Development Of Intraplaque Hemorrhage Research Articles

Variations in the Presence of Carotid Intraplaque Hemorrhage Across Age Categories: What Age Groups Are Most Likely to Benefit From Plaque Imaging?

Although carotid artery intraplaque hemorrhage (IPH) is a known risk-factor for cerebral ischemic events in patients of advanced age, its prevalence in younger cohorts is less certain. The purpose of this study was to assess the prevalence of carotid artery IPH across the age spectrum. A retrospective review was completed of all adult patients from our institution who underwent neck MRA with high-resolution carotid plaque imaging between 2017 and 2020. The mean ages of patients with and without IPH were calculated. The prevalence of IPH was compared between patients that were categorized into age groups. Patients with and without a cerebral ischemic event (e.g., stroke, retinal ischemia) were included. Unilateral anterior circulation ischemic events in patients without atrial fibrillation were presumed to be likely related to ipsilateral carotid artery disease. Multiple regression analysis was performed to determine independent associations with IPH. 634 patients were included (1,268 carotid arteries). Increasing age (OR: 1.04; 95% CI: 1.02–1.06; P = 0.001) was independently associated with IPH. 211 patients had unilateral anterior circulation ischemic events. The mean age of patients with carotid IPH was 71.4 years (SD = 9.9), compared to 62.8 years (SD = 15.8) of those without (P ≤ 0.0001). The prevalence of IPH increased with age in all patients (P = 0.0002). Among patients with ipsilateral anterior circulation ischemic events, each age category above 50 years had a significantly higher prevalence of IPH when compared to patients 18–50 years (P ≤ 0.05 for all comparisons). The prevalence of carotid IPH increases with age and is rare in patients under 50 years. The approximate threshold age for IPH development is likely around 50 years.

Carotid Intraplaque Hemorrhage Is Associated with Cardiovascular Risk Factors

Introduction: Intraplaque hemorrhage (IPH) is a known predictor of symptomatic cervical carotid artery disease. However, the association between IPH and modifiable cardiovascular risk factors, patient demographics, and pertinent laboratory values has not been extensively studied. Methods: A retrospective review was performed of consecutive patients who have undergone dedicated carotid plaque imaging over a 3-year period. Patients were excluded if the MR examination did not include high-resolution carotid plaque imaging. Intraplaque hyperintense signal on carotid plaque images was presumed to represent IPH. The presence or absence of IPH was compared to various demographic and clinical variables. Multivariable regression analysis was performed in order to determine an independent association between variables and IPH. Results: Of 643 included patients, 114 patients (17.7%) had IPH in one or both carotids, 529 patients (82.3%) did not; 39.5% of patients with IPH had coronary artery disease compared to 23.1% of patients without (p = 0.0003). Patients with IPH also had higher proportions of hypertension (77.2 vs. 60.7%, p = 0.009), hyperlipidemia (HLD; 89.5 vs. 62.4%, p < 0.0001), diabetes mellitus (29.0 vs. 18.7%, p = 0.01), and a history of tobacco smoking (63.2 vs. 52.6%, p = 0.003). Patients without IPH had, on average, higher high-density lipoprotein levels (46.1 vs. 56.7%, p = 0.003). Factors independently associated with IPH were advanced age (odds ratio [OR]: 1.1, 95% CI: [1.0–1.05], p <0.0001), male sex (OR: 2.5, 95% CI: [1.4–4.4], p = 0.0001), presence of carotid stenosis (OR: 8.4, 95% CI: [4.6–15.3], p < 0.0001), and HLD (OR: 2.6, 95% CI: [1.3–5.2], p = 0.009). Conclusions: IPH is associated with multiple cardiovascular risk factors, in particular advanced age, male sex, presence of carotid stenosis, and HLD. Such risk factors likely play a role in the development of IPH and may provide insight into the pathophysiology of unstable carotid plaques.

Dynamic change of carotid intraplaque hemorrhage volume in subjects with mild carotid stenosis

