Human Coronary Plaques Research Articles

Longitudinal heterogeneity of arterial remodeling and endothelial shear stress in human coronary artery plaques and their effects on the natural history of atherosclerosis

Purpose: Expansive remodeling (ER) and low endothelial shear stress (ESS) critically determine the natural history of atherosclerosis, but they have only been investigated in a cross-sectional arterial axis. In this study, we assessed the longitudinal variation of remodeling and ESS along the length of individual plaques in human coronary arteries and their relation to subsequent plaque growth. Methods: We performed 3D coronary reconstruction by angiography/IVUS at baseline and at 6-10 months follow-up as part of the PREDICTION Study. In discrete baseline plaques (max thickness >0.5 mm, length 9 to 30 mm), we assessed arterial remodeling and ESS (using computational fluid dynamics) in 3mm-long segments. Plaque growth was evaluated in the same locations at follow-up. Results: In 313 arteries from 220 patients, 371 plaques (average length 16.6±0.4 mm) were identified. Of these plaques, 237 (63.9%) had evidence of remodeling while the remaining 134 (36.1%) showed no remodeling. The vast majority of remodeled plaques (93.2%) displayed heterogeneous remodeling patterns along their length: 52 plaques (23.5%) exhibited two remodeling patterns, 14 (6.3%) exhibited three remodeling patterns and 155 plaques (70.1%) showed a combination of one remodeling pattern in some areas of the plaque with absence of remodeling elsewhere (p<0.001). Of plaques with homogeneous remodeling, 18.8% had Excessive ER, 6.2% Compensatory ER, 12.5% Inadequate ER and 62.5% Constrictive remodeling (p<0.05). Similarly, 75.7% of all plaques demonstrated heterogeneous ESS profiles along their length: 20 plaques (7.1%) exhibited both low and high ESS, 79 (28.1%) both low and moderate ESS, 67 (23.8%) both moderate and high ESS; and 115 plaques (40.9%) showed all three ESS patterns (p<0.001). Of plaques with homogeneous ESS, 40% had low ESS, 20% moderate ESS and 40% high ESS. Segments with Excessive ER were associated with low ESS while constrictively remodeled segments with high ESS (p<0.001). Plaque growth at follow-up was primarily evident in segments with baseline low ESS (OR 1.4, 95% CI 1.1-1.7, p<0.05). Conclusions: Arterial remodeling and ESS patterns are not homogeneously distributed along the length of individual coronary plaques, but show significant longitudinal heterogeneity. Since Excessive ER is related to low ESS and subsequent plaque growth, the detailed characterization of remodeling and ESS profiles along the longitudinal aspect of lesions may enhance early identification of highest-risk plaques.

GW24-e1023 Advanced Glycation End Product Modified Low Density Lipoprotein Activates Mast Cells via Toll-Like 4 Receptor Pathway

ObjectivesTo investigate the effects of AGE-LDL, in murine bone marrow-derived mast cells (mBMMCs), on mast cell degranulation and their possible signal pathways.MethodsCarotid plaques were excised during Carotid Endarterectomy of diabetic...

GW24-e2104 Epinephrine enhanced LPS-induced pro-inflammatory cytokines release by BMMCs: a cross-talking between catecholamine, circadian rhythm and inflammation

ObjectivesOccurring of acute coronary syndromes (ACSs) displayed circadian rhythms as well as the levels of catecholamines and pro-inflammatory cytokines in vivo. Such circadian rhythms were proved to exist also in...

Image-Based Modeling and Precision Medicine: Patient-Specific Carotid and Coronary Plaque Assessment and Predictions

Atherosclerotic plaques may rupture without warning and cause acute cardiovascular events such as heart attack and stroke. Current clinical screening tools are insufficient to identify those patients with risks early and prevent the adverse events from happening. Medical imaging and image-based modeling have made considerable progress in recent years in identifying plaque morphological and mechanical risk factors which may be used in developing improved patient screening strategies. The key steps and factors in image-based models for human carotid and coronary plaques were illustrated, as well as grand challenges facing the researchers in the field to develop more accurate screening tools.

