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How Might Bromodomain and Extra-Terminal (BET) Inhibitors Operate in Cardiovascular Disease?

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Abstract

Bromodomain and extra-terminal (BET) inhibitors, acting via epigenetic mechanisms, have been developed recently as potential new treatments for cancer, including prostate cancer, and inflammatory conditions. Some BET inhibitors, such as RVX-208, also raise high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 levels. A recent meta-analysis of three small trials (n = 798) found that RVX-208 protected against major adverse cardiovascular events (MACE), raising the question as to whether this protective effect was an artefact, a chance finding, or mediated by HDL-C, anti-inflammatory pathways, or other factors. Notably, the effect of RVX-208 on MACE was largely driven by revascularizations, but fewer interventions in the treatment arm could have arisen accidently from favorable effects of RVX-208 on HDL-C and C-reactive protein influencing decisions about patient care. A larger (n = 2400) trial of RVX-208, BETonMACE (NCT02586155), with a more restricted definition of MACE, excluding hospitalizations, will shortly provide clarity. A successful BETonMACE trial would raise the question as to whether RVX-208 operates via lipids, inflammation, or other means, because several previous HDL-C modulators and anti-inflammatories have not provided effective means of treating cardiovascular disease and reducing overall mortality. Re-conceptualizing cardiovascular disease within the well-established evolutionary biology theory that growth and specifically reproduction trade-off against longevity might provide a more comprehensive explanation. Drivers of the gonadotropic axis, particularly androgens, suppress both HDL-C and the immune system while promoting ischemic heart disease and stroke. As such, any effects of RVX-208 on cardiovascular disease might be the result of reducing androgens, of which higher HDL-C and reduced inflammation are biomarkers. Notably, several other effective treatments for cardiovascular disease, such as statins and spironolactone, are known anti-androgens. Results of the BETonMACE trial, and corresponding insight about the mechanism of BET inhibitors in cardiovascular disease, are eagerly awaited.

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No external funding was used in the preparation of this manuscript.

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CMS and JVZ have no potential conflicts of interest that might be relevant to the contents of this manuscript.

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  1. CUNY Graduate School of Public Health and Health Policy (CUNY SPH), 55 West 125th St, New York, NY, 10027, USA

    C. Mary Schooling

  2. School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China

    C. Mary Schooling & Jie V. Zhao

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  1. C. Mary Schooling
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Correspondence to C. Mary Schooling.

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Schooling, C.M., Zhao, J.V. How Might Bromodomain and Extra-Terminal (BET) Inhibitors Operate in Cardiovascular Disease?. Am J Cardiovasc Drugs 19, 107–111 (2019). https://doi.org/10.1007/s40256-018-00315-3

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