Non-ischemic Dilated Cardiomyopathy In A 42-year-old The Malignant Phenotype And The Role Of Des Gene Analysis

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Author Block: Bhupinder Grewal, Iyad Idries, Meena Farid, Ricardo Castillo. Brookdale Hospital Medical Center, Brooklyn, NY
Disclosure Block: B. Grewal: None. I. Idries: None.

Case Background: A 42-year-old male with no significant prior medical history presented with NYHA Class IV heart failure. Initial clinical suspicion focused on substance-induced cardiomyopathy due to the patient's age and severity of presentation. Transthoracic echocardiography (TTE) revealed a severely dilated left ventricle with an LVEF of 10-15%. The clinical course demonstrated a malignant phenotype, characterized by a left MCA stroke s/p thrombectomy and sustained ventricular tachycardia requiring a dual-chamber ICD. Despite optimization on quadruple goal-directed medical therapy (GDMT)—including sacubitril/valsartan, carvedilol, spironolactone, and dapagliflozin, the patient’s structural and electrical instability persisted.
Investigations and Results: Coronary angiography confirmed normal coronary arteries, and a comprehensive toxicology workup was negative. Electrocardiogram (as shown in Figure 1) demonstrated an atrial-paced rhythm with a severely prolonged PR interval (302 ms), left axis deviation, and non-specific ST-T changes. Given the early-onset severe phenotype and conduction disease, a 100-gene cardiomyopathy panel was performed. Results identified a heterozygous variant in the DES gene (c.934G>A, p.Asp312Asn). While currently classified as a variant of uncertain significance (VUS), this missense change has been shown in experimental studies to impair desmin intermediate filament function, providing a definitive biological explanation for the aggressive clinical course and conduction abnormalities.
Conclusion: This case highlights the necessity of early geneticist involvement and testing in young patients with unexplained HFrEF, particularly when a malignant phenotype (concomitant stroke and arrhythmia) is present. Beyond confirming a structural etiology, genetic identification shifts management toward early heart transplant evaluation and mandates life-saving cascade screening for family members. Early identification allows for pre-symptomatic monitoring and intervention in relatives at risk for sudden cardiac death, effectively transforming a diagnostic mystery into a proactive, family-centered prevention strategy.