SUMMARY Heart failure (HF) is driven by the interplay between master regulatory transcription factors and dynamic alterations in chromatin structure. While pathologic gene transactivation in this context is known to be associated with recruitment of histone acetyl-transferases and local chromatin hyperacetylation, the role of epigenetic reader proteins in cardiac biology is unknown. We therefore undertook a first study of acetyl-lysine reader proteins, or bromodomains, in HF. Using a chemical genetic approach, we establish a central role for BET-family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to activation of canonical master regulators and effectors that are central to HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers in cardiac biology and identifies BET co-activator proteins as therapeutic targets in HF.

Context: Excessive fat mass clearly has adverse effects on metabolic processes that can ultimately lead to the development of chronic disease. Early identification of high-risk status may facilitate referral for definitive diagnostic tests and implementation of interventions to reduce cardiometabolic risk.Objective: To document the prevalence of metabolic syndrome among collegiate football players and to develop a clinical prediction rule that does not require blood analysis to identify players who may possess a high level of cardiometabolic risk.Design: Cross-sectional cohort study. Setting: University athletic training research laboratory.Patients or Other Participants: Sixty-two National Collegiate Athletic Association Division I Football Championship Subdivision football players (age 5 19.9 6 1.2 years, height 5 182.6 6 6.1 cm, mass 5 97.4 6 18.3 kg).Main Outcome Measure(s): Anthropometric characteristics associated with body fat, isokinetic quadriceps strength, and biometric indicators associated with metabolic syndrome were measured. Participants were classified as high risk or low risk for future development of type 2 diabetes and cardiovascular disease.Results: The prevalence of metabolic syndrome in the cohort was 19% (12 of 62), and 79% (49 of 62) of the players exceeded the threshold for 1 or more of its 5 components. A 4-factor clinical prediction rule that classified individuals on the basis of waist circumference, blood pressure, quadriceps strength, and ethnic category had 92% sensitivity (95% confidence interval 5 65%, 99%) and 76% specificity (95% confidence interval 5 63%, 86%) for discrimination of high-risk or low-risk status.Conclusions: The risk for developing type 2 diabetes and cardiovascular disease appears to be exceptionally high among collegiate football players. A lack of race-specific criteria for the diagnosis of metabolic syndrome almost certainly contributes to an underestimation of the true level of cardiometabolic risk for African American collegiate football players.Key Words: metabolic syndrome, insulin resistance, abdominal fat Key Points N In this Division I football team, metabolic syndrome was found in 19% of players overall, 46% of the linemen, and 14% of the nonlinemen. The cardiometabolic risk in the African American players was almost certainly underestimated.N For identifying obesity-related health risk, waist circumference was a better discriminator than either body fat percentage or body mass index.N A quadriceps peak torque/body mass ratio of less than 2.93 (peak torque/body weight less than 0.98) was the optimal cut point for identifying players with metabolic syndrome.N Our clinical prediction rule identified 92% of players with metabolic syndrome on the basis of waist circumference, systolic or diastolic blood pressure, quadriceps peak torque/body mass ratio, and white ethnicity.

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