Plasma CTGF is independently related to an increased risk of cardiovascular events and mortality in patients with atherosclerotic disease: the SMART study

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.

• CTGF
• cardiovascular disease
• atherosclerosis
• myocardial infarction
• mortality

Acknowledgments

We gratefully acknowledge the contribution of the SMART research nurses, R. van Petersen (data-manager), A. G. Pijl (vascular manager), Danny Kanhai (research physician) and the participants of the SMART Study Group (A. Algra, Julius Center for Health Sciences and Primary Care and Rudolph Magnus Institute of Neuroscience, Department of Neurology; Y. van der Graaf, G.E.H.M. Rutten, D.E. Grobbee, Julius Center for Health Sciences and Primary Care; F.L.J. Visseren, Department of Vascular Medicine; P.A. Doevendans, Department of Cardiology; F.L. Moll, Department of Vascular Surgery; L.J. Kappelle, Department of Neurology; W.P.Th.M. Mali, Department of Radiology).

Declaration of interest

This work was supported the University Medical Center Utrecht, Utrecht, The Netherlands. LLF was funded by the Netherlands Institute of Regenerative Medicine (NIRM, FES0908).

Supplementary material available online

Supplementary Figures 1 and 2