Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene-Reference-Cited by-同舟云学术

Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene

Published:2020-10 Issue:10 Volume:13 Page:
ISSN:1941-3289
Container-title:Circulation: Heart Failure
language:en
Short-container-title:Circ: Heart Failure

Author:

Akhtar Mohammed Majid¹²,Lorenzini Massimiliano¹²,Cicerchia Marcos³⁴,Ochoa Juan Pablo³⁴^ORCID,Hey Thomas Morris⁵⁶^ORCID,Sabater Molina Maria⁷,Restrepo-Cordoba Maria Alejandra⁸⁹,Dal Ferro Matteo¹⁰,Stolfo Davide¹⁰,Johnson Renee¹¹,Larrañaga-Moreira José M.¹²,Robles-Mezcua Ainhoa¹³^ORCID,Rodriguez-Palomares Jose F.¹⁴,Casas Guillem¹⁴,Peña-Peña Maria Luisa¹⁵,Lopes Luis Rocha¹²,Gallego-Delgado Maria¹⁶^ORCID,Franaszczyk Maria¹⁷^ORCID,Laucey Gemma¹⁸^ORCID,Rangel-Sousa Diego¹⁵^ORCID,Basurte Mayte¹⁸,Palomino-Doza Julian¹⁹²⁰,Villacorta Eduardo¹⁶^ORCID,Bilinska Zofia²¹,Limeres Freire Javier¹⁴^ORCID,Garcia Pinilla José M.¹³,Barriales-Villa Roberto¹²,Fatkin Diane²²²³²⁴^ORCID,Sinagra Gianfranco¹⁰,Garcia-Pavia Pablo⁸⁹,Gimeno Juan R.⁷,Mogensen Jens⁵⁶^ORCID,Monserrat Lorenzo³⁴^ORCID,Elliott Perry M.¹²^ORCID,

Affiliation:

1. Department of Inherited Cardiovascular Diseases, Bart’s Heart Centre, St. Bartholomew’s Hospital, London, United Kingdom (M.M.A., M.L., L.R.L., P.M.E.).

2. Institute of Cardiovascular Science, University College London, United Kingdom (M.M.A., M.L., L.R.L., P.M.E.).

3. Health in Code S.L. Scientific Department, A Coruña, Spain (M.C., J.P.O., L.M.).

4. Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, Sergas, Universidade da Coruña, Spain (M.C., J.P.O., L.M.).

5. Department of Cardiology, Odense University Hospital, Denmark (T.M.H., J.M.).

6. Odense Patient Data Explorative Network, University of Southern Denmark (T.M.H., J.M.).

7. Inherited Cardiac Disease Unit, Hospital Universitario Virgen Arrixaca, Murcia, Spain (M.S.M., J.R.G.).

8. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Centro de Investigación en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain (M.A.R.-C., P.G.-P.).

9. Universidad Francisco de Vitoria, Pozuelo de Alarcon, Spain (M.A.R.-C., P.G.-P.).

10. Cardiovascular Department, Azienda Sanitaria Universitaria Integrata of Trieste, Trieste Hospital, Italy (M.D.F., D.S., G.S.).

11. Molecular Cardiology and Biophysics Division (R.J.), Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.

12. Unidad de Cardiopatías Familiares/Cardiology Service, CIBERCV, Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, Sergas, Universidade da Coruña, Spain (J.M.L.-M., R.B.-V.).

13. Heart Failure and Familial Heart Diseases Unit, Cardiology Department, Hospital Universitario Virgen de la Victoria, CIBERCV, IBIMA, Malaga, Spain (A.R.-M., J.M.G.P.).

14. Department of Cardiology, Vall d’ Hebron Institut de Recerca, Hospital Universitari Vall d’ Hebron, Universitat Autònoma de Barcelona, Spain (J.F.R.-P., G.C., J.L.F.).

15. Heart Failure and Heart Transplantation Unit, Virgen del Rocio University Hospital, Sevilla, Spain (M.L.P.-P., D.R.-S.).

16. Inherited Cardiovascular Disease Unit, Cardiology Department, Instituto de Investigación Biomédica de Salamanca, Complejo Asistencial Universitario de Salamanca, Spain (M.G.-D., E.V.).

17. Department of Medical Biology (M.F.), Cardinal Stefan Wyszynski Institute of Cardiology, Warsaw, Poland.

18. Complejo Hospitalario de Navarra, Pamplona, Spain (G.L., M.B.).

19. Inherited Cardiac Disease Unit, Instituto de investigación I+12, Hospital Universitario 12 de Octubre, Madrid, Spain (J.P.-D.).

20. Centro de Investigación Biomedica en Red en Enfermedades Cardiovasculares, CIBERCV, Madrid, Spain (J.P.-D.).

21. Unit for Screening Studies in Inherited Cardiovascular Diseases (Z.B.), Cardinal Stefan Wyszynski Institute of Cardiology, Warsaw, Poland.

22. Molecular Cardiology and Biophysics Division (D.F.), Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.

23. St. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, NSW, Australia (D.F.).

24. Cardiology Department, St. Vincent’s Hospital, Darlinghurst, NSW, Australia (D.F.).

Abstract

Background: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. Methods: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). Results: Median follow-up was 49 (18–105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P =0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04–3.44]; P =0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30–2.04]; P <0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis ( P =0.07). Conclusions: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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