Biomarkers of COX-2 inhibition and NSAID cardiovascular side effects
File(s)
Author(s)
Vaja, Ricky
Type
Thesis
Abstract
Non-steroidal anti-inflammatory drugs, which work by blocking cyclooxygenase-2 (COX-2) can increase a person’s risk of having a heart attack or stroke by around 30% after just 1-2 weeks of use. After more than 20 years of research in this field and despite being one the most commonly used medications world-wide, we still do not fully understand how COX-2 protects the cardiovascular system. In this thesis, I performed a multi-omic analysis of serum samples from healthy volunteers taking the COX-2 inhibitor celecoxib and linked these to cardiovascular and renal physiological endpoints measured in parallel. I also performed a similar multi-omic analysis of samples from patients having had cardiovascular events versus matched case controls taken from the SCOT (Standard Care versus Celecoxib Outcome Trial) biobank.
The key novel findings within this thesis include: I. In a double blind, placebo controlled, randomised trial in healthy volunteers, 7 days of NSAID (celecoxib) use was associated with a significant increase in augmentation index (surrogate for vascular stiffness). This was linked to changes in serum protein markers relating to the extracellular matrix (ECM) as well a reduction in arginine/ADMA ratio.
II. Similar changes in ECM proteins were also seen in serum samples from real world NSAID users who go onto have a cardiovascular event within 1 year.
III. GDF-15 was identified as a candidate biomarker to predict early NSAID cardiovascular events. What makes this a remarkable discovery is that GDF 15 is induced by NSAIDs and provides a novel mechanism for NSAID cardiovascular events.
Using a multi-omics approach has provided novel mechanistic insight into how COX 2 protects the cardiovascular system and has highlighted several key areas for future research in this field
The key novel findings within this thesis include: I. In a double blind, placebo controlled, randomised trial in healthy volunteers, 7 days of NSAID (celecoxib) use was associated with a significant increase in augmentation index (surrogate for vascular stiffness). This was linked to changes in serum protein markers relating to the extracellular matrix (ECM) as well a reduction in arginine/ADMA ratio.
II. Similar changes in ECM proteins were also seen in serum samples from real world NSAID users who go onto have a cardiovascular event within 1 year.
III. GDF-15 was identified as a candidate biomarker to predict early NSAID cardiovascular events. What makes this a remarkable discovery is that GDF 15 is induced by NSAIDs and provides a novel mechanism for NSAID cardiovascular events.
Using a multi-omics approach has provided novel mechanistic insight into how COX 2 protects the cardiovascular system and has highlighted several key areas for future research in this field
Version
Open Access
Date Issued
2022-10-09
Date Awarded
01/03/2023
License URL
Advisor
Mitchell, Jane
Kirkby, Nicholas
Ebbels, Tim
Sponsor
British Heart Foundation
Grant Number
FS/19/6/34129
RG/18/4/33541
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)