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

doi:10.1016/j.healun.2012.02.020

The Journal of Heart and Lung Transplantation

Volume 31, Issue 6, June 2012, Pages 642-647

https://doi.org/10.1016/j.healun.2012.02.020 Get rights and content

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 have explored 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 have demonstrated 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

In this single-center, prospective, cross-sectional study we 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, ranging in age from 6 to 20 years. 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.

Section snippets

Subject recruitment

All patients followed at our institution for a diagnosis of IPAH were considered for inclusion in this prospective, cross-sectional study. All charts were reviewed to obtain patients' history, including prior catheterization data, and to confirm eligibility for inclusion. Patients <5 years of age were excluded based on their inability to cooperate with the study protocol. Additional exclusion criteria included a history of any of the following: intrinsic airway or pulmonary parenchymal disease,

Results

Thirteen IPAH patients and 13 control subjects were included in the analysis. Data collection, including echocardiography and assessment of brachial artery FMD, was complete for all subjects. In addition, all IPAH patients completed a 6-minute walk test. There were no significant differences in the demographics or baseline blood pressures between the two groups (Table 1). Mean heart rate was higher in the group with IPAH (p = 0.014), likely reflecting a compensatory response to maintain

Discussion

In this study we have demonstrated that systemic endothelial function is impaired in pediatric patients with IPAH. This is the first study evaluating the systemic vasculature in children with this disease, and our findings validate and uniquely broaden the findings of previous studies. Several groups recently showed evidence of systemic endothelial dysfunction in adults with various types of pulmonary hypertension.19, 20, 21, 22 However, there are several clinical and histopathologic

Disclosure statement

The authors have no conflicts of interest to disclose.

This work was supported by grants from the Paige Foundation and the National Heart Lung and Blood Institute (5RC1HL099412-01) of the National Institutes of Health.

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Recent studies have also shown that both systemic and pulmonary vascular endothelium dysfunction might exist in PAH patients (Peled et al., 2009, 2008). This is manifested by excessive pulmonary vascular cell proliferation, smooth muscle cell apoptosis inhibition, endogenous vasoconstrictors and vasodilators imbalance, and a decrease in nitric oxide (NO) bioavailability (Friedman et al., 2012). Although the initial injury in PAH involves the pulmonary vasculature, systemic endothelial dysfunction has also been observed (Gabrielli et al., 2011; Peled et al., 2009).
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Original clinical scienceSystemic endothelial dysfunction in children with idiopathic pulmonary arterial hypertension correlates with disease severity

Background

Methods

Results

Conclusions

Section snippets

Subject recruitment

Results

Discussion

Disclosure statement

J Am Coll Cardiol

Chest

Am J Cardiol

J Am Coll Cardiol

Chest

Am Heart J

Respir Med

J Card Fail

Chest

Diabetes Res Clin Pract

Am J Cardiol

Circulation

Etiology, diagnosis, and pharmacologic treatment of pediatric pulmonary hypertension

Paediatr Drugs

Ventricular arrhythmias and autonomic profile in patients with primary pulmonary hypertension

Lung

Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension

Eur Heart J

Survival in patients with primary pulmonary hypertensionResults from a national prospective registry

Ann Intern Med

Pulmonary arterial hypertension: a comparison between children and adults

Eur Respir J

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