How should I evaluate and manage a patient suspected of desmoplakin (DSP)‑related arrhythmogenic cardiomyopathy, given a personal or family history of unexplained cardiomyopathy, ventricular arrhythmias, or sudden cardiac death?

Evaluation and Management of Suspected DSP-Related Arrhythmogenic Cardiomyopathy

Initial Clinical Assessment

In patients with suspected desmoplakin (DSP)-related arrhythmogenic cardiomyopathy, immediately refer for genetic counseling and testing, as DSP variants are associated with aggressive phenotypes carrying high risk for sudden cardiac death even in the absence of severe systolic dysfunction. 1, 2

Obtain Detailed Three-Generation Pedigree

• Document exact circumstances of any sudden deaths, including ages at death, preceding symptoms (syncope, chest pain, palpitations), and presence of implantable devices 1, 3
• Record family members with unexplained cardiomyopathy, ventricular arrhythmias, heart failure, or early-onset conduction disease (pacemaker before age 65) 1
• Note any relatives with unexplained drowning or single-vehicle accidents, which may represent unrecognized sudden cardiac death 3

Recognize High-Risk Clinical Features

• Myocardial injury pattern (chest pain with elevated troponin and normal coronary angiogram) occurs in 22% of DSP carriers and strongly predicts both ventricular arrhythmias (HR 2.53) and heart failure (HR 7.53) 4
• Presentation with conduction disease or ventricular arrhythmias raises particular concern for arrhythmogenic cardiomyopathy and sudden death risk 1
• First clinical manifestation may be sustained ventricular tachycardia, occurring even before overt cardiomyopathy develops 2

Mandatory Diagnostic Testing Battery

Electrocardiography

• Obtain 12-lead ECG to identify conduction abnormalities, ventricular hypertrophy, repolarization abnormalities, and pathological Q waves 3, 5
• Left bundle branch block is present in 30-40% of dilated cardiomyopathy cases and indicates more advanced disease 5
• T-wave inversions in lateral and inferior leads represent repolarization abnormalities common in DSP cardiomyopathy 5
• Low voltage QRS complexes suggest advanced disease 5

Ambulatory Monitoring

• Perform 24-hour Holter monitoring to detect nonsustained ventricular tachycardia and other arrhythmias not apparent on resting ECG 3
• Ambulatory monitoring is essential for risk stratification, particularly given that 30% of DCM patients have ventricular arrhythmias 5

Exercise Stress Testing

• Exercise testing is mandatory because certain arrhythmias manifest only during or immediately after physical exertion 3
• Can unmask latent conduction abnormalities and exercise-induced arrhythmias 3

Echocardiography

• Assess for left ventricular dilation, systolic dysfunction, right ventricular abnormalities, and regional wall motion abnormalities 1, 3
• Evaluate for mitral regurgitation and measure left atrial diameter 1
• Serial echocardiography every 1-2 years is required for first-degree relatives unless proven genotype-negative 1

Cardiac MRI

• Cardiac MRI is essential for DSP cardiomyopathy evaluation to characterize ventricular involvement, detect myocardial fibrosis with late gadolinium enhancement, and identify left ventricular non-compaction patterns 1, 4
• Mid-wall fibrosis on cardiac MRI is associated with higher mortality risk (HR 2.96) and sudden death (HR 4.61) 3
• Extensive fibrotic patterns and non-compaction phenotype are hallmarks of DSP cardiomyopathy 2
• Left-dominant disease shows high rates of atypical late gadolinium enhancement patterns 6

Genetic Testing Strategy

Proband Testing

• Genetic testing should be performed on the most clearly affected family member first to maximize diagnostic yield 1
• DSP variants account for a significant proportion of arrhythmogenic cardiomyopathy, particularly with left ventricular predominance 1, 7
• Testing identifies pathogenic variants in 25-40% of dilated cardiomyopathy patients with positive family history and 10-30% without recognized family history 1

Cascade Family Screening

• Cascade genetic testing of at-risk family members is recommended (Class I) for pathogenic and likely pathogenic variants 1
• First-degree relatives require genetic screening and counseling to detect cardiac disease and prompt treatments to decrease heart failure progression and sudden death 1
• Unless proven genotype-negative, first-degree relatives need periodic screening with echocardiography and electrocardiography 1

Genetic Counseling

• Consultation with trained genetic counselor before and after testing helps patients understand implications for themselves and family members, including possible genetic discrimination 1
• Genetic counseling is particularly important given the aggressive phenotype associated with DSP truncating mutations 2

Phenotypic Characterization of DSP Cardiomyopathy

Ventricular Involvement Patterns

• Left ventricular predominance is most common (28-36%), followed by biventricular (15-27%) and right ventricular predominance (6-22%) 7, 4
• The phenotype may change during follow-up in 35% of patients, requiring serial reassessment 7
• Although previously linked with arrhythmogenic right ventricular cardiomyopathy, desmosomal variants now recognized to affect left ventricle with or without right ventricle, and the term "arrhythmogenic cardiomyopathy" is preferred 1