Molecular Imaging of Apolipoprotein B-100 in Human Coronary Plaques by Color Fluorescent Angioscopy and Microscopy

Apolipoprotein B-100 (ApoB-100) is an important risk factor for coronary artery disease. However, its localization in human coronary plaques is not well understood. The present study was performed to visualize ApoB-100 in human coronary artery wall. Deposition of native ApoB-100 in excised human coronary plaques and normal segments classified by conventional angioscopy was investigated by color fluorescent angioscopy (CFA) and microscopy (CFM) using Nile blue dye (NB) which elicits a golden fluorescence characteristic of ApoB-100 as a biomarker. By CFA, the % incidence of ApoB-100 was 20 in 40 normal segments, 38 in 42 white, and 11 in 35 yellow plaques (P < 0.05 versus white plaques). There was no significant difference in detection sensitivity between CFA and luminal surface scan by CFM. By CFM transected surface scan, ApoB-100 deposited in superficial, deep, and/or in both layers. Deposition in both layers was frequently observed in white plaques and yellow plaques without necrotic core (NC), less frequently in normal segments, and rarely in yellow plaques with NC. (1) Taking into consideration the well known process of plaque growth, the results suggest that ApoB-100 begins to deposit before plaque formation, increasingly deposits with plaque growth, and disappears after necrotic core formation. (2) CFA is feasible for imaging of ApoB-100 in human coronary artery wall.

Molecular Imaging of Low-density Lipoprotein in Human Coronary Plaques by Color Fluorescent Angioscopy and Microscopy

ObjectivesLow-density lipoprotein (LDL) is an important risk factor for coronary artery disease. However, its localization in human coronary plaques is not well understood. The present study was performed to visualize LDL in human coronary artery wall.Methods(1) The fluorescence characteristic of LDL was investigated by color fluorescent microscopy (CFM) with excitation at 470-nm and emission at 515-nm using Nile blue dye (NB) as a biomarker. (2) Native LDL in 40 normal segments, 42 white plaques and 35 yellow plaques (20 with necrotic core) of human coronary arteries was investigated by color fluorescent angioscopy (CFA) and CFM.Results(1) NB elicited a brown, golden and red fluorescence characteristic of LDL, apolipoprotein B-100, and lysophosphatidylcholine/triglyceride, respectively. (2) The % incidence of LDL in normal segments, white, and yellow plaques was 25, 38 and 14 by CFA and 42, 42 and 14 by CFM scan of their luminal surface, respectively, indicating lower incidence (p<0.05) of LDL in yellow plaques than white plaques, and no significant differences in detection sensitivity between CFA and CFM. By CFM transected surface scan, LDL deposited more frequently and more diffusely in white plaques and yellow plaques without necrotic core (NC) than normal segments and yellow plaques with NC. LDL was localized to fibrous cap in yellow plaques with NC. Co-deposition of LDL with other lipid components was observed frequently in white plaques and yellow plaques without NC.Conclusions(1) Taken into consideration of the well-known process of coronary plaque growth, the results of the present study suggest that LDL begins to deposit before plaque formation; increasingly deposits with plaque growth, often co-depositing with other lipid components; and disappears after necrotic core formation. (2) CFA is feasible for visualization of LDL in human coronary artery wall.

IVUS-based computational modeling and planar biaxial artery material properties for human coronary plaque vulnerability assessment.

Image-based computational modeling has been introduced for vulnerable atherosclerotic plaques to identify critical mechanical conditions which may be used for better plaque assessment and rupture predictions. In vivo patient-specific coronary plaque models are lagging due to limitations on non-invasive image resolution, flow data, and vessel material properties. A framework is proposed to combine intravascular ultrasound (IVUS) imaging, biaxial mechanical testing and computational modeling with fluid-structure interactions and anisotropic material properties to acquire better and more complete plaque data and make more accurate plaque vulnerability assessment and predictions. Impact of pre-shrink-stretch process, vessel curvature and high blood pressure on stress, strain, flow velocity and flow maximum principal shear stress was investigated.

