Abstract Body (Do not enter title and authors here): Introduction
Cellular Communication Network 2 (CCN2, also known as CTGF and IGFBP8) is a cysteine-rich secreted matrix protein with four tandem modules and is an upstream regulator of TGFß, a key pathogenic molecule in pulmonary arterial hypertension (PAH). Altered right ventricular-pulmonary artery (RV-PA) coupling has been shown to be an early marker of right ventricular (RV) dysfunction associated with adverse outcomes in PAH.

Research Question
We studied the relationship between CCN2 and the diagnosis, disease severity, hemodynamics, and metrics of pathologic RV structure and function in a deeply-phenotyped cohort of patients with suspected and established PAH.

Methods
Adult PAH patients (N=38, median age 62 years, 79% female) and controls (N=8, median age 64.5 years, 100% female) had CCN2 levels measured from samples obtained the same day as simultaneous right heart catheterization, multi-beat pressure volume loop assessment, cardiac MRI and functional outcome assessment. CCN2 levels were log-transformed and adjusted for age and sex using linear and logistic regression to allow for comparison with clinical and hemodynamic variable. Analysis of composite outcome (death or transplant) was conducted using a Cox proportional hazard model and Kaplan Meier analysis.

Results
CCN2 levels were associated with lower RV stroke volume (p<0.05), lower RV end-systolic elastance (RV Ees, p<0.02), and impaired RV-pulmonary arterial coupling (RV Ees/Ea, p<0.05) by Spearman correlation. In linear regression models adjusted for age and sex, log(CCN2) was significantly associated with RV Ees and RV Ees/Ea (p<0.001 and p = 0.04, respectively). CCN2 levels were not significantly correlated with other hemodynamics or functional status (p >0.1 for all). Finally, higher log(CCN2) levels were correlated with lower transplant free survival with Cox Hazard Ratio of 3.99 (p<0.04) in patients with PAH. Kaplan-Meier demonstrates patients with CCN2 level above a Youden cutoff of 43 ng/mL had increased mortality with median survival less than 7.5 years (Figure 1).

Conclusions
CCN2 levels correlate with more impaired RV-PA coupling and worse outcomes for adults with PAH. This patient cohort were diagnosed early in the disease course with mild symptoms. There was an association between CCN2 levels with early markers of RV dysfunction, RV-PA uncoupling, RV stroke volume, and adverse outcomes. This implicates CCN2 as a potential biomarker of early RV dysfunction of PAH.