Filamin-C variant-associated cardiomyopathy: A pooled analysis of individual patient data to evaluate the clinical profile and risk of sudden cardiac death

Heart Rhythm. 2022 Feb;19(2):235-243. doi: 10.1016/j.hrthm.2021.09.029. Epub 2021 Oct 1.

Abstract

Background: Mutations in filamin-C (FLNC) are involved in the pathogenesis of arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy (DCM), and have been associated with a left ventricular (LV) phenotype, characterized by nonischemic LV fibrosis, ventricular arrhythmias, and sudden cardiac death (SCD).

Objective: The purpose of this study was to investigate the prevalence of FLNC variants in a gene-negative ACM population and to evaluate the clinical phenotype and SCD risk factors in FLNC-associated cardiomyopathies.

Methods: ACM probands who tested negative for mutations in ACM-related genes underwent FLNC genetic screening. Clinical and genetic data were collected and pooled together with those of previously published FLNC-ACM and FLNC-DCM patients.

Results: In a cohort of 270 gene-elusive ACM probands, 12 (4.4%) had FLNC variants, and 13 additional family members carried the same mutation. Eighteen FLNC variant carriers (72%) had a diagnosis of ACM (72% male; mean age 45 years). On pooled analysis, 145 patients with FLNC-associated cardiomyopathies were included. Electrocardiographic (ECG) low QRS voltages were detected in 37%, and T-wave inversion (TWI) in inferolateral/lateral leads in 24%. Among 67 patients who had cardiac magnetic resonance (CMR), LV nonischemic late gadolinium enhancement (LGE) was found in 75%. SCD occurred in 28 patients (19%), 15 of whom showed LV nonischemic LGE/fibrosis. Compared with patients with no SCD, those who experienced SCD more frequently had inferolateral/lateral TWI (P = .013) and LV LGE/fibrosis (P = .033).

Conclusion: Clinical phenotype of FLNC cardiomyopathies is characterized by late-onset presentation and typical ECG and CMR features. SCD is associated with the presence of LV LGE/fibrosis but not with severe LV systolic dysfunction.

Keywords: Arrhythmogenic cardiomyopathy; Cardiac magnetic resonance; Dilated cardiomyopathy; Filamin-C; Sudden cardiac death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Cardiomyopathies / genetics*
  • Child
  • Contrast Media
  • Death, Sudden, Cardiac / etiology*
  • Electrocardiography
  • Female
  • Filamins / genetics*
  • Humans
  • Magnetic Resonance Imaging, Cine
  • Male
  • Middle Aged
  • Mutation
  • Pedigree
  • Phenotype
  • Prevalence
  • Risk

Substances

  • Contrast Media
  • FLNC protein, human
  • Filamins