Clinical impact of acquired risk factors in TTN-mediated dilated cardiomyopathy. (25th November 2020)

• Record Type: Journal Article
• Authors: Giudicessi, J; Ackerman, M; Pereira, N
• Is Part Of: European heart journal. Volume 41:(2020)Supplement 2
• Publication Date: 2020-11-25
• Subjects: Dilated Cardiomyopathy and Non-ischemic Heart Failure; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/ehjci/ehaa946.0725
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Background/Introduction: Truncating variants in TTN-encoded titin (TTNtvs) underlie ∼25% of familial dilated cardiomyopathy (DCM) cases. In addition, TTNtvs are over-represented in alcoholic, peripartum, and chemotherapy-induced CM suggesting that risk factors may play a substantive role in the penetrance and expressivity of TTN-mediated DCM. Purpose: To determine the prevalence and clinical impact of risk factors for TTN-mediated DCM within a single center cohort of unrelated patients with pathogenic (P)/likely pathogenic (LP) TTNtvs. Methods: In this retrospective study, an institutionally developed natural language processing algorithm was used to identify all TTNtv-positive patients evaluated clinically between 01/2012 and 12/2019. Each TTNtv was then mapped to the TTN reference sequence (NM_133378.4) and classified according to a strict interpretation of the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. After exclusion of individuals with complex congenital heart disease, ischemic heart disease, and those without ACMG P/LP TTNtvs, available medical records were reviewed for risk factors such as long-term heavy alcohol consumption (>80 grams/day), cardiotoxic chemotherapy exposure, morbid obesity (body mass index >40), biopsy/imaging-confirmed myocarditis, peripartum/tachycardia-mediated CM, and valvular heart disease. Results: Overall, 33 ACMG P/LP TTNtv-positive patients were identified (40% female; mean age at presentation 45±16 years; mean LVEF at presentation 38%±17%). Of note, 17/33 (52%) presented with heart failure (HF) and 4/33 (12%) presented with sustained ventricular arrhythmias (VAs). The remaining 12 (36%) TTNtv-positive patients presented with incidentally detected asymptomatic left ventricular systolic dysfunction (n=9) or as a result of genetic cascade screening (n=3). In comparison to TTNtv-positive patients with non-HF presentations, those with HF had worse left ventricular function (mean LVEF: 26% ± 11% vs 51% ±12%; p<0.001) and were more likely to have ≥1 risk factor [11/17 (65%) vs 4/16 (25%); p=0.04]. Unexpectedly, the 7 TTNtv-positive patients that presented with (n=4) or subsequently developed (n=3) sustained VAs were younger at the time of presentation (34±13 years vs 48±15 years; p=0.04) and displayed a similar degree of left ventricular dysfunction to those without sustained VAs (mean LVEF: 42% ± 17% vs 36% ± 17%; p=ns). Interestingly, the only risk factor over-represented amongst those with sustained VAs was bileaflet mitral valve prolapse [3/7 (43%) vs 0/26 (0%); p=0.006]. Conclusion: The majority of TTNtv-positive patients (14/23; 61%) with a history of HF and/or sustained VAs possessed ≥1 acquired risk factor providing further evidence that gene-environment interaction(s) exert a crucial role in the manifestation of TTN-mediated disease. Funding Acknowledgement: Type of funding source: None