Abstract Body (Do not enter title and authors here): Introduction: Titin truncating variants (TTNtv) are a common cause of dilated (DCM) and non-dilated left ventricular cardiomyopathy (NDLVC). Mitral valve prolapse (MVP) occurs commonly in the general population and is characterized by myxomatous structural changes of the mitral valve apparatus. Both TTNtv-mediated DCMs and MVP have been associated independently with an increased risk of ventricular arrhythmias (VA) and sudden cardiac arrest/death (SCA/SCD). However, it remains unclear whether TTNtv-positive patients with co-existing MVP are at increased risk for major VA (MVA) events. Therefore, we sought to compare the prevalence of MVA events between TTNtv-positive patients with or without MVP in a large single-center cohort of genetic cardiomyopathy patients.

Methods: Retrospective review of 1,230 ACM/DCM patients was used to identify those with a pathogenic/likely pathogenic (P/LP) TTNtv. Independent review of available imaging data was subsequently used to identify TTNtv-positive patients with co-existing MVP. The prevalence of non-SCA MVA and SCA/SCD was then compared between TTNtv-positive patients with and without MVP.

Results: Overall, 253/1,230 (21%) of ACM/DCM patients were P/LP TTNtv-positive (43% female; mean age 44±17 years, mean LVEF 39±17%). Amongst these 253 TTNtv-positive patients, 15 (5.9%) had co-existing MVP (33% female, mean age 49±12 years, mean LVEF 48±12%). Collectively, TTNtv-positive patients with MVP were more likely to experience a MVA event than those without MVP [6/15 (40%) vs 41/238 (17%); p=0.03]. This included a higher risk of appropriate VT/VF-terminating ICD shocks [4/15 (27%) vs. 17/238 (7.1%); p=0.03] and SCA [3/15 (20%) vs 12/238 (5%); p=0.05]. However, despite the increased arrhythmic risk observed in TTNtv-positive patients with MVP, no deaths occurred in this subgroup and the overall cardiac mortality rate across the entire TTNtv-positive cohort was low [6/253 (2.4%)].

Conclusion: TTNtv-positive patients with concomitant MVP are at increased risk for MVA events, including SCA. Future studies are needed to i) better define the prognostic utility of MVP in the risk-stratification of TTN-NDLVC/DCM and other genetic cardiomyopathies and ii) determine whether some patients diagnosed with arrhythmogenic MVP syndrome may have TTNtv-mediated NDLVC exacerbated in a focal manner by the increased mechanical strain generated by the presence of the common and likely genetically unrelated myxomatous MVP.