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

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 PicardDaniela 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1600-1611
Number of pages	12
Journal	Circulation
Volume	144
Issue number	20
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.121.053521
Publication status	Published - 16 Nov 2021

Keywords

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

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10.1161/CIRCULATIONAHA.121.053521

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Gigli, M., Stolfo, D., Graw, S. L., Merlo, M., Gregorio, C., Nee Chen, S., Dal Ferro, M., Paldinomd, A., De Angelis, G., Brun, F., Jirikowic, J., Salcedo, E. E., Turja, S., Fatkin, D., Johnson, R., Van Tintelen, J. P., Te Riele, A. S. J. M., Wilde, A. A. M., Lakdawala, N. K., ... Mestroni, L. (2021). Phenotypic Expression, Natural History, and Risk Stratification of Cardiomyopathy Caused by Filamin C Truncating Variants. Circulation, 144(20), 1600-1611. https://doi.org/10.1161/CIRCULATIONAHA.121.053521

@article{5be7eaf6baf2452bbd95783bf97d66e1,

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

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",

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

year = "2021",

month = nov,

day = "16",

doi = "10.1161/CIRCULATIONAHA.121.053521",

language = "English",

volume = "144",

pages = "1600--1611",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams & Wilkins",

number = "20",

}

Gigli, M, Stolfo, D, Graw, SL, Merlo, M, Gregorio, C, Nee Chen, S, Dal Ferro, M, Paldinomd, A, De Angelis, G, Brun, F, Jirikowic, J, Salcedo, EE, Turja, S, Fatkin, D, Johnson, R, Van Tintelen, JP , Te Riele, ASJM, Wilde, AAM, Lakdawala, NK, Picard, K, Miani, D, Muser, D, Maria Severini, G, Calkins, H, James, CA, Murray, B, Tichnell, C, Parikh, VN, Ashley, EA, Reuter, C, Song, J, Judge, DP, McKenna, WJ, Taylor, MRG, Sinagra, G & Mestroni, L 2021, 'Phenotypic Expression, Natural History, and Risk Stratification of Cardiomyopathy Caused by Filamin C Truncating Variants', Circulation, vol. 144, no. 20, pp. 1600-1611. https://doi.org/10.1161/CIRCULATIONAHA.121.053521

TY - JOUR

T1 - Phenotypic Expression, Natural History, and Risk Stratification of Cardiomyopathy Caused by Filamin C Truncating Variants

AU - Gigli, Marta

AU - Stolfo, Davide

AU - Graw, Sharon L.

AU - Merlo, Marco

AU - Gregorio, Caterina

AU - Nee Chen, Suet

AU - Dal Ferro, Matteo

AU - Paldinomd, Alessia

AU - De Angelis, Giulia

AU - Brun, Francesca

AU - Jirikowic, Jean

AU - Salcedo, Ernesto E.

AU - Turja, Sylvia

AU - Fatkin, Diane

AU - Johnson, Renee

AU - Van Tintelen, J. Peter

AU - Te Riele, Anneline S.J.M.

AU - Wilde, Arthur A.M.

AU - Lakdawala, Neal K.

AU - Picard, Kermshlise

AU - Miani, Daniela

AU - Muser, Daniele

AU - Maria Severini, Giovanni

AU - Calkins, Hugh

AU - James, Cynthia A.

AU - Murray, Brittney

AU - Tichnell, Crystal

AU - Parikh, Victoria N.

AU - Ashley, Euan A.

AU - Reuter, Chloe

AU - Song, Jiangping

AU - Judge, Daniel P.

AU - McKenna, William J.

AU - Taylor, Matthew R.G.

AU - Sinagra, Gianfranco

AU - Mestroni, Luisa

PY - 2021/11/16

Y1 - 2021/11/16

N2 - 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.

AB - 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.

KW - FLNC protein, human

KW - arrhythmogenic right ventricular dysplasia

KW - death, sudden, cardiac

KW - heart failure

KW - outcome studies

KW - prognosis

UR - http://www.scopus.com/inward/record.url?scp=85125619755&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.121.053521

DO - 10.1161/CIRCULATIONAHA.121.053521

M3 - Article

C2 - 34587765

SN - 0009-7322

VL - 144

SP - 1600

EP - 1611

JO - Circulation

JF - Circulation

IS - 20

ER -

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

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