doi: 10.1161/ATVBAHA.108.177659
© 2009 American Heart Association, Inc.
Editorials |
Carotid Plaque Stabilization and Progression After Stroke or TIA
From CVPath Institute Inc (R.V., F.D.K.), Gaithersburg, Md; and the Department of Medicine (A.V.F.), Emory University School of Medicine, Atlanta, Ga.
Correspondence to Renu Virmani, MD, Medical Director, CVPath Institute Inc, 19 Firstfield Road, Gaithersburg, MD 20878. E-mail rvirmani{at}cvpath.org
Although plaque rupture is the predominant etiology of carotid artery thrombosis, the stages of lesion progression culminating in a cerebral vascular accident with subsequent plaque passivation is poorly understood. Indeed, the previous largest series of carotid plaques removed at surgery by Redgrave et al implicates plaque rupture as dominant lesion morphology in symptomatic lesions.1 Notwithstanding, removal of even asymptomatic plaques has been shown to reduce the 5-year incidence of stroke and death as reported by the collaborative group Asymptomatic Carotid Surgery Trial, where 3210 patients undergoing carotid endarterectomy for substantial carotid narrowing of >70% were studied.2 Taken together these studies exemplify the importance of plaque rupture and thrombosis as the major contributor of embolization in ischemic stroke. Indeed, these studies are highly reminiscent of coronary disease where the main culprit lesion which gives rise to thrombosis is identified as plaque rupture.3 Moreover, although reports in the literature contend that further lesion progression in coronary arteries manifests through repeated ruptures,4,5 this concept applied to the carotid, as suggested by Wasserman et al,6 has never been confirmed in large patient population presenting with stroke or TIAs.
See accompanying article on page 128
In the largest reported series of carotid endarterectomy specimens acquired from patients with durations <30 days to beyond 180 days after presentation, Peeters et al in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology studied the pathophysiology of lesion stabilization after symptomatic stroke.7 Of the plaque characteristics measured with time elapse between the most recent event and surgery, there was a significant decrease in macrophage infiltration and capsase-3 activity limited to patients presenting with stroke in lesions removed beyond 60 days of onset of symptoms.7 Protein analysis of carotid lesions showed a concomitant decrease in the expression interleukins-6 and -8, further supporting the finding of reduced macrophage infiltration. Although carotid lesions from patients with recent stroke (<30 days) demonstrated increased matrix metalloproteinase (MMP) activity for MMPs-8 relative to asymptomatic plaques, sustained expression of this marker along with MMPs-2 and-9 beyond 180 days was not evident. In contrast, no differences were found in macrophage infiltration or MMP expression over time in plaques from patients who experienced TIAs, indicating that plaques in patients presenting with stroke behave differently than those with TIAs.7
Acute thrombosis in the coronary artery arises from three independent mechanisms, namely plaque rupture, plaque erosion, and calcified nodule. Rates of plaque rupture in the coronary (occurring in 65% to 70% of patients with ACS) are similar for those reported for the carotid. Morphological parameters identified with lesion instability include the presence of a necrotic core and thin fibrous cap infiltrated by macrophages, which can be further complicated by accumulated iron or calcium. These morphological attributes together with high shear stress are thought to promote rupture of the fibrous cap.8,9 Of further importance, the carotid distribution is anatomically different from the coronary bed because vessel size is larger and blood flow significantly higher, which may be responsible for higher rates of distal embolization responsible for strokes or TIAs. In contrast to the coronary, the thrombus forming at the rupture site of the carotid often leaves an ulcerated plaque and only rarely a luminal thrombus is present where it is generally small (Figure 1).
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Of the two less frequent mechanisms of thrombosis, plaque erosion, a poorly understood process, is thought related to the loss of endothelium either secondary to vasospasm or from the inability of endothelial cells to adhere to an underlying matrix rich in hyaluronan.10,11 Although plaque erosion is well described in carotid thrombosis, its prevalence is greater in patients presenting with TIAs (12%) than those with stroke (7%).12 The relative frequency of plaque erosion is even greater in the coronary bed, representing an underlying cause of thrombosis in 25% to 30% of sudden coronary death. In particular, plaque erosion is common in young women <50 years of age and young men mostly in their 3rd or 4th decade.13 Lastly, the least common mechanism of thrombosis is caused by eruptive or shedding of calcified nodule observed protruding into the lumen space in areas lacking endothelium. The frequency of nodular calcification is slightly more common in the carotid than the coronary, where in both locations it is associated with heavily calcified arteries (R.V., personal communication, 2008).
