyopathy, while skeletal muscle involvement may be subtle or clinically unapparent in the early stages [9,17]. This presentation fully aligns with the ESC 2023 concept that early arrhythmias and conduction disturbances may represent sentinel manifestations of genetic or syndromic cardiomyopathies [9].

3.1.2. Neuromuscular Involvement: The Diagnostic Core of EDMD

Despite increasing attention to the cardiac phenotype, neuromuscular involvement remains the most characteristic and diagnostically specific feature of EDMD, particularly in classical forms [5,13]. Early and selective musculo-tendinous contractures are often the first clinical manifestation and may appear in childhood or adolescence [13]. Typical sites include the elbows (loss of extension), Achilles tendons (limited dorsiflexion or equinus deformity), and cervical and paraspinal muscles, leading to progressive spinal rigidity (“rigid spine”) [5,19]. These contractures frequently precede overt muscle weakness and represent one of the most discriminating clinical features of EDMD compared with other muscular dystrophies [19]. The associated myopathy is slowly progressive and displays a highly characteristic humeroperoneal distribution, with involvement of the scapulo-humeral muscles in the upper limbs (often with scapular winging) and distal/peroneal compartments in the lower limbs, resulting in foot drop and steppage gait [5,13]. Progression is typically slow, and muscle strength may remain relatively preserved for years, a feature that may delay diagnosis unless contractures are actively sought [18]. Spinal rigidity constitutes an additional hallmark. Progressive limitation of cervical and thoracic mobility may be disproportionate to the degree of muscle weakness and contributes significantly to functional impairment. Together, the triad of early contractures, humeroperoneal weakness, and rigid spine constitutes a powerful pattern-recognition framework for clinical diagnosis [13,18]. From a laboratory and electrophysiological standpoint, serum creatine kinase levels are often normal or only mildly elevated and therefore lack exclusionary value. Electromyography typically demonstrates non-specific myopathic changes. Muscle biopsy, historically used in the diagnostic work-up, is now reserved for selected cases, as genetic testing has become the diagnostic gold standard [9,13].

3.1.3. Peripheral Neuropathy: Accessory Feature and Overlap Phenotypes

In contrast to the prominent myopathic features, peripheral neuropathy is not considered a cardinal feature of classical EDMD [13]. Nevertheless, a limited number of reports, mainly involving LMNA-related disease, have described patients with combined myopathic and neurogenic features on nerve conduction studies and electromyography, suggesting a myopathy-neuropathy overlap phenotype [20,21]. Experimental and pathological data indicate that nuclear envelope dysfunction may, in rare cases, affect peripheral nerves or Schwann cells [21]. Clinically, the presence of mild peripheral neuropathy does not exclude EDMD when typical contractures and humeroperoneal myopathy are present. Conversely, a phenotype dominated by sensory-motor neuropathy in the absence of early contractures should prompt consideration of alternative diagnoses [13].

3.1.4. Integrated Diagnostic Criteria

Although no universally codified major/minor criteria exist, contemporary diagnosis of EDMD relies on an integrated clinical-instrumental-genetic approach, consistent with the ESC 2023 cardiomyopathy framework [9,22]:

• Typical neuromuscular phenotype: early selective contractures plus humeroperoneal myopathy and/or rigid spine.
• Compatible cardiac phenotype: conduction disease, early atrial arrhythmias, ventricular arrhythmias and/or heart failure.
• Genetic confirmation: identification of a pathogenic or likely pathogenic variant in EMD, LMNA, or related nuclear envelope genes, followed by genetic counselling and cascade family screening.

This approach enables accurate diagnosis, prognostic stratification, and early identification of at-risk relatives. An integrated clinical–genetic diagnostic framework for EDMD is summarized in Table 1, highlighting how the combination of early contractures, humeroperoneal myopathy, cardiac involvement, and molecular confirmation supports timely diagnosis and family-based risk stratification.

Genotype-phenotype correlations in EDMD are summarized in Table 2, highlighting the clinically relevant distinction between the typically atrial-dominant course of EMD-related disease and the more malignant ventricular-arrhythmic profile usually observed in LMNA-related phenotypes.

3.2. Cardiac Involvement

3.2.1. Overview of Cardiac Complications in Emery-Dreifuss

Cardiac involvement in EDMD typically becomes clinically apparent from late adolescence to early adulthood, although subclinical abnormalities may precede overt manifestations [5,13,16]. Initial symptoms may include palpitations, presyncope, syncope, or reduced exercise tolerance, reflecting early electrical instability or chronotropic incompetence [2,5]. In some patients, sudden cardiac death may be the first manifestation, highlighting the malignant arrhythmic potential of the disease even in the absence of advanced structural remodeling [16,23].