Background and PurposeEarly detection of intraplaque hemorrhage (IPH) in the carotid artery is important as it is correlated with an increased risk of cerebral ischemic events. We examined changes in IPH with magnetic resonance imaging (MRI) over an extended follow-up period in patients with mild carotid stenosis. Materials and MethodsFrom November 2013 to November 2015, we retrospectively reviewed cerebral MRI of 2036 patients, including magnetization-prepared rapid acquisition with gradient-echo (MPRAGE) sequences obtained with a 3.0 T (T) MRI unit. An experienced neuroradiologist reviewed all studies and found 38 patients with carotid IPH and carotid stenosis that were categorized as mild (<30%), according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. Twenty-five patients agreed to join this study and signed informed consent for (MPRAGE) sequence imaging. We used semi-automated software to measure IPH volume on both the initial and follow up scans. ResultsThe median follow-up time of patients with mild carotid stenosis and IPH was 33.3 months. IPH volume increased in 10 of 27 carotid arteries (37.0%), with a mean volume increase of 42.6 ± 44.0 mm3. IPH volume decreased in 17 of 27 carotid arteries (63%), with a mean volume decrease of 17.2 ± 22.8 mm3. Two patients without IPH at baseline showed IPH development on follow-up imaging. There were no significant differences in patient demographics between the two groups. ConclusionsCarotid IPH volume in subjects with mild carotid stenosis can change over time and may not be correlated with any typical patient demographics.

Use of Antiplatelet Agents Is Associated With Intraplaque Hemorrhage on Carotid Magnetic Resonance Imaging: The Plaque at Risk Study.

Intraplaque hemorrhage (IPH), visualized by magnetic resonance imaging, has shown to be associated with the risk of stroke in patients with carotid artery stenosis. The mechanisms of IPH development are poorly understood. In this study, we investigated the association between clinical patient characteristics and carotid IPH on high-resolution magnetic resonance imaging. Patients participate in the Plaque at Risk (PARISK) study. This prospective, multicenter cohort study included patients with recent amaurosis fugax, hemispheric transient ischemic attack, or nondisabling stroke in the internal carotid artery territory and an ipsilateral carotid stenosis of <70%, who were not scheduled for carotid revascularization procedure. One hundred patients, recruited between 2010 and 2012, underwent a 3-T high-resolution carotid magnetic resonance imaging. We documented clinical patient characteristics and performed multivariable logistic regression analysis to investigate their association with IPH. IPH was observed in 45 patients (45%) in 1 or both carotid arteries. Male sex and the use of antiplatelet agents before the index event were associated with IPH in univariable analysis. In a multivariable analysis, only previous use of antiplatelet agents was significantly associated with IPH (odds ratio, 2.71; 95% confidence interval, 1.12-6.61). Risk factors of atherosclerotic arterial disease, including a history of symptomatic arterial diseases, were not associated with IPH. In this cohort of 100 patients with recently symptomatic carotid stenosis, the previous use of antiplatelet agents is associated with carotid IPH on magnetic resonance imaging. Antiplatelet therapy may increase the risk of IPH, but our findings need to be confirmed in larger patient cohorts. The implications for risk stratification remain to be determined.

Communication of inwardly projecting neovessels with the lumen contributes to symptomatic intraplaque hemorrhage in carotid artery stenosis.

Recent studies have demonstrated that plaque morphology can contribute to identification of patients at high risk of carotid artery atherosclerosis as well as the degree of stenosis in those with carotid atherosclerosis. Neovascularization of carotid plaques is associated with plaque vulnerability. However, the mechanism of neovascularization in intraplaque hemorrhage (IPH) and its clinical contribution remain undetermined. In this study, the authors aimed to clarify the characteristics of neovessel appearance with a focus on inwardly projecting neovessels, which are reportedly important in plaque advancement. Consecutive patients with moderate to severe carotid atherosclerosis who underwent carotid endarterectomy were prospectively analyzed from 2010 to 2014. The neovessel appearance was categorized into 3 groups based on intraoperative indocyanine green (ICG) videoangiography: early appearance of neovessels from the endothelium (NVe), late appearance of neovessels from the vasa vasorum (NVv), and no appearance of vessels. Each neovessel pattern was evaluated with respect to clinical, radiological, and pathological findings including IPH, neovascularization, hemosiderin spots, and inflammation. Of 57 patients, 13 exhibited NVe, 33 exhibited NVv, and 11 exhibited no neovessels. Overall, the interobserver and intraobserver reproducibilities of neovessel appearance were substantial for ICG videoangiography (κ=0.76) and at 7 days postoperatively (κ=0.76). There were no significant differences in baseline characteristics among the 3 groups, with the exception of a higher percentage of symptomatic presentations in patients with NVe (artery-to-artery embolic infarction in 61.5% and transient ischemic attack in 23.1%). Moreover, patients with NVe exhibited larger infarctions than did those with NVv (9675.0±5601.9 mm3 vs 2306.6±856.9 mm3, respectively; p=0.04). Pathologically, patients with NVe had more severe IPH (47.2±8.3 mm2 vs 19.8±5.2 mm2, respectively; p<0.01), hemosiderin spots (0.5±0.2 mm2 vs 0.2±0.1 mm2, respectively; p=0.04), neovessels (0.4±0.7 mm2 vs 0.1±0.4 mm2, respectively; p=0.11), and inflammation (1.0±1.1 mm2 vs 0.6±0.9 mm2, respectively; p=0.26) around the endothelium than did patients with NVv, and all of these parameters were correlated with hyperintensity on time-of-flight MRI. However, the neovessel and inflammation differences were nonsignificant. Interestingly, inflammation was significantly correlated with neovessel formation (r=0.43, p=0.0008), hemosiderin spots (r=0.62, p<0.0001), and IPH (r=0.349, p=0.0097), suggesting that inflammation may be a key factor in plaque vulnerability. Communication of inwardly projecting neovessels with the lumen and inflammation synergistically contribute to IPH and symptomatic presentations in patients with carotid stenosis and are more specific than the vasa vasorum. This condition could be a new therapeutic target, and regression of luminal neovessel sprouting and inflammation may help to prevent IPH development and a symptomatic presentation.

