Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Basis of Cardiomyopathies

Background:

• Dilated cardiomyopathy (DCM) is a significant cause of heart failure with a strong genetic component.
• Understanding the genetic architecture of DCM is crucial for diagnosis, prognosis, and potential therapeutic strategies.
• Left ventricular reverse remodelling (LVRR) is a key indicator of improved outcomes in DCM patients.

Purpose of the Study:

• To investigate the genetic landscape of a well-characterized DCM cohort using next-generation sequencing (NGS).
• To assess the relationship between distinct genotype groups and the occurrence of left ventricular reverse remodelling (LVRR).
• To explore the clinical implications of genotype-specific findings in DCM management.

Main Methods:

• A cohort of 152 DCM patients was analyzed using next-generation sequencing (NGS).
• Patients were categorized into 'gene-clusters' based on functional genetic similarities.
• LVRR was defined by improvements in left ventricular ejection fraction and dimensions over a 24-month follow-up period.

Main Results:

• Pathogenic variants were identified in 57% of DCM patients, with notable frequencies in TTN, LMNA, and structural cytoskeleton Z-disk genes.
• A significant association was observed between gene cluster subgroups and LVRR.
• Carriers of rare variants in structural cytoskeleton Z-disk genes exhibited a significantly lower rate of LVRR (6%) and were independently associated with reduced LVRR.

Conclusions:

• NGS provides a high diagnostic yield for identifying genetic causes of DCM.
• A functional 'gene-clusters' classification may aid in the clinical management of genetically determined DCM.
• Rare variants in structural cytoskeleton Z-disk genes are independently associated with a lower likelihood of LVRR in DCM patients.