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Circulating delta‐like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus‐based immunosuppression
Author(s) -
Norum Hilde M.,
Michelsen Annika E.,
Lekva Tove,
Arora Satish,
Otterdal Kari,
Olsen Maria Belland,
Kong Xiang Yi,
Gude Einar,
Andreassen Arne K.,
Solbu Dag,
Karason Kristjan,
Dellgren Göran,
Gullestad Lars,
Aukrust Pål,
Ueland Thor
Publication year - 2019
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15141
Subject(s) - medicine , everolimus , heart transplantation , immunosuppression , notch signaling pathway , heart failure , pathogenesis , transplantation , calcineurin , sirolimus , cardiology , receptor
Cardiac allograft vasculopathy ( CAV ) causes heart failure after heart transplantation ( HT x), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus ( EVR ), is essential for processes involved in CAV . We hypothesized that circulating Notch ligands would be dysregulated after HT x. We studied circulating delta‐like Notch ligand 1 ( DLL 1) and periostin ( POSTN ) and CAV in de novo HT x recipients (n = 70) randomized to standard or EVR ‐based, calcineurin inhibitor‐free immunosuppression and in maintenance HT x recipients (n = 41). Compared to healthy controls, plasma DLL 1 and POSTN were elevated in de novo ( P < .01; P < .001) and maintenance HT x recipients ( P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL 1. For de novo HT x recipients, a change in DLL 1 correlated with a change in CAV at 1 ( P = .021) and 3 years ( P = .005). In vitro , activation of T cells increased DLL 1 secretion, attenuated by EVR . In vitro data suggest that also endothelial cells and vascular smooth muscle cells ( VSMC s) could contribute to circulating DLL 1. Immunostaining of myocardial specimens showed colocalization of DLL 1 with T cells, endothelial cells, and VSMC s. Our findings suggest a role of DLL 1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL 1. Trial registration numbers— SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962.