Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic basis of heart disease

Background:

• The BAG3 gene encodes an anti-apoptotic protein crucial for sarcomere Z-disc integrity.
• Mutations in BAG3 are linked to dilated cardiomyopathy (DCM), but their clinical spectrum and natural history are not well-defined.
• Limited case reports highlight the need for understanding BAG3-associated cardiomyopathy.

Purpose of the Study:

• To elucidate the clinical phenotype and long-term prognosis of individuals with BAG3 mutations.
• To analyze the penetrance and age of onset of DCM in a large cohort with BAG3 mutations.
• To identify factors associated with adverse cardiac events in BAG3 cardiomyopathy.

Main Methods:

• A multicenter cohort study involving 129 individuals with BAG3 mutations across 18 European centers.
• Clinical data collection including diagnosis of DCM, disease progression, and adverse cardiac events.
• Immunohistochemical analysis of cardiac tissue from patients with truncating BAG3 mutations to assess BAG3 protein localization and sarcomeric structure.

Main Results:

• At initial assessment, 57.4% of individuals had DCM; this increased to 68.4% during follow-up, with 26.1% developing DCM later.
• Disease penetrance reached 80% in carriers over 40 years old, with a trend towards earlier DCM onset in males.
• Adverse cardiac events occurred at a rate of 5.1% per year in DCM patients. Male sex, reduced ejection fraction, and increased ventricular diameter predicted poor outcomes.
• Immunohistochemistry revealed myofibril disarray and BAG3 protein mislocalization in affected cardiac tissue.

Conclusions:

• BAG3-mediated DCM exhibits high penetrance in older adults and a substantial risk of progressive heart failure.
• Key clinical predictors of adverse outcomes include male sex, diminished left ventricular ejection fraction, and enlarged left ventricular end-diastolic diameter.
• Understanding these factors is crucial for managing patients with BAG3-associated cardiomyopathy and improving prognostication.