Abstract 170: Luminal Neovascular Sprouting with Inflammation Contributes to Symptomatic Intraplaque Hemorrhage in Carotid Stenosis

Background and Purpose: Neovascularization of carotid plaques is associated with plaque vulnerability. However, the role of neovascularization in the development of intraplaque hemorrhage (IPH) and the clinical contribution of neovascularization to IPH and symptomatic presentation remain undetermined. Methods: Consecutive patients with moderate to severe carotid atherosclerosis who underwent carotid endarterectomy were prospectively analyzed from 2010 to 2014. The neovessel appearance was categorized into three groups based on dynamic intraoperative indocyanine green videoangiography: neovessels derived from the endothelium (NVe), neovessels derived from the vasa vasorum (NVv), and no neovessels. Each neovessel pattern was evaluated with respect to clinical, radiological, and pathological findings. Results: Of 57 patients, 13 exhibited NVe, 33 exhibited NVv, and 11 exhibited no neovessels. There were no significant differences in baseline characteristics among the three groups with the exception of a higher percentage of symptomatic presentations among patients with NVe. Moreover, patients with NVe exhibited larger infarctions than did those with NVv (P=0.04). Pathologically, patients with NVe had more severe IPH (P=0.002), hemosiderin spots (P=0.04), neovessels (P=0.11) and inflammation (P=0.26), all of which were correlated with hyperintensity on time-of-flight magnetic resonance imaging. Interestingly, inflammation was significantly correlated with neovessel formation (R=0.43, P=0.008), hemosiderin spots (R=0.62, P&lt;0.0001), and IPH (R=0.349, P=0.0097), suggesting that inflammation may be a key factor in plaque vulnerability. Conclusions: Luminal neovascular sprouting with inflammation and lumen communication could clinically contribute to IPH and symptomatic presentation in patients with carotid stenosis. This condition may thus be a key therapeutic target against neovessel formation and inflammation.

Sustained Acceleration in Carotid Atherosclerotic Plaque Progression With Intraplaque Hemorrhage: A Long-Term Time Course Study

This study sought to determine the immediate and long-term effects of intraplaque hemorrhage (IPH) on plaque progression in the carotid artery. Previous studies have associated IPH in the carotid artery with more rapid plaque progression. However, the time course and long-term effect remain unknown. Carotid magnetic resonance imaging is a noninvasive imaging technique that has been validated with histology for the accurate in vivo detection of IPH and measurement of plaque burden. Asymptomatic subjects with 50% to 79% carotid stenosis underwent carotid magnetic resonance imaging at baseline and then serially every 18 months for a total of 54 months. Subjects with IPH present in at least 1 carotid artery at 54 months were selected. Subsequently, presence/absence of IPH and wall volume were determined independently in all time points for both sides. A piece-wise progression curve was fit by using a linear mixed model to compare progression rates described as annualized changes in wall volume between periods defined by their relationship to IPH development. From 14 subjects who exhibited IPH at 54 months, 12 arteries were found to have developed IPH during the study period. The progression rates were -20.5 ± 13.1, 20.5 ± 13.6, and 16.5 ± 10.8 mm(3)/year before, during, and after IPH development, respectively. The progression rate during IPH development tended to be higher than the period before (p = 0.080) but comparable to the period after (p = 0.845). The progression rate in the combined period during/after IPH development was 18.3 ± 6.5 mm(3)/year, which indicated significant progression (p = 0.008 compared with a slope of 0) and was higher than the period before IPH development (p = 0.018). No coincident ischemic events were noted for new IPH. The development of IPH posed an immediate and long-term promoting effect on plaque progression. IPH seems to alter the biology and natural history of carotid atherosclerosis. Early identification of patients with IPH may prove invaluable in optimizing management to minimize future sequelae.

