The homeostatic chemokine CCL21 predicts mortality in aortic stenosis patients and modulates left ventricular remodeling.
BACKGROUND
CCL21 acting through CCR7, is termed a homeostatic chemokine. Based on its role in concerting immunological responses and its proposed involvement in tissue remodeling, we hypothesized that this chemokine could play a role in myocardial remodeling during left ventricular (LV) pressure overload.


RESULTS
Our main findings were: (i) Serum levels of CCL21 were markedly raised in patients with symptomatic aortic stenosis (AS, n = 136) as compared with healthy controls (n = 20). (ii) A CCL21 level in the highest tertile was independently associated with all-cause mortality in these patients. (iii) Immunostaining suggested the presence of CCR7 on macrophages, endothelial cells and fibroblasts within calcified human aortic valves. (iv). Mice exposed to LV pressure overload showed enhanced myocardial expression of CCL21 and CCR7 mRNA, and increased CCL21 protein levels. (v) CCR7-/- mice subjected to three weeks of LV pressure overload had similar heart weights compared to wild type mice, but increased LV dilatation and reduced wall thickness.


CONCLUSIONS
Our studies, combining experiments in clinical and experimental LV pressure overload, suggest that CCL21/CCR7 interactions might be involved in the response to pressure overload secondary to AS.
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
Alexandra Vanessa
AV
Finsen
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Endocrinology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G.Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
Thor
T
Ueland
Institute for Experimental Medical Research, Oslo University Hospital Ullevål, Oslo, Norway; Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
Ivar
I
Sjaastad
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
Trine
T
Ranheim
Institute for Surgical Research, Oslo University Hospital Rikshospitalet, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
Mohammed S
MS
Ahmed
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
Christen P
CP
Dahl
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway; Department of Medicine, Lovisenberg Diakonale Hospital, Oslo, Norway.
Erik T
ET
Askevold
Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
Svend
S
Aakhus
Institute for Experimental Medical Research, Oslo University Hospital Ullevål, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
Cathrine
C
Husberg
Department of Cardiothoracic Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
Arnt E
AE
Fiane
Department of Molecular Tumor Genetics and Immunogenetics, Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
Martin
M
Lipp
Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
Lars
L
Gullestad
Institute for Experimental Medical Research, Oslo University Hospital Ullevål, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
Geir
G
Christensen
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
Pål
P
Aukrust
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
Arne
A
Yndestad
D000368:Aged; D000818:Animals; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000503:physiopathology*; D002114:Calcinosis / Q000097:blood / Q000378:metabolism; D054421:Chemokine CCL21 / Q000097:blood*; D003094:Collagen / Q000378:metabolism; D004108:Dilatation, Pathologic; D004562:Electrocardiography; D005260:Female; D006706:Homeostasis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D011312:Pressure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling
C515478:CCL21 protein, human; C515370:CCR7 protein, human; D054421:Chemokine CCL21; D012333:RNA, Messenger; D054400:Receptors, CCR7; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9