BETs that cover the spread from acquired to heritable heart failure

Abstract

Heart failure (HF) with reduced contractile function is a common and lethal syndrome in which the heart cannot pump blood to adequately meet bodily demands, resulting in high mortality despite the current standard of care. In modern societies, the most common drivers of HF are ischemic heart disease and hypertension. However, in a substantial subset of cases, patients present with dilated and poorly contracting hearts without evidence of common inciting stressors, a syndrome called dilated cardiomyopathy (DCM). Genome sequencing has identified a host of deleterious germline variants in key cardiomyocyte genes as causes of heritable DCM, including mutations in LMNA, which encodes the nuclear lamina-associated protein lamin A/C. In this issue of the JCI, Auguste et al. generate a mouse model of DCM in which they delete Lmna in cardiomyocytes and discover that bromodomain and extraterminal (BET) protein activation is a druggable epigenetic mechanism of disease pathogenesis in this heritable HF syndrome.

Figure 1. Cardiomyocyte-specific Lmna deletion triggers hallmark features of DCM and reveals BET proteins as druggable targets.

Lmna-cKO results in cardiomyocyte dysfunction, immune cell and myofibroblast activation, and collagen deposition. BET bromodomain inhibition (BET-BDi) with JQ1 improves cardiac function and attenuates induction of stress response genes. As JQ1 is administered systemically and acts upon multiple cell types simultaneously, its therapeutic effects could depend on transcription modulation of cardiomyocyte and noncardiomyocyte populations. The figure was adapted from a schematic created by Ana Catarina Silva (ana@anasilvaillustrations.com).