Association of Titin-Truncating Genetic Variants With Life-threatening Cardiac Arrhythmias in Patients With Dilated Cardiomyopathy and Implanted Defibrillators

Abstract

Importance: There is a need for better arrhythmic risk stratification in nonischemic dilated cardiomyopathy (DCM). Titin-truncating variants (TTNtvs) in the TTN gene are the most common genetic cause of DCM and may be associated with higher risk of arrhythmias in patients with DCM.

Objective: To determine if TTNtv status is associated with the development of life-threatening ventricular arrhythmia and new persistent atrial fibrillation in patients with DCM and implanted cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) devices.

Design, setting, and participants: This retrospective, multicenter cohort study recruited 148 patients with or without TTNtvs who had nonischemic DCM and ICD or CRT-D devices from secondary and tertiary cardiology clinics in the United Kingdom from February 1, 2011, to June 30, 2016, with a median (interquartile range) follow-up of 4.2 (2.1-6.5) years. Exclusion criteria were ischemic cardiomyopathy, primary valve disease, congenital heart disease, or a known or likely pathogenic variant in the lamin A/C gene. Analyses were performed February 1, 2017, to May 31, 2017.

Main outcome and measures: The primary outcome was time to first device-treated ventricular tachycardia of more than 200 beats/min or first device-treated ventricular fibrillation. Secondary outcome measures included time to first development of persistent atrial fibrillation.

Results: Of 148 patients recruited, 117 adult patients with nonischemic DCM and an ICD or CRT-D device (mean [SD] age, 56.9 [12.5] years; 76 [65.0%] men; 106 patients [90.6%] with primary prevention indications) were included. Having a TTNtv was associated with a higher risk of receiving appropriate ICD therapy (shock or antitachycardia pacing) for ventricular tachycardia or fibrillation (hazard ratio [HR], 4.9; 95% CI, 2.2-10.7; P < .001). This association was independent of all covariates, including midwall fibrosis measured by late gadolinium enhancement on cardiac magnetic resonance images (adjusted HR, 8.3; 95% CI, 1.8-37.6; P = .006). Having a TTNtv was also associated with the risk of receiving a shock (HR, 3.6; 95% CI, 1.1-11.6; P = .03). Individuals with a TTNtv and fibrosis had a greater rate of receiving appropriate device therapy than those with neither (HR, 16.6; 95% CI, 3.5-79.3; P < .001). Having a TTNtv was also a risk factor for developing new persistent atrial fibrillation (HR, 3.9; 95% CI, 1.3-12.0; P = .01).

Conclusions and relevance: Having a TTNtv was an important risk factor for clinically significant arrhythmia in patients with DCM and ICD or CRT-D devices. Having a TTNtv, especially in combination with midwall fibrosis confirmed with cardiovascular magnetic resonance imaging, may provide a risk stratification approach for evaluating the need for ICD therapy in patients with DCM. This hypothesis should be tested in larger studies.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mason reported grants and personal fees from Boston Scientific and serving on the advisory board for Medtronic outside the submitted work. Dr Pennell reported grants from Siemens during the conduct of the study, grants from La Jolla Pharmaceutical and Bayer outside the submitted work, and share ownership and being the director of Cardiovascular Imaging Solutions. Dr Barton reported grants from the Health Innovation Challenge Fund (HICF) Wellcome Trust and the UK Department of Health during the conduct of the study. Dr Prasad reported grants from the UK National Institute for Health Research (NIHR), Alexander Jansons Foundation, and British Heart Foundation during the conduct of the study. Dr Cook reported being a founder and director of Enleofen Bio. Drs Cook and Ware reported having a patent for methods, systems, and apparatus for identifying pathogenic gene variants (US 62383189). Dr Ware reported grants and nonfinancial support from the HICF Wellcome Trust, UK Medical Research Council, the NIHR Royal Brompton Cardiovascular Biomedical Research Unit, and the NIHR Imperial College Biomedical Research Centre during the conduct of the study and grants and personal fees from MyoKardia outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Associations of Titin-Truncating Variants (TTNtvs) With Implanted Cardioverter Defibrillator (ICD) Therapy for Ventricular Tachycardia or Ventricular Fibrillation

Kaplan-Meier plots for appropriate ICD therapy (antitachycardia pacing or shock) (A) or appropriate shock for ventricular tachycardia more than 200 beats/min or ventricular fibrillation (B). Crosses indicate censoring; CRT-D, cardiac resynchronization therapy defibrillator; and HR, hazard ratio.

Figure 2.. Associations of Titin-Truncating Variants (TTNtvs) and Midwall Fibrosis With Implanted Cardioverter Defibrillator (ICD) Therapy

Kaplan-Meier plots for the time to first appropriate ICD therapy by TTNtv status and presence (A) or absence (B) of midwall fibrosis. Midwall fibrosis and TTNtvs are independently associated with appropriate ICD therapy and are additive. Of the 41 patients who did not have TTNtvs or midwall fibrosis, there were only 2 episodes of ICD therapy (5%) and no ICD shocks. In contrast, of the 13 patients who had TTNtvs and midwall fibrosis, there were 8 appropriate ICD therapies (62%) and 5 shocks (38%). Patients with both risk factors had a 16-fold increased hazard ratio (HR) of ICD therapy compared with patients with neither. Crosses indicate censoring; CRT-D, cardiac resynchronization therapy defibrillator.