BET Bromodomain Inhibitors and Pulmonary Arterial Hypertension: Take Care of the Heart.

To the Editor:

We read with great interest the article by Van der Feen and colleagues (1), who reported the promising results from a multicenter preclinical validation of BET (bromodomain and extraterminal motif) family inhibition for the treatment of pulmonary arterial hypertension (PAH). The BET family members are epigenetic readers that bind acetylated proteins, facilitating the localization of transcription factors and other coactivators to upregulate transcription (2). BET family proteins have been implicated in cardiac pathologic gene induction and heart failure pathogenesis. Indeed, pharmacological administration of several BET inhibitors had significant therapeutic effects in a diverse range of small animal models of heart failure via a mechanism that converges on suppression of profibrotic and proinflammatory gene expression programs in the heart (3). The role of BET proteins has also been studied in the frame of PAH and associated right ventricle (RV) hypertrophy and failure (4). In their study, Van der Feen and colleagues (1) demonstrated that RVX208, a clinically available BET inhibitor, modulates pro-proliferative, prosurvival, and proinflammatory pathways. This reversed the PAH phenotype in cultured pulmonary vascular cells and improved pulmonary hemodynamics and RV function in several animal models of PAH and isolated RV pressure load.

Paradoxically, we recently demonstrated that in vivo administration of BET inhibitor I-BET-151 induces structural and functional alterations of the heart mitochondria in healthy male mice and rats (5). We showed the occurrence of specific ultrastructural alterations and progressive destruction of cardiomyocyte mitochondria after I-BET-151 exposure, whereas the skeletal muscles of exposed animals were unaffected. In rats, I-BET-151 decreased the oxidative capacities of cardiac mitochondria in a dose-dependent manner, and at high dose (10 mg/kg/d during 3 wk), it also decreased mitochondrial mass. I-BET-151 reduced the right and left ventricular fractional shortening and decreased the velocity–time integral in the aorta and the pulmonary artery. Both functional reductions are suggestive of impaired heart function under I-BET-151 exposure. Although a 3-week washout period allowed a partial restoration of mitochondrial structure in the RV and an improvement of left ventricle function, full normalization of both mitochondrial morphology and ventricular function was not observed in either the RV nor the left ventricle. The ultrastructural alterations of heart mitochondria we observed in healthy mice and rat exposed to I-BET-151 may be partly a result of c-Myc inhibition (5, 6).

Several BET inhibitors are currently being evaluated in phase 1 clinical trials, and promising results have been obtained in several lymphomas, as well as some solid tumors. One of these trials was conducted to evaluate for the first time the toxicity and efficacy of BET inhibitor BAY1238097 in humans (2). Although this study showed that the drug did inhibit its target, several patients reported unexpected pain (headache and back pain) occurring shortly after taking the drug. These toxicities were not observed in the preclinical tests and differed from the reported toxicities with the other BET inhibitors, suggesting they were related to an off-target effect. Further study of the clinical and preclinical data revealed that BAY1238097 also binds the adenosine receptor, potentially increasing the concentration of mediators involved in the pain. The occurrence of these pains at doses lower than doses that would have been effective in clinics led to the cessation of the development of this drug. However, this negative test has been reported because it could inform the development of other BET inhibitors.

In conclusion, BET inhibitors hold promising potential as a new therapy for left and right heart failure and PAH. However, the BET family of proteins regulates a vast network of transcriptional pathways, raising concerns regarding their safety. Attention must be paid about possible off-target effects of BET inhibitors, as well as potential cardiotoxicity of this new therapeutic class.