Author + information
- Received May 2, 2019
- Revision received June 13, 2019
- Accepted June 29, 2019
- Published online September 9, 2019.
- Marta Gigli, MDa,b,∗,
- Marco Merlo, MDa,∗,
- Sharon L. Graw, PhDb,
- Giulia Barbati, PhDc,
- Teisha J. Rowland, PhDb,
- Dobromir B. Slavov, PhDb,
- Davide Stolfo, MDa,
- Mary E. Haywood, PhDb,
- Matteo Dal Ferro, MDa,
- Alessandro Altinier, MDa,
- Federica Ramani, PhDa,
- Francesca Brun, MDa,
- Andrea Cocciolo, MDa,b,
- Ilaria Puggia, MDa,b,
- Gaetano Morea, MDa,b,
- William J. McKenna, MD, DScd,e,
- Francisco G. La Rosa, MDf,
- Matthew R.G. Taylor, MD, PhDb,∗ (, )@CUAnschutz@CUMedicalSchool,
- Gianfranco Sinagra, MDa and
- Luisa Mestroni, MDb,∗ ()
- aCardiovascular Department, Azienda Sanitaria-Universitaria Integrata Trieste “ASUITS,”, Trieste, Italy
- bCardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- cBiostatistics Unit, Department of Medical Sciences, University of Trieste, Trieste, Italy
- dInstitute of Cardiovascular Science, University College London, London, United Kingdom
- eHeart Hospital, Hamad Medical Corporation, Doha, Qatar
- fDepartment of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- ↵∗Address for correspondence:
Dr. Luisa Mestroni OR Dr. Matthew Taylor, Molecular Genetics, Cardiovascular Institute, University of Colorado Denver Anschutz Medical Campus, 12700 East 19th Avenue #F442, Aurora, Colorado 80045-2507.
Background Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood.
Objectives The purpose of this study was to investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients.
Methods A total of 487 DCM patients were analyzed by next-generation sequencing and categorized the disease genes into functional gene groups. The following composite outcome measures were assessed: 1) all-cause mortality; 2) heart failure–related death, heart transplantation, or destination left ventricular assist device implantation (DHF/HTx/VAD); and 3) sudden cardiac death/sustained ventricular tachycardia/ventricular fibrillation (SCD/VT/VF).
Results A total of 183 pathogenic/likely pathogenic variants were found in 178 patients (37%): 54 (11%) Titin; 19 (4%) Lamin A/C (LMNA); 24 (5%) structural cytoskeleton-Z disk genes; 16 (3.5%) desmosomal genes; 46 (9.5%) sarcomeric genes; 8 (1.6%) ion channel genes; and 11 (2.5%) other genes. All-cause mortality was no different between variant carriers and noncarriers (p = 0.99). A trend toward worse SCD/VT/VF (p = 0.062) and DHF/HTx/VAD (p = 0.061) was found in carriers. Carriers of desmosomal and LMNA variants experienced the highest rate of SCD/VT/VF, which was independent of the left ventricular ejection fraction.
Conclusions Desmosomal and LMNA gene variants identify the subset of DCM patients who are at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless of the left ventricular ejection fraction.
↵∗ Drs. Gigli and Merlo contributed equally to this work.
This study was supported by National Institutes of Health grants R01 HL69071, HL116906, and AHA17GRNT33670495 (to Dr. Mestroni); National Institutes of Health grants 1K23HI067915 and R01HL109209 (to Dr. Taylor); and the CRTrieste Foundation and Cassa di Risparmio of Gorizia Foundation (to Dr. Sinagra). This work is also supported in part by a Trans-Atlantic Network of Excellence grant from the Fondation Leducq (14-CVD 03), the National Center for Advancing Translation Sciences (NCATS) at the National Institutes of Health, Colorado CTSA Grant Number UL1 TR001082, and the EU FP7 grant SarcoSi IRSES. Dr. McKenna is a U.K. National Institute for Health Research Senior Investigator. Dr. Mestroni has served as a consultant for MyoKardia and Array Biopharma. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received May 2, 2019.
- Revision received June 13, 2019.
- Accepted June 29, 2019.
- 2019 American College of Cardiology Foundation
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