Beyond the Lungs: Systemic Manifestations of Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a disease characterized by progressive loss and remodeling of the pulmonary arteries, resulting in right heart failure and death. Until recently, PAH was seen as a disease restricted to the pulmonary circulation. However, there is growing evidence that patients with PAH also exhibit systemic vascular dysfunction, as evidenced by impaired brachial artery flow-mediated dilation, abnormal cerebral blood flow, skeletal myopathy, and intrinsic kidney disease. Although some of these anomalies are partially due to right ventricular insufficiency, recent data support a mechanistic link to the genetic and molecular events behind PAH pathogenesis. This review serves as an introduction to the major systemic findings in PAH and the evidence that supports a common mechanistic link with PAH pathophysiology. In addition, it discusses recent studies describing morphological changes in systemic vessels and the possible role of bronchopulmonary anastomoses in the development of plexogenic arteriopathy. On the basis of available evidence, we propose a paradigm in which metabolic abnormalities, genetic injury, and systemic vascular dysfunction contribute to systemic manifestations in PAH. This concept not only opens exciting research possibilities but also encourages clinicians to consider extrapulmonary manifestations in their management of patients with PAH.

Keywords: cerebrovascular disease; coronary artery disease; kidney disease; pulmonary hypertension; respiratory muscle dysfunction.

Figure 1.

(A) Slit-lamp photographs show bilaterally dilated port wine–stained episcleral vessels in a 25-year-old patient with heritable pulmonary arterial hypertension (PAH) associated with BMPR2 mutation. The mother, who also had heritable PAH, had the same finding. (B) Nailfold capillaroscopy of patients with scleroderma (Scl). The picture on the left demonstrates nailfold vessels in a patient with Scl without PAH compared with a patient with Scl-PAH (right). Arrows point toward abnormal (left) and normal (right) nailfold capillaries. (C) Sublingual vessels in a healthy subject (left) and a patient with PAH (right).

Figure 2.

Features of skeletal and respiratory muscle dysfunction in pulmonary arterial hypertension. Illustration by Patricia Ferrer Beals.

Figure 3.

Plexiform lesion in the lungs of a patient with heritable pulmonary arterial hypertension (positive for BMPR2 mutation). The overview depicts a pulmonary artery of subsegmental level (left) with its adjacent airway (right); the magnification of the selected area (black square) shows a plexiform lesion that appears to connect to a bronchial artery within the wall of the bronchiole. Scale bar, 1,000 μm.

Figure 4.

Proposed model for mechanisms of pulmonary and systemic vascular manifestations in pulmonary arterial hypertension. Illustration by Patricia Ferrer Beals. CBF = cerebral blood flow; FFA = free fatty acids; FMD = flow-mediated vasodilation; RV = right ventricle.