Hilde Margrethe Norum has investigated circulating Notch ligands in patients with heart failure and heart transplant recipients.

MAIN RESULTS:

1. High levels of delta-like 1 in heart failure is linked to worse prognosis.
2. Delta-like 1 and periostin are increased in patients with dilated cardiomyopathy.
3. Also heart transplant recipients have higher levels of Notch ligands.

THESIS DEFENCE:

Thesis: Soluble Notch Ligands in Heart Failure
Candidate: Hilde Margrethe Norum
Time: May 27, 2019 at 13:15
Place: Oslo University Hospital, Rikshospitalet: Green Auditorium
Link to university website

SUMMARY:

(1) The levels of the Notch ligand delta-like 1 is markedly increased in patients with chronic heart failure. Moreover, the patients with the highest levels also have more prevalent diastolic dysfunction, higher inflammation and cholesterol levels, and lower exercise capacity. The patients in Norum’s study were followed for a median of 4.6 years, and the risk of heart transplantation and death during follow-up tended to be higher with increased delta-like 1 levels.

The study includes blood work from 183 patients with chronic heart failure and 50 healthy control persons. A third of the patients died or were transplanted during the follow-up period.

(2) Also patients with dilated cardiomyopathy have increased levels of delta-like 1. 102 patients were compared with 32 healthy controls of the same sex and age. Periostin levels were also increased in the patients, and both delta-like 1 and periostin were strongly associated with the degree of diastolic dysfunction.

A higher expression of delta-like 1 in explanted hearts was linked to better preserved cardiac function, wheres periostin expression was associated with worse heart function. The results might indicate that different Notch ligands affect cardiac function differently in dilated cardiomyopathy. 25 explanted heart were used in these experiments.

(3) The levels of delta-like 1 and periostin are increased also in de novo and maintenance heart transplant recipients. Immunosuppresion with everolimus is assocaited with lower delta-like 1 compared to calcineurin-based treatment, and a change in delta-like 1 during follow-up correlates with change in cardiac allograft vasculopathy.

The study includes 70 patients who went through heart transplantation and were randomized to everolimus- or calcineurin-based immunosuppression. Experimental research on T cells, endothelial cells and vascular smooth muscle cells strengthened the indication that everolimus has a suppressive effect on delta-like 1.

REFERENCES:

(1) 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.

(2) Norum, H. M., Broch, K., Michelsen, A. E., Lunde, I. G., Lekva, T., Abraityte, A., Dahl, C. P., Fiane, A. E., Andreassen, A. K., Christensen, G., Aakhus, S., Aurkrust, P., Gullestad, L., & Ueland, T. (2017). The notch ligands DLL1 and periostin are associated with symptom severity and diastolic function in dilated cardiomyopathy. Journal of cardiovascular translational research, 10(4), 401-410.

(3) Norum, H. M., Michelsen, A. E., Lekva, T., Arora, S., Otterdal, K., Olsen, M. B., Kong, X. Y., Gude, E., Andreassen, A. K., Solbu, D., Karason, K., Dellgren, G., Gullestad, L., Aukrust, P., & Ueland, T. (2019). Circulating delta‐like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus‐based immunosuppression. American Journal of Transplantation, 19(4), 1050-1060.