The molecules delta-like 1 (DLL1) and Wingless-type family member 5a (Wnt5a) can be interesting targets in heart failure therapy, shows the PhD research of Aurelija Abraityte.

MAIN RESULTS:

1. DLL1 is elevated in aortic stenosis and chronic heart failure.
2. DLL1 is associated with mortality in aortic stenosis and mortality or heart transplantation in heart failure.
3. Heart failure patients have increased levels of Wnt5a, and higher Wnt5a is associated with increased mortality in dilated cardiomyopathy.

THESIS DEFENCE:

Thesis: Delta-like 1 and Wnt5a as potential biomarkers and mediators of cardiac disease
Candidate: Aurelija Abraityte
Time: May 2, 2018 at 12:15
Place: University of Oslo: Domus odontologica, Small auditorium
Link to university website (in Norwegian)

SUMMARY:

During heart failure, the heart returns to fetal gene programs to work more efficiently, and the notch and Wingless (Wnt) signalling pathways are reactivated.

(1) The notch-ligand delta-like 1 is elevated and associated with mortality in patients with symptomatic aortic stenosis. Both low and high levels of DLL1 seems to be linked to increased mortality. Moreover, DLL1 is expressed in calcified aortic valves and correlates with systemic DLL1 concentrations. DLL1 levels also associate with established biomarkers of cardiovascular disease.

A total of 136 patients with aortic stenosis were included in the study and compared to 95 healthy controls. The researchers aslo obtained aortic valve specimens from 14 patients undergoing surgery.

(2) Serum levels of DLL1 are elevated in chronic heart failure. Higher levels associate with increased risk of death or heart transplantation, but only before multivariable adjustment. Furthermore, higher levels are linked to diastolic dysfunction and reduced exercise capacity, as well as neurohormonal activation, systemic inflammation and impaired kidney function.

183 patients and 50 age- and sex-matched healthy controls were included in the study.

(3) Wnt5a is elevated in heart failure and affects cardiac fibroblast function by inducing inflammatory markers. Thus, Wnt5a can contribute to progression of heart failure. mRNA expression of Wnt5a is upregulated in the failing heart. Wnt5a is also associated with hemodynamic, neurohormonal, and clinical measures of heart failure severity.

The study includes 155 patients with stable heart failure with reduced ejection fraction, as well as 25 age- and sex-matched healthy persons and cardiac fibroblasts from mice.

(4) Wnt5a is associated with adverse outcome in dilated cardiomyopathy, especially in the more severly affected patients. Elevated levels are also linked to increased pulmonary artery pressures and decreased right ventricular function. Furthermore, the experiments indicate that Wnt5a may promote the progression of dilated cardiomyopathy through activation of NFAT signalling.

102 patients with dilated cardiomyopathy contributed to the study.

REFERENCES:

(1) Abraityte, A., Gullestad, L., Askevold, E. T., Nymo, S., Dahl, C. P., Aakhus, S., Aukrust, P., & Ueland, T. (2015). The Notch ligand Delta-like 1 is elevated and associated with mortality in patients with symptomatic aortic stenosis. International journal of cardiology, 180, 18-20.

(2) Norum, H. M., Gullestad, L., Abraityte, A., Broch, K., Aakhus, S., Aukrust, P., & Ueland, T. (2016). Increased serum levels of the notch ligand dll1 are associated with diastolic dysfunction, reduced exercise capacity, and adverse outcome in chronic heart failure. Journal of cardiac failure, 22(3), 218-223.

(3) Abraityte, A., Vinge, L. E., Askevold, E. T., Lekva, T., Michelsen, A. E., Ranheim, T., Alfsnes, K., Fiane, A., Aakhus, S., Lunde, I. G., Dahl, C. P., Aukrust, P., Christensen, G., Gullestad, L., Yndestad, A., & Ueland, T. (2017). Wnt5a is elevated in heart failure and affects cardiac fibroblast function. Journal of molecular medicine, 95(7), 767-777.

(4) Abraityte, A., Lunde, I. G., Askevold, E. T., Michelsen, A. E., Christensen, G., Aukrust, P., Yndestad, A., Fiane, A. Andreassen, A., Aakhus, S., Dahl, C. P., Gullestad, L., Broch, K., & Ueland, T. (2017). Wnt5a is associated with right ventricular dysfunction and adverse outcome in dilated cardiomyopathy. Scientific Reports, 7(1), 3490.