Osteoprotegerin and Myocardial Fibrosis in Patients with Aortic Stenosis

Brodie L Loudon,Dudley J Pennell,Paul D Flynn,Vassilios S Vassiliou,Tamir Malley,Nikhil Aggarwal,Willis Lam,Dominque Auger,Sanjay K Prasad,Brian Halliday,Subothini Selvendran,Jackie Donovan,Eleana Ntatsaki,Simon Newsome,Claire E Raphael,Amrit Lota,Aamir Ali

doi:10.1038/s41598-018-32738-y

Abstract

Left ventricular myocardial fibrosis in patients with aortic stenosis (AS) confers worse prognosis. Plasma osteoprotegerin (OPG), a cytokine from the TNF receptor family, correlates with the degree of valve calcification in AS, reflecting the activity of the tissue RANKL/RANK/OPG (receptor activator of nuclear factor κΒ ligand/RANK/osteoprotegerin) axis, and is associated with poorer outcomes in AS. Its association with myocardial fibrosis is unknown. We hypothesised that OPG levels would reflect the extent of myocardial fibrosis in AS. We included 110 consecutive patients with AS who had undergone late-gadolinium contrast enhanced cardiovascular magnetic resonance (LGE-CMR). Patients were characterised according to pattern of fibrosis (no fibrosis, midwall fibrosis, or chronic myocardial infarction fibrosis). Serum OPG was measured with ELISA and compared between groups defined by valve stenosis severity. Some 36 patients had no fibrosis, 38 had midwall fibrosis, and 36 had chronic infarction. Patients with midwall fibrosis did not have higher levels of OPG compared to those without fibrosis (6.78 vs. 5.25 pmol/L, p = 0.12). There was no difference between those with midwall or chronic myocardial infarction fibrosis (6.78 vs. 6.97 pmol/L, p = 0.27). However, OPG levels in patients with chronic myocardial infarction fibrosis were significantly higher than those without fibrosis (p = 0.005).

Highlights

In whom greatest benefit may be gained from early aortic valve replacement surgery (AVR)
NT-proBNP levels were higher in patients with severe aortic stenosis (AS) compared to those with mild/moderate disease (1232 pg/ml vs. 3813 pg/ml; p = 0.002); serum CRP levels did not differ between the groups (12 mg/L vs. 15 mg/L; p = 0.52)
We have shown that severe AS is independently associated with raised serum OPG, and that patients with chronic ischaemia pattern fibrosis on cardiovascular magnetic resonance (CMR) have raised OPG on univariate analysis

Summary

Introduction

In whom greatest benefit may be gained from early AVR. Recently, the RANKL/RANK/OPG (receptor activator of nuclear factor κΒ ligand/RANK/osteoprotegerin) system, known to play an important role in bone turnover and vascular calcification[8], has gained much interest in AS9. Patients with severe AS and cardiovascular magnetic resonance (CMR)-derived measures of myocardial replacement fibrosis (either midwall or chronic myocardial infarction) have poorer outcomes[28,29]. In an isoproterenol-induced rat model of heart failure, RANKL/RANK were shown to be crucial mediators of interleukin-17 (IL-17) induced activation of matrix metalloproteinase-1 (MMP-1) in cardiac fibroblasts[33] In this model, treatment with both OPG and inhibitors of IL-17 reduced myocardial fibrosis. The main aim of our study was to determine whether serum OPG was associated with the presence of (1) myocardial midwall and (2) myocardial infarction fibrosis in patients with AS, and compare patients with mild/moderate and severe disease. We investigated the prognostic role of OPG in patients with AS

Objectives

Methods

Results

Discussion

Conclusion