Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH

Autoimmunity is a significant feature of idiopathic pulmonary arterial hypertension.

RATIONALE: Autoimmunity is thought to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear if this is causative or a bystander of disease and if it carries any prognostic or treatment significance. OBJECTIVE: To study autoimmunity in IPAH using a large cross-sectional cohort. METHODS: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry and the profile of serum immunoglobulins was generated using a standardised multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 controls. Additional GST-fusion array and ELISA data were used to identify a serum autoantibody to BMPR2. Clustering analyses and clinical correlations were employed to determine associations between immunogenicity and clinical outcomes. MEASUREMENTS AND MAIN RESULTS: Flow cytometric immune profiling demonstrates IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: 'high autoantibody', 'low autoantibody', and a small 'intermediate' cluster exhibiting high levels of RNP-complex. The high autoantibody cluster had worse haemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. CONCLUSIONS: This study establishes aberrant immune regulation and presence of autoantibodies as a key feature in the profile of a significant proportion of IPAH patients and is associated with clinical outcomes. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/)

Assessment and clinical relevance of right ventricular failure in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a right heart failure syndrome. The dominant symptom of PAH is shortness of breath. However, in spite of widespread pulmonary vascular remodeling and obstruction, gas exchange in PAH is generally well maintained, with moderate hypoxemia mainly caused by a low cardiac output. Patients with PAH are hypocapnic, but this is explained by increased chemosensitivity, and there is no ventilatory limitation to exercise capacity. Thus lung function is normal or near-normal in PAH. The symptomatology of PAH is principally related to right ventricular (RV) failure. Right ventricular function is altered as soon as pulmonary vascular resistance increases. In early stage PAH, the RV tends to remain adapted to afterload, with little or no increase in right heart chamber dimensions, but less than optimal RV-arterial coupling is a cause of decreased aerobic exercise capacity by limiting maximum cardiac output. In more advanced stages, homeometric adaptation of the RV becomes insufficient for daily life activities resulting in a progressive dilatation of right heart chambers and systolic dysfunction. Along with decreased contractile reserve of the RV, diastolic dysfunction occurs, due to RV fibrosis and sarcomeric stiffening; these changes lead to limitation of flow output and increased right sided filling pressures. These in turn lead to a combination of systemic venous congestion and dyspnea occurring at lower levels of exercise and, eventually, at rest. Imaging of RV function is of major diagnostic and prognostic relevance. Treatment of RV failure in PAH relies on decreasing afterload with therapies targeting the pulmonary circulation, optimal fluid management of ventricular diastolic interaction, and inotropic interventions to reverse cardiogenic shock states. The potential of chronic low-dose β-blocker therapies is currently investigated.SCOPUS: ch.binfo:eu-repo/semantics/publishe

Echocardiography of the right heart

Echocardiography allows for accurate measurements of pulmonary vascular resistance and hydraulic load, and thus the estimation of afterload in severe pulmonary hypertension as a cause of right ventricular (RV) failure. The procedure also provides a series of estimates of RV systolic function, such as fractional area change, tricuspid annular plane excursion, tricuspid annulus tissue Doppler imaging of the velocities of isovolumic contraction and ejection, strain and strain rate. These indices help to evaluate the adequacy of RV systolic function adaptation to afterload (Anrep mechanism) but suffer from variable degrees of preload-dependency. Failure of RV-arterial coupling results in Starling's mechanism of preservation of stroke volume through increased myocardial fibre length, or end-diastolic volume. This can be appreciated by echocardiographic measurements of increased right heart chamber dimensions, dilatation and loss of inspiratory collapsibility of the inferior vena cava, and pericardial effusion, along with altered indices of left ventricular diastolic function such as prolonged isovolumic relaxation time, deceleration of E waves, and decreased ratio of E over A waves. Echocardiographic dimension measurements are currently limited to a series of planes, with difficult instantaneous volume reconstruction of the RV, which has an irregular crescent shape and inhomogenous contraction. Echocardiography is limited by operator-dependency, and is sometimes implemented in low clinical probability contexts. This may be a cause of false positive or negative diagnosis of RV failure. Recent advances in echocardiography technology open the perspective of RV volume measurements with assessment of regional function and asynchrony.SCOPUS: ch.binfo:eu-repo/semantics/publishe