Phenotypic Expression, Natural History, and Risk Stratification of Cardiomyopathy Caused by Filamin C Truncating Variants

Marta Gigli; Davide Stolfo; Sharon L Graw; Marco Merlo; Caterina Gregorio; Suet Nee Chen; Matteo Dal Ferro; Alessia PaldinoMD; Giulia De Angelis; Francesca Brun; Jean Jirikowic; Ernesto E Salcedo; Sylvia Turja; Diane Fatkin; Renee Johnson; J Peter van Tintelen; Anneline S J M Te Riele; Arthur A M Wilde; Neal K Lakdawala; Kermshlise Picard; Daniela Miani; Daniele Muser; Giovanni Maria Severini; Hugh Calkins; Cynthia A James; Brittney Murray; Crystal Tichnell; Victoria N Parikh; Euan A Ashley; Chloe Reuter; Jiangping Song; Daniel P Judge; William J McKenna; Matthew R G Taylor; Gianfranco Sinagra; Luisa Mestroni

doi:10.1161/CIRCULATIONAHA.121.053521

Phenotypic Expression, Natural History, and Risk Stratification of Cardiomyopathy Caused by Filamin C Truncating Variants

Circulation. 2021 Nov 16;144(20):1600-1611. doi: 10.1161/CIRCULATIONAHA.121.053521. Epub 2021 Sep 30.

Authors

Marta Gigli^#¹, Davide Stolfo^#^{1

2}, Sharon L Graw³, Marco Merlo¹, Caterina Gregorio^{4

5}, Suet Nee Chen³, Matteo Dal Ferro¹, Alessia PaldinoMD¹, Giulia De Angelis¹, Francesca Brun¹, Jean Jirikowic³, Ernesto E Salcedo³, Sylvia Turja³, Diane Fatkin^{6

7}, Renee Johnson⁶, J Peter van Tintelen^{8

9}, Anneline S J M Te Riele^{8

9}, Arthur A M Wilde¹⁰, Neal K Lakdawala¹¹, Kermshlise Picard¹¹, Daniela Miani¹², Daniele Muser¹², Giovanni Maria Severini¹³, Hugh Calkins¹⁴, Cynthia A James¹⁴, Brittney Murray¹⁴, Crystal Tichnell¹⁴, Victoria N Parikh¹⁵, Euan A Ashley¹⁵, Chloe Reuter¹⁵, Jiangping Song¹⁶, Daniel P Judge¹⁷, William J McKenna¹⁸, Matthew R G Taylor³, Gianfranco Sinagra¹, Luisa Mestroni³

Affiliations

¹ Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), University of Trieste, Trieste, Italy (M.G., D.S., M.M., M.D.F., A.P., G.D.A., F.B., G.S.).
² Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden (D.S.).
³ Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora (S.G., S.N.C., J.J., E.E.S., S.T., M.R.G.T., L.M.).
⁴ Biostatistics Unit, Department of Medical Sciences, University of Trieste, Italy (C.G.).
⁵ MOX-Modeling and Scientific Computing Laboratory, Department of Mathematics, Politecnico di Milano, Milan, Italy (C.G.).
⁶ Molecular Cardiology Division, Victor Chang Cardiac Research Institute, and St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Australia (D.F., R.J.).
⁷ Cardiology Department, St Vincent's Hospital, Sydney, Australia (D.F.).
⁸ Division of Medicine, Department of Genetics and Cardiology, University Medical Center, Utrecht, the Netherlands (J.P.v.T., A.S.J.M.T.R.).
⁹ Netherlands Heart Institute, Utrecht (J.P.v.T., A.S.J.M.T.R.).
¹⁰ Heart Centre, Department of Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, the Netherlands (A.W.).
¹¹ Brigham and Women's Hospital, Harvard Medical School, Boston, MA (N.K.L., K.P.).
¹² University Hospital of Udine, Italy (D. Miani, D. Muser).
¹³ Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy (G.M.S.).
¹⁴ Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, MD (H.C., C.A.J., B.M., C.T.).
¹⁵ Stanford Center for Inherited Cardiovascular Disease, CA (V.N.P., E.A.A., C.R.).
¹⁶ National Center for Cardiovascular Diseases in Beijing, China (J.S.).
¹⁷ Medical University of South Carolina, Charleston (D.J.).
¹⁸ Institute of Cardiovascular Science, University College of London, United Kingdom (W.J.M.).

^# Contributed equally.

Abstract

Background: Filamin C truncating variants (FLNCtv) cause a form of arrhythmogenic cardiomyopathy: the mode of presentation, natural history, and risk stratification of FLNCtv remain incompletely explored. We aimed to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of FLNCtv carriers.

Methods: FLNCtv carriers were identified from 10 tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), nonarrhythmic death/HT/LVAD, and sudden cardiac death/major ventricular arrhythmias. Previously established cohorts of 46 patients with LMNA and 60 with DSP-related arrhythmogenic cardiomyopathies were used for prognostic comparison.

Results: Eighty-five patients carrying FLNCtv were included (42±15 years, 53% men, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) experienced nonarrhythmic death/HT/LVAD, and 23 (27%) experienced sudden cardiac death/major ventricular arrhythmias. The sudden cardiac death/major ventricular arrhythmias incidence of FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, left ventricular ejection fraction was associated with the risk of D/HT/LVAD and nonarrhythmic death/HT/LVAD.

Conclusions: Among patients referred to tertiary referral centers, FLNCtv arrhythmogenic cardiomyopathy is phenotypically heterogeneous and characterized by a high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of left ventricular dysfunction.

Keywords: FLNC protein, human; arrhythmogenic right ventricular dysplasia; death, sudden, cardiac; heart failure; outcome studies; prognosis.

Publication types

Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alleles
Cardiomyopathies / diagnosis
Cardiomyopathies / epidemiology
Cardiomyopathies / etiology*
Cardiomyopathies / therapy
Combined Modality Therapy
Disease Management
Echocardiography
Female
Filamins / genetics*
Genetic Association Studies
Genetic Predisposition to Disease*
Genetic Variation*
Genotype
Humans
Male
Middle Aged
Outcome Assessment, Health Care
Phenotype*
Prognosis
Registries

Substances

FLNC protein, human
Filamins

Abstract

Publication types

MeSH terms

Substances

Grants and funding