Heterogeneity of Coronary Plaque Morphology and Natural History: Current Understanding and Clinical Significance.

PURPOSE OF REVIEW: Despite the important progress in identifying high-risk atherosclerotic plaques, many key elements are elusive. Advanced imaging modalities provide valuable information about the anatomic and functional plaque characteristics and underscore the presence of multiple plaque morphologies. However, how the heterogeneity of atherosclerotic plaque can alter our current understanding of coronary artery disease is not fully understood. RECENT FINDINGS: Along the length of an individual plaque, the morphology patterns display marked heterogeneity. Contrary to previous beliefs, plaque morphology is also highly dynamic over time, with the vast majority of high-risk plaques becoming quiescent and mild plaques becoming severely obstructive in a short period of time. Endothelial shear stress, a local hemodynamic factor known for its critical effects in plaque initiation and progression, also displays longitudinal heterogeneity contributing to the arterial wall response in all time points. Risk stratification of plaques based on the morphological characteristics at one region of the plaque, usually the minimal lumen diameter, and at one point in time may be misleading. The evaluation of both morphological and hemodynamic characteristics along the length of a plaque will improve the risk assessment of individual plaques.

Clearing of psoriasis documented by laser Doppler perfusion imaging contrasts remaining elevation of dermal expression levels of CD31.

BACKGROUND: Vascular modifications represent a key feature in psoriatic plaques. Previous research with Laser Doppler Perfusion Imaging (LDPI) revealed a remarkable heterogeneity in the cutaneous perfusion within homogenous-appearing psoriatic lesions. Insights in the relation between perfusion during treatment and related biological changes are lacking. OBJECTIVES: To study the effect of calcipotriol-betamethasone dipropionate ointment on the microcirculation and the expression levels of immunohistochemical markers in psoriatic lesions compared to the distant uninvolved skin. METHODS: Psoriatic lesions of fourteen patients were treated once a day during 8 weeks. Clinical SUM scores and the perfusion intensity by means of LDPI were assessed every 2 weeks. After 8 weeks, a biopsy from the target lesion and one from the distant uninvolved skin were taken and stained for psoriasis-related markers, like IL-17 and CD31. RESULTS: After 8 weeks, seven patients reached a SUM score of 0 or 1, and were classified as good-responders. The other patients were classified moderate-responders. The perfusion intensity decreased in all lesions during therapy. In the good-responders, all investigated psoriasis-related proteins within the treated lesions reached the expression level found within the distant uninvolved skin. The expression of CD31, however, was significantly higher in the treated lesions as compared to the distant uninvolved skin (p = 0.0156). In the moderate responders, almost all expression levels remained significantly elevated compared to the uninvolved skin. CONCLUSIONS: In the skin of good-responders the expression of dermal CD31(+) endothelium remains significantly elevated within the treated lesions compared with the distant uninvolved skin, whereas a marked reduction in the perfusion intensity and SUM score was found. This indicates that clinical improvement might outrun endothelial changes.

Unveiling Atherosclerotic Plaque Heterogeneity and SPP1+/VCAN+ Macrophage Subtype Prognostic Significance Through Integrative Single-Cell and Bulk-Seq Analysis.

Background: Dysregulated macrophages are important causes of Atherosclerosis (AS) formation and increased plaque instability, but the heterogeneity of these plaques and the role of macrophage subtypes in plaque instability have yet to be clarified. Methods: This study integrates single-cell and bulk-seq data to analyze atherosclerotic plaques. Unsupervised clustering was used to reveal distinct plaque subtypes, while survival analysis and gene set variation analysis (GSVA) methods helped in understanding their clinical outcomes. Enrichment of differential expression of macrophage genes (DEMGs) score and pseudo-trajectory analysis were utilized to explore the biological functions and differentiation stages of macrophage subtypes in AS progression. Additionally, CellChat and the BayesPrism deconvolution method were used to elucidate macrophage subtype interaction and their prognostic significance at single-cell resolution. Finally, the expression of biomarkers was validated in mouse experiments. Results: Three distinct AS plaque subtypes were identified, with cluster 3 plaque subtype being particularly associated with higher immune infiltration and poorer prognosis. The DEMGs score exhibited a significant elevation in three macrophage subtypes (SPP1+/VCAN+ macrophages, IL1B+ macrophages, and FLT3LG+ macrophages), associated with cluster 3 plaque subtype and highlighted the prognostic significance of these subtypes. Activation trajectory of the macrophage subtypes is divided into three states (Pre-branch, Cell fate 1, and Cell fate 2), and Cell fate 2 (SPP1+/VCAN+ macrophages, IL1B+ macrophages, and FLT3LG+ macrophages dominant) exhibiting the highest DEMGs score, distinct interactions with other cell components, and relating to poorer prognosis of ischemic events. This study also uncovered a unique SPP1+/VCAN+ macrophage subtype, rare in quantity but significant in influencing AS progression. Machine learning algorithms identified 10 biomarkers crucial for AS diagnosis. The validation of these biomarkers was performed using Mendelian Randomization analysis and in vitro methods, supporting their relevance in AS pathology. Conclusion: Our study provides a comprehensive view of AS plaque heterogeneity and the prognostic significance of macrophage subtypes in plaque instability.

