Human Coronary Plaques Research Articles

Pericoronary Adipose Tissue as Storage and Supply Site for Oxidized Low-Density Lipoprotein in Human Coronary Plaques.

ObjectivesIt is generally believed that low-density lipoprotein enters the vascular wall from its lumen and oxidized (oxLDL), after which it plays an important role in atherosclerosis. Because voluminous epicardial adipose tissue is a risk factor for coronary events, there is a possibility that the pericoronary adipose tissue (PCAT), which is a part of epicardial adipose tissue, acts as a risk factor by supplying oxLDL to the coronary arterial wall. The present study was performed whether PCAT stores and supplies oxLDL to the coronary wall.MethodsLocalization of oxLDL in PCAT and its relation to plaque morphology were examined by immunohistochemical techniques in 27 epicardial coronary arteries excised from 9 human autopsy cases.ResultsOxLDL deposited in all PCAT of the studied cases. The percent (%) incidence of oxLDL in the intima of 25 normal segment, 19 white plaques, 15 yellow plaques without necrotic core (NC) and 10 yellow plaques with NC, was 32, 84, 93 (p<0.05 vs normal segments and yellow plaques with NC), and 30, respectively. OxLDL deposited either in dotted or diffuse pattern. Double immunohistochemical staining revealed that the dotted oxLDL was that contained in CD68(+)-macrophages. The oxLDL-containing macrophages were observed in the interstitial space but not inside of the vasa vasorum, and they traversed PCAT, adventitia, external and internal elastic laminae, suggesting their migration towards the intima. Diffuse oxLDL deposits were observed in 17 preparations, the majority of which were co-localized with the vasa vasorum in outer or in both inner and outer halves of intima, and rarely in the inner half alone.ConclusionsThe results suggested that PCAT is a supply source of oxLDL to coronary intima and acts as a risk factor for coronary events, that oxLDL increasingly deposits in the intima with plaque growth and decreases after plaque maturation, and therefore molecular therapies targeting the PCAT before plaque growth could be effective in preventing human coronary atherosclerosis.

A Broadband Polyvinylidene Difluoride-Based Hydrophone with Integrated Readout Circuit for Intravascular Photoacoustic Imaging

Intravascular photoacoustic (IVPA) imaging can visualize the coronary atherosclerotic plaque composition on the basis of the optical absorption contrast. Most of the photoacoustic (PA) energy of human coronary plaque lipids was found to lie in the frequency band between 2 and 15 MHz requiring a very broadband transducer, especially if a combination with intravascular ultrasound is desired. We have developed a broadband polyvinylidene difluoride (PVDF) transducer (0.6 × 0.6 mm, 52 μm thick) with integrated electronics to match the low capacitance of such a small polyvinylidene difluoride element (<5 pF/mm2) with the high capacitive load of the long cable (∼100 pF/m). The new readout circuit provides an output voltage with a sensitivity of about 3.8 μV/Pa at 2.25 MHz. Its response is flat within 10 dB in the range 2 to 15 MHz. The root mean square (rms) output noise level is 259 μV over the entire bandwidth (1–20 MHz), resulting in a minimum detectable pressure of 30 Pa at 2.25 MHz.

Additive Value of Integrated Backscatter IVUS for Detection of Vulnerable Plaque by Optical Frequency Domain Imaging: An Ex Vivo Autopsy Study of Human Coronary Arteries

