Pedro R. Moreno

Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture.

BackgroundRupture of atherosclerotic plaques is probably the most important mechanism underlying the sudden onset of acute coronary syndromes. Macrophages may release lytic enzymes that degrade the fibrous cap and therefore produce rupture of the atherosclerotic plaque. This study was designed to quantify macrophage content in coronary plaque tissue from patients with stable and unstable coronary syndromes. Methods and ResultsHematoxylin and eosin and immuno-staining with anti-human macrophage monoclonal antibody (PG-M1) were performed. Computerized planimetry was used to analyze 26 atherectomy specimens comprising 524 pieces of tissue from 8 patients with chronic stable angina, 8 patients with unstable angina, and 10 patients with non-Q-wave myo-cardial infarction. Total plaque area was 417±87 mm2× 10−2 in patients with stable angina, 601±157 mm2×10−2 in patients with unstable angina, and 499±87 mm2× 10−2in patients with non-Q-wave myocardial infarction (P=NS). The macrophage-rich area was larger in plaques from patients with unstable angina (61±18 mm2x 102) and non-Q-wave myocardial infarction (87±32 mm2× 10−2) than in plaques from patients with stable angina (14±5 mm2×10−2) (P=.024). The percentage of the total plaque area occupied by macrophages was also larger in patients with unstable angina (13.3 ±5.6%) and non-Q-wave myocardial infarction (14.6±4.6%) than in patients with stable angina (3.14±1%) (P=.018). Macrophagerich sclerotic tissue was largest in patients with non-Q-wave myocardial infarction (67±30 mm2× 1010−2) and unstable angina (55±19 mm2× 10−2) than in patients with stable angina (11.5±4.1 mm2× 10−2) (P=.046). Macrophage-rich atheromatous gruel was also larg-est in patients with non-Q-wave myocardial infarction (15±4 mm2×10−2) than in patients with unstable angina (3.3±1.7 mm2×10−2) or stable angina (2.4±1.2 mm2× 10−2) (P=.026). ConclusionsMacrophage-rich areas are more frequently found in patients with unstable angina and non-Q-wave myocardial infarction. This suggests that macrophages are a marker of unstable atherosclerotic plaques and may play a significant role in the pathophysiology of acute coronary syndromes.

Plaque Neovascularization Is Increased in Ruptured Atherosclerotic Lesions of Human Aorta Implications for Plaque Vulnerability

Background—Growth of atherosclerotic plaques is accompanied by neovascularization from vasa vasorum microvessels extending through the tunica media into the base of the plaque and by lumen-derived microvessels through the fibrous cap. Microvessels are associated with plaque hemorrhage and may play a role in plaque rupture. Accordingly, we tested this hypothesis by investigating whether microvessels in the tunica media, the base of the plaque, and the fibrous cap are increased in ruptured atherosclerotic plaques in human aorta. Methods and Results—Microvessels, defined as CD34-positive tubuloluminal capillaries recognized in cross-sectional and longitudinal profiles, were quantified in 269 advanced human plaques by bicolor immunohistochemistry. Macrophages/T lymphocytes and smooth muscle cells were defined as CD68/CD3-positive and &agr;-actin–positive cells. Total microvessel density was increased in ruptured plaques when compared with nonruptured plaques (P=0.0001). Furthermore, microvessel density was increased in lesions with severe macrophage infiltration at the fibrous cap (P=0.0001) and at the shoulders of the plaque (P=0.0001). In addition, microvessel density was also increased in lesions with intraplaque hemorrhage (P=0.04) and in thin-cap fibroatheromas (P=0.038). Logistic regression analysis identified plaque base microvessel density (P=0.003) as an independent correlate to plaque rupture. Conclusions—Thus, neovascularization as manifested by the localized appearance of microvessels is increased in ruptured plaques in the human aorta. Furthermore, microvessel density is increased in lesions with inflammation, with intraplaque hemorrhage, and in thin-cap fibroatheromas. Microvessels at the base of the plaque are independently correlated with plaque rupture, suggesting a contributory role for neovascularization in the process of plaque rupture.