Conduction system disease is a hallmark of EDMD and may affect multiple levels of the cardiac conduction axis [6,13]. Reported abnormalities include sinus bradycardia, sinoatrial block, atrial standstill, atrioventricular (AV) conduction delay, bundle branch block, and progression to complete AVB, frequently requiring permanent pacemaker implantation [6,8,24].

However, in selected patients with additional markers of arrhythmic risk, an implantable cardioverter-defibrillator (ICD) may be more appropriate than pacing alone [16,25]. Both atrial and ventricular arrhythmias are common during the disease course [26]. Atrial fibrillation and atrial flutter may occur at a young age and contribute substantially to thromboembolic risk, particularly in the setting of atrial mechanical dysfunction [8,27].

Ventricular ectopy and ventricular tachyarrhythmias also occur and are major determinants of prognosis [16,26]. With disease progression, structural cardiomyopathy and heart failure may emerge, most commonly with a dilated phenotype, while hypertrophic forms have been reported less frequently [16,28]. Importantly, sudden death may occur despite prior pacemaker implantation, indicating that pacing does not abolish arrhythmic risk [16,23,24]. In advanced cases, progression to end-stage heart failure may ultimately require heart transplantation as a definitive therapeutic option [16,29].

The progressive cardiac trajectory of EDMD is illustrated in Figure 3, highlighting the transition from early atrial myopathy and conduction disease to atrial standstill, ventricular arrhythmias, cardiomyopathy, and major clinical outcomes.

The broad spectrum of cardiac involvement in EDMD is outlined in Table 3, underscoring that atrial disease, conduction abnormalities, ventricular arrhythmias, and progressive cardiomyopathy represent interconnected components of a single evolving cardio-neuromuscular phenotype.

3.2.2. Cardiac Imaging: Echocardiography and Cardiac Magnetic Resonance

Cardiac imaging, particularly echocardiography and cardiac magnetic resonance (CMR), plays a central role within a structured management strategy [2]. Transthoracic echocardiography commonly demonstrates a phenotype in which atrial remodelling may predominate over ventricular dilatation, with variable degrees of LV systolic impairment and occasional diastolic dysfunction. In a comparative echocardiographic study including both major genetic subgroups (EDMD1/EMD and EDMD2/LMNA), chamber enlargement (particularly atrial) was frequent, and a substantial subset had LVEF below the normal range, supporting the concept that structural and functional abnormalities may be present even in clinically “mild” skeletal phenotypes. Earlier echocardiographic series likewise documented that LV function can be subtly reduced compared with controls and that a minority may fulfil criteria for dilated cardiomyopathy, reinforcing the need for systematic baseline and longitudinal echocardiographic surveillance [28,30]. A case-control echocardiographic study evaluated left ventricular (LV) morphology and function in 27 men with confirmed EDMD (age 16–40 years; mean ~26 years), including 23 X-linked and 4 autosomal-dominant cases, compared with 16 age-matched healthy male controls (mean ~25 years). LV end-diastolic diameter was similar between groups, although three X-linked patients showed LV dilatation. Despite comparable wall thickness, EDMD patients had evidence of LV remodeling, with higher relative wall thickness and a higher LV mass index. LV systolic function was significantly reduced in EDMD, with a lower mean ejection fraction and 6/27 (22.2%) showing LVEF <50%; the most severe impairment (EF 19%, 32%, 34%) occurred in X-linked disease, and overt heart failure was documented in one patient. Doppler assessment (in those in sinus rhythm) indicated impaired relaxation, with prolonged isovolumetric relaxation time, higher A-wave velocity, and reduced E/A ratio; applying age-specific criteria, slow early filling was present in four patients and a restrictive pattern in two with advanced systolic dysfunction. Overall, subclinical LV dysfunction was frequent even in young adults. A substantial proportion, often minimally symptomatic, shows LV dysfunction, supporting the need for ongoing cardiology and echocardiographic surveillance [30].