Plaque heterogeneity and the spatial distributions of its components dictate drug-coated balloon therapy.

Drug-coated balloon (DCB) angioplasty is one of the potential approaches to alleviating in-stent restenosis and treating peripheral artery disease. An in-silico model has been developed for sirolimus drug eluted from an inflated balloon in a patient-specific arterial cross-section consisting of fibrous tissue, fibrofatty tissue, dense calcium, necrotic core, and healthy tissue. The convection-diffusion-reaction equation represents the transport of drug, while drug binding, both specific and non-specific, can be modelled as a reaction process. The Brinkman equations describe the interstitial flow in porous tissue. An image processing technique is leveraged for reconstructing the computational domain. The Marker and Cell, and Immersed Boundary Methods are used to solve the set of governing equations. The no-flux interface condition and convection do amplify the tissue content, and the regions of dense calcium and necrotic core limited to or extremely close to the interface pose a clinical threat to DCB therapy. Simulations predict the effects of the positioning and clustering of plaque components in the domain. This study demands extensive intravascular ultrasound-derived virtual histology (VH-IVUS) imaging to understand the plaque morphology and determine the relative positions of different plaque compositions about the lumen-tissue interface, which have a significant impact on arterial pharmacokinetics.

A Single-Cell Atlas of the Atherosclerotic Plaque in the Femoral Artery and the Heterogeneity in Macrophage Subtypes between Carotid and Femoral Atherosclerosis.

Atherosclerosis of femoral arteries can cause the insufficient blood supply to the lower limbs and lead to gangrenous ulcers and other symptoms. Atherosclerosis and inflammatory factors are significantly different from other plaques. Therefore, it is crucial to observe the cellular composition of the femoral atherosclerotic plaque and identify plaque heterogeneity in other arteries. To this end, we performed single-cell sequencing of a human femoral artery plaque. We identified 14 cell types, including endothelial cells, smooth muscle cells, monocytes, three macrophages with four different subtypes of foam cells, three T cells, natural killer cells, and B cells. We then downloaded single-cell sequencing data of carotid atherosclerosis from GEO, which were compared with the one femoral sample. We identified similar cell types, but the femoral artery had significantly more nonspecific immune cells and fewer specific immune cells than the carotid artery. We further compared the differences in the proportion of inflammatory macrophages, and resident macrophages, and the proportion of inflammatory macrophages was greater within the carotid artery. Through comparing one femoral sequencing sample with carotid samples from public datasets, our study reveals the single-cell map of the femoral artery and the heterogeneity of carotid and femoral arteries at the cellular level, laying the foundation for mechanistic and pharmacological studies of the femoral artery.

Identification of Multicolor Fluorescent Probes for Heterogeneous Aß Deposits in Alzheimer's Disease.

Accumulation of amyloid-beta (Aß) into amyloid plaques and hyperphosphorylated tau into neurofibrillary tangles (NFTs) are pathological hallmarks of Alzheimer's disease (AD). There is a significant intra- and inter-individual variability in the morphology and conformation of Aß aggregates, which may account in part for the extensive clinical and pathophysiological heterogeneity observed in AD. In this study, we sought to identify an array of fluorescent dyes to specifically probe Aß aggregates, in an effort to address their diversity. We screened a small library of fluorescent probes and identified three benzothiazole-coumarin derivatives that stained both vascular and parenchymal Aß deposits in AD brain sections. The set of these three dyes allowed the visualization of Aß deposits in three different colors (blue, green and far-red). Importantly, two of these dyes specifically stained Aß deposits with no apparent staining of hyperphosphorylated tau or α-synuclein deposits. Furthermore, this set of dyes demonstrated differential interactions with distinct types of Aß deposits present in the same subject. Aß aggregate-specific dyes identified in this study have the potential to be further developed into Aß imaging probes for the diagnosis of AD. In addition, the far-red dye we identified in this study may serve as an imaging probe for small animal imaging of Aß pathology. Finally, these dyes in combination may help us advance our understanding of the relation between the various Aß deposits and the clinical diversity observed in AD.