Author: Nicholas Houska, DO - University of Colorado - Children’s Hospital Colorado
An 11-year-old boy with a family history of desmoplakin cardiomyopathy presents for cardiac magnetic resonance imaging. He was recently found to be a carrier for a DSP gene mutation. Which of the following features is MOST likely to be present in desmoplakin cardiomyopathy as compared to other types arrhythmogenic cardiomyopathy?
EXPLANATION
Desmoplakin (DSP) is a desmosomal protein encoded by the DSP gene located on chromosome 6. It is expressed in both cardiomyocytes and skin and plays an important role in linking the cardiac desmosome to intermediate filaments. It is essential for normal force transmission in myocardial tissue. Mutations in the DSP gene have been identified in arrhythmogenic right ventricular cardiomyopathy (ARVC) and in familial dilated cardiomyopathy (DCM). However, more recently, mutations in the DSP gene have been associated with a distinct form of cardiomyopathy with a high prevalence of left ventricular fibrosis and systolic dysfunction, which differs from ARVC and DCM. Termed desmoplakin (DSP) cardiomyopathy, this disease has distinct features as compared to other forms of arrhythmogenic cardiomyopathy. Recently, the Padua criteria has categorized arrhythmogenic cardiomyopathy (ACM) into three phenotypes including arrhythmogenic right ventricular cardiomyopathy (ARVC), arrhythmogenic left ventricular cardiomyopathy (ALVC), and biventricular arrhythmogenic cardiomyopathy.
The pathophysiology of DSP cardiomyopathy includes episodic inflammatory myocardial injury that leads to progressive ventricular fibrosis and myocardial scarring, left ventricular systolic dysfunction, and ventricular arrythmias. This clinically manifests as episodic chest pain, heart failure, and ventricular arrythmias. Patients will often exhibit ST segment changes and troponin elevations but will have normal coronary angiography. There is heterogeneity in phenotype regarding single or biventricular systolic dysfunction and arrhythmogenic burden. Ventricular arrythmias may be life-threatening and the initial presentation may include syncope or cardiac arrest. Varying criteria have been established for diagnosis, but typically include left ventricular (LV) or biventricular systolic dysfunction, ECG abnormalities, cardiac magnetic resonance imaging (CMRI) demonstrating late LV gadolinium enhancement due to scar, ventricular arrhythmias, and personal or familial DSP mutation. CMRI is the most sensitive test for phenotype in DSP cardiomyopathy as extensive fibrosis may be detected prior to echocardiographic or ECG changes. Due to the expression of DSP in skin, more than 50% of patients also exhibit palmoplantar keratoderma (callused skin on hands and soles of the feet).
Therapy includes management of underlying heart failure and arrythmias with prevention of sudden cardiac death (SCD). Recommendations for risk stratification and management specific to DSP cardiomyopathy continue to evolve. Studies by Wang and Smith have differed on the prognostic markers, such as male gender and ejection fraction (EF), which predispose patients to an increased risk of arrhythmia and SCD. An EF below 35% has consistently been associated with high risk for malignant ventricular arrhythmias, though some events may also be associated with an EF of 35% to 55%. Without specific guidelines for DSM cardiomyopathy, the current recommendations for primary prevention of SCD with an implantable cardioverter-defibrillator (ICD) are to follow guidelines for other ventricular arrhythmias and heart failure.
In contrast to other types of arrhythmogenic and dilated cardiomyopathy, DSP cardiomyopathy predominantly involves the left ventricle, often without any RV involvement, and has a unique pathophysiology, clinical presentation, and outcome. Episodes of myocardial injury and epicardial fibrosis occur and precede overt systolic dysfunction in DSP cardiomyopathy. Ventricular arrhythmias are common to all forms of arrhythmogenic cardiomyopathy. Left ventricular systolic dysfunction rather than biventricular systolic dysfunction is more common in DSP cardiomyopathy. Right ventricular dysfunction is more typical of ARVC.
REFERENCES
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Smith ED, Lakdawala NK, Papoutsidakis N et al. Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation. 2020;141(23):1872-1884. doi: 10.1161/CIRCULATIONAHA.119.044934.
Wang W, Murray B, Tichnell C et al. Clinical characteristics and risk stratification of desmoplakin cardiomyopathy.Europace. 2022;24(2):268-277. doi: 10.1093/europace/euab183.
Di Lorenzo F, Marchionni E, Ferradini V et al. DSP-Related Cardiomyopathy as a Distinct Clinical Entity? Emerging Evidence from an Italian Cohort.Int J Mol Sci. 2023;24(3):2490. doi: 10.3390/ijms24032490.
Graziano F, Zorzi A, Cipriani A et al. The 2020 "Padua Criteria" for Diagnosis and Phenotype Characterization of Arrhythmogenic Cardiomyopathy in Clinical Practice. J Clin Med. 2022;11(1):279. doi: 10.3390/jcm11010279.