Beyond standard parameters, deformation-based assessment suggests that myocardial dysfunction may be detectable at an early, subclinical stage. In autosomal dominant EDMD (LMNA-related), tissue Doppler and CMR-based strain identified abnormal LV functional indices despite preserved conventional chamber dimensions and the absence of late gadolinium enhancement, implying that functional impairment can precede overt scar formation [31]. In broader LMNA cardiomyopathy cohorts (highly relevant to EDMD2 and overlapping laminopathy phenotypes), speckle-tracking–derived mechanical dispersion has been proposed as a marker associated with ventricular arrhythmic risk beyond LVEF, supporting the rationale for incorporating strain mechanics into integrated phenotyping and follow-up when available [32]. CMR data are very limited but it is increasingly used to define an early myocardial phenotype beyond conventional echocardiography. In the single-centre cohort described by Ditaranto et al., clinical trajectories differed according to neuromuscular onset, supporting the concept that LMNA-related disease spans heterogeneous cardiac phenotypes and progression patterns, with imaging playing a role in longitudinal characterization [33]. CMR is increasingly emphasized as the reference technique in muscular dystrophies to detect subclinical myocardial involvement and to support risk stratification, particularly through tissue characterization (e.g., LGE and mapping) and functional assessment [34]. Extending EDMD relevance to EMD variants, Bulmer et al. reported a large family with X-linked isolated DCM due to an EMD missense variant, where CMR demonstrated late gadolinium enhancement with mixed ischaemic and non-ischaemic patterns, alongside conduction disease and ventricular arrhythmias, highlighting that fibrosis/structural substrate may be present even when skeletal muscle involvement is minimal [35]. In EDMD2, feature-tracking/strain analyses have reported reduced inferior wall contractility versus controls, suggesting that regional dysfunction may precede clinical cardiac manifestations; the absence of LGE argues against scar-driven impairment, unlike Duchenne muscular dystrophy where LGE is common [31,36]. In LMNA mutation carriers, CMR more consistently identifies fibrosis: in a small cohort of asymptomatic or mildly symptomatic individuals, 88% had non-coronary, predominantly mid-myocardial basal septal LGE, often linear and involving <50% of the affected segment [37]. Even with preserved LV systolic function, LMNA carriers may show longer phantom-normalized T2, higher ECV, more LGE, and impaired radial strain, consistent with subclinical cardiomyopathy; greater LGE burden and worse myocardial mechanics independently predicted higher MACE risk [36,38].

As summarized in Table 4, multimodality imaging in EDMD extends beyond conventional assessment of chamber size and ejection fraction, enabling earlier detection of subclinical myocardial dysfunction and more refined phenotypic characterization.

3.2.3. Heart Failure and Heart Transplantation

Unlike young patients with X-linked muscular dystrophies such as Duchenne muscular dystrophy, only a smaller proportion of individuals with EDMD develop dilated cardiomyopathy and heart failure [39]. In a longitudinal study of 18 patients with EDMD, progression to severe heart failure occurred in only one individual with an autosomal dominant form and severe limb-girdle muscular dystrophy, with markedly reduced LVEF (30%), atrial flutter, and AVB requiring pacemaker implantation. Owing to refractory heart failure, the patient was ultimately referred for heart transplantation [27].

A non-negligible proportion of patients already exhibited advanced heart failure symptoms (NYHA functional class ≥III–IV) at the time of diagnosis, and they tended to progress further during follow-up. In some patients, heart failure severity may progress to the point of requiring heart transplantation. Most deaths in individuals with EDMD are attributable to sudden cardiac death or advanced heart failure [26].

Reversible forms of right-sided heart failure have been reported in patients with EDMD, particularly in the setting of venous congestion due to AVB with a very low heart rate, with improvement after pacemaker pacing [27].

3.2.4. ECG Abnormalities, Conduction Alterations and Brady-Arrhythmias

Atrial fibrillation and AV conduction disorders represent the most frequently observed arrhythmias, whereas life-threatening ventricular arrhythmias and sudden cardiac death occur less often but remain major complications [36].

Clinically relevant conduction abnormalities are commonly present already after the first cardiological assessment and tend to progress over time toward more advanced degrees of conduction block during longitudinal follow-up [40]. The surface ECG may show baseline abnormalities reflecting progressive involvement of the cardiac conduction system and/or an associated cardiomyopathic substrate, even in the absence of symptomatic rhythm events. Typical findings include low amplitude P wave, AV conduction delay (PR prolongation up to higher-degree AV block) and intraventricular conduction disease with QRS widening (bundle-branch block patterns or non-specific intraventricular conduction delay). Low QRS voltages and non-specific repolarization abnormalities (ST-T changes) may also be observed and should be interpreted in the broader clinical and imaging context, supporting the need for serial ECG surveillance as part of cardiac follow-up in EDMD/laminopathy phenotypes [16,25,41,42,43].