Coronary Composition and Macrophage Infiltration in Atherectomy Specimens From Patients With Diabetes Mellitus

BackgroundLipid-rich, inflamed atherosclerotic lesions are associated with plaque rupture and thrombosis, which are the most important causes of death in patients with diabetes mellitus. This study was designed to quantify lipid composition and macrophage infiltration in the coronary lesions of patients with diabetes mellitus. Methods and ResultsA total of 47 coronary atherectomy specimens from patients with diabetes mellitus were examined and compared with 48 atherectomy specimens from patients without diabetes. Plaque composition was characterized by trichrome staining. Macrophage infiltration was characterized by immunostaining. Clinical and demographic data were similar in both groups. The percentage of total area occupied by lipid-rich atheroma was larger in specimens from patients with diabetes (7±2%) than in specimens from patients without diabetes (2±1%;P =0.01), and the percentage of total area occupied by macrophages was larger in specimens from patients with diabetes (22±3%) than in specimens from patients without diabetes (12±1%;P =0.003). The incidence of thrombus was also higher in specimens from patients with diabetes than in specimens from patients without diabetes (62% versus 40%;P =0.04). Plaque composition, macrophage infiltration, and thrombus were similar in lesions from diabetic patients treated with insulin compared with lesions from patients treated with sulfonylureas or diet. ConclusionsCoronary tissue from patients with diabetes exhibits a larger content of lipid-rich atheroma, macrophage infiltration, and subsequent thrombosis than tissue from patients without diabetes. These differences suggest an increased vulnerability for coronary thrombosis in patients with diabetes mellitus.

Macrophages, Smooth Muscle Cells, and Tissue Factor in Unstable Angina Implications for Cell-Mediated Thrombogenicity in Acute Coronary Syndromes

Background Macrophage expression of tissue factor may be responsible for coronary thrombogenicity in patients with plaque rupture. In patients without plaque rupture, smooth muscle cells may be the thrombogenic substrate. This study was designed to identify the cellular correlations of tissue factor in patients with unstable angina. Methods and Results Tissue from 50 coronary specimens (1560 pieces) from patients with unstable angina and 15 specimens from patients with stable angina were analyzed. Total and segmental areas (in square millimeters) were identified with trichrome staining. Macrophages, smooth muscle cells, and tissue factor were identified by immunostaining. Tissue factor content was larger in unstable angina (42±3%) than in stable angina (18±4%) ( P =.0001). Macrophage content was also larger in unstable angina (16±2%) than in stable angina (5±2%) ( P =.002). The percentage of tissue factor located in cellular areas was larger in coronary samples from patients with unstable angina (67±8%) than in samples from patients with stable angina (40±5%) ( P =.00007). Multiple linear stepwise regression analysis showed that coronary tissue factor content correlated significantly ( r =.83, P r =.98, P Conclusions Tissue factor content is increased in unstable angina and correlates with areas of macrophages and smooth muscle cells, suggesting a cell-mediated thrombogenicity in patients with acute coronary syndromes.

Macrophages, Smooth Muscle Cells, and Tissue Factor in Unstable Angina

BACKGROUND Macrophage expression of tissue factor may be responsible for coronary thrombogenicity in patients with plaque rupture. In patients without plaque rupture, smooth muscle cells may be the thrombogenic substrate. This study was designed to identify the cellular correlations of tissue factor in patients with unstable angina. METHODS AND RESULTS Tissue from 50 coronary specimens (1560 pieces) from patients with unstable angina and 15 specimens from patients with stable angina were analyzed. Total and segmental areas (in square millimeters) were identified with trichrome staining. Macrophages, smooth muscle cells, and tissue factor were identified by immunostaining. Tissue factor content was larger in unstable angina (42 +/- 3%) than in stable angina (18 +/- 4%) (P = .0001). Macrophage content was also larger in unstable angina (16 +/- 2%) than in stable angina (5 +/- 2%) (P = .002). The percentage of tissue factor located in cellular areas was larger in coronary samples from patients with unstable angina (67 +/- 8%) than in samples from patients with stable angina (40 +/- 5%) (P = .00007). Multiple linear stepwise regression analysis showed that coronary tissue factor content correlated significantly (r = .83, P < .0001) with macrophage and smooth muscle cell areas only in tissue from patients with unstable angina, with a strong relationship between tissue factor content and macrophages in the atheromatous gruel (r = .98, P < .0001). CONCLUSIONS Tissue factor content is increased in unstable angina and correlates with areas of macrophages and smooth muscle cells, suggesting a cell-mediated thrombogenicity in patients with acute coronary syndromes.

