Systemic endothelial dysfunction in children with idiopathic pulmonary arterial hypertension correlates with disease severity

Abstract

Background Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disease manifested by progressive pulmonary vascular remodeling, compromised pulmonary blood flow and right heart failure. Most studies explore how pulmonary endothelial function modulates disease pathogenesis. We hypothesize that IPAH is a progressive panvasculopathy, affecting both pulmonary and systemic vascular beds, and that systemic endothelial dysfunction correlates with disease severity. Recent studies demonstrate systemic endothelial dysfunction in adults with pulmonary hypertension, however adults often have additional comorbidities affecting endothelial function. Systemic endothelial function has not been explored in children with IPAH. Methods This single-center, prospective, cross-sectional study examined brachial artery flow mediated dilation (FMD), a nitric oxide mediated, endothelial-dependent response, in children with IPAH and matched controls. FMD measurements were compared with clinical and echocardiographic measures of IPAH severity. Results Thirteen patients and 13 controls were studied, ages 6–20 years old. FMD was decreased in IPAH subjects compared with controls (5.1 +/− 2.1% vs 9.7 +/− 2.0%; p<0.0001). In IPAH subjects, FMD correlated directly with cardiac index (R2=0.34, p=0.035), and inversely with tricuspid regurgitation velocity (R2=0.57, p=0.019) and right ventricular myocardial performance index (R2= 0.44, p=0.028). Conclusions The presence of systemic endothelial dysfunction in children with IPAH and its strong association with IPAH severity demonstrate that IPAH is a global vasculopathy. Although morbidity in IPAH is typically associated with pulmonary vascular disease, systemic vascular changes may also relate to disease pathogenesis and progression. Further study into shared mechanisms of systemic and pulmonary endothelial dysfunction may contribute to future therapies for IPAH.

Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension

“…A reflection of endothelial function, brachial artery FMD is associated with cardiac index and RV performance in children with idiopathic PAH (13) and with pulmonary vasoreactivity in adults with idiopathic PAH (49). Brachial artery FMD is also associated with increased mortality in patients with congestive heart failure (50).…”

“…Higher levels of BNP and NT-pro-BNP, indicators of ventricular stretch, are associated with an increased risk of death in patients with PAH (11,12). Brachial artery flowmediated dilation (FMD) is a measure of nitric oxide (NO)-dependent vasodilation in response to shear stress from transient flow restriction and is associated with disease severity in children with idiopathic PAH (13).…”

Treprostinil Iontophoresis in Idiopathic Pulmonary Arterial Hypertension

“…Initial studies characterized idiopathic PAH (IPAH) as a disease of the pulmonary circulation; however, recent data from us (2,3) and other investigators (4)(5)(6) showed evidence of extrapulmonary vascular involvement.…”

Association of Systemic Arterial Properties With Right Ventricular Morphology: The Multi‐Ethnic Study of Atherosclerosis (MESA)‐Right Ventricle Study

“…Second, the systemic vascular endothelial layer is exposed to altered hemodynamic forces in the setting of increased stiffness, leading to endothelial dysfunction and release of a cascade of inflammatory markers 7, 8, 9. Third, systemic vascular function could serve as an indicator of pulmonary vascular health 10, 11, 12, 13…”