Often, sinus node disease and conduction abnormalities occur before the development of ventricular dysfunction [44]. Moreover, different degrees of AVB may occur [3,41]. However, in a systematic review by Valenti et al., sinus node disease or sinoatrial block was reported at baseline in only a small proportion of the included studies evaluating patients with cardiomyopathy [26].

It has been observed that patients carrying LMNA mutations often undergo pacemaker implantation for conduction disturbances, yet their risk of sudden cardiac death remains unchanged [45]. In EDMD, a true “conduction system disease” is present, manifesting with sinus node dysfunction (including atrial standstill) and AV conduction blocks, such as Mobitz type II AV block and complete AV block, which may ultimately require permanent pacemaker implantation [16]. It is uncommon to observe both bradyarrhythmias and supraventricular tachyarrhythmias concomitantly, particularly in younger patients; nonetheless, individuals with EDMD carry a substantial lifetime risk of developing both. Moreover, given the low escape-rhythm rates that may occur in this patients, bradyarrhythmias have been reported as a potential mechanism of sudden cardiac death [27].

Regarding symptom burden, manifestations associated with complete AVB or sinoatrial block, such as syncope and/or fatigue, appear to be better tolerated in patients with EDMD. This may reflect adaptation to chronically lower heart rates and/or lower habitual physical activity compared with otherwise healthy young individuals [24].

3.2.5. Atrial Arrhythmias

Atrial involvement is a common component of the cardiac phenotype, and supraventricular tachyarrhythmias (SVT) may precede the onset of overt cardiomyopathy, along a continuum ranging from atrial premature beats and atrial tachycardias to atrial fibrillation (AF) or flutter (AFL) and, particularly in more “atrial-dominant” phenotypes, progressing towards “atrial standstill” (atrial paralysis related to fibrosis). Atrial standstill represents an extreme expression of atrial injury, characterized by absence of P waves on ECG, atrial electrical silence with a junctional or ventricular escape rhythm, and lack of mechanical atrial contraction. Atrial ectopy should be interpreted as an early expression of a primary atrial myopathy related to nuclear envelope pathology, rather than merely an isolated electrical trigger [46]. From a pathophysiological perspective, the atrium is the target of progressive structural and electrical remodelling (substrate), upon which atrial premature beats act as markers and/or triggers of tachyarrhythmias. Atrial premature beats (APBs) and other supraventricular arrhythmias in EDMD arise from a distinctive substrate of primary atrial cardiomyopathy driven by mutations in EMD (emerin) or LMNA (lamin A/C). Nuclear lamina proteins play a critical role in nuclear architecture, mechanotransduction, and transcriptional regulation in cardiac cells; their dysfunction promotes interstitial fibrosis, fibro-fatty infiltration, and disruption of the atrial extracellular matrix, thereby generating abnormal conduction substrates with areas of slow conduction and re-entrant circuits that predispose to APBs, atrial tachycardias, and atrial fibrillation/flutter. This atrial remodelling phenotype reduces local refractoriness, facilitates re-entry dependence and abnormal automaticity, and may account for the high prevalence of supraventricular arrhythmias even in young patients, irrespective of the severity of ventricular dysfunction [27]

A systematic review reports that atrial tachyarrhythmias (AF, AFL, atrial tachicardia and atrial standstill) are among the most frequently reported and quantifiable outcomes, consistent with the concept of progressive and clinically relevant atrial damage. [26] In a cohort of 45 patients with muscular dystrophies due to EMD/LMNA mutations and long median follow-up, atrial arrhythmias (including atrial premature beats) were common and often emerged at a young age (in the second or third decade of life), particularly in emerinopathy, suggesting that atrial electrical instability can precede overt heart failure and ventricular remodelling. Conversely, in laminopathy, ventricular arrhythmias appear more prevalent and tend to manifest earlier, underscoring distinct natural histories with an “early atrial-dominant” trajectory in EMD versus an “early ventricular-dominant” trajectory in LMNA. This suggest that atrial electrical instability may precede overt ventricular remodelling by years [46].

The overall reported prevalence of arrhythmias is 89%, with atrial standstill in 31% and AF/AFL in 29%. [46] The incidence rate for AF/AFL/AT ranges from 6.1 to 13.9 events per 100 patient-years, whereas the incidence of atrial standstill ranges from 0 to 2 events per 100 patient-years [26]. Half of the EMD patients develops atrial standstill, whereas no atrial standstill are observed in the LMNA subgroup, suggesting another difference in natural history between emerinopathy and laminopathy [46].