Classification of human coronary atherosclerotic plaques with T1, T2 and Ultrashort TE MRI

Summary Multicontrast MRI with T1, T2 and Ultrashort TE (UTE) sequences is used to image atherosclerotic plaque in human coronary arteries. MRI classification of the plaques is compared with their histological classification and found to correlate extremely well. The addition of UTE MRI adds significant value to the imaging of human coronary artery plaque by MRI. Background The differentiation of atherosclerotic plaque components in the carotid arteries with MRI has been successfully demonstrated. The detection of plaque calcification by MRI, however has been challenging. In addition, few studies have evaluated the ability of MRI to characterize atherosclerotic plaques in human coronary arteries (1). Here we use a combination of T1, T2 and ultrashort TE (UTE) MRI to evaluate atherosclerotic plaques in fixed post-mortem human coronary arteries. We hypothesized that the addition of UTE to T1and T2 weighted MRI would allow both calcified and lipid rich plaques to be accurately detected and distinguished from one another. Methods Twenty eight plaques from human donor hearts with proven coronary artery disease were imaged on 9.4T horizontal bore MRI scanner (Biospec, Bruker). The specimens were imaged with a T1W 3D FLASH sequence (250 um isotropic resolution, TR/TE 30/2.5ms), a T2W Rare sequence (slice thickness 0.4 mm, in plane resolution 0.156mm, TR/TE 3000/40ms), and an UTE sequence (200-300um resolution, TE of 20us). Plaques showing selective hypointensity on T2W MRI were classified as lipid rich. Areas of hypointesnity on the T1W images but not the UTE images were classified as calcified. After MRI, the plaques were sectioned for histological characterization with a pentachrome stain, which was used as the gold standard readout. The histological sections were digitized and co-registered with the MR images for analysis. Results Plaque classification by MRI was performed by 4 readers who were blinded to the histological plaque classification. The sensitivity and specificity of MRI for the detection of plaque calcification were 100.0% and 90.0% respectively. The sensitivity and specificity of MRI for the detection of lipid rich necrotic cores were 90.0%, 75.0%, respectively. Good inter-observer agreement was found for plaque classification by MRI ( = 0.7829, p<0.0001). More importantly, MRI categorization of coronary artery plaques agreed well with the histological classification (weighted =0.6945, p<0.0001). An example of a lipid-rich necrotic plaque with calcification is shown in Figure 1. A fibrocalcific coronary artery plaque is shown in Figure 2. Conclusions MRI with T1, T2 and UTE contrast is able to accurately classify atherosclerotic plaques in human coronary arteries. This underscores the need to develop techniques to image the coronary artery wall in patients in vivo.

Abstract 17102: Atherosclerotic Plaques in Mice Experience Greatest Biomechanical Stress Remote From the Fibrous Cap

Introduction: Although the atherosclerosis-prone mouse model is widely studied and has contributed much to the current understanding of atherogenesis, rupture of plaques in mice has not been conclusively observed. Consequently, uncertainty of the utility of the mouse model for studying endpoints like plaque rupture pervades in the field. In this study, we investigated the biomechanical likelihood of plaque rupture in mice. Hypothesis: The highest stresses are located away from the fibrous cap of lesions in mice. Methods: We studied acute models of atherosclerosis (15 ApoE-/- and 15 LDLr-/- mice, high-fat diet 8 weeks with simultaneous Angiotensin II osmotic pumps) and a chronic model (15 ApoE-/- mice aged 1 year, regular chow diet). The ascending and descending aortas and brachiocephalic artery were harvested for histological staining of morphology. To preserve in vivo anatomy as accurately as possible, vessels were perfused with a vascular casting compound at each mouse's measured diastolic blood pressure and then embedded in methyl methacrylate resin blocks, which minimize sectioning artifacts. Histology sections were the input geometry for a lesion-specific finite element analysis (FEA) computer model of solid mechanics within the vessel wall. For comparison, we performed similar FEA simulation on 15 human coronary plaques of the thin-cap fibroatheroma (TCFA) phenotype. Results: In human lesions, highest stresses tended to be located on the fibrous cap or shoulders of the plaque, consistent with current understanding of plaque rupture. However, in mouse plaque simulations, the highest stresses and strains were located away from the lesions on the thin plaque-free wall. Conclusion: The characteristic difference in peak stress location explains the lack of plaque rupture in mice. This study demonstrates that local mechanical strains in the fibrous cap of murine atherosclerotic lesions are insufficient to cause plaque rupture, in contrast to human lesions.

