Treatment-related biomarkers in pulmonary hypertension

Abstract

Significant advances in the treatment of pulmonary arterial hypertension (PAH) over the last two decades have led to the introduction of multiple classes of oral therapy, but the disease remains devastating for many patients. Disease progression, in spite of oral monotherapy, is a major problem, and alternative therapy, such as infusion of prostacyclins, is cumbersome and carries considerable potential morbidity. Use of combination oral therapy, including drugs from both the endothelin receptor antagonist and phosphodiesterase-5 inhibitor classes, has increased, and there is some evidence to support this approach. Given the multiple options now available in pulmonary hypertension (PH) therapy, biomarkers to guide treatment decisions could be helpful. Here, we review the evidence for and against the clinical use of molecular biomarkers relevant to PH pathogenesis, emphasizing assayable markers that may also inform more rational selection of agents that influence pathways targeted by treatment. We emphasize the interactive nature of changes in mediators and messengers, such as endothelin-1, prostacyclin, brain natriuretic peptide (which has demonstrated biomarker utility), nitric oxide derivatives, and cyclic guanosine monophosphate, which play important roles in processes central to progression of PAH, such as vascular remodeling, vasoconstriction, and maladaptive right ventricular changes, and are relevant to its therapy. Accordingly, we propose that the identification and use of a molecular biomarker panel that assays these molecules in parallel and serially might, if validated, better inform unique patient phenotypes, prognosis, and the rational selection and titration of combination oral and other therapy in individual patients with PH/PAH.

Keywords: biomarker; endothelin; nitric oxide; right ventricle.

Figure 1.

Vasoregulatory mediators and/or biomarkers relevant to current pulmonary arterial hypertension (PAH) therapy, and their interactions. Endogenous mediators (blue ovals), enzymes or other protein targets (both shown as pink rectangles), mediator-relevant drugs (green [stimulatory] or red [inhibitory]), and PAH-associated derangements are interconnected (also red). Mediators produced by a sensor cell may influence an adjacent or distant effector cell. Classically, this involves signaling by endothelial cells (ECs; “sensor cells”) to influence “effector cells” (e.g., vascular smooth muscle cells [SMCs]), but, in PAH, many cell types are involved. Relevant mediators may act in an autocrine fashion also. The vasoconstrictor and mitogenic peptide, endothelin (ET)-1, acting at ET_A or ET_B receptors, is antagonized by ET-1 receptor antagonists (ERA). ECs also produce nitric oxide (NO) from the precursor amino acid, L-arginine (L-Arg); asymmetric dimethyl arginine (ADMA) and symmetric dimethyl arginine (SDMA) (red) may antagonize this. Levels of ADMA depend, in part, on its catabolism by dimethylarginine dimethylaminohydrolase (DDAH). Antiproliferative and pulmonary vasodilator actions of NO produced by lung ECs can be mediated by the activation of soluble guanylate cyclase (sGC) in, for example, vascular SMCs, or by more durable S-nitroso (SNO) modification (S-nitrosylation) of regulatory thiols (SH) on key proteins. Cyclic guanosine monophosphate (cGMP) formation from GTP is the result when sGC is stimulated by NO. Notably, brain natriuretic peptide (BNP; or atrial natriuretic peptide [ANP]) can also elicit the formation of cGMP from GTP via a membrane-bound GC enzyme (particulate GC), possibly contributing to the (paradoxically) elevated cGMP levels typical of advanced PAH. Other mediator interactions include prostacyclin receptor- and endothelin receptor (ETR)-triggered NO synthesis, and cyclic adenosine monophosphate (cAMP)/cGMP cross-talk via phosphodiesterases (PDEs). For example, PDE3 can catabolize either, while PDE5 is selective for cGMP. Mediators that are also potential or proven biomarkers are in italics. AC, adenylate cyclase; CAT, cationic amino acid transporter; IPR, prostacyclin receptor; NOS, nitric oxide synthase; NP_R, natriuretic peptide receptor; pGC, particulate guanylate cyclase; Pgl2, prostacyclin.