From a prognostic standpoint, the onset of atrial tachyarrhythmias (and, plausibly, an increasing burden of atrial ectopy) should be regarded as a marker of progression of atrial disease toward atrial paralysis and thromboembolic complications, and therefore as a signal to intensify surveillance and refine the antithrombotic strategy [6,27].

Atrial standstill in EDMD is clinically pivotal because it often represents the end stage of a continuum of atrial tachyarrhythmias and bradyarrhythmias, with direct implications for pacing strategy, anticoagulation decisions, and ischaemic risk. Notably, reports that atrial standstill may emerge after phases of atrial fibrillation or flutter, followed by a progressively electrically “silent” atrium, support an evolution toward extensive atrial fibrosis, low-voltage substrate, and loss of atrial capture, rather than a mere disorder of atrial automaticity [25,27,46].

Operational diagnosis of atrial ectopy and atrial tachycardias should be proactive and longitudinal, combining a baseline 12-lead ECG, 24-h Holter monitoring (preferably extended over multiple days), and, when available, pacemaker/ICD diagnostics, because continuous surveillance can capture nocturnal or intermittent atrial arrhythmias that may be missed during routine outpatient assessment [6,46,47].

Thromboembolic event rates in EDMD have been reported as high as 8.9 events per 100 patient-years, consistent with the substantial ischaemic burden observed in cohort studies and supporting a proactive (non-watchful-waiting) thromboembolic prevention strategy [26]. Anticoagulation should be recommended when AF/AFL occurs in EDMD and should also be considered in atrial standstill, given the consistently reported high thromboembolic risk and its disproportionate prognostic impact relative to patients’ age, despite the absence of EDMD-specific trials or dedicated guidelines, with management therefore extrapolated from standard AF anticoagulation principles in structural cardiomyopathies and individualized to the disease context. The 2022 HRS consensus statement on neuromuscular diseases (including EDMD) emphasizes systematic arrhythmia surveillance and structured thromboembolic risk assessment, explicitly noting that the combination of atrial arrhythmias/atrial standstill and stroke warrants a rigorous, guideline-consistent approach to anticoagulation when indicated [6,25,27].

In a long-term longitudinal study including X-linked and autosomal-dominant EDMD, AF/AFL developed in 11/18 patients (61%), followed by atrial standstill in 5/11 (45%), while embolic stroke occurred in 4/11 (36%) of AF/AFL patients, often with disabling sequelae. This suggests a clinically relevant temporal sequence of “AF/AFL → atrial standstill → stroke” in a non-negligible proportion of cases. Accordingly, the most robust clinical rationale for anticoagulation in EDMD derives from these longitudinal data, where the authors conclude that anti-thromboembolic prophylaxis should be recommended in the presence of AF/AFL or atrial standstill [6,9,25].

In “cardiac emerinopathy” (the X-linked cardiac phenotype related to EMD, even in the absence of a full syndromic presentation), a trajectory of progressive atrial arrhythmias culminating in atrial standstill has been described, frequently in association with left ventricular non-compaction and a familial thromboembolic burden, reinforcing the concept of a structured cardiomyopathy/ atriomyopathy with an intrinsic embolic risk [8].

As shown in a multicentre cohort of EMD variant carriers, even when the earliest clinical manifestations are predominantly atrial, early and structured surveillance remains essential, given the substantial risk of subsequent malignant ventricular arrhythmias and progression to end-stage heart failure [16].

There are no dedicated randomised trials assessing the efficacy of antiarrhythmic drugs for atrial arrhythmias; therefore, pharmacological management is extrapolated from general principles for atrial tachyarrhythmias, with particular attention to the underlying conduction substrate and the frequent coexistence of bradyarrhythmias that characterise these dystrophies. Medical therapy is based on rate and/or rhythm control using antiarrhythmic agents selected according to ventricular function, conduction disturbances, and pro-arrhythmic risk, bearing in mind that management is often device-integrated in the context of a brady-tachy syndrome [6,9,25].

3.2.6. Ventricular Arrhythmias and Sudden Cardiac Death

Malignant ventricular arrhythmias are common in patients with EDMD, irrespective of left ventricular ejection fraction, and are associated with an increased risk of sudden cardiac death [44].

The risk of ventricular arrhythmias (VA) in this condition has been recognized for a long time [23,48]. The incidence of VA appears to be higher in the presence of significant left ventricular systolic dysfunction, similar to other forms of heart disease [49]. However, the true progression to sudden death in EDMD patients receiving prophylactic device implantation despite preserved left ventricular function remains unknown [27].