ObjectivesThis study sought to evaluate the diagnostic performance of optical frequency domain imaging (OFDI) for recognition of coronary plaque morphologies and to assess additive values of integrated backscatter intravascular ultrasound (IB-IVUS) in detection of vulnerable plaque. BackgroundPrecise diagnosis of coronary lesions susceptible to plaque rupture and thrombosis may serve to stratify the risk of future coronary events and to make decisions for appropriate treatment of choice. MethodsTwenty-seven coronary arteries from 14 human autopsy hearts were interrogated ex vivo by OFDI and IB-IVUS. Imaged segments were sectioned at 3 mm intervals where a total of 360 pairs of cross-sectional images coregistered to histology were investigated. ResultsOverall, OFDI could depict various plaque components and structures such as fibrous tissue, sheet and nodular calcification, lipid, cholesterol crystals, and healed plaque rupture. OFDI could detect 14 of 18 thin-cap fibroatheroma (TCFA), however, the diagnostic accuracy was not high (positive predictive value [PPV] = 60.9%, κ = 0.664; area under the curve [AUC]: 0.88) mainly because of signal interference from macrophages. Further, we defined IB-IVUS–derived TCFA by recursive partitioning analysis as: 1) cross-sectional % lipid area >65.1%; 2) % lipid area >32.3 but <65.1% with plaque area >10.5 mm2, where TCFA detection by IB-IVUS alone was marginal (PPV = 50.0%, κ = 0.545; AUC: 0.82). However, when IB-IVUS was combined with OFDI, all pseudo OFDI-derived TCFA (non-TCFA on histology) were excluded. Accordingly, PPV of TCFAs diagnosed by both OFDI and IB-IVUS was improved to 100.0% (κ = 0.704; AUC: 0.93). ConclusionsOFDI could recognize detailed morphologies of human coronary plaque. However, diagnostic accuracy of both OFDI alone and IB-IVUS alone to identify TCFA is limited. Combination of IB-IVUS with OFDI improved the accuracy for TCFA detection, suggesting hybrid imaging or further development of novel devices will be required to identify coronary lesions responsible for future events.

Molecular Imaging of Native Low-Density Lipoprotein by Near-Infrared Fluorescent Angioscopy in Human Coronary Plaques

Low-density lipoprotein (LDL) is an important risk factor for coronary artery disease, but its localization within the human coronary arterial wall is poorly understood. Imaging of LDL in 30 coronary arteries excised from 15 subjects who underwent autopsy was performed using near-infrared fluorescent angioscopy system and using indocyanine green dye as a biomarker of LDL. The percentage incidence of LDL in 28 normal segments, 24 white plaques (early stage of plaque growth), and 21 yellow plaques (mature stage of plaque) classified by conventional angioscopy, was 14.2, 79.1 (p <0.01 vs normal segments and p <0.05 vs yellow plaques), and 28.5, respectively. Coronary near-infrared fluorescent angioscopy showed similar results in 7 patients in vivo. Our results suggested that LDL begins to deposit in the human coronary arterial wall in the early stage of atherosclerosis, increasingly deposits with plaque growth and decreases in the mature stage; and therefore, molecular therapy targeting LDL should be started before plaque maturation.

Morphological and Stress Vulnerability Indices for Human Coronary Plaques and Their Correlations with Cap Thickness and Lipid Percent: An IVUS-Based Fluid-Structure Interaction Multi-patient Study.

Plaque vulnerability, defined as the likelihood that a plaque would rupture, is difficult to quantify due to lack of in vivo plaque rupture data. Morphological and stress-based plaque vulnerability indices were introduced as alternatives to obtain quantitative vulnerability assessment. Correlations between these indices and key plaque features were investigated. In vivo intravascular ultrasound (IVUS) data were acquired from 14 patients and IVUS-based 3D fluid-structure interaction (FSI) coronary plaque models with cyclic bending were constructed to obtain plaque wall stress/strain and flow shear stress for analysis. For the 617 slices from the 14 patients, lipid percentage, min cap thickness, critical plaque wall stress (CPWS), strain (CPWSn) and flow shear stress (CFSS) were recorded, and cap index, lipid index and morphological index were assigned to each slice using methods consistent with American Heart Association (AHA) plaque classification schemes. A stress index was introduced based on CPWS. Linear Mixed-Effects (LME) models were used to analyze the correlations between the mechanical and morphological indices and key morphological factors associated with plaque rupture. Our results indicated that for all 617 slices, CPWS correlated with min cap thickness, cap index, morphological index with r = -0.6414, 0.7852, and 0.7411 respectively (p<0.0001). The correlation between CPWS and lipid percentage, lipid index were weaker (r = 0.2445, r = 0.2338, p<0.0001). Stress index correlated with cap index, lipid index, morphological index positively with r = 0.8185, 0.3067, and 0.7715, respectively, all with p<0.0001. For all 617 slices, the stress index has 66.77% agreement with morphological index. Morphological and stress indices may serve as quantitative plaque vulnerability assessment supported by their strong correlations with morphological features associated with plaque rupture. Differences between the two indices may lead to better plaque assessment schemes when both indices were jointly used with further validations from clinical studies.