In vivo characterization of coronary plaques: novel findings from comparing greyscale and virtual histology intravascular ultrasound and near-infrared spectroscopy

To test the hypothesis that near-infrared spectroscopy (NIRS) combined with intravascular ultrasound (IVUS) would provide novel information of human coronary plaque characterization. Greyscale-IVUS, virtual histology (VH)-IVUS, and NIRS were compared in 131 native lesions (66 vessels) that were interrogated during catheterization by all three modalities. Greyscale-IVUS detected attenuated and echolucent plaques correlated with NIRS-detected lipid-rich areas. Attenuated plaques contained the highest NIRS probability of lipid core, followed by echolucent plaques. By VH-IVUS, 93.5% of attenuated plaques contained confluent necrotic core (NC) and were classified as VH-derived fibroatheromas (FAs). Although 75.0% of echolucent plaques were classified as VH-FAs, VH-NC was seen surrounding an echolucent zone, but not within any echolucent zone; and echolucent zones themselves contained fibrofatty and/or fibrous tissue. All calcified plaques with arc >90° contained >10% VH-NC (range 16.0-41.2%) and were classified as calcified VH-FAs, but only 58.5% contained NIRS-detected lipid core. A positive relationship between VH-derived %NC and NIRS-derived lipid core burden index was found in non-calcified plaques, but not in calcified plaques. Combining NIRS with IVUS contributes to the understanding of plaque characterization in vivo. Further studies are warranted to determine whether combining NIRS and IVUS will contribute to the assessment of high-risk plaques to predict outcomes in patients with coronary artery disease.

Optical Coherence Tomography and Fibrous Cap Characterization

The pathophysiology of acute coronary syndromes has long been associated with atherosclerotic plaque rupture. Inflammation, thinning, and disruption of the fibrous cap have been implicated with the final processes leading to plaque rupture, but confirmation of these mechanisms of coronary thrombosis in humans has been hampered by the lack of imaging methods with sufficient resolution to resolve fibrous cap characterization and thickness in vivo. Intravascular optical coherence tomography (OCT) provides images with micron-level axial and lateral resolution, enabling detailed visualization of micro-structural changes of the arterial wall. The present article provides an overview of the potential role of OCT in identifying and characterizing fibrous cap morphology, thickness, and inflammation in human coronary plaques.

High shear stress induces a strain increase in human coronary plaques over a 6-month period

Atherosclerotic plaques develop in low shear stress regions. In the more advanced phase of the disease, plaques are exposed to altered shear stress levels, which could influence plaque composition. We investigated changes in plaque composition in human coronary arteries over a 6-month period and how these changes are related to shear stress. We took images of eight coronary arteries to obtain the 3D shape of the arteries. Lumen data were combined with computational fluid dynamics to obtain shear stress. Palpography was applied to measure strain at baseline and at 6-month follow-up. The change in strain from baseline to follow-up served as a marker for the change in plaque composition. We identified 17 plaques, and each plaque was divided into four regions: the upstream, throat, shoulder and downstream region. Shear stress and strain in the downstream region was significantly lower than in the other regions. There was no significant change in strain for the four different plaque regions. However, we observed that those plaque regions exposed to high shear stress showed a significant increase in strain. Plaque regions exposed to high shear stress showed an increase in strain over time. This indicates that shear stress may modulate plaque composition in human coronary arteries.