In EDMD (both EMD/emerin and LMNA/lamin A/C phenotypes), ventricular arrhythmias may occur as part of a broader “conduction–cardiomyopathy” continuum and can emerge even before advanced LV dysfunction is evident. From an ECG standpoint, the most reproducible correlations are not with a single lead “location,” but with conduction disease burden and its progression over time: marked PR prolongation/AV conduction delay and QRS widening (bundle-branch block or non-specific intraventricular conduction delay), particularly when these parameters worsen on serial ECGs, are associated with a more arrhythmogenic phase in cardiac laminopathies [16,25,50]. Cardiac MRI adds anatomical specificity: septal late gadolinium enhancement (LGE), a typical pattern in LMNA-related disease, has been linked to a higher incidence of major ventricular arrhythmias and helps refine risk beyond surface ECG alone [51].

In EDMD, LMNA-related cardiomyopathy appears to follow a particularly malignant course compared with other DCM aetiologies, with malignant ventricular arrhythmias and progressive end-stage, medically refractory heart failure being more frequently observed in LMNA mutation carriers [40,52,53]. A similar trend has also been reported in LMNA mutation carriers with a left ventricular ejection fraction >35% [52]. Patients with LMNA mutations have a high risk of premature sudden death, seemingly driven by ventricular tachyarrhythmias; this risk does not parallel the onset of heart failure or bradyarrhythmias and, accordingly, is not prevented by pacemaker implantation alone [45,54]. In a multicentre study including 59 patients with EDMD type 1 (EMD variant-carriers), a 50-year-old man with a permanent pacemaker died suddenly. Post-mortem device interrogation documented rapid sustained ventricular tachycardia coinciding with collapse, and an echocardiogram performed two weeks earlier showed only mildly reduced LVEF (43%), supporting the concept that malignant ventricular arrhythmias may occur despite the absence of severe LV systolic dysfunction [16].

In LMNA mutation carriers, the use of a recently validated risk score has been suggested. It is an interesting and highly useful tool developed based on the results of a multicenter study involving 839 patients, recruited from two different registries: 660 from the French Nationwide Registry and 179 from other countries. The aim of the study was to validate a model to estimate the 5-year absolute risk of developing life- threatening ventricular tachyarrhythmias (LTVTA) in patients with dilated cardiomyopathy (DCM) caused by LMNA mutations (i.e., patients with laminopathies in general) with adult-onset disease. The study population included 55 patients with Emery–Dreifuss muscular dystrophy (EDMD) from the French registries and 6 patients with EDMD from other registries (such as London, the United States, Bern, and Melbourne). The term LTVTA refers to the occurrence of:

• Sudden cardiac death
• Appropriate ICD shock for the termination of ventricular tachyarrhythmias (VT)
• Ventricular tachyarrhythmias associated with hemodynamic instability and other clinical manifestations

The exclusion criteria were: history of tachyarrhythmias before baseline, age < 16 years, development of neuromuscular or systemic disease before the age of 16, cardiomyopathies associated with other genetic mutations, lack of clinical data, first cardiological evaluation performed before January 2000.

The risk score is based on the presence or absence of several factors considered adverse in patients with laminopathies, as they are associated with an increased risk of malignant tachyarrhythmias:

• Male sex
• Baseline left ventricular ejection fraction <45%
• Non-missense genetic mutations
• Non-sustained ventricular tachycardia
• AVB

The score can be easily calculated in these patients, including those with EDMD due to LMNA mutations and adult-onset DCM, using the dedicated online calculator (https://lmna-risk-vta.fr/). Risk estimation is crucial for identifying patients who may benefit from implantable cardioverter-defibrillator (ICD) implantation, helping to avoid both underestimation and overestimation of risk [55].