Impact of the everolimus-eluting stent on stent thrombosis: a meta-analysis of 13 randomized trials

OBJECTIVES We evaluated the impact of the everolimus-eluting stent (EES) on the frequency of stent thrombosis (ST), target vessel revascularization (TVR), myocardial infarction (MI), and cardiac death in randomized controlled trials comparing the EES to non-everolimus-eluting drug-eluting stents (EE-DES). BACKGROUND Whether or not the unique properties of the EES translate into reductions in ST remains unknown. METHODS We searched MEDLINE, Scopus, the Cochrane Library, and Internet sources for articles comparing outcomes between EES and non-EE-DES without language or date restriction. Randomized controlled trials reporting the frequency of ST were included. Variables relating to patient and study characteristics and clinical endpoints were extracted. RESULTS We identified 13 randomized trials (n = 17,101) with a weighted mean follow-up of 21.7 months. Compared with non-EE-DES, the EES significantly reduced ST (relative risk [RR]: 0.55; 95% confidence interval [CI]: 0.38 to 0.78; p = 0.001), TVR (RR: 0.77; 95% CI: 0.64 to 0.92; p = 0.004), and MI (RR: 0.78; 95% CI: 0.64 to 0.96; p = 0.02). There was no difference in cardiac mortality between the groups (RR: 0.92; 95% CI: 0.74 to 1.16; p = 0.38). The treatment effect was consistent by different follow-up times and duration of clopidogrel use. The treatment effects increased with higher baseline risks of the respective control groups with the strongest correlation observed for ST (R(2) = 0.89, p < 0.001). CONCLUSIONS Intracoronary implantation of the EES is associated with highly significant reductions in ST with concordant reductions in TVR and MI compared to non-EE-DES. Whether these effects apply to different patient subgroups and DES types merits further investigation.

Intimomedial Interface Damage and Adventitial Inflammation Is Increased Beneath Disrupted Atherosclerosis in the Aorta Implications for Plaque Vulnerability

Background—Atherosclerotic plaque progression is frequently accompanied by compensatory enlargement to preserve the lumen. These enlarging plaques develop features of vulnerability, however, leading to disruption and lumen obstruction. This complex transition from compensatory expansion to plaque disruption may not derive solely from progressive intimal disease. Concurrent changes at the intimomedial interface and within the tunica media and adventitia may play a role in plaque instability. We tested this hypothesis by investigating whether interface changes, including internal elastic lamina (IEL) rupture, and medial and adventitial changes, including inflammation, fibrosis, and atrophy, more frequently accompany disrupted than nondisrupted atherosclerotic plaques. Methods and Results—Computerized planimetry and ocular micrometry were used for systematic quantification of intimal, medial, and adventitial histopathological features in 598 human aortic plaques according to the AHA classification. Disrupted plaques exhibited larger plaque and lipid pool areas (P =0.0001) and a higher incidence of rupture of the IEL (P =0.0001). Medial and adventitial inflammation (P =0.01), medial fibrosis (P =0.0001), and medial atrophy (P =0.0001) were also higher in disrupted plaques. Furthermore, medial thickness was reduced in disrupted plaques (P =0.0001). Logistic regression analysis identified rupture of the IEL as an independent predictor for fibrous cap disruption (P =0.0001). Conclusions—Compared with nondisrupted plaques, disrupted plaques have an increased incidence of IEL rupture, medial and adventitial inflammation, medial fibrosis, and medial atrophy. These intimomedial interface and adventitial changes may play a role in the natural history of complex atherosclerotic lesions. The interaction between medial and adventitial pathology and the intimal atherosclerotic process deserves further investigation.

Cellular Senescence, Vascular Disease, and Aging: Part 2 of a 2-Part Review: Clinical Vascular Disease in the Elderly

