Introduction:

Cysteine-rich angiogenic inducer 61 (Cyr61, CCN1) is a member of the CCN family of matricellular proteins exerting key functions in inflammation and fibrotic turnover. Recently it has been shown that CCN1 improves risk stratification for all-cause mortality in patients with acute coronary syndromes.

Purpose:

Since both inflammation and fibrosis are key processes involved in the pathogenesis of dilated cardiomyopathy (DCM), we aimed to investigate the prognostic value of CCN1 serum levels for survival in a large cohort of DCM patients.

Methods:

The cohort compromised patients with a primary diagnosis of DCM, defined as a reduced left ventricular ejection fraction (LVEF < 45%) and an increased left ventricular enddiastolic diameter according to the HENRY score (LVEDD according to HENRY > 117%) at the time of diagnosis. Exclusion criteria were primary valvular diseases (≥ second degree), acute myocarditis, active infectious diseases, pulmonary diseases, cancer, chronic alcoholism and heart failure due to other known causes. CCN1 levels were determined in human serum using an enzyme-linked immunosorbent assay (R&D Systems, USA). Multivariable cox regression models for the association between CCN1 and all-cause mortality were adjusted for age, sex, disease duration, LVEF, estimated glomerular filtration rate (eGFR) calculated based on the CKD-EPI formula, high-sensitivity C-reactive protein (hs-CRP) and aminoterminal-proB-type natriuretic peptide (NT-proBNP) levels.

Results:

306 DCM patients had available biomarker and clinico-demographic data in this single-center cohort (79.3 % males) with a mean age of 55.2 years [interquartile range [IQR] 47.9, 64.8]). On average, disease duration was 1.9 years (IQR 0.9, 1.9), LVEF 30.9 % (IQR 25, 37), LVEDD 68.2 mm (IQR 63, 72), and eGFR 87.8 ml/min/1.73 m² (IQR 74.1, 102.4). During a median follow-up of 12.1 years (IQR 10.4, 13.9), a total of 114 (37.3 %) patients died. Multivariable-adjusted cox regression models revealed an increasing all-cause mortality risk across CCN1 tertiles (p for trend = 0.03), with the highest incidence in the highest tertile (hazard ratio [HR] 1.76; 95%-CI: 1.05, 2.99; P=0.034) as compared to the lowest tertile (Figure 1).

Conclusions:

CCN1 predicts long-term survival in DCM patients independent of NT-pro-BNP and other risk determinants. Further research needs to evaluate whether this novel biomarker also plays a causal role in the pathogenesis of DCM.

Figure 1: