Abstract
Background: The Cellular Communication Network (CCN) protein family has been implicated in various lung diseases and in states of pulmonary vascular remodeling. CCN2 has been shown to be involved in right ventricle maladaptation in pulmonary arterial hypertension (PAH) in a large-scale observational study. No other studies have evaluated all CCN proteins for relevance in PAH.
Research Question: This study assessed all CCN family protein levels in adults with PAH compared to controls and investigated associations of protein levels with markers of clinical severity, hemodynamics and outcomes in PAH.
Methods: Serum levels of CCN1, CCN2, CCN3 and CCN6 were measured in a pilot study (N= 36) and then followed up in a separate, larger validation cohort (N=225) in patients with WHO Group 1 PAH. Pilot samples were obtained from a Johns Hopkins institutional biorepository and the validation cohort samples were obtained from NHLBI PAH Biobank (PAHB). Control samples were from healthy adults (N=40). Statistical analyses compared CCN levels in PAH and controls, and evaluated associations of CCN levels with hemodynamic measurements, six-minute walk distance (6-MWD), and other PAH biomarker levels. Analysis of composite outcome (death or lung transplant) was conducted using Cox proportional hazard model. For the pilot cohort, a p-value of <0.15 was used to denote a significant signal in variables warranting follow up. A p-value of <0.05 was used to denote significance in the validation cohort.
Results: In both cohorts, levels of all four CCN proteins were significantly different than controls (Figure 1). In the pilot cohort, CCN1 and CCN2 levels were associated with worse NYHA FC, while only CCN1 was inversely associated with 6MWD. CCN1 and CCN6 levels were associated with worse composite outcome and NT-proBNP levels, and CCN6 levels were associated with lower cardiac output, and higher pulmonary vascular resistance. In the validation cohort, CCN1 and CCN3 levels correlated with a worse 6MWD. CCN3 was also associated with worse NYHA FC (p=0.02, Figure 2), worse composite outcome (p=0.03), higher NT-proBNP, and ST2 levels.
Conclusions: Within the CCN protein family, CCN1 and CCN3 show the most potential in the role of prognostication and association with clinical severity by NYHA FC and 6MWD in PAH. Further research should investigate the pathobiological cellular mechanisms of the CCN protein family in PAH development.