Current Understanding of Circulating Biomarkers in Pulmonary Hypertension Due to Left Heart Disease

Abstract

Pulmonary hypertension due to left heart disease (PH-LHD; Group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most frequent cause of PH. Despite its prevalence, no effective therapies for PH-LHD are available at present. This is largely due to the lack of a concise definition for hemodynamic phenotyping, existence of significant gaps in the understanding of the underlying pathology and the impact of associated comorbidities, as well as the absence of specific biomarkers that can aid in the early diagnosis and management of this challenging syndrome. Currently, B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are guideline-recommended biomarkers for the diagnosis and prognosis of heart failure (HF) and PH. Endothelin-1 (ET-1), vascular endothelial growth factor-D (VEGF-D), and microRNA-206 have also been recently identified as new potential circulating biomarkers for patients with PH-LHD. In this review, we aim to present the current state of knowledge of circulating biomarkers that can be used to guide future research toward diagnosis, refine specific patient phenotype, and develop therapeutic approaches for PH-LHD, with a particular focus on PH-HFpEF. Potential circulating biomarkers identified in pre-clinical models of PH-LHD are also summarized here.

Keywords: HFpEF - heart failure with preserved ejection fraction; PH-HFpEF; biomarkers; group 2 PH; pulmonary hypertension.

Figure 1

Updated hemodynamic definition and clinical classification of pulmonary hypertension (based on the 6th World Symposium on PH, Nice 2018). mPAP, mean pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; TPG, transpulmonary gradient (defined as mPAP–PAWP); PVR, pulmonary vascular resistance (defined as TPG/cardiac output); DPG, diastolic pressure gradient (defined as diastolic PAP–PAWP).

Figure 2

Production and release of endothelin-1 (ET-1) and ET receptors-mediated actions in vascular smooth muscle cells and endothelial cells. ET-1 is derived from prepro-ET-1, which is first proteolytically cleaved to yield a 39-amino acid intermediate Big ET-1, followed by a subsequent production of the 21-amino acid vasoactive peptide by endothelin converting enzymes (ECEs). ET-1 can active endothelin receptors type A (ET_A) and type B (ET_B). ET_A is located predominantly in vascular smooth muscle cells, while ET_B resides in vascular smooth muscle cells and endothelial cells. Activation of ET_A or ET_B in vascular smooth muscle cells results in vasoconstriction and proliferation. Activation of ET_B induces transient vasodilation in endothelial cells by releasing nitric oxide (NO) and prostacyclin (PGI₂).

Figure 3

Occurrence locations of potential circulating biomarkers in PH-LHD. BNP, brain/B-type natriuretic peptide; NT-proBNP, N-terminal proBNP; miR-206, microRNA-206; sST2, soluble suppression of tumorigenicity 2; H-FABP, heart type fatty acid binding protein; GDF-15, growth differentiation factor 15; suPAR, soluble urokinase plasminogen activator receptor; MIF, macrophage migration inhibitory factor; CRP, C-reactive protein; ET-1, endothelin-1; CT-proET-1, C-terminal pro-ET-1; VEGF-D, vascular endothelial growth factor-D.