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Ligation of macrophage Fcγ receptors recapitulates the gene expression pattern of vulnerable human carotid plaques.

ABSTRACT: Stroke is a leading cause of death in the United States. As ∼60% of strokes result from carotid plaque rupture, elucidating the mechanisms that underlie vulnerability is critical for therapeutic intervention. We tested the hypothesis that stable and vulnerable human plaques differentially express genes associated with matrix degradation. Examination established that femoral, and the distal region of carotid, plaques were histologically stable while the proximal carotid plaque regions were vulnerable. Quantitative RT-PCR was used to compare expression of 22 genes among these tissues. Distal carotid and femoral gene expression was not significantly different, permitting the distal carotid segments to be used as a paired control for their corresponding proximal regions. Analysis of the paired plaques revealed differences in 16 genes that impact plaque stability: matrix metalloproteinases (MMP, higher in vulnerable), MMP modulators (inhibitors: lower, activators: higher in vulnerable), activating Fc receptors (FcγR, higher in vulnerable) and FcγR signaling molecules (higher in vulnerable). Surprisingly, the relative expression of smooth muscle cell and macrophage markers in the three plaque types was not significantly different, suggesting that macrophage distribution and/or activation state correlates with (in)stability. Immunohistochemistry revealed that macrophages and smooth muscle cells localize to distinct and non-overlapping regions in all plaques. MMP protein localized to macrophage-rich regions. In vitro, treatment of macrophages with immune complexes, but not oxidized low density lipoprotein, C-reactive protein, or TNF-α, induced a gene expression profile similar to that of the vulnerable plaques. That ligation of FcγR recapitulates the pattern of gene expression in vulnerable plaques suggests that the FcγR → macrophage activation pathway may play a greater role in human plaque vulnerability than previously appreciated.

SUBMITTER: Lennartz MR

PROVIDER: S-EPMC3140977 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Vulnerable carotid plaques are closely related to the occurrence of ischemic stroke. Therefore, accurate and rapid identification of the nature of carotid plaques is essential. This study aimed to determine whether texture analysis based on a vascular ultrasound can be applied to identify vulnerable plaques. Data from a total of 150 patients diagnosed with atherosclerotic plaque (AP) by carotid ultrasound (CDU) and high-resolution magnetic resonance imaging (HRMRI) were collected. HRMRI is the in vivo reference to assess the nature of AP. MaZda software was used to delineate the region of interest and extract 303 texture features from ultrasonic images of plaques. Following regression analysis using the least absolute shrinkage and selection operator (LASSO) algorithm, the overall cohort was randomized 7:3 into the training (n = 105) and testing (n = 45) sets. In the training set, the conventional ultrasound model, the texture feature model, and the conventional ultrasound-texture feature combined model were constructed. The testing set was used to validate the model's effectiveness by calculating the area under the curve (AUC), accuracy, sensitivity, and specificity. Based on the combined model, a nomogram risk prediction model was established, and the consistency index (C-index) and the calibration curve were obtained. In the training and testing sets, the AUC of the prediction performance of the conventional ultrasonic-texture feature combined model was higher than that of the conventional ultrasonic model and the texture feature model. In the training set, the AUC of the combined model was 0.88, while in the testing set, AUC was 0.87. In addition, the C-index results were also favorable (0.89 in the training set and 0.84 in the testing set). Furthermore, the calibration curve was close to the ideal curve, indicating the accuracy of the nomogram. This study proves the performance of vascular ultrasound-based texture analysis in identifying the vulnerable carotid plaques. Texture feature extraction combined with CDU sonogram features can accurately predict the vulnerability of AP.

Project description:BackgroundThe risk factors for coronary and carotid plaque development are consistent. Coronary plaque rupture is a major cause of adverse cardiovascular events. Ultrasound can evaluate vulnerable carotid plaques and provide information for predicting vulnerable coronary plaques identified by optical coherence tomography (OCT). This study aimed to investigate the predictive role of non-invasive carotid ultrasound in OCT diagnosis of atherosclerotic vulnerable plaque.MethodsA total of 70 participants, including 35 patients with and 35 without vulnerable coronary plaque, were enrolled in this case-control study at Beijing Anzhen Hospital from 2016 to 2021. The data of 70 patients with suspected coronary heart disease who had undergone OCT examination during percutaneous coronary intervention (PCI) surgery and completed carotid ultrasound examination within 3 days before PCI were analyzed retrospectively. According to the OCT diagnostic criteria for vulnerable plaques, the patients were divided into the vulnerable-plaque group and the stable-plaque group. Univariate and binary logistic regression analyses assessed risk factors for vulnerable coronary plaque. Receiver operating characteristic (ROC) curve analysis was used to determine the predictive power of carotid plaque features.ResultsThe univariate analysis demonstrated that the differences in high-sensitivity C-reactive protein levels and carotid plaque characteristics (irregular fibrous cap, heterogeneous plaque, hypoechoic plaque, plaque calcification, and a plaque thickness of greater than 3 mm) between the two groups were statistically significant. The logistic multivariate regression analysis revealed that an irregular fibrous cap of a carotid plaque [odds ratio (OR) =4.819; 95% confidence interval (CI): 1.106-22.867; P=0.048] and a hypoechoic plaque (OR =9.632; 95% CI: 2.138-43.384; P<0.05) were independent risk factors for predicting vulnerable plaques of the coronary artery.ConclusionsNoninvasive carotid ultrasound is feasible and clinically valuable for predicting vulnerable and asymptomatic coronary plaques defined by OCT. With this method, adverse events can be diagnosed and treated in advance.

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Ligation of macrophage Fcγ receptors recapitulates the gene expression pattern of vulnerable human carotid plaques.

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