Atherothrombosis and ischaemic stroke

Abstract

Unstable plaque is the main mechanism of stroke in patients with carotid stenosis

Thrombosis due to “unstable” atherosclerotic plaque is the main mechanism underlying acute coronary syndromes, and vascular research has focused mostly on this model. Plaque also causes a substantial proportion of ischaemic stroke, although multiple mechanisms are involved and “stable” plaque is sometimes responsible. For example, in the basilar and proximal middle cerebral arteries, stroke can result from occlusion of a small branch vessel by slow growth of otherwise “stable” plaque in the parent vessel. Slowly growing but stable plaque can also cause cerebral ischaemia due to stenosis and hypoperfusion without thromboembolism. Recent evidence, however, suggests that the predominant mechanism of stroke, at least in patients with carotid stenosis, is similar to the coronary model and involves mainly unstable plaque.¹,²,³ This observation has implications for the way we manage and prevent strokes.

Carotid plaques are typically slow growing or quiescent for long periods but may suddenly develop ruptures, fissures, or endothelial erosions, triggering platelet aggregation and formation of thrombus, which leads to local occlusion or embolisation to more distal vessels. Recent studies have correlated histology of the plaque with time since last symptoms in patients with symptomatic stenosis undergoing endarterectomy.²,³ Spagnoli and colleagues studied 187 symptomatic plaques and reported that the frequency of thrombotically active plaque was greater after stroke than after transient ischaemic attack, and that it fell with time from first ischaemic symptoms to surgery.² A similar study of 565 symptomatic carotid plaques found a high frequency of features that mark unstable plaque (for example, rupture of cap in 56.7%, a large lipid core in 59.6%, marked inflammatory infiltrate in 66.9%) and found that many of these features, particularly inflammation, were most frequent in patients with recent cerebral ischaemic events, especially after stroke.³ Interestingly, cap thickness in ruptured carotid plaques is much greater than that reported in ruptured coronary plaques,³ which has implications for identifying at risk plaques by imaging. However, rupture is still associated with a relatively thin cap and with pronounced macrophage infiltration.³

The finding that coronary-type “unstable” plaque is responsible for a high proportion of transient ischaemic attacks and strokes in patients with carotid stenosis has important implications for prevention. Firstly, it highlights the need for urgency in investigation and treatment. The risk of major stroke distal to symptomatic carotid stenosis is up to 30% during the first month after the presenting event,⁴ but this risk falls rapidly with time, as does benefit from endarterectomy.⁵ In relevant trials, for patients with 50% or higher stenosis, the number needed to undergo surgery (number needed to treat) to prevent one ipsilateral stroke in five years was five for patients randomised within two weeks after their last ischaemic event versus 125 for patients randomised after 12 weeks.⁵ Unfortunately, the current average delay before endarterectomy in the United Kingdom is about 12 weeks,⁴ and many patients have a major stroke before investigation or surgery. The rapid fall in risk of stroke with time since presenting event could be due to the development of collateral circulation or the loss of a small subgroup of patients who are particularly susceptible to stroke for some other reason, but this fall is most likely to be due to healing of unstable plaque.

Secondly, the role of unstable plaque in the aetiology of ischaemic stroke indicates that sheer induced platelet aggregation could be involved in thrombus formation and that antiplatelet agents may have potential in the prevention of ischaemic stroke. This is consistent with recent data on the potential benefit of a short course of combinations of antiplatelet agents in patients with acutely symptomatic carotid stenosis,⁶ and the lack of efficacy of warfarin in patients with intracranial stenosis.⁷

There are also important implications for research. Firstly, unstable carotid plaque can be imaged in vivo, so imaging might have a role in risk stratification. Ulceration of the surface of the plaque on conventional arterial angiography, which is strongly associated with unstable plaque on histology,¹ is a strong independent predictor of stroke,⁵ and has been included in risk models for patients with symptomatic carotid stenosis.⁸ Carotid ultrasound can identify lipid-rich echolucent plaques, and magnetic resonance imaging can detect both lipid core and intraplaque haemorrhage, although more research is needed to determine whether these assessments predict stroke. Novel imaging techniques using magnetic resonance imaging, positron emission tomography, and molecular radiolabelling also allow quantification of macrophage infiltration, neovascularisation, metabolic activity, and even protease activity and apoptosis.⁹

Secondly, carotid plaques also provide an indirect window on the coronary circulation. Non-invasive measurements of carotid stenosis can predict severe coronary artery disease in patients with suspected ischaemic heart disease and future acute coronary events in patients with coronary artery disease. Importantly, ruptured carotid plaques are more likely than smooth plaques to be associated with future coronary events,¹⁰ which suggests that plaque instability is a systemic phenomenon and that non-invasive assessment of carotid plaque instability might also be a useful index of coronary risk.

Thirdly, the importance of instability of stenosing carotid plaques as a cause of transient ischaemic attack and stroke raises the possibility that, as in the coronary circulation, many acute carotid ischaemic events might be caused by instability in non-stenosing plaque. Although the average risk of stroke in patients without appreciable carotid stenosis is insufficient to merit endarterectomy, recent developments in imaging techniques allow the subgroup of patients with unstable plaques to be better identified⁹ and will necessitate further research to determine optimal treatment.

Finally, most of what we know about atherosclerotic plaque and stroke relates to disease at the carotid bifurcation—the only arterial segment routinely imaged after a stroke or transient ischaemic attack in most centres. However, many other points of branching, tortuosity, or confluence of the arterial supply to the brain are also prone to disease. Common sites of extracranial atheroma include the aortic arch, where large plaques are an important risk factor for ischaemic stroke¹¹; the proximal subclavian and common carotid arteries; and the origins of the vertebral arteries.¹² The intracranial arteries are prone to atherosclerosis at the carotid siphon, the proximal middle cerebral artery, the intracranial vertebral arteries, and the basilar artery origin.¹³,¹⁴ Although intracranial disease does appear to be associated with a high risk of recurrent stroke on medical treatment,⁷ the proportion of all strokes caused by plaque at sites other than the carotid bifurcation is unknown and will differ between populations. Carotid and other extracranial atherosclerosis is most common in white men, whereas intracranial disease is most common in black, Hispanic, and oriental populations, in patients with type 1 diabetes, and in younger women.¹³,¹⁴ More research is required into imaging and treatment of disease at sites other than the carotid bifurcation, particularly in patients with ischaemic events in the posterior circulation, in whom the early risk of recurrent stroke is probably as high as in patients with carotid stenosis.¹⁵