Abstract 13076: Lipid-lowering Therapy Stabilizes the Complexity of Non-culprit Plaques in Human Coronary Artery: A Quantitative Assessment Using OCT Bright Spot Algorithm

Introduction: Recent studies using optical coherence tomography (OCT) reported that statin therapy increases the thickness of fibrous cap in human coronary plaques. However, the efficacy on the stabilization of plaque complexity remains unknown. Aim: To quantitatively evaluate the statin efficacy on the change of plaque complexity using an OCT bright spot algorithm. Methods: From a randomized trial (NCT01023607), we identified 59 lipid-rich coronary plaques in non-culprit lesions from 40 patients who were randomized to receive atorvastatin 60mg (AT60), rosuvastatin 10mg (RT10) or atorvastatin 20mg (AT20), and had serial image acquisition at baseline, 6-month, and 12-month by time-domain OCT. We applied an OCT algorithm which is able to identify bright spots representing variety of plaque components including macrophage. The density of bright spots was measured within superficial 250μm of the vessel wall as the number of bright pixels divided by the number of pixels in each frame through the entire plaque length. Results: Significant reduction of bright spot density was observed from baseline to 12-month, particularly during the second 6 months (Figure). All three types of statin demonstrated the marked reduction of bright spot density from the baseline to 12-month (-0.61% [-0.93, -0.34], P&lt;0.001, -0.45% [-0.99, -0.34], P=0.001 and -0.41% [-0.98, -0.19], P&lt;0.001, in AT60 (n=22), RT10 (n=15) and AT20 (n=22), respectively) without significant difference among the groups (P=0.76). There was no significant difference in the reduction of bright spot density from baseline to 12-month between patients with acute coronary syndrome (n=47) and those with stable angina (n=12) (-0.49% [-0.97, -0.28] vs. -0.41% [-0.89, -0.21], P=0.62). Conclusions: Coronary plaque complexity evaluated by a quantitative OCT algorithm was significantly improved by 12-month statin therapy irrespective of the statin type and baseline clinical presentation.

TCT-315 Variation in Collagen in the Caps of Human Coronary Lipid-core Plaque Autopsy Specimens: A Possible Measure of Cap Weakness

TCT-315 Variation in Collagen in the Caps of Human Coronary Lipid-core Plaque Autopsy Specimens: A Possible Measure of Cap Weakness

Insights on atherosclerosis by non-invasive assessment of wall stress and arterial morphology along the length of human coronary plaques.

Wall stress (WS) is associated with high arterial pressure and affects the localization of atherosclerotic lesions. We sought to non-invasively investigate the distribution of WS along the length of human coronary arteries and investigate its potential effect on atherosclerosis in association with vascular stiffness, local arterial curvature and plaque volume. We reconstructed three-dimensionally 28 coronary arteries from 22 subjects who had undergone coronary computed tomography angiography. Coronary arteries were divided in 2 mm-long segments. WS, vascular stiffness, plaque volume and curvature were calculated in each segment using computational fluid dynamics and morphology measurements. Plaque segments exhibited lower WS compared to their adjacent normal segments. Within plaques, WS was lower in the mid plaque portion compared to the upstream portion. Plaque volume was higher in the mid plaque portion compared to upstream and downstream portions. Low WS was associated with high curvature and both low WS and high curvature were associated with increased plaque volume. The current study demonstrates that WS and plaque volume are not uniform in the longitudinal axis of human coronary plaque. Calculation of WS could serve as a surrogate for the localization of plaque development and the identification of plaques at a more advanced stage of progression.