Effect of Statins on Cholesterol Crystallization and Atherosclerotic Plaque Stabilization

Pleiotropic effects of statins have not been fully elucidated. Recently we demonstrated that cholesterol expands when crystallizing and may trigger plaque rupture. The present study evaluated the potential direct effects of statins in altering cholesterol crystallization as a possible mechanism for plaque stabilization independent of cholesterol lowering. Cholesterol powder was dissolved in oil with and without pravastatin, simvastatin, or atorvastatin (10 to 90 mg) and then allowed to crystallize to measure peak volume expansion (ΔVE) in graduated cylinders. Effect of ΔVE on fibrous membrane damage was also evaluated. Human coronary, carotid, and peripheral arterial plaques (65 plaques from 55 patients) were incubated with statin or saline solution using matched plaque segments to evaluate direct effects of statins on preformed crystals. Also, the effect of in vivo use of oral statins on crystal structure was examined by scanning electron microscopy and crystal content in plaques scored from 0 to +3. For all statins, ΔVE decreased significantly in a dose-dependent fashion (0.76 ± 0.1 vs 0 ml at 60 mg, p <0.001). By scanning electron microscopy crystal structure with statins had loss of pointed tip geometries, averting fibrous membrane damage. Cholesterol crystal density was markedly decreased and appeared dissolved in human plaques incubated with statins (+2.1 ± 1.1 vs +1.3 ± 1.0, p = 0.0001). Also, plaques from patients taking oral statins compared to controls had significantly more dissolving crystals (p = 0.03). In conclusion, statins decreased ΔVE by altering cholesterol crystallization and blunting sharp-tipped crystal structure and dissolving cholesterol crystals in human arteries in vivo and in vitro, providing plaque stabilization.

Lipoprotein associated phospholipase A2: role in atherosclerosis and utility as a biomarker for cardiovascular risk

Atherosclerosis and its clinical manifestations are widely prevalent throughout the world. Atherogenesis is highly complex and modulated by numerous genetic and environmental risk factors. A large body of basic scientific and clinical research supports the conclusion that inflammation plays a significant role in atherogenesis along the entire continuum of its progression. Inflammation adversely impacts intravascular lipid handling and metabolism, resulting in the development of macrophage foam cell, fatty streak, and atheromatous plaque formation. Given the enormous human and economic cost of myocardial infarction, ischemic stroke, peripheral arterial disease and amputation, and premature death and disability, considerable effort is being committed to refining our ability to correctly identify patients at heightened risk for atherosclerotic vascular disease and acute cardiovascular events so that they can be treated earlier and more aggressively. Serum markers of inflammation have emerged as an important component of risk factor burden. Lipoprotein-associated phospholipase A2 (Lp-PLA2) potentiates intravascular inflammation and atherosclerosis. A variety of epidemiologic studies support the utility of Lp-PLA2 measurements for estimating and further refining cardiovascular disease risk. Drug therapies to inhibit Lp-PLA2 are in development and show considerable promise, including darapladib, a specific molecular inhibitor of the enzyme. In addition to substantially inhibiting Lp-PLA2 activity, darapladib reduces progression of the necrotic core volume of human coronary artery atheromatous plaque. The growing body of evidence points to an important role and utility for Lp-PLA2 testing in preventive and personalized clinical medicine.

Histological Characteristics of Glistening Yellow Coronary Plaques Seen on Angioscopy - With Special Reference to Vulnerable Plaques -

Glistening yellow coronary plaques (GY) seen on angioscopy are considered vulnerable to disruption. Collagen fiber (CF) is the main substance that protects coronary plaques against mechanical stress. Therefore, whether angioscopically defined vulnerable plaques correlate with those defined histologically was investigated. One hundred and thirty-two excised human coronary plaques were classified by angioscopy into 19 GY, 49 non-glistening yellow plaques (non-GY) and 64 white plaques, and their relation to CF density was examined. CF-dense (>15/100 µm), CF-loose (>5 and <15/100 µm), and CF-scanty (<5/100 µm) plaques were hypothesized to be stable, relatively stable, and vulnerable, respectively. Histologically the plaques were classified into non-lipid deposition, superficial lipid deposition and diffuse lipid deposition groups; the diffuse lipid deposition group was classified into necrotic core (NC) and non-NC types. Nineteen GY were composed of 4 with superficial lipid deposition, 4 with non-NC type of diffuse lipid deposition, and 11 with NC type. Sixteen (84%) of these were CF scanty. Forty-nine (100%) of non-GY and 57 (89%) of white plaques were CF dense or CF loose The sensitivity, specificity and predictive value of GY in detecting histologically vulnerable plaques were 90%, 97% and 84%, respectively, indicating that GY represented histologically vulnerable plaques. These pathohistological characteristics might indicate that GY, less-protected plaques against mechanical stress, are vulnerable plaques.