脳血管障害の最先端 頚部頚動脈狭窄性病変の分子機構におけるＶＥＧＦの役割とその制御機構

Recently it has been reported that vascular endothelial growth factor (VEGF) and its receptor (Flt-1) may alter the role of atherosclerotic plaque development and that anti-Flt-1 antibody inhibits atherosclerosis. Since VEGF is an angiogenesis/permeable factor, it can promote angiogenesis and may lead to intraplaque hemorrhage. In addition, VEGF is up-regulated by hypoxia-inducible factor (HIF), which is down-regulated by von Hippel-Lindau (VHL) protein. We studied the roles of these factors in cervical carotid stenotic lesion, examining 39 specimens of carotid plaques obtained during carotid endarterectomy for patients with symptomatic carotid stenosis. Immunohistochemical study was performed with antibodies against VEGF, Flt-1, HIF-1α, VHL and α-actin for smooth muscle cells, and CD68 for macrophage. VEGF was expressed distinctly in foamy cells in the fibrous cap and plaque shoulder in the deep layer of atherosclerotic carotid plaques. Most of the foamy cells were derived from macrophages, but some of them came from smooth muscle cells. Flt-1 positive cells were identified among most VEGF-positive cells. HIF-1α-positive cells constituted a majority of VEGF-positive cells while VHL-positive cells constituted a minority of VEGF-positive cells, particularly at newly formed vessels in carotid plaques. In conclusion, VEGF expression in carotid plaque is identified in foamy cells mostly derived from macrophages in the deep layer of carotid plaque. It is suggested that VEGF expression is up-regulated by HIF-1α, which is partially down-regulated by VHL. Since it is reported that VEGF expression is regulated by oxidated LDL, a VEGF-related pathway might play a critical role in the advancement of atherosclerotic carotid plaque and the development of intraplaque hemorrhage.

Induction of angiogenesis by smooth muscle cell‐derived factor: Possible role in neovascularization in atherosclerotic plaque

The development of atherosclerotic plaque is associated with neovascularization in the thickened intima and media of vascular walls. Neovascularization may have a role in the progression of atherosclerotic plaque as well as in the development of intraplaque hemorrhage. However, the mechanism and stimulus for neovascularization in atherosclerotic plaque are unknown. We postulated that smooth muscle cells (SMCs), a major cellular component in the vascular wall, might contribute to the induction of neovascularization in atherosclerotic plaque through the secretion of an angiogenic factor. We observed that endothelial cells (ECs) cultured on collagen gel with SMC-conditioned medium became spindle shaped, invaded the underlying collagen gel, and organized a capillary-like branching cord structure in the collagen gel. The conditioned medium also stimulated EC proliferation and increased the EC-associated plasminogen activator activity. The angiogenic factor in SMC-conditioned medium was retained in a heparin-Sepharose column and eluted with 0.9 M NaCl. Neutralizing anti-vascular endothelial growth factor (VEGF) antibody attenuated the angiogenic activity in the conditioned medium, including the induction of morphologic changes in ECs, mitogenic activity, and increased plasminogen activator activity associated with ECs. Immunoblotting analysis confirmed the secretion of VEGF from SMCs. These observations indicate that SMC may be responsible for the neovascularization in atherosclerotic plaque through the secretion of VEGF.

Carotid artery intraplaque hemorrhage and stenotic velocity.

One of the proposed mechanisms for sudden expansion of a carotid bifurcation plaque is hemorrhage within the lesion. It has been postulated that the sudden increase in plaque size will acutely reduce blood flow to the ipsilateral hemisphere and induce either a transient ischemic attack or a stroke. In this study, the relation between peak systolic velocity at the site of narrowing and its potential role in the development of intraplaque hemorrhage were investigated. Ten patients who had carotid endarterectomy were examined by duplex Doppler sonography before surgery to determine the peak systolic velocity at the site of maximal narrowing. The excised carotid plaques were sectioned at 1-mm intervals and examined for histological evidence of intraplaque hemorrhage. The recorded peak systolic velocities in patients with intraplaque hemorrhage were compared with the velocities in cases in which no hemorrhage was identified. Five of the ten patients had intraplaque hemorrhage. Four of the five patients with intraplaque hemorrhage had a peak systolic velocity of > 420 cm/sec and diastolic velocities of > 160 cm/sec; none of the patients without intraplaque hemorrhage had such high values. Peak systolic velocity is significantly higher in patients with intraplaque hemorrhage. The specificity and sensitivity of a peak systolic velocity of > 420 cm/sec in predicting intraplaque hemorrhage remains to be determined.