Pathobiology of pulmonary arterial hypertension and right ventricular failure

Abstract

Pulmonary arterial hypertension (PAH) is no longer an orphan disease. There are three different classes of drugs for the treatment of PAH that are currently being used and an increasing number of patients are being treated with a single drug or combination therapy. During the last 25 yrs, new insights into the pathobiology of PAH have been gained. The classical mechanical concepts of pressure, flow, shear stress, right ventricle wall stress and impedance have been complemented with the new concepts of cell injury and repair and interactions of complex multicellular systems. Integrating these concepts will become critical as we design new medical therapies in order to change the prognosis of patients with these fatal diseases. This review intends to summarise recent pathobiological concepts of PAH and right ventricle failure mainly derived from human studies, which reflect the progress made in the understanding of this complex group of pulmonary vascular diseases.

FIGURE 1

Hallmarks of severe angioproliferative pulmonary arterial hypertension. Genetic determinants, epigenetic factors and other conditions synergise and result in the injury and apoptosis of pulmonary arteriolar endothelial cells. Endothelial cell apoptosis triggers compensatory proliferation of phenotypically abnormal endothelial cells. Apoptosis may also be the initiating event, activating the bone marrow to release precursor and stem cells and eliciting a local immune response of the vascular wall. The end result is the complex vascular lesion, the plexiform lesion. These complex lesions obliterate the lumen of small arteries, predominantly localised to vessel bifurcations. The mature lesions are composed of endothelial cells (dark purple), smooth muscle cells (yellow), apoptotic cells (purple) and phenotypically altered apoptosis-resistant endothelial cells (red). These cells, together inflammatory cells, populate a microenvironment of exuberant cell growth. BMPR2: bone morphogenic type II receptor; ALK-1: activin A receptor type-II like-1; HSC: hematopoietic stem cell; EPC: endothelial progenitor cell.

FIGURE 2

Participation of the immune system in pulmonary vascular remodelling. The initial arteriolar endothelial cell injury can be due to mechanical stress, toxins or antibodies. The “two-hit” hypothesis considers that defective immune regulation, such as in HIV/AIDS and scleroderma, participates in the lumen-obliterating cell growth [1] and in the impaired injury resolution [2]. The disease model depicted here reflects the complexity of multicellular interactions within and around the vascular wall and the active role of the bone marrow and inflammatory and immune cells in the pathobiology of pulmonary arterial hypertension. The multi-growth factor-producing mast cell was the first of several immune cells to be identified in the perivascular space of pulmonary arterioles in lungs from patients with severe pulmonary hypertension. It may populate these vessels because of hyperplasia (in situ expansion of mast cell number) or after being recruited from the bone marrow. An impaired activity of regulatory T-cells may facilitate the angio-obliteration. HSC: hematopoietic stem cell.

FIGURE 3

The sick lung circulation–right heart failure axis. Increased pulmonary vascular resistance generates a significant afterload for the right ventricle resulting in right ventricular hypertrophy. The structural and functional changes during the development of right ventricular failure can be characterised clinically [2]. Right ventricular dysfunction is probably associated with multiple cellular changes [3], such as oxidative stress, apoptosis, inflammation, fibrosis and metabolic remodelling. These factors also contribute to right ventricle (RV) dysfunction and failure. The cellular changes are either the result of chronic RV pressure overload or the effect of circulating factors released from the sick lung circulation. RVF: right ventricle failure; LV: left ventricle.

FIGURE 4

Integration of haemodynamic and cellular events that characterise the cardiopulmonary disease of severe pulmonary arterial hypertension (PAH). The pathophysiology of PAH, which operates via mechanical concepts, is complemented with concepts of cell injury and repair and interactions of complex multicellular systems. The model is built on the principle of abnormal pulmonary blood flow. Regional blood flow abnormalities underlie the pulmonary vascular remodelling, which in turn causes further alterations of the regional blood flow, perpetuating a cycle of cell death and cell proliferation. Vascular rarefaction occurs in the form of pruning of the small lung vessels, and in the right ventricle in the form of myocardial capillary rarefaction.