10-year outcomes of triple-site versus standard cardiac resynchronization therapy randomized trial (TRUST CRT)

Background Triple-Site versus Standard Cardiac Resynchronization Therapy Randomized Trial (TRUST CRT) was initiated in 2009 to verify the hypothesis whether triple-site (single right, double left) cardiac resynchronization therapy (CRT) may be superior to conventional, biventricular resynchronization in patients with advanced heart failure. Objectives To report 6-month outcomes and 10-year survival in TRUST CRT. Methods 100 consecutive patients with moderate to severe heart failure, ejection fraction of 35% or less, electrical and mechanical dyssynchrony, were randomly assigned in a 1:1 fashion to triple-site CRT defibrillator (TRIV) or to conventional CRT-D. The primary objective evaluated response-rate, defined as the 6-month's combined end point of alive status, freedom from hospitalization for heart failure or heart transplantation, relative≥10% increase in ejection fraction, ≥10% in peak oxygen consumption, and ≥10% in 6-minute walking distance. The secondary objective was to assess the occurrence of major adverse cardiovascular events (hospitalization for exacerbated heart failure requiring modification of pharmacotherapy, heart transplant or death) at month 6 and during remote observation. Results At month 6, the response-rate was higher in triple-site than conventional CRT-D group (51.1 vs. 26.5%, P=0.014). There were 2 deaths or heart failure events in the triple-site group (4%) as compared with 8 in the group assigned to conventional CRT-D (16%). A triple-site resynchronization resulted in 12% absolute risk reduction for secondary end point (hazard ratio 0.25; 95 percent confidence interval, 0.05 to 1.17, P=0.056, in comparison with the conventional CRT-D group). After 10 years of observation (median follow up of 7.1 years; range: 1.2–10.4) 57 patients (58.2%) died: 24 (53.3%) in the triple-site group, 31 (60.8%) in the conventional group (P=0.46) and 2 patients with and ICD (failed CRT implantation) [Figure]. Conclusions In patients with advanced heart failure, triple-site resynchronization combined with an ICD did not result in better survival than conventional resynchronization therapy in a median observation of 7.1 years. Figure 1 Funding Acknowledgement Type of funding source: None

Exploring the variance in complex traits captured by DNA methylation assays

ABSTRACTFollowing years of epigenome-wide association studies (EWAS), traits analysed to date tend to yield few associations. Reinforcing this observation, we conducted EWAS on 400 traits and 16 yielded at least one association at the conventional significance threshold (P<1×10−7). To investigate why EWAS yield is low, we formally estimated the proportion of phenotypic variation captured by 421,693 blood derived DNA methylation markers (h2EWAS) across all 400 traits. The mean h2EWAS was zero, with evidence for regular cigarette smoking exhibiting the largest association with all markers (h2EWAS=0.42) and the only one surpassing a false discovery rate < 0.1. Though underpowered to determine the h2EWAS value for any one trait, h2EWAS was predictive of the number of EWAS hits across the traits analysed (AUC=0.7). Modelling the contributions of the methylome on a per-site versus a per-region basis gave varied h2EWAS estimates (r=0.47) but neither approach obtained substantially higher model fits across all traits. Our analysis indicates that most complex traits do not heavily associate with markers commonly measured in EWAS within blood. However, it is likely DNA methylation does capture variation in some traits and h2EWAS may be a reasonable way to prioritise traits that are likely to yield associations.