3.2.7. Cardiac Implantable Electronic Device and Ablation Therapy

In EDMD normal myocardium is gradually replaced by the fibrous and adipose tissue, process that usually starts in the atria, then involving AV node and ventricles. This electro-anatomical substrate is responsible for frequent bradi- and tachyarrhythmias, usually predominant feature of disease. Conduction abnormalities, such as “sick sinus syndrome” (often associated with atrial standstill phenomenon) and various degrees of atrio-ventricular blocks, are common and can be associated with the development of cardiomyopathy. In according to ESC guidelines, in cases of any second or third degree AVB or HV ≥70ms, with or without symptoms, permanent pacing is indicated (class of recommendation I), while may be considered with PR ≥240msec or QRS duration ≥120ms (class of recommendation IIb) [56]. In a cases series by Steckiewicz et al. on 21 EMD patients followed for a mean period of 11 ± 8 years after pacemaker (PM) implantation, pacing mode was often changed from DDD to VVI during follow-up, because of atrial electrical silence, which is responsible of considerable atrial spike-to-P-wave delay and loss-of-capture and high incidence of atrial fibrillation/flutter [24]. Whenever pacing is indicated in this disease, an implantable cardioverter defibrillator (ICD) should be considered according to guidelines indications. In the report by Golzio et al., ventricular lead extraction was required only 18 months after pacemaker implantation. The patient subsequently underwent device upgrade to an ICD for ventricular tachycardia; nine months later, multiple appropriate ICD therapies successfully averted sudden cardiac death [57].

Sudden death is not uncommon in EDMD, so risk stratification is necessary [58]. As indicated in the 2022 ESC guidelines for the management of ventricular arrhythmias, should be considered not only in patients with heart failure and ejection fraction <35%, but also in cases that don’t meet the usual criteria, if they are factors, such as age, CTG expansion, sudden death in family history, ECG conduction abnormalities, PR prolongation, left bundle branch block, atrial arrhythmias, non-sustained VT, LV dysfunction with an ejection fraction of less than than 45%, structural abnormalities in CMR and lamin A/C mutation [59]. Cardiac resynchronization therapy may also find a place in the management of patients with EDMD, given the high incidence of heart failure in dilated cardiomyopathy, particularly in LMNA-mutated carriers, and intraventricular conduction disturbances. In 1999, Walker et al. published the first anecdotal case of biventricular ICD [60]. To date, there are no systematic studies on the outcomes and responsiveness of resynchronization therapy in Emery-Dreifuss disease. Moreover, no cases have been published on emerging selective pacing techniques, such as left bundle branch area pacing and His bundle pacing in this setting.

The prevalence of atrial arrhythmias ranged from 12.5% to 63% in the LMNA patient cohort, and from 10% to 73.3% in the EMD patients’ cohort, while malignant ventricular arrhythmias can be common, especially in LMNA-mutated patients. In a systematic review the ICD implantation resulted in device activation in 24 to 52.4% of ICD carriers [26]. Ablation therapy can be challenging, because of regional and transmural repolarization heterogeneity and electrical instability linked to diffuse fibrosis. Only three reported cases of ablation can be identified in EDMD patients. Blagova described a case of atrial flutter ablation in this setting, initially successful, but with recurrence within 4 months, complicated by worsening LV systolic function necessitating a heart transplant [29]. Carvalho reported a case involving an EDMD patient who underwent multiple ablations for atrial and ventricular tachyarrhythmias [61]. In 2020, Butt showed the only successful case of atrial flutter treatment through cavotricuspid isthmus ablation with arrhythmias freedom after thirty-five months’ follow-up [62]. Anecdotal cases demonstrate the complexity of electrical substrate in these patients. In addition, there is a lack of data concerning ventricular arrhythmias ablation in EDMD patients which could depend on reduced accessibility to ablative therapy or because it may be considered futile or ineffective. Valverde Soria described an Emery-Dreifuss dilated cardiomyopathy patient (EMD-related phenotype) with an ICD who developed recurrent ventricular fibrillation (VF) episodes consistently triggered by a short-coupled, monomorphic ventricular ectopic beat compatible with a Purkinje-related focus, in the context of an intraseptal arrhythmogenic substrate. The authors adopted a pragmatic, mechanism-oriented strategy combining substrate ablation with ICD-guided pace mapping to reproduce and localize the initiating ectopy, achieving successful elimination of the VF trigger and control of recurrences. Collectively, the case supports catheter ablation of Purkinje triggers as a potential adjunctive option in selected dilated cardiomyopathy patients suffering recurrent ICD shocks due to VF initiated by monomorphic ectopy [63]. Zeppenfeld’s review provides a practical, mechanism-based framework for VT ablation in non-ischemic cardiomyopathy, but it does not report data specifically addressing EDMD and it is not discussed as a distinct cardiomyopathy subtype. Still, the concepts can be reasonably extrapolated to EDMD when patients develop sustained monomorphic VT or recurrent ICD shocks. Non-ischemic VT is often driven by scar-related re-entry with heterogeneous, sometimes intramural/epicardial substrate distribution, features that can limit lesion effectiveness and contribute to recurrence. It is important to highlight the recognition of His-Purkinje system-dependent VTs (including bundle branch re-entry), because these may be comparatively “high-yield” targets for ablation in selected non-ischemic phenotypes [64].

