Marta Gigli1, Davide Stolfo1,2, Sharon L Graw3, Marco Merlo1, Caterina Gregorio4,5, Suet Nee Chen3, Matteo Dal Ferro1, Alessia PaldinoMD1, Giulia De Angelis1, Francesca Brun1, Jean Jirikowic3, Ernesto E Salcedo3, Sylvia Turja3, Diane Fatkin6,7, Renee Johnson6, J Peter van Tintelen8,9, Anneline S J M Te Riele8,9, 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. 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.).
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.
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.
Authors: Frank I Marcus; William J McKenna; Duane Sherrill; Cristina Basso; Barbara Bauce; David A Bluemke; Hugh Calkins; Domenico Corrado; Moniek G P J Cox; James P Daubert; Guy Fontaine; Kathleen Gear; Richard Hauer; Andrea Nava; Michael H Picard; Nikos Protonotarios; Jeffrey E Saffitz; Danita M Yoerger Sanborn; Jonathan S Steinberg; Harikrishna Tandri; Gaetano Thiene; Jeffrey A Towbin; Adalena Tsatsopoulou; Thomas Wichter; Wojciech Zareba Journal: Circulation Date: 2010-02-19 Impact factor: 29.690
Authors: Eric D Smith; Neal K Lakdawala; Nikolaos Papoutsidakis; Gregory Aubert; Andrea Mazzanti; Anthony C McCanta; Prachi P Agarwal; Patricia Arscott; Lisa M Dellefave-Castillo; Esther E Vorovich; Kavitha Nutakki; Lisa D Wilsbacher; Silvia G Priori; Daniel L Jacoby; Elizabeth M McNally; Adam S Helms Journal: Circulation Date: 2020-05-06 Impact factor: 29.690
Authors: Marta Gigli; Marco Merlo; Sharon L Graw; Giulia Barbati; Teisha J Rowland; Dobromir B Slavov; Davide Stolfo; Mary E Haywood; Matteo Dal Ferro; Alessandro Altinier; Federica Ramani; Francesca Brun; Andrea Cocciolo; Ilaria Puggia; Gaetano Morea; William J McKenna; Francisco G La Rosa; Matthew R G Taylor; Gianfranco Sinagra; Luisa Mestroni Journal: J Am Coll Cardiol Date: 2019-09-17 Impact factor: 24.094
Authors: Anita Spezzacatene; Gianfranco Sinagra; Marco Merlo; Giulia Barbati; Sharon L Graw; Francesca Brun; Dobromir Slavov; Andrea Di Lenarda; Ernesto E Salcedo; Jeffrey A Towbin; Jeffrey E Saffitz; Frank I Marcus; Wojciech Zareba; Matthew R G Taylor; Luisa Mestroni Journal: J Am Heart Assoc Date: 2015-10-16 Impact factor: 5.501
Authors: Charlotte L Hall; Mohammed M Akhtar; Maria Sabater-Molina; Marta Futema; Angeliki Asimaki; Alexandros Protonotarios; Chrysoula Dalageorgou; Alan M Pittman; Mari Paz Suarez; Beatriz Aguilera; Pilar Molina; Esther Zorio; Juan Pedro Hernández; Francisco Pastor; Juan R Gimeno; Petros Syrris; William J McKenna Journal: Int J Cardiol Date: 2019-10-08 Impact factor: 4.164
Authors: Andre E Minoche; Claire Horvat; Renee Johnson; Velimir Gayevskiy; Sarah U Morton; Alexander P Drew; Kerhan Woo; Aaron L Statham; Ben Lundie; Richard D Bagnall; Jodie Ingles; Christopher Semsarian; J G Seidman; Christine E Seidman; Marcel E Dinger; Mark J Cowley; Diane Fatkin Journal: Genet Med Date: 2018-07-02 Impact factor: 8.822
Authors: Adam S Helms; Andrea D Thompson; Amelia A Glazier; Neha Hafeez; Samat Kabani; Juliani Rodriguez; Jaime M Yob; Helen Woolcock; Francesco Mazzarotto; Neal K Lakdawala; Samuel G Wittekind; Alexandre C Pereira; Daniel L Jacoby; Steven D Colan; Euan A Ashley; Sara Saberi; James S Ware; Jodie Ingles; Christopher Semsarian; Michelle Michels; Iacopo Olivotto; Carolyn Y Ho; Sharlene M Day Journal: Circ Genom Precis Med Date: 2020-08-25
Authors: Stephane Heymans; James S Ware; Sanjay K Prasad; Amrit S Lota; Mark R Hazebroek; Pantazis Theotokis; Rebecca Wassall; Sara Salmi; Brian P Halliday; Upasana Tayal; Job Verdonschot; Devendra Meena; Ruth Owen; Antonio de Marvao; Alma Iacob; Momina Yazdani; Daniel J Hammersley; Richard E Jones; Riccardo Wage; Rachel Buchan; Fredrik Vivian; Yakeen Hafouda; Michela Noseda; John Gregson; Tarun Mittal; Joyce Wong; Jan Lukas Robertus; A John Baksi; Vassilios Vassiliou; Ioanna Tzoulaki; Antonis Pantazis; John G F Cleland; Paul J R Barton; Stuart A Cook; Dudley J Pennell; Pablo Garcia-Pavia; Leslie T Cooper Journal: Circulation Date: 2022-09-26 Impact factor: 39.918
Authors: Eric D Carruth; Maria Qureshi; Amro Alsaid; Melissa A Kelly; Hugh Calkins; Brittney Murray; Crystal Tichnell; Amy C Sturm; Aris Baras; H Lester Kirchner; Brandon K Fornwalt; Cynthia A James; Christopher M Haggerty Journal: Circ Genom Precis Med Date: 2022-06-14
Authors: J Lukas Laws; Megan C Lancaster; M Ben Shoemaker; William G Stevenson; Rebecca R Hung; Quinn Wells; D Marshall Brinkley; Sean Hughes; Katherine Anderson; Dan Roden; Lynne W Stevenson Journal: Circ Res Date: 2022-05-26 Impact factor: 23.213