The clinical utility of desmosine as a biomarker in inherited and acquired aortopathies

  • Zaid Iskandar

Student thesis: Doctoral ThesisDoctor of Medicine

Abstract

Aortopathies as a group of diseases are heterogenous – comprising of both thoracic and abdominal aortic aneurysms across many different clinical phenotypes. Together, they confer an increased risk of cardiovascular morbidity and mortality, primarily from the risk of aortic dissection. This risk which was previously thought to be linear over time, is now understood to be less so and in fact there remains a degree of unpredictability with aortic aneurysm growth both for thoracic and abdominal aortic aneurysms (AAA).

he management strategy for these conditions centre on imaging surveillance either through echocardiogram for thoracic aortopathies and abdominal ultrasound for AAAs. This guides timing for surgical intervention. Imaging surveillance by its nature, exposes patients to a degree of unpredictable risk of disease progression in between scan intervals and therefore it is recognised that adverse events can occur during this period despite a reassuring previous scan. This realisation has led to studies on biomarkers in aortopathies, not only to better understand the disease mechanism but also to hopefully improve the prediction model of risk beyond imaging alone.

This main aim of this thesis was to explore the role of desmosine, an elastin specificdegradation product in thoracic and abdominal aortopathies. Specifically, whether desmosine correlates to disease severity and/or predicts clinical outcomes. Elastin degradation is a common pathophysiological pathway shared between both thoracic and abdominal aortic aneurysms, and desmosine is specific to this process. We investigated this via three separate studies – DESMA3RS, DESMA-2, and a biomarker substudy of the Irbesartan in Marfan Syndrome randomised controlled trial (AIMS).

In DESMA3RS, we investigated the levels of plasma desmosine (pDES) in patients with AAAs compared to controls, its correlation with disease severity, and its prognostic value in predicting clinical AAA events. We demonstrated that log-pDES remained significantly associated with risk of an AAA event after correction for AAA diameter (hazard ratio 2.03 per standard deviation increase, CI 1.02-4.02, p=0.044). In addition, patients with a pDES level of ≥ 0.56 ng/ml were at significantly higher risk of AAA event (unadjusted hazard ratio 6.77; 95% confidence interval 1.86-24.62, p=0.004; adjusted for AAA diameter hazard ratio 4.97; 95% confidence interval 1.31-18.90, p=0.019). We demonstrated that pDES is significantly elevated in patients with AAA compared to controls, predicts clinical AAA events independently of AAA diameter and offers incremental prognostic value in addition to AAA diameter.

In DESMA-2, we investigated the levels of pDES and urinary desmosine (uDES) in patients with inherited aortopathies which mainly comprised of patients with bicuspid aortic valve (BAV) compared to controls. There was no significant difference between pDES levels in the two groups (0.28 ± 0.1 ng/ml vs 0.26 ± 0.1 ng/ml, p=0.39). Similarly, in patients with aortopathy, neither aortic root size (mm) nor aortic Z-score was significantly correlated with baseline pDES (r=0.26, p=0.13, r=-0.08, p=0.66). uDES showed a significant correlation with pDES (r=0.56, p=0.002). In addition, uDES had a more significant correlation with aortic root size (r=0.47, p=0.01) and Z-score (r=0.42, p=0.022) compared to pDES. We demonstrated that in patients with inherited thoracic aortopathy, pDES is not significantly different from age and gender matched controls and does not correlate to disease severity. uDES is however significantly correlated with aortic root size in patients with inherited thoracic aortopathy and could be a viable biomarker in the future.

Finally, in our final study we analysed desmosine levels as part of a biomarker substudy for the recently published AIMS study. The AIMS study was a study of Irbesartan vs placebo in patients with Marfan Syndrome and we analysed pDES levels at baseline and at 1 year follow-up. We demonstrated a few key findings. Firstly, treatment with the angiotensin receptor blocker Irbesartan is not associated with reduced levels of pDES compared to placebo at 1 year. There was no significant difference in the absolute values of pDES (p=0.49) and the change in pDES levels at 1 year between the two groups (p=0.52). Secondly, pDES is not correlated with aortic root diameter or annual rate of aortic root dilatation but is significantly correlated with the degree of change of pDES at 1 year. Thirdly, pDES levels are strongly influenced by age and being of male gender. In conclusion, desmosine remains a potential biomarker for aortopathies. The relationship with aortic root size is not consistently seen across different disease phenotypes, and is strongly influenced by age as desmosine is likely to be closely related to vascular ageing. Future studies on desmosine should ideally have longer term follow-up and frequent serial measurements of the biomarker to further understand its relationship with disease progression.
Date of Award2022
Original languageEnglish
SponsorsBritish Heart Foundation & Tenovus Scotland
SupervisorAnna-Maria Choy (Supervisor) & Chim Lang (Supervisor)

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