Finally, a pragmatic management framework for the principal cardiac scenarios encountered in EDMD is provided in Table 5, emphasizing the need for proactive surveillance, early recognition of thromboembolic risk, and individualized device-based decision-making.

3.3. Current and Future Directions

The 2023 ESC cardiomyopathy guidance supports earlier primary-prevention ICD consideration in genotype-positive dilated/NDLVC settings, including high-risk genotypes with additional markers (e.g., syncope or LGE) even without overt LV dysfunction, and allows that an ICD may be considered in genotype-positive patients with LVEF >35% even in the absence of additional risk factors (Class IIb) [9]. In EDMD, these principles are biologically plausible but remain insufficiently validated; future studies should therefore test genotype-substrate-event links prospectively, define actionable thresholds, and explore precision therapeutics (including pathway-targeted strategies and emerging gene/RNA-based approaches) within multidisciplinary cardio-neuromuscular programmes.

Future research in EDMD should become genotype-driven, integrating systematic panel testing (EMD/LMNA/SYNE1-2 and related nuclear-envelope/LINC genes) with deep phenotyping and cascade screening, to refine prognostication and enable earlier, mechanism-based interventions. Patient-derived cellular models now provide actionable biological hypotheses: across EDMD1/2/5, dermal fibroblasts show a convergent profibrotic programme with increased TGFβ signalling and miR-21 upregulation, alongside α-SMA-positive myofibroblast over-representation. Importantly, CRISPR/Cas correction (or allele-specific disruption) rescues nuclear-envelope abnormalities and largely normalizes the disease miRNA signature, supporting proof-of-principle precision gene correction and biomarker discovery pipelines using isogenic lines and iPSC-based platforms [4].

Future directions in EDMD should pivot from a predominantly phenotype approach to a genotype-driven pathway, integrating systematic molecular diagnosis (EMD/LMNA-first, with expanded cardiomyopathy/arrhythmia panels where appropriate), variant reclassification over time, and cascade testing to refine penetrance, sex-specific expressivity, and age-related risk. This will require EDMD-specific longitudinal cohorts combining genomics with deep phenotyping (ECG/Holter burden, atrial myopathy metrics, CMR tissue characterization, biomarkers, and digital surveillance), and the development/validation of EDMD-tailored risk models for malignant ventricular arrhythmias and end-stage heart failure.

A pragmatic surveillance and management pathway for EDMD is proposed in Figure 4, integrating baseline phenotyping with subsequent decisions on anticoagulation, pacing or defibrillator therapy, arrhythmia management and advanced heart failure referral.

4. Conclusions

EDMD is a paradigmatic nuclear-envelope disorder in which cardiac disease is not a late “complication” of skeletal myopathy but often an early and independent driver of morbidity and mortality. Across genotypes, the dominant clinical trajectory is characterized by a progressive atriomyopathy-conduction disease axis (early atrial arrhythmias evolving toward atrial standstill and advanced bradyarrhythmias), variably accompanied by ventricular arrhythmias, cardiomyopathy, and heart failure. Critically, malignant ventricular tachyarrhythmias and sudden cardiac death may occur out of proportion to left ventricular dysfunction and are not neutralized by pacemaker therapy alone, supporting an earlier and more individualized consideration of ICD therapy, particularly in LMNA-related disease, within an aetiology-driven framework aligned with contemporary ESC cardiomyopathy and ventricular arrhythmia guidance.

From a clinical standpoint, EDMD mandates lifelong, structured cardiac surveillance that integrates serial ECG and extended rhythm monitoring, device diagnostics when present, and imaging (echocardiography and, when available, CMR tissue characterization) to capture evolving substrate and refine risk. Management should be explicitly proactive regarding thromboembolic prevention, given the high burden of atrial disease and the recurrent sequence of AF/AFL progressing to atrial standstill and stroke. While pharmacological and device strategies remain the backbone of care, evidence for catheter ablation in EDMD is sparse, yet selected cases suggest that mechanism-targeted approaches may be feasible in highly selected scenarios.

Finally, the field is poised to shift from descriptive phenotyping to genotype-driven precision care, leveraging deep longitudinal cohorts, EDMD-tailored risk models, and translational pipelines (isogenic systems and emerging gene/RNA-based strategies) aimed at disease modification. Until such data mature, optimal outcomes will depend on early recognition, multidisciplinary cardio-neuromuscular management, and anticipatory prevention of stroke, heart failure progression, and sudden death.