189 Genetic Variation in ADAMTS7 is Associated with Severity of Coronary Artery Disease

Purpose Genome-wide association studies have identified ADAMTS7 as a risk locus for coronary artery disease (CAD) and myocardial infarction (MI). Functional studies suggest ADAMTS7 may promote cellular processes in atherosclerosis. We studied if risk variant carriers exhibit a greater burden of angiographic CAD. Methods We genotyped ADAMTS7 in the Southampton Atherosclerosis Study (SAS, n = 1359), and replicated in the Emory Genebank (Emory GB, n = 2684). Angiographic CAD was phenotyped as presence of >50% stenosis in epicardial vessel and semi-quantitative scores including the Gensini Score (GS), Sullivan Extent Score (SES) and the Duke Severity Index (DSI); and ex-vivo immunohistochemical analysis of human coronary plaques (n = 48). Results We confirmed an association between ADAMTS7 genotype and presence of CAD under an additive genotype model in SAS (p = 0.05) and Emory GB (p = 0.017), but found no associations with MI in the presence of CAD. ADAMTS genotypes were associated with all of the angiographic severity scores in SAS (GS p = 0.017, SES p = 0.045, DSI p = 0.029), and independently replicated in Emory GB (GS p Conclusions The ADAMTS7 risk variant is associated with multiple angiographic measures of CAD burden and plaque remodelling, further supporting the role of this protease in promoting atherosclerosis.

Vascular wall hypoxia promotes arterial thrombus formation via augmentation of vascular thrombogenicity.

Atherosclerotic lesions represent a hypoxic milieu. However, the significance of this milieu in atherothrombosis has not been established. We aimed to assess the hypothesis that vascular wall hypoxia promotes arterial thrombus formation. We examined the relation between vascular wall hypoxia and arterial thrombus formation using a rabbit model in which arterial thrombosis was induced by 0.5 %-cholesterol diet and repeated balloon injury of femoral arteries. Vascular wall hypoxia was immunohistochemically detected by pimonidazole hydrochloride, a hypoxia marker. Rabbit neointima and THP-1 macrophages were cultured to analyse prothrombotic factor expression under hypoxic conditions (1 % O2). Prothrombotic factor expression and nuclear localisation of hypoxia-inducible factor (HIF)-1α and nuclear factor-kappa B (NF-κB) p65 were immunohistochemically assessed using human coronary atherectomy plaques. Hypoxic areas were localised in the macrophage-rich deep portion of rabbit neointima and positively correlated with the number of nuclei immunopositive for HIF-1α and NF-κB p65, and tissue factor (TF) expression. Immunopositive areas for glycoprotein IIb/IIIa and fibrin in thrombi were significantly correlated with hypoxic areas in arteries. TF and plasminogen activator inhibitor-1 (PAI-1) expression was increased in neointimal tissues and/or macrophages cultured under hypoxia, and both were suppressed by inhibitors of either HIF-1 or NF-κB. In human coronary plaques, the number of HIF-1α-immunopositive nuclei was positively correlated with that of NF-κB-immunopositive nuclei and TF-immunopositive and PAI-1-immunopositive area, and it was significantly higher in thrombotic plaques. Vascular wall hypoxia augments the thrombogenic potential of atherosclerotic plaque and thrombus formation on plaques via prothrombotic factor upregulation.

Using 2D in Vivo Ivus-based Models for Human Coronary Plaque Progression Analysis and Comparison with 3d Fsi Models

It is believed that mechanical stress plays an important role in atherosclerotic plaque progression and rupture process. However, 3D model construction is very time consuming and not practical for clinical implementation. This paper is investigating if 2D models could be used to replace 3D models to perform correlation analysis and achieve similar results. Patient follow-up in vivo intravascular ultrasound coronary plaque data were acquired to construct 2D structure-only and 3D FSI models to obtain plaque wall stress (PWS) and strain (PWSn) data and investigate correlations between plaque progression measured by wall thickness increase(WTI) and three risk factors: wall thickness (WT), PWS and PWSn. Our results indicated that while stress/strain differences between 2D and 3D models were about 30%, correlation results from 2D models were in general consistent with those obtained from 3D models.

TCT-345 Distribution of Excessive Expansive Remodeling and Low Endothelial Shear Stress in the Long Axis of Human Coronary Plaque and Their Combined Effects on the Natural History of Atherosclerosis

TCT-345 Distribution of Excessive Expansive Remodeling and Low Endothelial Shear Stress in the Long Axis of Human Coronary Plaque and Their Combined Effects on the Natural History of Atherosclerosis

TCT-369 Human coronary plaque characterization using a fully integrated intravascular ultrasound and optical coherence tomography (IVUS-OCT) system

The comparisons of diagnostic accuracy of OCT/IVUS have been investigated. Combined use of IVUS and OCT was proposed to increase accuracy. Fully-integrated OCT-IVUS system has also been reported. However, the diagnostic accuracy of this system for classifying different plaque types has not been

Alternatively spliced tissue factor promotes plaque angiogenesis through the activation of hypoxia-inducible factor-1α and vascular endothelial growth factor signaling.