Two‐Dimensional Visualization of Cholesterol and Cholesteryl Esters Within Human Coronary Plaques by Near‐Infrared Fluorescence Angioscopy

Cholesterol (C) and cholesteryl esters (CE) within coronary plaques are minimally visualized directly by any of the available imaging modalities in vivo. If they are rendered visible in vivo, the progression of coronary plaques and the effects of respective therapies on these plaques can be objectively evaluated. The C and CE within human coronary plaques can be visualized by near-infrared fluorescence angioscopy (NIRFA). By exciting at 710 ± 25 nm and emitting at 780 nm, near-infrared fluorescence (NIRF) of lipid components was examined by microscopy in vitro. Lipid components in 49 plaques of 32 excised human coronary arteries were examined by NIRFA in vitro. Coronary plaques were examined by NIRFA in 25 patients with coronary artery disease. C, CE, and calcium (Ca) individually did not exhibit NIRF but did in the presence of β-carotene, which is known to coexist with lipids in the vascular wall. Other substances that are contained in atherosclerotic plaques did not.² The excised human coronary plaques were classified as those with NIRF and those without. The former plaques were classified into homogenous, doughnut-shaped, and spotty types. Histological examinations revealed that these image patterns were determined by the differences in the locations of C, CE, and Ca, and that those deposited within 700 μm in depth from the plaque surface were imaged by NIRFA. Homogenous, doughnut-shaped, or spotty NIRFA images were also observed in patients. NIRFA is feasible for 2-dimensional imaging of C and CE deposited in human coronary plaques.

The Transcription Factor Erg Inhibits Vascular Inflammation by Repressing NF-κB Activation and Proinflammatory Gene Expression in Endothelial Cells

To test whether ETS-related gene (Erg) inhibits tumor necrosis factor (TNF)-α-dependent endothelial activation and inflammation. Endothelial activation underlies many vascular diseases, including atherosclerosis. Endothelial activation by proinflammatory cytokines decreases expression of the ETS transcription factor Erg. By using human umbilical vein endothelial cells (HUVECs), we showed that Erg overexpression by adenovirus (AdErg) repressed basal and TNF-α-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM), and interleukin 8 (IL-8). Erg inhibited TNF-α-dependent activation of the ICAM-1 promoter, nuclear factor (NF)-κB activity, and NF-κB p65 phosphorylation. Basal NF-κB activity was also inhibited by Erg overexpression. Chromatin immunoprecipitation showed that Erg binds to the ICAM-1 proximal promoter region, which contains 7 putative ETS binding sites. To test the anti-inflammatory role of Erg in vivo, we used a murine model of TNF-α-dependent acute inflammation. The injection of AdErg into the paw decreased TNF-α-induced inflammation compared with control. Finally, staining of human coronary plaques showed loss of Erg expression from the endothelium overlaying active plaque shoulders. We have identified a novel physiological anti-inflammatory pathway under the control of the transcription factor Erg; this pathway inhibits NF-κB-dependent transcription and TNF-α-induced inflammation in vivo. These results suggest a novel approach to anti-inflammatory therapies.

