The homeostatic chemokine CCL21 predicts mortality in aortic stenosis patients and modulates left ventricular remodeling

Alexandra Vanessa Finsen; Thor Ueland; Ivar Sjaastad; Trine Ranheim; Mohammed S Ahmed; Christen P Dahl; Erik T Askevold; Svend Aakhus; Cathrine Husberg; Arnt E Fiane; Martin Lipp; Lars Gullestad; Geir Christensen; Pål Aukrust; Arne Yndestad

doi:10.1371/journal.pone.0112172

The homeostatic chemokine CCL21 predicts mortality in aortic stenosis patients and modulates left ventricular remodeling

PLoS One. 2014 Nov 14;9(11):e112172. doi: 10.1371/journal.pone.0112172. eCollection 2014.

Authors

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
⁵ Institute for Surgical Research, Oslo University Hospital Rikshospitalet, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
⁶ 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.
⁷ Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
⁸ Institute for Experimental Medical Research, Oslo University Hospital Ullevål, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
⁹ Department of Cardiothoracic Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
¹⁰ Department of Molecular Tumor Genetics and Immunogenetics, Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
¹¹ 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.
¹² 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.
¹³ 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.
¹⁴ 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.

Abstract

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.

Methods and 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Animals
Aortic Valve / metabolism
Aortic Valve / pathology
Aortic Valve Stenosis / blood
Aortic Valve Stenosis / genetics
Aortic Valve Stenosis / metabolism
Aortic Valve Stenosis / mortality*
Aortic Valve Stenosis / physiopathology*
Calcinosis / blood
Calcinosis / metabolism
Chemokine CCL21 / blood*
Collagen / metabolism
Dilatation, Pathologic
Electrocardiography
Female
Homeostasis*
Humans
Immunohistochemistry
Male
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 9 / metabolism
Mice, Inbred C57BL
Myocardium / enzymology
Myocardium / pathology
Pressure
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, CCR7 / genetics
Receptors, CCR7 / metabolism
Ventricular Remodeling*

Substances

CCL21 protein, human
CCR7 protein, human
Chemokine CCL21
RNA, Messenger
Receptors, CCR7
Collagen
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9

Supplementary concepts

Aortic Valve, Calcification of

Grants and funding

This work was funded by Center for Heart Failure Research, University of Oslo, the Regional Health Authorities of South-Eastern Norway and the Norwegian Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.