Abstract
Aims: Connective tissue growth factor (CTGF) plays a key role in tissue fibrogenesis and growing evidence indicates a pathogenic role in cardiovascular disease. Aim of this study is to investigate the association of connective tissue growth factor (CTGF/CCN2) with cardiovascular risk and mortality in patients with manifest vascular disease. Methods and results: Plasma CTGF was measured by ELISA in a prospective cohort study of 1227 patients with manifest vascular disease (mean age 59.0 ± 9.9 years). Linear regression analysis was performed to quantify the association between CTGF and cardiovascular risk factors. Results are expressed as beta (β) regression coefficients with 95% confidence intervals (CI). The relation between CTGF and the occurrence of new cardiovascular events and mortality was assessed with Cox proportional hazard analysis. Adjustments were made for potential confounding factors. Plasma CTGF was positively related to total cholesterol (β 0.040;95%CI 0.013–0.067) and LDL cholesterol (β 0.031;95%CI 0.000–0.062) and inversely to glomerular filtration rate (β −0.004;95%CI −0.005 to −0.002). CTGF was significantly lower in patients with cerebrovascular disease. During a median follow-up of 6.5 years (IQR 5.3–7.4) 131 subjects died, 92 experienced an ischemic cardiac complication and 45 an ischemic stroke. CTGF was associated with an increased risk of new vascular events (HR 1.21;95%CI 1.04–1.42), ischemic cardiac events (HR 1.41;95%CI 1.18–1.67) and all-cause mortality (HR 1.18;95%CI 1.00–1.38) for every 1 nmol/L increase in CTGF. No relation was observed between CTGF and the occurrence of ischemic stroke. Conclusions: In patients with manifest vascular disease, elevated plasma CTGF confers an increased risk of new cardiovascular events and all-cause mortality.
Highlights
Cardiovascular risk is a growing concern and major health burden
Plasma Connective tissue growth factor (CTGF) was inversely related to estimated GFR (eGFR), adjusted for age and gender (b À0.004 using the natural logarithm of CTGF; 95%confidence intervals (CI) À0.005 to À0.002), which implies that for every 1 mL/min/1.73m2 increase in eGFR plasma CTGF decreased with 0.4% (95%CI 0.2 to 0.5) (Table 3)
After the adjustment for age, gender and eGFR, plasma CTGF remained positively associated with total cholesterol (b 0.040; 95% confidence intervals (95%CI) 0.013 to 0.067) and low-density lipoprotein (LDL) cholesterol (b 0.031; 95%CI 0.000 to 0.062)
Summary
Cardiovascular risk is a growing concern and major health burden. Several management strategies exist, but healthcare could benefit from additional interventional strategies.Connective tissue growth factor (CTGF/CCN2) is a key mediator of tissue fibrogenesis in various chronic diseases (Dendooven et al, 2011). CTGF is upregulated by Plasma CTGF is elevated in patients with type 1 diabetes mellitus (DM), chronic kidney disease and chronic heart failure (Cheng et al, 2006; Ito et al, 2011; Koitabashi et al, 2008; Nguyen et al, 2008; Roestenberg et al, 2004; Slagman et al, 2011). Reduction of vascular stiffness in hypertensive patients is associated with a reduction in CTGF expression levels (Gomez-Garre et al, 2006). In patients with both acute and chronic heart failure plasma CTGF is related to brain natriuretic peptide, NYHA class and echocardiographic parameters of diastolic dysfunction (Behnes et al, 2014; Koitabashi et al, 2008). While being minimally expressed in healthy tissue, CTGF is strongly upregulated in atherosclerotic plaques, in cardiac tissue after myocardial infarction, in cardiac fibrosis and in vascular and cardiac tissues in experimental hypertension (Daniels et al, 2009; Koitabashi et al, 2008; Leeuwis et al, 2010; Ponticos, 2013; Rickard et al, 2014)
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