Alternatively spliced tissue factor (asTF) is a novel isoform of full-length tissue factor, which exhibits angiogenic activity. Although asTF has been detected in human plaques, it is unknown whether its expression in atherosclerosis causes increased neovascularization and an advanced plaque phenotype. Carotid (n=10) and coronary (n=8) specimens from patients with stable or unstable angina were classified as complicated or uncomplicated on the basis of plaque morphology. Analysis of asTF expression and cell type-specific expression revealed a strong expression and colocalization of asTF with macrophages and neovessels within complicated, but not uncomplicated, human plaques. Our results showed that the angiogenic activity of asTF is mediated via hypoxia-inducible factor-1α upregulation through integrins and activation of phosphatidylinositol-3-kinase/Akt and mitogen-activated protein kinase pathways. Hypoxia-inducible factor-1α upregulation by asTF also was associated with increased vascular endothelial growth factor expression in primary human endothelial cells, and vascular endothelial growth factor-Trap significantly reduced the angiogenic effect of asTF in vivo. Furthermore, asTF gene transfer significantly increased neointima formation and neovascularization after carotid wire injury in ApoE(-/-) mice. The results of this study provide strong evidence that asTF promotes neointima formation and angiogenesis in an experimental model of accelerated atherosclerosis. Here, we demonstrate that the angiogenic effect of asTF is mediated via the activation of the hypoxia-inducible factor-1/vascular endothelial growth factor signaling. This mechanism may be relevant to neovascularization and the progression and associated complications of human atherosclerosis as suggested by the increased expression of asTF in complicated versus uncomplicated human carotid and coronary plaques.

PTX3: A modulator of human coronary plaque vulnerability acting by macrophages type 2

BackgroundAcute myocardial infarction (AMI), is related to a diffuse active inflammation of the coronary tree associated with rupture of one of the multiple vulnerable plaques. The presence of soluble mediators of inflammation with their synergic or antagonistic actions coordinates the physiological response determining the plaque fate and the fatal event.The present study focus on the cytokines network operating in human coronary plaques of patients died from AMI and controls, pointing out that coronaries of AMI patients produce PTX3 protein twice as that of controls and express high level of PTX3 mRNA. ResultsThe presence of CX3CR1 polymorphisms is significantly correlated with the incidence and the outcome of acute myocardial infarction inducing in the whole coronary tree a strong recruitment of Th1 polarized inflammation that is directly correlated to PTX3 expression. ConclusionsMoreover we found a positive correlation between the expression of PTX3 in the plaque and the content of macrophage cells showing a M2 polarization indicating the possible role of this chemokine as mediator of immune response that would orchestrate plaque evolution and inflammatory cell type activation.

Human coronary plaque wall thickness correlated positively with flow shear stress and negatively with plaque wall stress: an IVUS-based fluid-structure interaction multi-patient study

BackgroundAtherosclerotic plaque progression and rupture are believed to be associated with mechanical stress conditions. In this paper, patient-specific in vivo intravascular ultrasound (IVUS) coronary plaque image data were used to construct computational models with fluid-structure interaction (FSI) and cyclic bending to investigate correlations between plaque wall thickness and both flow shear stress and plaque wall stress conditions.MethodsIVUS data were acquired from 10 patients after voluntary informed consent. The X-ray angiogram was obtained prior to the pullback of the IVUS catheter to determine the location of the coronary artery stenosis, vessel curvature and cardiac motion. Cyclic bending was specified in the model representing the effect by heart contraction. 3D anisotropic FSI models were constructed and solved to obtain flow shear stress (FSS) and plaque wall stress (PWS) values. FSS and PWS values were obtained for statistical analysis. Correlations with p < 0.05 were deemed significant.ResultsNine out of the 10 patients showed positive correlation between wall thickness and flow shear stress. The mean Pearson correlation r-value was 0.278 ± 0.181. Similarly, 9 out of the 10 patients showed negative correlation between wall thickness and plaque wall stress. The mean Pearson correlation r-value was -0.530 ± 0.210.ConclusionOur results showed that plaque vessel wall thickness correlated positively with FSS and negatively with PWS. The patient-specific IVUS-based modeling approach has the potential to be used to investigate and identify possible mechanisms governing plaque progression and rupture and assist in diagnosis and intervention procedures. This represents a new direction of research. Further investigations using more patient follow-up data are warranted.

