Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the underlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation.

Therapeutic options for pulmonary arterial hypertension (PAH) have increased over the last decades. The advent of pharmacological therapies targeting the prostacyclin, endothelin, and NO pathways has significantly improved outcomes. However, for the vast majority of patients, PAH remains a life-limiting illness with no prospect of cure.PAH is characterised by pulmonary vascular remodelling. Current research focusses on targeting the underlying pathways of aberrant proliferation, migration, and apoptosis. Despite success in preclinical models, using a plethora of novel approaches targeting cellular GPCRs, ion channels, metabolism, epigenetics, growth factor receptors, transcription factors, and inflammation, successful transfer to human disease with positive outcomes in clinical trials is limited. This review provides an overview of novel targets addressed by clinical trials and gives an outlook on novel preclinical perspectives in PAH.Abbreviations: 6MWD, 6-min walk distance; ALK1, activin receptor-like kinase 1; ANP, atrial natriuretic peptide; ASK1, apoptosis signal-regulating kinase 1, MAP3K5; Bcl-2, B-cell lymphoma 2; BMP, bone morphogenetic protein; BMPR2, bone morphogenetic protein receptor 2; BNP, brain natriuretic peptide; BRD4, bromodomain-containing protein 4; CO, cardiac output; CTD-PAH, connective tissue disease-associated pulmonary arterial hypertension; CTEPH, chronic thromboembolic pulmonary hypertension; DCA, dichloroacetate; DHEA, dehydroepiandrosterone; DMT, DNA methyltransferase; E2, oestradiol; ERAs, endothelin receptor antagonists; FDA, U.S. Food and Drug Administration; FHIT, fragile histidine triad; FKBP12, FK506-binding protein; FOX, forkhead box protein; HDACs, histone deacetylases; HIF, hypoxia-inducible factor; HMGB1, high mobility group box-1; IPAH, idiopathic pulmonary arterial hypertension; KCNK3, potassium channel subfamily K member 3 gene; mPAP, mean pulmonary arterial pressure; mTOR, mechanistic target of rapamycin; NAD+, nicotinamide adenine dinucleotide; NFAT, nuclear factor of activated T-cells; Nrf2, nuclear factor erythroid 2-related factor 2; p21, cyclin-dependent kinase inhibitor 1; p27, cyclin-dependent kinase inhibitor 1B; PA, pulmonary artery; PAEC, pulmonary arterial endothelial cells; PAH, pulmonary arterial hypertension; PASMCs, pulmonary arterial smooth muscle cells; PAWP, pulmonary arterial wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RCT, randomised controlled trial; ROCK, Rho-associated protein kinase; RTK, receptor TK; RUNX2, runt-related transcription factor 2; RV, right ventricle; SIRT, Sirtuin; SMURF-1, Smad ubiquitin regulatory factor 1; STAT, signal transducer and activator of transcription; TGFβR, TGFβ receptor; TPH1, tryptophan hydroxylase 1; UCP2, uncoupling protein 2; VCAM1, vascular cell adhesion molecule 1; VE/VCO2, minute ventilation/carbon dioxide production; VIP, vasoactive intestinal peptide; VO2max, maximal oxygen uptake.

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These findings indicate that despite worsening of lung function by approximately 30% after pneumonectomy, most patients can adjust to living with only 1 lung. Pulmonary hypertension is uncommon and in most cases only mild to moderate.