THE CLINICAL UTILITY OF PLASMA DESMOSINE AS A BIOMARKER OF ATHEROSCLEROSIS AND PLAQUE INSTABILITY

Abstract

Background: Atherosclerosis represents the number one cause of death and disability worldwide. Atherosclerosis is a progressive inflammatory disease that leads to degradation and remodelling of the extracellular matrix, especially elastic fibres and elastin. Elastic degradation products are pathologically relevant disease biomarkers, but their use in this role has been limited in the past by poor reproducibility and specificity.

Desmosine is a structural cross-linking amino acid of four lysine residues, released in circulation following elastin breakdown from precursor elastin peptides. In our laboratory we have developed a highly specific assay for analysis of plasma desmosine (pDES), which is a specific marker of mature elastin degradation. We have explored the relationship between pDES and clinical outcomes in independent clinical studies involving at risk patients with chronic conditions including chronic obstructive pulmonary disease, bronchiectasis and abdominal aortic aneurysm. A striking observation from all these studies is the consistent relationship between the elevation of pDES and increased global cardiovascular risk and mortality. pDES may therefore serve as a pathologically relevant, cost-effective marker for predicting disease severity and risk stratification in cardiovascular disease.

Objectives: This main aim of this thesis was to explore the role of pDES, an elastin specific- degradation product, in atherosclerosis and plaque instability. Specifically, the objectives were to find out answers to the following research questions:

1. Is there a relationship between pDES and whole atherosclerotic burden as assessed by Whole Body MRA?
2. Can pDES predict cardiac events in at-risk population (stable angina)?
3. Does pDES reflect unstable atherosclerotic disease activity?
4. Can pDES predict cardiovascular outcomes in patients with Acute Myocardial Infarction (MI)?

Methods: We investigated the research questions via four separate studies.

Study 1. pDES and Systemic Atherosclerosis: Banked plasma samples were analysed for pDES in Huang’s Lab from a study population with available data for whole body MRA. We examined whether circulating pDES levels are associated with total atherosclerotic burden in these patients.

Study 2. pDES in at risk population (stable angina): Banked plasma samples were analysed for pDES in Huang’s Lab from stable symptomatic outpatients with suspected coronary artery disease who attended for coronary angiography for stable angina symptoms. We assessed whether pDES predicts outcomes in these stable angina patients.

Study 3. pDES in acute MI: We measured pDES in 100 patients diagnosed with Type 1 and Type 2 MI in Ninewells Hospital. pDES levels were also measured in 50 stable angina subjects. Patients were recruited over a period of one year. We assessed the difference in pDES level in acute MI vs stable angina subjects, and the difference of pDES levels in Type1 and Type2 MI.

Study 4. pDES and outcomes in acute MI: We analysed banked plasma samples for pDES in Huang’s Lab from acute MI patients. Overall, in our study we selected 236 patients with MI from a cohort of 1141 patients with MI who were admitted with MI to University Hospitals of Leicester, UK, between August 2004 and April 2007. We assessed whether pDES predicts outcomes in patients with acute MI.

Results:

Study 1. pDES levels correlates with global atheroma burden as measured by whole body contrast enhanced magnetic resonance angiography. Furthermore, elevated levels of pDES are also associated with the presence of clinical CVD.

Study 2. In the study of stable angina patients, we found that pDES levels were high in those who had a poor outcome as compared to those who did not have an event. Elevated pDES levels is associated with adverse outcomes in stable angina patients in univariable analysis. This association was lost in multivariable analysis, but on the basis of the 95% confidence interval around this outcome, the results may not rule out a benefit of pDES in this cohort of patients.

Study 3. In the pilot study of MI vs stable angina patients, there was no difference in the pDES levels between the two groups. pDES levels were also not different between Type1 and Type MI.

Study 4. pDES levels were elevated in patients who had death/MI at 2 years compared to those without (median pDES 0.45 vs 0.36 ng/mL, p=0.002)). Multivariable analysis showed that pDES was associated with adverse outcome at 6 months, 1 year & at 2 years [HR 3.58-5.91 (95% CI 1.05-26.00) p≤0.041].
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Conclusions: pDES is a potential biomarker for atherosclerosis and plaque instability. pDES is correlated with the overall systemic atherosclerosis burden. Though pDES could not diagnose patients with MI perhaps because of it being a marker of systemic atherosclerosis rather than coronary atherosclerosis, it can predict cardiovascular events mainly in patients with acute MI. On the other hand, pDES was not associated with cardiovascular events in patients with stable angina but hazard ratio for multivariable analysis were too wide, suggesting that the sample size and the number of MACE events in our study were not enough. Future studies on pDES should ideally have longer term follow-up and frequent serial measurements of the biomarker to further understand its relationship with disease progression.

Date of Award	2025
Original language	English
Awarding Institution	University of Dundee
Supervisor	Anna-Maria Choy (Supervisor) & Jeffrey Huang (Supervisor)