Beyond arterial remodelling: pulmonary venous and cardiac involvement in patients with systemic sclerosis-associated pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) represents a heterogeneous group of disorders characterised by elevated pulmonary vascular resistance and a normal pulmonary artery wedge pressure that occurs in the absence of left heart disease, chronic lung diseases/hypoxia or chronic thromboembolic pulmonary disease 1. Entities within the PAH group share not only similar symptoms and haemodynamic profiles but also a common therapeutic approach 2. Unfortunately, outcome among PAH patients remains poor and a cure for the disease remains elusive 3. One additional, although less well described, feature that favours the distinction of a PAH group is the histomorphological correlate of elevated blood pressures within the pulmonary vasculature. Indeed, PAH that is idiopathic, heritable, or associated with anorexigen exposure, HIV infection, portopulmonary hypertension and connective tissue disease (comprising mostly systemic sclerosis (SSc)-associated PAH (SSc-PAH)) appear to have a similar pulmonary arterial and arteriolar remodelling pattern. Typical PAH lesions consist mainly of widely and uniformly distributed vascular alterations, including intimal fibrosis, and endothelial and smooth muscle cell proliferation, without obvious involvement of the bronchoalveolar architecture. These histological features are markedly different from pulmonary hypertension that arises as a consequence of chronic thromboembolic disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and sarcoidosis, in which vascular occlusion develops as a consequence of emboli, arteriolar rarification, interstitial scarring or obstructing granulomas, respectively. Despite similarities in pathological anatomy, clinical management and outcome among the different forms of PAH, there are, nonetheless, important differences that remain unexplained. In patients with SSc, PAH is a leading cause of mortality that requires intensive medical management. However, therapeutic responses are frequently less favourable compared to other forms of PAH 4–6. SSc-PAH treatment with vasodilators such as continuous intravenous epoprostenol is associated with improvements in exercise capacity and cardiopulmonary haemodynamics. However, therapeutic responses using prostanoid therapy in …