Medical Management for Desmoplakin (DSP) Cardiomyopathy
Patients with confirmed DSP mutations and cardiomyopathy require immediate initiation of guideline-directed medical therapy for heart failure, aggressive arrhythmia surveillance with strong consideration for primary prevention ICD placement, strict exercise restriction, and cascade genetic testing of all first-degree relatives. 1
Immediate Risk Stratification and Genetic Counseling
All patients with suspected or confirmed DSP-related arrhythmogenic cardiomyopathy must be referred immediately for genetic counseling and testing because DSP pathogenic variants are linked to aggressive phenotypes and high risk of sudden cardiac death even when systolic function is preserved. 1 DSP variants are particularly likely to cause arrhythmogenic left ventricular cardiomyopathy (ALVC) with associated heart failure risk. 2
Detection of a desmosomal variant in patients initially diagnosed with dilated cardiomyopathy heralds a worse arrhythmic course and increased risk of sudden death independent of left ventricular ejection fraction. 2
Arrhythmia Prevention and Device Therapy
Primary Prevention ICD Indications
Primary-prevention ICD placement should be strongly considered in asymptomatic carriers of pathogenic DSP variants because genetic testing results should be incorporated into risk stratification and influence ICD decisions. 1 The following high-risk features warrant ICD consideration:
- Personal history of cardiac arrest or sustained ventricular tachycardia 1
- Personal history of syncope suspected to be arrhythmic 1
- Family history of premature sudden death, cardiac arrest, or sustained ventricular arrhythmias in close relatives 1
- Left ventricular ejection fraction <35% after ≥3 months of optimal medical therapy 2
- Right ventricular dysfunction combined with LVEF <35% 3
Decisions regarding prophylactic ICDs should not depend on ejection fraction alone in DSP cardiomyopathy, as desmosomal mutations often cause cardiac conduction disease and life-threatening ventricular arrhythmias. 2
Antiarrhythmic Drug Therapy
For recurrent ventricular arrhythmias despite beta-blocker therapy, amiodarone is the most effective agent, reducing ICD shocks from 38.5% to 10.3%. 4 Alternative agents include sotalol, mexiletine, or dofetilide, chosen based on age, comorbidities, disease severity, and patient preferences. 4
Catheter ablation should be considered as adjunctive therapy for recurrent ventricular tachycardia despite optimal antiarrhythmic drug therapy. 4 In refractory cases, epicardial ablation may be necessary. 5
Program antitachycardia pacing in patients with ICDs to minimize the risk of shocks. 4
Heart Failure Medical Management
When ventricular dysfunction develops, guideline-directed medical therapy for heart failure must be initiated promptly, including ACE inhibitors (or ARB/ARNI), beta-blockers, and mineralocorticoid receptor antagonists to reduce the risk of sudden death and progressive heart failure. 4, 1
Evaluate for and treat arrhythmogenic factors and comorbidities that may worsen the condition, including atrial fibrillation, which occurs in a subset of DSP patients. 4
Atrial Fibrillation Management
If atrial fibrillation develops:
- Direct-acting oral anticoagulants (DOACs) are first-line treatment regardless of CHA₂DS₂-VASc score 4
- For rate control, use beta-blockers, verapamil, or diltiazem based on patient comorbidities 4
- For rhythm control, sotalol and amiodarone are preferred options, with amiodarone often being most effective despite side effects 4
Exercise Restriction
Exercise restriction is mandatory for individuals with desmosomal (including DSP) variants, mirroring recommendations for hypertrophic cardiomyopathy. 2, 1 Endurance exercise is associated with penetrance and incident arrhythmias in family members with desmosomal variants. 2
Decisions about participation in competitive sports should consider family history of sudden cardiac death, the type of sport, and the patient's/family's risk tolerance. 1 Frequent high-intensity endurance exercise should be avoided to reduce phenotypic expression. 2
Diagnostic Imaging and Surveillance
Initial Evaluation
Transthoracic echocardiography is required to evaluate left-ventricular size, systolic function, right-ventricular morphology, and regional wall-motion abnormalities. 1
Cardiac magnetic resonance imaging is essential for DSP cardiomyopathy to delineate ventricular involvement, detect myocardial fibrosis with late gadolinium enhancement (typically subepicardial pattern), and identify left-ventricular non-compaction patterns. 1 LGE is present in 53% of probands and is mostly subepicardial (87%). 6
12-lead ECG and ambulatory ECG monitoring (Holter) are required to detect conduction abnormalities, premature ventricular contractions (>500/24hr in 66% of probands), and nonsustained ventricular tachycardia (29% of probands). 6
Ongoing Surveillance
Perform a comprehensive, systematic, non-invasive sudden-cardiac-death risk assessment at initial evaluation and repeat every 1–2 years. 1
Ambulatory electrocardiographic monitoring is reasonable every 1 to 3 years, based on age, ejection fraction, and clinical assessment. 2
Cascade Testing and Family Screening
Cascade genetic testing of at-risk relatives for pathogenic or likely-pathogenic DSP variants is a Class I recommendation. 1 First-degree relatives should receive genetic screening and counseling to enable early detection and timely treatment aimed at reducing heart-failure progression and sudden cardiac death. 1
After diagnosis of arrhythmogenic cardiomyopathy in a proband, initial cardiovascular screening is recommended for all first-degree relatives age 10 or older, including 12-lead ECG, ambulatory ECG, and cardiac imaging. 2
Serial echocardiography every 1–2 years is recommended for first-degree relatives who are genotype-positive (or of unknown genotype) to monitor disease progression. 1 Unless proven genotype-negative, first-degree relatives require periodic surveillance with ECG and echocardiography. 1
Genetic counseling before and after testing helps patients understand implications, including potential genetic discrimination. 1
Skin Care Considerations
DSP mutations can be associated with cutaneous abnormalities, similar to Carvajal syndrome. 7 While specific dermatologic management guidelines are not established for heterozygous DSP mutations, patients should be evaluated for:
- Woolly hair
- Palmoplantar keratoderma
- Skin fragility
Referral to dermatology is reasonable if cutaneous manifestations are present. 7
Advanced Heart Failure Management
For patients with advanced heart failure refractory to medical therapy, evaluate for heart transplantation according to current guidelines. 4 Heart transplantation evaluation is indicated for refractory life-threatening ventricular arrhythmias unresponsive to maximal antiarrhythmic therapy and ablation. 4
Left ventricular assist device support may be considered in highly selected patients who decompensate while awaiting transplant, with better outcomes observed in those with larger LV cavities (>46-50 mm). 4
Critical Pitfalls to Avoid
Do not delay ICD consideration based solely on preserved ejection fraction, as DSP cardiomyopathy carries high arrhythmic risk independent of LVEF. 2, 1
Do not use traditional arrhythmogenic right ventricular cardiomyopathy Task Force Criteria alone for diagnosis, as sensitivity for left-dominant disease is only 0.73, and 23% of patients with sustained ventricular arrhythmias do not meet these criteria. 3
Do not withhold anticoagulation in patients with atrial fibrillation based on low CHA₂DS₂-VASc scores, as guidelines mandate anticoagulation regardless of score in cardiomyopathy patients. 4
Avoid vasodilators, excessive diuresis, and positive inotropic agents if there is any component of left ventricular outflow tract obstruction. 4
Do not overlook myocardial injury presentations (chest pain, elevated troponin, normal coronary angiogram), which occur in 22% of DSP patients and are associated with worse disease outcomes (HR 2.53 for sustained ventricular arrhythmia, HR 7.53 for heart failure). 3, 5