The complement component C5a is present in human coronary lesions in vivo and induces the expression of MMP‐1 and MMP‐9 in human macrophages in vitro

The complement component C5a is formed during activation of the complement cascade and exerts chemotactic and proinflammatory effects. Macrophages, which are localized in the rupture-prone shoulder regions of coronary plaques, are thought to play a major role in plaque destabilization and rupture through the production of matrix metalloproteinases (MMPs). When human monocyte-derived macrophages were stimulated in vitro with C5a, MMP-1 and MMP-9 mRNA levels were significantly increased. Furthermore, C5a up-regulated MMP-1 and MMP-9 antigens and activity, as determined by ELISA and specific activity assays. These effects were blocked by antibodies against the receptor C5aR/CD88. In addition, blocking experiments revealed that MMP-1 expression was mediated by activation of the transcription factor AP-1, and MMP-9 expression was induced by activation of NF-κB and AP-1. Immunohistochemical analysis of human coronary plaques demonstrated the colocalization of C5a, MMP-1, and MMP-9 in vivo. Together, these observations indicate that activation of the complement cascade and formation of C5a may play a role in the onset of acute coronary events by induction of MMPs in atherosclerotic lesions.

Darapladib and its potential for plaque stabilization and prevention of cardiac events

Darapladib is a novel oral compound that selectively inhibits lipoprotein-associated phospholipase A2 (Lp-PLA2). Lp-PLA2 is intimately involved in inflammation and postulated to play an important role in the development of unstable atherosclerotic plaques. Lp-PLA2 is found in vulnerable human coronary and carotid plaques.Epidemiological studies have shown that Lp-PLA2 is related to the occurrence of myocardial infarction, stroke and vascular death. Darapladib inhibits the activity of Lp-PLA2 in plasma and reduces Lp-PLA2 in human carotid plaques. In a trial of 330 patients with coronary artery disease receiving standard of care medications, darapladib halted necrotic core progression in coronary arteries over a 12-month period. Two large Phase III trials, the Stabilization of Atherosclerotic Plaque By Initiation of Darapladib Therapy and the Stabilization of Plaques Using Darapladib – Thrombolysis in Myocardial Infarction 52 trials, are expected to randomize approximately 27,000 patients with chronic coronary heart disease and acute coronary syndromes, respectively, to darapladib or placebo with a primary composite outcome of cardiovascular death, myocardial infarction or stroke. Darapladib has the potential to provide clinical benefit by modulating mechanisms of disease that have not been addressed by current treatments.

Elevated level of ADAMTS4 in plasma and peripheral monocytes from patients with acute coronary syndrome

A recent study shows that ADAMTS4 is expressed in macrophage-rich areas of human atherosclerotic carotid plaques and coronary unstable plaques, suggesting a pathogenic role of ADAMTS4 in the development of acute coronary syndrome (ACS). We investigated (a) whether the expression level of ADAMTS4 in plasma and peripheral blood mononuclear cells was affected; and (b) whether there was a relationship with hs-CRP level and the stability of coronary atherosclerotic plaque in patients with ACS. Our study included 30 normal controls and 120 patients including 40 with stable angina (SA), 50 with unstable angina (UA), and 30 with acute myocardial infarction (AMI). The expression of ADAMTS4 in monocytes was analyzed by RT-PCR and plasma ADAMTS4 level was determined by ELISA. All coronary stenosis with >30% diameter reduction was assessed by angiographic coronary stenosis morphology. Patients with ACS showed a significant increase of ADAMTS4 (2.7 ± 0.4) expression in monocytes compared with controls (1.1 ± 0.2) and the SA group (1.3 ± 0.2) (P < 0.001). Plasma ADAMTS4 also showed a higher level in ACS patients (100.2 ± 31.6 ng/ml) than in control (47.5 ± 9.0 ng/ml, P < 0.001) and the SA group (54.3 ± 13.2 ng/ml, P < 0.001). Moreover, we found a positive correlation between hs-CRP and ADAMTS4 expression in monocytes as well as in plasma. There was also a positive correlation of ADAMTS4 expression in monocytes and plasma with complex coronary stenosis (r (1) = 0.61, r (2) = 0.57, P < 0.001). Patients with ACS showed increased ADAMTS4 expression, which may aggravate the development of atherosclerosis and instability of atherosclerotic plaques. Therefore, the ADAMTS4 expression may be a valuable marker for predicting the severity of ACS.