Trial Lecture – time and place
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Adjudication committee
- First opponent: Professor Truls Myrmel, UiT – The Arctic University
- Second opponent: Professor Bjørn Tore Gjertsen, University of Bergen
- Third member and chair of the evaluation committee: Professor Ingrid Os, University of Oslo
Chair of the Defence
Associate Professor Are Martin Holm, University of Oslo
Principal Supervisor
Researcher Thor Ueland, University of Oslo
Summary
Heart failure (HF) is a feared condition, with a five-year survival of only 50%. The life-time risk of developing HF is one in five. The Notch signaling system, whose Notch receptors interact with Notch ligands, is active in myocardial tissue in HF, but little is known about circulating Notch ligands in HF.
We hypothesized involvement of Notch signaling in HF development, as well as in development and progression of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). We aimed at studying circulating Notch ligands and their relation to clinical and hemodynamic characteristics in four HF and post-HTx populations.
Levels of circulating Notch ligands like DLL1 and periostin from patients and controls, as well as expression of myocardial Notch proteins were measured, and additional experiments were conducted to elucidate potential sources of Notch ligands.
In chronic HF, serum DLL1 was elevated. High levels of DLL1 were associated with diastolic dysfunction, reduced exercise capacity and adverse outcome.
In dilated cardiomyopathy, severely affected patients had increased plasma DLL1 and periostin, associated with indices of diastolic dysfunction. In myocardial biopsies, expression of DLL1 and periostin correlated with indices of more preserved and more impaired cardiac function, respectively.
Plasma DLL1 and periostin were increased in de novo and maintenance HTx recipients. Everolimus based immunosuppression, compared to standard regimen, was associated with weakened DLL1 response. In de novo recipients, long-term changes in plasma DLL1 correlated with changes in CAV indices. Myocardial DLL1 shared its distribution pattern with T cells, vascular smooth muscle cells and endothelial cells. In vitro, these cells secreted DLL1. Everolimus attenuated DLL1 secretion from T cells and endothelial cells.
Notch signaling may thus be involved in development of HF and progression of CAV.
Additional information
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