Inflammation has been described to be an important component of unstable atherosclerotic plaque (thin-cap fibroatheroma and rupture plaque) whether in the coronary or the carotid.15,16 Quantification of inflammation is considered more accurate in the coronary because these vessels are generally without surgical artifacts represented by tissue loss. In the coronary, severe inflammation is not considered a major component of the plaque because it does not extend beyond 2% to 5% of total lesion area. Inflammation remains, however, an important determinant of lesion instability because it contributes to necrotic core size, plaque angiogenesis, and thinning of the fibrous cap through the release of potent MMPs.17 Regions of the plaque with high-density macrophages are reported to contain MMPs-1, -2, -3, -8, -9, -11, -12, -13, -14, and -16; furthermore, MMPs-1, -3, -8, and -13 are colocalized with cleaved collagen.18–20 Therefore, recent emphasis has been placed on macrophages as the primary component of rupture. This notion, however, is inconsistent with findings in the study by Peeters et al, because there was no change in the activity of MMPs-2, -8, and -9 in lesions from patients presenting with stroke despite a significant decrease in macrophage infiltration and proinflammatory markers interleukin (IL)-6 and IL-8 with increasing time of event presentation to surgery. These negative findings, however, do not negate the possibility of other sources of MMPs within the plaque.
Further, although the presence of smooth muscle cells (SMCs) in lesions from stroke patients increased with time, values did not reach statistical significance, perhaps because recognition of SMCs was based on a single marker (
-actin immunostaining) which has been shown to be variable in atherosclerotic plaques21; other SMC recognition markers were not assessed. Moreover, the lack of a significant change in SMC density in lesion from patients from TIAs may be related to the decreased incidence of thrombosis relative to lesions associated with stroke.
Another protein indicator of plaques stabilization after rupture is the apoptotic indicator caspase-3, where its expression in lesions from patients with stroke was highest at the time of presentation but decreased thereafter. In contrast, caspase-3 activity was essentially unchanged in lesions from patients with TIAs, suggesting differential mechanisms of healing after luminal thrombosis relative to stroke patients. In the coronary lesions, sites with acute plaque rupture selectively demonstrate increased apoptotic macrophages colocalized with activated caspase-3,22 and therefore it would be reasonable to assume that levels of activated caspase-3 would be highest at the time of rupture in stroke patients. The rationale behind why the activity of caspase-3 remains variable and low in carotid plaques from TIAs is unclear, unless the mechanism of thrombosis as suggested by Redgrave et al and Spagnoli et al is secondary to plaque erosion where the extent of apoptosis may be less apparent.1,12 Moreover, the incidence of thrombosis is lower in TIAs (35%) versus stroke (74%), at least as reported by Spagnoli et al but not confirmed by Redgrave.12
Plaque progression in the coronary artery has been attributed to repeated silent ruptures with asymptomatic luminal thrombi that heal over time contributing to increased vessel narrowing. Healed repair sites are recognized morphologically by a discontinuous fibrous cap, filled in by smooth muscle cells, proteoglycans, and type III collagen.4 In an unrelated autopsy study, Davies showed that the frequency of healed plaque ruptures (HPRs) increased with the degree of luminal narrowing. For example, the incidence of HPRs in lesions (with 0% to 20% diameter stenosis) was 16% (21% to 50% stenosis), 19%, and vessels with (>50% narrowing), 73%.5 In our experience, 61% of hearts from sudden coronary deaths show HPRs.4 The incidence of HPR is highest in stable plaques (80%), followed by ruptures (75%) then erosions (9%). Multiple healed ruptures with layering were common in segments with acute and healed ruptures where percent cross-sectional luminal narrowing was dependent on the number of healed repair sites. Notably, the underlying percent luminal narrowing for acute ruptures exceeds that for healed ruptures (79±15% versus 66±14%, P=0.0001).4 Although the presence of previous healed rupture sites may influence natural processes of atherosclerotic plaque healing, the incidence of repeat ruptures in the article by Peeters et al7 was not discussed.
In today’s clinical environment, it is essential to consider the impact of statins on carotid plaque morphology. In the study by Peeters et al there was no indication of reduced lesional macrophages or proinflammatory proteins in carotid plaque of patients receiving statin therapy. The absence of a statin effect on plaque healing is difficult to interpret, although it may be related to the crude assessment of macrophages or artifacts introduced at the time of surgery when endarterectomy are often removed piecemeal. The efficacy of statins on plaque stabilization is well proven in recent animal models and biomarker studies of human sera collected from patients receiving statins, in particular with more potent third generation drugs such as rosuvastatin. Pathological studies in animal models demonstrate marked reductions in plaque macrophages in lesions with less advanced phenotypes,23 whereas studies of patients on statins show decreased circulating proinflammatory cytokines such as IL-6, IL-8, and CRP.24 Nonetheless, the current study does show the temporal relationship of healing of carotid plaques in patients presenting with stroke.
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, and tumor necrosis factor (TNF)- |
Acknowledgments |
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Disclosures
None.
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References |
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