Thinking Outside the Lungs: Extrapulmonary Manifestations in PAH

It is well known that a range of comorbidities affect patients with pulmonary arterial hypertension (PAH), including thyroid dysfunction, diabetes, depression, and renal insufficiency. Emerging evidence suggests that these conditions may arise from some of the same mechanisms that drive the development of PAH, reflecting systemic effects of the disease beyond the lungs.

“In fact, there is evidence of vascular dysfunction in multiple extrapulmonary organs which has led us to reconsider the concept of PAH as a disease exclusive to the lungs and the right heart,” according to a recent review by Nils P Nickel, MD, postdoctoral medical fellow in the division of pulmonary and critical care medicine at Stanford University Medical Center, and colleagues.¹ “While 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.”

The authors reviewed study results that point to systemic manifestations in PAH.

Vascular Dysfunction in Systemic Circulation in PAH

Cerebral circulation. Reduced cerebral blood flow at rest and with exercise has been observed in PAH. Studies have shown reduced cerebrovascular reactivity to blood partial pressure of carbon dioxide in patients with PAH, as well as “increased central chemoreceptor sensitivity, which further blunts cerebral blood flow increase to exercise,” wrote Nickel et al.^1,2 Such findings indicate that “intrinsic vascular dysfunction in the cerebral circulation might contribute to cognitive impairment and could contribute to the perception of dyspnea and sleep-disordered breathing” in PAH.¹

Peripheral circulation. Several studies have demonstrated endothelial dysfunction in the brachial artery in PAH using flow-mediated dilation. In a study involving 10 patients with idiopathic PAH and 10 of their relatives as well as 10 patients with scleroderma-PAH, significant reductions in brachial artery dilation were noted in 2.7% of the patients with idiopathic PAH (with unknown BMPR2 mutation status) and in 6.3% of the patients with scleroderma-PAH.³ “Interestingly, there was a trend toward a reduced response in family members of the [people with] idiopathic PAH, suggesting a possible genetic contribution,” as stated in the paper.¹

Renal circulation. High rates of chronic kidney disease (4%-46%) have been found among patients with PAH and vice versa (high rates of PAH in chronic kidney disease; 16%), reflecting the reciprocal nature of the cardiopulmonary-renal interaction.¹ Studies have reported significant albumin secretion in 15% to 23% of patients with PAH without known kidney disease and traditional risk factors for cardiovascular disease, and among unaffected BMPR2 mutation carriers compared with healthy controls.¹