The Biological Bases of Group 2 Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a potentially fatal condition with a prevalence of around 1% in the world population and most commonly caused by left heart disease (PH-LHD). Usually, in PH-LHD, the increase of pulmonary pressure is only conditioned by the retrograde transmission of the left atrial pressure. However, in some cases, the long-term retrograde pressure overload may trigger complex and irreversible biomechanical and biological changes in the pulmonary vasculature. This latter clinical entity, designated as combined pre- and post-capillary PH, is associated with very poor outcomes. The underlying mechanisms of this progression are poorly understood, and most of the current knowledge comes from the field of Group 1-PAH. Treatment is also an unsolved issue in patients with PH-LHD. Targeting the molecular pathways that regulate pulmonary hemodynamics and vascular remodeling has provided excellent results in other forms of PH but has a neutral or detrimental result in patients with PH-LHD. Therefore, a deep and comprehensive biological characterization of PH-LHD is essential to improve the diagnostic and prognostic evaluation of patients and, eventually, identify new therapeutic targets. Ongoing research is aimed at identify candidate genes, variants, non-coding RNAs, and other biomarkers with potential diagnostic and therapeutic implications. In this review, we discuss the state-of-the-art cellular, molecular, genetic, and epigenetic mechanisms potentially involved in PH-LHD. Signaling and effective pathways are particularly emphasized, as well as the current knowledge on -omic biomarkers. Our final aim is to provide readers with the biological foundations on which to ground both clinical and pre-clinical research in the field of PH-LHD.

Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

“…Therefore, research in group 2 PH mostly focuses on left ventricular dysfunction and not so much the lung vasculature. However, features of EC dysfunction are also observed in PH-LHD [ 139 ]. An experimental model of chronic HF showed reduced NO activity and responsiveness to NO in pulmonary arteries [ 140 ].…”

“…Furthermore, polymorphisms that are found in eNOS also contribute to PH development in patients with LHD [ 143 ]. Despite the presence of similar perturbations in vasoactivity between PAH and PH-LHD, treating PH-LHD patients with drugs used to treat PAH patients was not beneficial and even harmful [ 139 , 144 ].…”

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

“…Collectively, the available evidence suggests that VEGF-D could be a potential biomarker for distinguishing PH-HFrEF from other etiologies of PH, but this needs to be further evaluated in large multi-center studies. (22,78,79); however, only a few miRNAs have been studied in PH-LHD. Among them, circulating levels of muscle-specific miR-204 were reported to be uniquely elevated across the pulmonary vasculature in patients with PAH, but not in patients with PH-LHD (80).…”

“…Increased LA pressure can then back up into the pulmonary circulation, leading to increased pulmonary venous pressure, which is in turn transferred to pulmonary capillaries, causing damage to the alveolar-capillary barrier (also known as alveolar-capillary stress failure). As the disease progresses, structural and functional changes regulated by chronic elevation in capillary pressure may trigger pulmonary vasoconstriction, reduce nitric oxide (NO) bioavailability, increase endothelin-1 (ET-1) production, and promote remodeling in the pulmonary arteries and veins, with various combinations of intimal proliferation, medial hypertrophy, and adventitial thickening (13,17,(19)(20)(21)(22). These pulmonary vascular abnormalities may then lead to a further increase in mPAP in addition to PAWP elevation, resulting in elevated right ventricular (RV) afterload and ultimately causing right-side heart failure.…”

Cancer and pulmonary hypertension: Learning lessons and real-life interplay

“…A very good example of impaired or suppressed immune system in promoting pulmonary vascular remodeling is human immunodeficiency virus infection, which is associated with increased prevalence of PAH 52 . In addition to class 1 PH (PAH), the importance of inflammation and immunity has been shown in classes 2 (PH due to left heart diseases) 53 , 3 (PH due to hypoxia and lung diseases) 54 , and 4 (CTEPH) 55 PH patients.…”