Increased Serum Levels of the Notch Ligand DLL1 are Associated with Diastolic Dysfunction, Reduced Exercise Capacity, and Adverse Outcome in Chronic Heart Failure

Abstract

Background: Notch receptors and ligands have been demonstrated in myocardial tissue in experimental as well as clinical heart failure (HF), and a role for Notch signaling in myocardial remodeling and disease progression may be anticipated. We hypothesized that serum levels of the Notch ligand Delta-like-1 (DLL1) would be associated with clinical and hemodynamic variables in patients with HF.

Methods and results: We measured serum DLL1 in 183 patients with chronic HF and 50 age- and sex-matched healthy control subjects by means of enzyme immunoassay. Our main findings were that (i) HF patients had significantly higher serum DLL1 levels than healthy control subjects, (ii) DLL1 levels were significantly correlated with neurohormonal activation, systemic inflammation, and impaired kidney function, (iii) high DLL1 levels were associated with diastolic dysfunction and reduced exercise capacity, but not with impaired systolic function, and (iv) in univariate analysis, but not after multivariable adjustment, high levels of DDL1 were associated with adverse outcome.

Conclusions: Our findings may imply that DLL1 and the Notch signaling pathways are involved in the pathophysiology of HF, potentially affecting diastolic function.

Keywords: Chronic heart failure; DLL1; Notch signaling; adverse outcome; diastolic dysfunction; exercise capacity.