The increasing prevalence of older-age people in our society represents the culmination of centuries of medical, scientific, and social endeavors. At least in Western society, now relatively freed from pestilence, abject poverty, gross malnutrition, and polluted water and food sources, an increasing proportion of the population can expect to make it to old age. However, although US age-adjusted death rates from cardiovascular disease, coronary heart disease, and stroke continue to fall, a disproportionate number of people who reach old age (80% of people aged 80 years) suffer from these diseases.1a In this 2-part review, we consider important pathobiological changes that occur with aging in the cardiovascular system, exploring promising areas of recent scientific progress and novel insights that may be translatable into targeted clinical strategies to help to alleviate the excess morbidity and mortality imposed by cardiovascular disease in the elderly. In this second installment, we focus specifically on vascular disease states of the elderly, including systolic hypertension, vascular calcification, and dementia, and we review relevant basic and clinical discoveries that further elucidate these conditions. Hardening of the Arteries: Calcification, Glycosylation, and the Vasculature in Old Age The Elderly Vascular Phenotype Aging is associated with various changes in the vascular system at differing structural and functional levels. At the macroscopic level, an increase in arterial lumen size and arterial wall thickening, mainly of the intima, are observed. 2 In addition, increased vascular calcification and a generalized stiffening of the arterial tree lead to increased arterial wave reflectance, increased systolic blood pressure, decreased diastolic blood pressure, and a widened pulse pressure. An interesting aspect of vascular biology in which significant inroads have been made is our understanding of pulse wave velocity, which is partly a consequence and partly a cause of the elderly vascular phenotype. In the healthy human arterial tree, the arterial pulse wave is reflected back toward the heart from branch points and other structures in the peripheral circulation, with the reflected wave arriving back at the aortic root during diastole. In older people, the stiffening of the vasculature results in higher forward and reflected pulse wave velocities, with the reflected wave arriving back at the aortic root in late systole, leading to an augmentation of the late systolic pressure (Figure 1). 3 This

Chronic Thrombus Detection With In Vivo Magnetic Resonance Imaging and a Fibrin-Targeted Contrast Agent

Background—Arterial thrombosis plays a critical role in acute coronary syndromes and stroke. Therefore, the ability to detect thrombus in vivo has a significant clinical implication. Magnetic resonance imaging (MRI) has shown promise in noninvasive thrombus detection. However, thrombus characterization and age definition remain difficult. We sought to evaluate the use of a fibrin-targeted peptide (EP-2104R) for MR thrombus detection and to compare this modality with non–contrast-enhanced (NCE) MRI and with Gd-DTPA injection at various ages and time points after thrombus generation. Methods and Results—Carotid artery thrombosis was induced by external injury and stasis in 18 rabbits. T1-weighted MRI was performed before and after contrast agent injection, within 6 hours of thrombus induction, at 48 hours, at 1 week, and every week up to 8 weeks after injury. Correlation with histopathology was performed. The fibrin-targeted contrast agent accurately detected all thrombi, regardless of their size, location, and age. Although thrombus signal intensity after injection decreased with thrombus age (P<0.001), enhancement at 8 weeks was still present. Gd-DTPA injection was not associated with an improvement of thrombus detection. EP-2104R was superior to both NCE and Gd-DTPA injection (P<0.001). Histopathologic examination showed thrombus organization over time. Fibrin was gradually replaced by fibrous tissue. A strong correlation was found between thrombus enhancement and collagen content of the organizing thrombus with time (R=−0.89; P<0.001). Conclusions—In an experimental animal model of carotid thrombosis, we have demonstrated the superiority of a fibrin-targeted MR contrast agent for in vivo detection of chronic or organized thrombus, compared with NCE MRI and Gd-DTPA injection.

Detection of Lipid-Core Plaques by Intracoronary Near-Infrared Spectroscopy Identifies High Risk of Periprocedural Myocardial Infarction

Background— Percutaneous coronary intervention (PCI) is associated with periprocedural myocardial infarction (MI) in 3% to 15% of cases (depending on the definition used). In many cases, these MIs result from distal embolization of lipid-core plaque (LCP) constituents. Prospective identification of LCP with catheter-based near-infrared spectroscopy (NIRS) may predict an increased risk of periprocedural MI and facilitate development of preventive measures. Methods and Results— The present study analyzed the relationship between the presence of a large LCP (detected by NIRS) and periprocedural MI. Patients with stable preprocedural cardiac biomarkers undergoing stenting were identified from the COLOR Registry, an ongoing prospective observational study of patients undergoing NIRS before PCI. The extent of LCP in the treatment zone was calculated as the maximal lipid-core burden index (LCBI) measured by NIRS for each of the 4-mm longitudinal segments in the treatment zone. A periprocedural MI was defined as new cardiac biomarker elevation above 3× upper limit of normal. A total of 62 patients undergoing stenting met eligibility criteria. A large LCP (defined as a maxLCBI4 mm ≥500) was present in 14 of 62 lesions (22.6%), and periprocedural MI was documented in 9 of 62 (14.5%) of cases. Periprocedural MI occurred in 7 of 14 patients (50%) with a maxLCBI4 mm ≥500, compared with 2 of 48 patients (4.2%) patients with a lower maxLCBI4 mm (P=0.0002). Conclusions— NIRS provides rapid, automated detection of extensive LCPs that are associated with a high risk of periprocedural MI, presumably due to embolization of plaque contents during coronary intervention.