Arrhythmogenic cardiomyopathy

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Arrhythmogenic right ventricular cardiomyopathy - histology

The epsilon wave (marked by red triangle), seen in ARVD.

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MRI in a patient affected by ARVC/D (long axis view of the right ventricle): note the transmural diffuse bright signal in the RV free wall on spin echo T1 (a) due to massive myocardial atrophy with fatty replacement (b).

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In vitro MRI and corresponding cross section of the heart in ARVD show RV dilatation with anterior and posterior aneurysms (17-year-old asymptomatic male athlete who died suddenly during a soccer game).

Monomorphic ventricular tachycardia originating from the right ventricular outflow tract

​Arrhythmogenic Cardiomyopathy (ACM), also known as arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic right ventricular dysplasia (ARVD), is an inherited heart disease characterized by the replacement of myocardial tissue with fibrofatty tissue, predominantly affecting the right ventricle. This pathological change disrupts the heart's electrical activity, leading to arrhythmias and an increased risk of sudden cardiac death.​

Etiology and Pathogenesis

ACM is primarily linked to genetic mutations affecting desmosomal proteins, which are crucial for cell-to-cell adhesion in cardiac muscle. Mutations in genes encoding desmoglein-2 (DSG2), desmocollin-2 (DSC2), plakophilin-2 (PKP2), desmoplakin (DSP), and junction plakoglobin (JUP) have been implicated in the disease. These genetic defects compromise the structural integrity of myocardial cells, leading to cell detachment, death, and subsequent replacement by fibrofatty tissue. This remodeling process creates a substrate for electrical instability and arrhythmogenesis.

The pathogenesis of ACM involves progressive loss of myocardial cells due to apoptosis, inflammation, and fibrosis. The disease typically initiates in the subepicardial region and advances toward the endocardium, resulting in transmural involvement. Aneurysmal dilatation often occurs in specific regions, notably the right ventricular inflow tract, outflow tract, and apex, collectively termed the "triangle of dysplasia." While the right ventricle is predominantly affected, the left ventricle can also be involved, especially in advanced stages, leading to biventricular failure.​

Clinical Presentation

Individuals with ACM may be asymptomatic or present with a range of symptoms, often manifesting during adolescence or early adulthood. Common clinical features include:​

Palpitations: Sensation of rapid or irregular heartbeats due to ventricular arrhythmias.​

Syncope: Transient loss of consciousness, often precipitated by exertion or emotional stress, resulting from hemodynamically significant arrhythmias.​

Sudden cardiac death: ACM is a notable cause of sudden cardiac death, particularly in young athletes.​

Heart failure: Progressive right ventricular dysfunction can lead to symptoms such as fatigue, peripheral edema, and, in advanced cases, left ventricular involvement causing pulmonary congestion and dyspnea.​

Diagnosis

Diagnosing ACM requires a comprehensive evaluation, integrating clinical findings, imaging studies, electrocardiographic features, and genetic testing. The diagnostic criteria encompass:​

Electrocardiogram (ECG): Common findings include T-wave inversions in leads V1 to V3, epsilon waves (distinctive low-amplitude signals at the end of the QRS complex), and ventricular arrhythmias exhibiting a left bundle branch block morphology.​

Echocardiography: May reveal right ventricular dilation, wall motion abnormalities, and reduced ejection fraction.​

Cardiac Magnetic Resonance Imaging (MRI): Provides detailed visualization of myocardial tissue, identifying fibrofatty infiltration and ventricular aneurysms.​

Endomyocardial biopsy: Histological analysis can detect fibrofatty replacement of myocardium, though its sensitivity is limited due to the patchy nature of the disease.​

Genetic testing: Identifies pathogenic mutations in desmosomal genes, aiding in diagnosis and family screening.​

Management

Management strategies for ACM focus on preventing sudden cardiac death, controlling arrhythmias, and managing heart failure. Key approaches include:​

Lifestyle modification: Patients are advised to avoid strenuous physical activity, which can exacerbate the disease progression and increase arrhythmic risk.​

Pharmacotherapy: Beta-blockers are commonly prescribed to suppress adrenergic stimulation and reduce arrhythmic events. Antiarrhythmic drugs may be used, but their efficacy varies.​

Implantable cardioverter-defibrillator (ICD): Indicated for patients with a history of ventricular arrhythmias or those at high risk for sudden cardiac death. The ICD monitors heart rhythms and delivers shocks to terminate life-threatening arrhythmias.​

Catheter ablation: A minimally invasive procedure targeting and destroying arrhythmogenic foci to prevent recurrent ventricular tachycardia.​

Heart transplantation: Considered in cases of refractory heart failure or incessant ventricular arrhythmias unresponsive to other treatments.​

Prognosis

The clinical course of ACM is variable, with some individuals remaining asymptomatic while others experience rapid disease progression. Factors associated with a poorer prognosis include extensive right ventricular involvement, left ventricular dysfunction, frequent ventricular arrhythmias, and a history of syncope or sudden cardiac arrest. Regular follow-up with a multidisciplinary team is essential to monitor disease progression and adjust management strategies accordingly.​

Epidemiology

ACM is estimated to affect approximately 1 in 5,000 individuals, though the prevalence may be higher due to underdiagnosis. It accounts for up to 20% of sudden cardiac deaths in individuals under 35 years old. The disease exhibits a male predominance and shows considerable geographic variation, with higher prevalence reported in certain regions, such as Italy and Greece.​

Research Directions

Ongoing research in ACM aims to elucidate the molecular mechanisms underlying the disease, identify novel genetic mutations, and develop targeted therapies. Advancements in imaging techniques and the discovery of biomarkers hold promise for earlier diagnosis and better risk stratification. Gene therapy and pharmacological interventions targeting specific molecular pathways are being explored as potential future treatments.

See also

• Woolly hair nevus

External links

Classification	ICD-10: I42.8 OMIM: 107970 MeSH: D019571 DiseasesDB: 29750
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