Spectroscopic intravascular photoacoustic imaging of lipids in atherosclerosis

The natural history of atherosclerosis is marked by changes in the lipid biochemistry in the diseased arterial wall. As lesions become more vulnerable, different cholesterol species accumulate in the plaque. Understanding unstable atherosclerosis as a pharmacological and interventional therapeutic target requires chemically specific imaging of disease foci. In this study, we aim to image atherosclerotic plaque lipids and other vessel wall constituents with spectroscopic intravascular photoacoustics (sIVPA). sIVPA imaging can identify lipids in human coronary atherosclerotic plaque by relying on contrast in the near-infrared absorption spectra of the arterial wall components. Using reference spectra acquired on pure compounds, we analyzed sIVPA data from human coronary plaques ex vivo, to image plaque composition in terms of cholesterol and cholesterol ester content. In addition, we visualized the deeper lying connective tissue layers of the adventitia, as well as the fatty acid containing adipose cells in the peri-adventitial tissue. We performed simultaneous coregistered IVUS imaging to obtain complementary morphological information. Results were corroborated by histopathology. sIVPA imaging can distinguish the most prevalent lipid components of human atherosclerotic plaques and also visualize the connective tissue layers of the adventitia and the fatty acid containing adipose cells in the peri-adventitial tissue.

Image-based modeling for better understanding and assessment of atherosclerotic plaque progression and vulnerability: Data, modeling, validation, uncertainty and predictions

Medical imaging and image-based modeling have made considerable progress in recent years in identifying atherosclerotic plaque morphological and mechanical risk factors which may be used in developing improved patient screening strategies. However, a clear understanding is needed about what we have achieved and what is really needed to translate research to actual clinical practices and bring benefits to public health. Lack of in vivo data and clinical events to serve as gold standard to validate model predictions is a severe limitation. While this perspective paper provides a review of the key steps and findings of our group in image-based models for human carotid and coronary plaques and a limited review of related work by other groups, we also focus on grand challenges and uncertainties facing the researchers in the field to develop more accurate and predictive patient screening tools.

Imaging of native high-density lipoprotein in human coronary plaques by color fluorescent angioscopy.

High-density lipoprotein (HDL) plays a key role in reverse cholesterol transport, and halts the progression of atherosclerosis. The aim of the present study was to visualize native HDL in the human coronary arterial wall. The fluorescence characteristics of HDL were investigated by color fluorescent microscopy (CFM) using excitation at 470 nm and emission at 515 nm with Fast green dye (FG) as the biomarker. HDL in 30 normal coronary segments, and in 25 white and 25 yellow plaques in excised human coronary arteries, was visualized by color fluorescent angioscopy (CFA) and CFM. Localization of HDL visualized by CFM was compared with that stained by immunostaining using an anti-HDL antibody. FG elicited a characteristic brown fluorescence of HDL. By CFA, the percent incidence of HDL in normal segments, white (early stage of plaque growth) and yellow (advanced stage of plaque growth) plaques was, respectively, 33%, 76% (P<0.05 vs. normal segments and yellow plaques) and 21%. Localization of HDL visualized by CFM did not differ from that stained by immunostaining. In the human coronary arterial wall, HDL deposits infrequently in normal segments, but increasingly deposits with plaque formation, and decreases in the advanced stage of plaque growth.

TCT-638 Plaque Characteristics and Local Release of C-reactive Protein: An Integrated Backscatter Intravascular Ultrasound Study

Local release of C-reactive protein (CRP) in human coronary arterial plaque was reported to be greater in acute coronary syndrome than in the stable plaque. Recently, integrated backscatter intravascular ultrasound (IB-IVUS) based tissue characterization has been reported to be useful to detect