Sex-Based Differences

• Females more commonly show left ventricular involvement and have better outcomes 7
• Males demonstrate higher incidence of major ventricular arrhythmias (52% vs 24%, p=0.036), heart failure (31% vs 3%, p=0.004), and cardiac death (31% vs 0%, p<0.001) 7
• Right ventricular forms are more frequently detected in males (61% vs 38%) 7

Risk Stratification for Sudden Cardiac Death

High-Risk Features Requiring ICD Consideration

• Left ventricular ejection fraction <35% is prognostic for sustained ventricular arrhythmias 4
• Right ventricular dysfunction predicts sustained ventricular arrhythmias 4
• Myocardial injury pattern (chest pain, elevated troponin, normal coronaries) strongly predicts ventricular arrhythmias 4
• Personal history of cardiac arrest or sustained ventricular arrhythmias 1
• Personal history of syncope suspected to be arrhythmic 1
• Family history of premature HCM-related sudden death, cardiac arrest, or sustained ventricular arrhythmias in close relatives 1

Critical Distinction from Traditional Risk Models

• In DSP cardiomyopathy with left ventricular predominance, major ventricular arrhythmias occur even with normal or mildly reduced systolic function 7, 2
• This contrasts with other cardiomyopathies where severe dysfunction typically precedes arrhythmic events 7, 2
• Truncating mutations in desmoplakin are consistently associated with aggressive phenotypes and must be considered a risk factor for sudden death 2
• Since ventricular tachycardia occurs even without severe systolic dysfunction, ICD should be indicated promptly in DSP carriers with high-risk features 2

Incidence of Adverse Events

• Sustained ventricular arrhythmia incidence: 5.9 per 100 person-years (95% CI: 3.9-9.1) 4
• Heart failure incidence: 6.7 per 100 person-years (95% CI: 4.5-9.8) 4
• Major ventricular arrhythmias detected in 29% overall, with higher rates in right ventricular (56%) and biventricular (40%) forms compared to left ventricular forms (15%) 7

Management Implications

ICD Decision-Making

• Genetic testing contributes to risk stratification and has implications for ICD decisions for primary prevention of sudden death 1
• ICD placement for primary prevention in asymptomatic carriers of malignant pathogenic variants shows significant impact on long-term clinical outcome 1
• Consideration of LMNA pathogenic variants for ICD primary prevention applies similarly to DSP truncating mutations given their aggressive phenotype 1, 2

Exercise Restriction

• Exercise limitation should be considered for desmosomal variants, similar to hypertrophic cardiomyopathy 1
• Decisions about competitive sports participation require consideration of family history of sudden cardiac death, type of sports activity, and patient/family risk tolerance 1

Heart Failure Management

• Heart failure occurred in 8% of DSP carriers overall, with no cases in isolated left ventricular forms 7
• Proband status and myocardial injury pattern are prognostic for heart failure development 4
• Standard guideline-directed medical therapy for heart failure should be initiated when ventricular dysfunction develops 1

Diagnostic Criteria Limitations

Task Force Criteria Performance

• The sensitivity of arrhythmogenic right ventricular cardiomyopathy Task Force Criteria for diagnosing left-dominant disease is only 0.73 4
• 23% of patients with sustained ventricular arrhythmias did not meet Task Force Criteria, highlighting need for refined diagnostic approaches 4
• In genomic screening settings, consideration of pathogenic/likely pathogenic variant as a major criterion for diagnosis is inappropriate 6

Common Pitfalls to Avoid

• Do not rely on symptoms alone, as many inherited cardiac conditions causing sudden death are asymptomatic until a fatal event 3
• Do not perform only resting ECG, as normal ECG does not exclude life-threatening conditions 3
• Do not delay testing, as patients with strong family history are already at significantly elevated risk and early identification allows preventive interventions 3
• Do not wait for severe systolic dysfunction before considering ICD in DSP carriers, as ventricular arrhythmias occur with preserved or mildly reduced function 7, 2
• Do not assume right ventricular predominance based on historical arrhythmogenic right ventricular cardiomyopathy literature, as left ventricular involvement is most common with DSP variants 7, 4

Ongoing Surveillance

• Comprehensive systematic noninvasive sudden cardiac death risk assessment at initial evaluation and every 1-2 years thereafter 1
• Serial echocardiography and electrocardiography for genotype-positive family members 1
• Ambulatory ECG monitoring for risk stratification, particularly with LVEF <30-35% 5
• Reassessment of phenotype given that 35% of patients show phenotypic changes during follow-up 7