Abstract
Inflammatory mechanisms may be involved in atherosclerotic plaque rupture. By using a novel histology-based method to quantify plaque instability here, we assess whether lectin pathway (LP) of complement activation, a major inflammation arm, could represent an index of plaque instability. Plaques from 42 consecutive patients undergoing carotid endarterectomy were stained with hematoxylin-eosin and the lipid core, cholesterol clefts, hemorrhagic content, thickness of tunica media, and intima, including or not infiltration of cellular debris and cholesterol, were determined. The presence of ficolin-1, -2, and -3 and mannose-binding lectin (MBL), LP initiators, was assessed in the plaques by immunofluorescence and in plasma by ELISA. LP activation was assessed in plasma by functional in vitro assays. Patients presenting low stenosis (≤75%) had higher hemorrhagic content than those with high stenosis (>75%), indicating increased erosion. Increased hemorrhagic content and tunica media thickness, as well as decreased lipid core and infiltrated content were associated with vulnerable plaques and therefore used to establish a plaque vulnerability score that allowed to classify patients according to plaque vulnerability. Ficolins and MBL were found both in plaques’ necrotic core and tunica media. Patients with vulnerable plaques showed decreased plasma levels and intraplaque deposition of ficolin-2. Symptomatic patients experiencing a transient ischemic attack had lower plasma levels of ficolin-1. We show that the LP initiators are present within the plaques and their circulating levels change in atherosclerotic patients. In particular, we show that decreased ficolin-2 levels are associated with rupture-prone vulnerable plaques, indicating its potential use as marker for cardiovascular risk assessment in atherosclerotic patients.
Highlights
Acute cardiovascular events, such as myocardial infarction and ischemic stroke, are associated with progression and rupture of unstable atherosclerotic plaques
By analyzing the plasma levels of each lectin pathway (LP) initiator, stratifying patients using the median values of the four histological parameters associated with plaque vulnerability—hemorrhagic content, lipid core area, media thickness, and infiltrated content—we found that mannose-binding lectin (MBL) and ficolin-3 were higher in plasma from patients with increased media thickness (Figures 7C,D)
This study demonstrates the potential use of LP components as markers for cardiovascular risk in atherosclerotic patients showing that: [1] ficolins and MBL, initiators of the LP activation, Figure 7 | Activation and initiators of the lectin pathway comparing patients with stable vs. unstable plaques
Summary
Acute cardiovascular events, such as myocardial infarction and ischemic stroke, are associated with progression and rupture of unstable atherosclerotic plaques. Key to advance prevention of neurologic complications and to improve therapy is the early detection of rupture-prone atherosclerotic carotid plaques. The degree of carotid stenosis is the only valid criterion currently used in clinical decision-making to assess the severity of atherosclerotic disease [2]. Stenosis alone is insufficient to reliably predict plaque instability. Vulnerable, plaques may erode causing thromboembolic complications [3] and increased risk of transient ischemic attack and stroke recurrence [4, 5]. Several morphologic studies using non-invasive imaging techniques have been published [6, 7]; a clear-cut clinical definition of vulnerable plaques is not available; a meaningful surrogate of lesion instability detecting vulnerable plaques before symptomatology is needed
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