Association of Matricellular Biomarker CCN1 prior to Balloon Pulmonary Angioplasty with functional and hemodynamic parameters in Chronic Thromboembolic Pulmonary Hypertension

Background: Cellular communication network factor 1 (CCN1) is an independent predictor of major adverse cardiovascular events (MACE) after acute coronary syndrome, and elevated levels correlate with infarct size after ST-elevated myocardial infarction myocardial infarction (STEMI). Baseline levels of CCN1 after STEMI were associated with LVEDV and infarct size determined by cardiac MRI twelve months later.

Aims: We hypothesize an association between CCN1, N-terminal fragment of pro-brain natriuretic protein (NTproBNP), and high-sensitivity troponin T (hsTNT) levels at baseline in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and their functional and hemodynamic parameters six months after balloon pulmonary angioplasty (BPA).

Methods: A single-center database of patients with inoperable CTEPH treated by BPA was evaluated for available serum levels of CCN1, hsTNT, and NTproBNP at baseline and six-month follow-up. Right heart catheterization was used to determine hemodynamic parameters at baseline and follow-up:  pulmonary (arterial) wedge pressure (PCWP), pulmonal artery pressure (PAP), tricuspid annular plane systolic excursion (TAPSE), oxygen uptake (VO2), transpulmonary gradient (TPG), pulmonary artery pulsatility index (PAPi), pulmonary artery compliance (PAC), heart time volume (HTV), pulmonary vascular resistance (PVR), ejection fraction (EF), and cardiac index (CI). Clinical measurements of  systolic blood pressure (RRsys), diastolic blood pressure (RRdiast), heart frequency, and six-minute walking distance (6MWD) were included. Using body plethysmography total lung capacity (TLC), residual volume (RV), diffusion capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), and vital capacity (VC) were determined. To evaluate the association between baseline levels of biomarkers in serum and the described parameters we created a correlation matrix using Spearman correlation. Significant correlation in the correlation matrix was further examined using linear regression analysis to determine the Pearson coefficient. A p value of < 0.05 was defined as significant.

Results: We identified 76 CTEPH patients who received BPA and completed six months follow-up between 02.2015 and 09.2020. The mean age for all patients was 61 ± 13.7 (SD) years. Sex distribution was nearly even with 39 males and 37 females. At baseline 11 patients were in WHO functional class (FC) 4, 63 patients in FC 3, 2 patients in FC 2. A similar pattern of significant associations between baseline biomarker levels of CCN1, hsTNT, and NTproBNP with functional and hemodynamic parameters six months after BPA was found in the correlation matrix: PAC (CCN1 ϱ=-0.27; hsTNT ϱ=-0.43; NTproBNP ϱ= -0.65), PAP (CCN1 ϱ=0.28; hsTNT ϱ=0.28; NTproBNP ϱ=0.55), PVR (CCN1 ϱ=0.24; hsTNT ϱ=0.35; NTproBNP ϱ=0.59), TPG (CCN1 ϱ=0.24; hsTNT ϱ=0.28; NTproBNP ϱ=0.58). CCN1 was not associated with 6MWD (CCN1 n.s.; hsTNT ϱ = -0.37; NTproBNP ϱ=-0.26). Using linear regression analysis, a similar pattern was found; however, CCN1 was significantly associated with 6MWD (R=-0.27), albeit only weakly.

Conclusion: In CTEPH patients, we found a homogeneous pattern of associations for CCN1, NTproBNP and hsTnT with hemodynamic parameters (PAC, PAP, PVR, TPG). The strongest association was found for baseline NTproBNP with hemodynamic and functional follow-up parameters.