More Insights into the Association between RVX-208 and Pulmonary Arterial Hypertension.

To the Editor:

We read with great interest the recent publication by Van der Feen and colleagues (1) highlighting that RVX-208 could normalize the hyperproliferative, apoptosis-resistant, and proinflammatory phenotype of microvascular endothelial cells and smooth muscle cells isolated from patients with pulmonary arterial hypertension (PAH). A previous study demonstrated that low-plasma high-density lipoprotein cholesterol (HDL-C) was associated with higher mortality and clinical worsening outcomes, including hospitalization and lung transplantation in the patients with PAH (2). Administration of RVX-208 in the patients with coronary artery disease for 12 weeks was significantly associated with modulation of lipids metabolism, including increases in HDL-C level and concentration of large HDL particles (3). Hence, we considered whether, first, the change of HDL-C would be one feasible clinical biomarker to reflect the responsiveness of drugs or prognostic value in the patients with PAH. For example, the enhancement of HDL-C in plasma through RVX-208 treatment would improve the clinical outcomes in patients with PAH, and second, based on the beneficial effects of RVX-208 on the amelioration of vascular remodeling, pulmonary hemodynamics, and right ventricle in different preclinical models of PAH (1), the casual link among these observed outcomes, efficacy of RVX-208 therapy, and the change of HDL-C level or HDL components could be worthy of further investigation. Metabolic disorders characterized by increases of proinflammatory cytokine IL-6 level in lung and circulating leptin could exacerbate pulmonary hypertension as a result of left heart disease (PH-LHD), and patients diagnosed with this type of PAH have more severe symptoms and worse prognosis relative to patients with LHD alone (4). Notably, in light of pulmonary vascular remodeling in such a novel preclinical model of PH-LHD relieved by metformin though improvement of metabolic states and decrease of inflammation, and positive effects of RVX-208 on the regulation of both inflammation and metabolism (3, 4), we thought that providing more insights about the efficacy of RVX-208 in PH-LHD might be more favorable to its clinical use. Epigenetic regulation plays a key role in the pathogenesis of PAH, such as drug/toxin susceptibility, female predominance, and quasimalignant lung vessel cell growth (5). In view of BET protein BRD4 (bromodomain-containing protein 4) as an epigenetic driver of inflammation and atherogenesis, the reduction of vascular inflammation in vitro and major adverse cardiac events in the patients with cardiovascular disease by the administration of RVX-208 has been considered to rely on a BET-dependent epigenetic mechanism (6). Therefore, we considered that clarifying additional epigenetic mechanisms underlying the therapeutic process of RVX-208 in PAH might be in favor of identifying putative biomarkers and risk or resilience factors for making new-type prevention and treatment to answer epigenetic-sensitive clinical challenges in PAH.