Association of Galectin-3 and Fibrosis Markers with Long-Term Cardiovascular Outcomes in Patients with Heart Failure, Left Ventricular Dysfunction, and Dyssynchrony: Insights from the CARE-HF (Cardiac Resynchronization in Heart Failure) Trial

AIMS: Circulating biomarkers of collagen turnover reflect extracellular cardiac matrix (ECCM) remodelling. The extent to which the success of cardiac resynchronization therapy (CRT) is influenced by the degree of cardiac fibrosis and whether CRT can influence matrix remodelling has yet to be studied. Our aim was to determine, in patients with heart failure (HF) and cardiac dyssynchrony, whether ECCM biomarkers are influenced by CRT and can predict cardiovascular outcomes and response to CRT. METHODS AND RESULTS: Serum levels of ECCM biomarkers galectin-3 (Gal-3), N-terminal propeptides of type I and III procollagens (PINP and PIIINP), type I collagen telopeptide (ICTP), and matrix metalloproteinase 1 (MMP-1) were measured in 260 patients, in a substudy of CARE-HF, a randomized controlled trial which evaluated the effects of CRT in patients with left ventricular systolic dysfunction and cardiac dyssynchrony. ECCM biomarkers did not change throughout the 18-month follow-up period. In age- and gender-adjusted analyses, Gal-3 and PIIINP were associated with death or HF hospitalization. In a further multivariate model, Gal-3 >30 ng/mL was associated OR (95% CI):2.98 (1.43-6.22), P = 0.004 with death or HF hospitalization, along with left ventricular end-systolic volume >200 mL 3.42 (OR: 1.65-7.10), P = 0.001. The outcome death or left ventricular ejection fraction (LVEF) ≤35% was associated with MMP-1 ≤3 ng/mL: 3.04 (1.37-6.71), P = 0.006. No significant interaction was observed between the tested biomarkers and the treatment group. CONCLUSIONS: Increased Gal-3 and PIIINP, and low MMP-1 are associated with adverse long-term cardiovascular outcomes but did not predict response to CRT. CRT did not favourably affect serum concentrations of ECCM markers.