CILP1 as a biomarker for right ventricular maladaptation in pulmonary hypertension

Abstract

The aim of our study was to analyse the protein expression of cartilage intermediate layer protein 1 (CILP1) in a mouse model of right ventricular (RV) pressure overload and to evaluate CILP1 as a biomarker of cardiac remodelling and maladaptive RV function in patients with pulmonary hypertension (PH).Pulmonary artery banding was performed in 14 mice; another 9 mice underwent sham surgery. CILP1 protein expression was analysed in all hearts by western blotting and immunostaining. CILP1 serum concentrations were measured in 161 patients (97 with adaptive and maladaptive RV pressure overload caused by PH; 25 with left ventricular (LV) hypertrophy; 20 with dilative cardiomyopathy (DCM); 19 controls without LV or RV abnormalities)In mice, the amount of RV CILP1 was markedly higher after banding than after sham. Control patients had lower CILP1 serum levels than all other groups (p<0.001). CILP1 concentrations were higher in PH patients with maladaptive RV function than those with adaptive RV function (p<0.001), LV pressure overload (p<0.001), and DCM (p=0.003). CILP1 showed good predictive power for maladaptive RV in ROC analysis (AUC 0.79). There was no significant difference between the AUCs of CILP1 and NT-pro-BNP (AUC 0.82). High CILP1 (≥cut-off value for maladaptive RV of 4373 pg·mL−1) was associated with lower TAPSE/PASP ratios (p<0.001) and higher NT-pro-BNP levels (p<0.001).CILP1 is a novel biomarker of RV and LV pathological remodelling that is associated with RV maladaptation and ventriculoarterial uncoupling in patients with PH.

Prognostic value of cartilage intermediate layer protein 1 in chronic heart failure

“…Keranov et al . 14 reported that serum CILP‐1 levels are significantly higher in patients with HF than in healthy controls, which is in line with our results showing that serum CILP‐1 levels are positively correlated with NT‐proBNP. However, Park et al .…”

“…Transforming growth factor‐β1 plays an important role in the pathogenesis of cardiac remodelling by activating pro‐fibrotic signalling pathways that promote ECM synthesis and myofibroblast transdifferentiation. 18 As an antagonist of TGF‐β1 signalling, cardiac CILP‐1 can be rapidly induced by TGF‐β1, 7 , 10 , 14 thus creating a negative feedback loop. However, opposing observations regarding the circulating CILP‐1 expression have been reported.…”

“…However, a recent study by Keranov et al . 14 found that circulating CILP‐1 levels are significantly increased in patients with HF, especially with maladaptive right ventricular function. To date, no studies have evaluated the potential of CILP‐1 as a prognostic biomarker for HF.…”

“…found that although cardiac CILP‐1 expression was significantly elevated, the level of F‐CILP‐1 in the serum of patients with HF was significantly lower than that in normal subjects. However, a recent study by Keranov et al 14 . found that circulating CILP‐1 levels are significantly increased in patients with HF, especially with maladaptive right ventricular function.…”

Exploring Functional Differences between the Right and Left Ventricles to Better Understand Right Ventricular Dysfunction

“…Furthermore, cartilage intermediate layer protein 1 (CILP1), an extracellular matrix (ECM) protein involved in profibrotic signaling in the myocardium [ 138 ], was recently described as a novel biomarker of RV and LV pathological remodeling in patients with pulmonary hypertension. In one study, maladaptive RV patients had higher CILP1 concentrations than controls and those with LV hypertrophy and dilated cardiac myopathy in [ 139 ]. Previously, expression at the RNA level in heart mouse models was shown to be more pronounced in RV pressure overload than in LV pressure overload [ 140 ].…”