A study of the relationship between clinical characteristics, outcomes and the pathological features of carotid plaques in patients following stroke or transient ischaemic attack (TIA)
The carotid arteries run up the front of the neck, and are crucial to the supply of blood to the brain. Narrowing of the carotid arteries (known as carotid stenosis) is due to a build-up of fatty material, called atherosclerotic plaque. If this plaque ruptures, blood clots form and these can cause a stroke, TIA or sometimes a temporary loss of vision in one eye.
Carotid stenosis causes a fifth of all strokes, and in patients who have had a TIA or stroke the diameter of the carotid arteries is commonly assessed, either by ultrasound or during a brain CT or MRI scan. If severely narrowed, a surgical operation called a carotid endarterectomy may be recommended, widening the artery to improve blood flow to the brain and reducing the risk of stroke.
Previous research
Research by the Centre for Prevention of Stroke and Dementia, University of Oxford (formerly Stroke Prevention Research Unit) has shown unstable or ruptured carotid plaques are associated with a high risk of ischaemic stroke, when compared to stable plaques without symptoms. They also found that there are major sex-differences in the appearance of carotid plaques on imaging, with men being much more likely than women to develop irregular or ulcerated plaques. Further studies revealed messengers that act on blood vessels and/or cells to promote an inflammatory response (inflammatory mediators) are involved in destabilizing the atherosclerotic plaques, and are more abundant in unstable symptomatic carotid plaques than in stable asymptomatic lesions. However, these studies have been too small to determine whether or not there are systematic differences in the expression of inflammatory mediators according to particular clinical characteristics, such as sex or age.
Aims of the study
The aim of the Oxford Plaque Study was to determine whether features of the plaque and differences in the expression of inflammatory mediators are related to clinical characteristics of patients, such as age, sex, genotype, and to the risks of strokes and heart attacks in the future.
Recruitment and methods
Patients admitted for carotid endarterectomy to the John Radcliffe Hospital, Oxford were eligible to take part in the study. They were asked for consent to allow the carotid plaque removed during surgery to be collected by the study team, together with blood samples and information from them and their medical records about life style factors and medical history e.g. time from stroke/TIA to surgery, smoking, high blood pressure, diabetes. In total, 472 participants were included in the study and were followed up over time to see whether they would go on to have any other problems caused by atherosclerosis, such as a heart attack, recurrent stroke or TIA.
The results have been combined with data collected as part of other carotid plaque collections from Oxford and the Netherlands and has resulted in several published papers.
The main findings were:
- Specific “vulnerable” carotid plaque characteristics correlate with predicted stroke risk. Plaques removed within 30-days of last symptomatic event are most strongly correlated with predicted stroke risk whereas those removed greater than 30-days reveal no such relation.
- Diabetes is known to accelerate progression of atherosclerotic disease. However, we found diabetes does not appear to be associated with specific plaque characteristics in patients suffering from significant carotid artery disease.
- Carotid plaques from patients undergoing endarterectomy for previous ocular ischemic events have fewer vulnerable plaque features than those from patients with recent cerebral ischaemic events, possibly explaining some of the differences in risk of stroke between these groups.
- Smoking is associated with a lower age at carotid endarterectomy, suggesting that it may accelerate the development and/or progression of atherosclerosis. However, the mechanisms of plaque instability seem largely unrelated to smoking. Plaques from younger patients had greater inflammatory cell infiltration, whereas those from older patients had a larger lipid core, but there were no age trends in overall plaque instability. This implies the increased risk of stroke in the elderly with symptomatic carotid stenosis is due to other factors.
Related publications
Risk of stroke in relation to degree of asymptomatic carotid stenosis: a population-based cohort study, systematic review, and meta-analysis. Howard DPJ, Gaziano L, Rothwell PM; Oxford Vascular Study. Lancet Neurol. 2021 Mar;20(3):193-202.
Symptomatic carotid atherosclerotic disease: correlations between plaque composition and ipsilateral stroke risk. Howard DP, van Lammeren GW, Rothwell PM, Redgrave JN, Moll FL, de Vries JP, de Kleijn DP, den Ruijter HM, de Borst GJ, Pasterkamp G. Stroke. 2015 Jan;46(1):182-189.
Type 2 diabetes is not associated with an altered plaque phenotype among patients undergoing carotid revascularization. A histological analysis of 1455 carotid plaques. Scholtes VP, Peeters W, van Lammeren GW, Howard DP, de Vries JP, de Borst GJ, Redgrave JN, Kemperman H, Schalkwijk CG, den Ruijter HM, de Kleijn DP, Moll FL, Rothwell PM, Pasterkamp G. Atherosclerosis. 2014 Aug;235(2):418-23.
Histological features of carotid plaque in patients with ocular ischemia versus cerebral events. Howard DP, van Lammeren GW, Redgrave JN, Moll FL, de Vries JP, de Kleijn DP, de Borst GJ, Pasterkamp G, Rothwell PM. Stroke. 2013 Mar;44(3):734-9.
Histological features of symptomatic carotid plaques in relation to age and smoking. Redgrave JN, Lovett JK, Rothwell PM. Stroke. 2010 Oct;41(10):2288-94.
Potential for further research
It is hoped that newly available techniques to stain and evaluate the plaques will complement and add to these findings. To facilitate this, remaining carotid plaque tissue (wax blocks/stained slides) and blood samples will be retained under HTA licence 12217 (Oxford Brain Bank, John Radcliffe Hospital, Oxford).
Principal Investigator: Professor Peter M Rothwell Contact: Dr Louise Silver louise.silver@ndcn.ox.ac.uk