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Background: Atherosclerotic plaque ruptures, triggered by blood flow-associated biomechanical forces, cause most myocardial infarctions and strokes., Objectives: This study aims to investigate the exact location and underlying mechanisms of atherosclerotic plaque ruptures, identifying therapeutic targets against cardiovascular events., Methods: Histology, electron microscopy, bulk and spatial RNA sequencing on human carotid plaques were studied in proximal, most stenotic, and distal regions along the longitudinal blood flow direction. Genome-wide association studies were used to examine heritability enrichment and causal relationships of atherosclerosis and stroke. Associations between top differentially expressed genes (DEGs) and preoperative and postoperative cardiovascular events were examined in a validation cohort., Results: In human carotid atherosclerotic plaques, ruptures predominantly occurred in the proximal and most stenotic regions but not in the distal region. Histologic and electron microscopic examination showed that proximal and most stenotic regions exhibited features of plaque vulnerability and thrombosis. RNA sequencing identified DEGs distinguishing the proximal and most stenotic regions from the distal region which were deemed as most relevant to atherosclerosis-associated diseases as shown by heritability enrichment analyses. The identified pathways associated with the proximal rupture-prone regions were validated by spatial transcriptomics, firstly in human atherosclerosis. Of the 3 top DEGs, matrix metallopeptidase 9 emerged particularly because Mendelian randomization suggested that its high circulating levels were causally associated with atherosclerosis risk., Conclusions: Our findings show plaque site-specific transcriptional signatures associated with proximal rupture-prone regions of carotid atherosclerotic plaques. This led to the geographical mapping of novel therapeutic targets, such as matrix metallopeptidase 9, against plaque rupture., Competing Interests: Funding Suport and Author Disclosures This work was supported by grants from Novo Nordisk A/S, the Swedish Research Council, the Swedish Heart and Lung Foundation, Skåne University Hospital funds, Swedish Society for Medical Research, Swedish Stroke Association, Crafoord foundation, The Swedish Society of Medicine, Diabetes foundation, Southern Sweden Regional Research Funding, Albert Påhlssons foundation and Lund University Diabetes Center (Swedish Research Council - Strategic Research Area Exodiab Dnr 2009-1039, Linnaeus grant Dnr 349-2006-23 and the Swedish Foundation for Strategic Research Dnr IRC15-006). The Knut and Alice Wallenberg Foundation, the Medical Faculty at Lund University, and Region Skåne are also acknowledged for generous financial support. Dr Edsfeldt has received consulting fees from Novo Nordisk, Sanofi, and Amgen outside of this study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Mood disorders and strokes are often comorbid, and their health toll worldwide is huge. This study characterizes prognostic and causal roles of mood disorders in stroke., Methods: We tested if genetic susceptibilities for mood disorders were associated with all strokes, ischemic strokes in the Malmö Diet and Cancer cohort (24 631 individuals with a median follow-up of 21.3 (interquartile range: 16.6-23.2) years. We further examined the causal effects for mood disorders on all strokes and ischemic strokes using summary statistics from large genome-wide association studies of mood disorders (up to 609 424 individuals, Psychiatric Genomics Consortium), all strokes and ischemic strokes (up to 446 696 individuals, MEGASTROKE Consortium)., Results: Among 24 366 stroke-free participants at baseline, 2632 individuals developed strokes, 2172 of them ischemic, during follow-up. After properly adjusting for well-known risk factors, participants in the highest quintile of polygenic risk scores for mood disorders had 1.45× (95% CI, 1.21-1.74) higher risk of strokes and 1.44× (95% CI, 1.18-1.76) higher risk of ischemic strokes compared with the lowest quintile in women. Mendelian randomization analyses suggested that mood disorders had a causal effect on strokes (odds ratio, 1.07 [95% CI, 1.03-1.11]) and ischemic strokes (odds ratio, 1.09 [95% CI, 1.04-1.13])., Conclusions: Our results suggest a causal role of mood disorders in the risk of stroke. High-risk women could be identified early in life using polygenic risk scores to ultimately prevent mood disorders and strokes.

Background and Aims: A vulnerable plaque is an atherosclerotic plaque that is rupture-prone with a higher risk to cause cardiovascular symptoms such as myocardial infarction or stroke. Mimecan or osteoglycin is a small leucine-rich proteoglycan, important for collagen fibrillogenesis, that has been implicated in atherosclerotic disease, yet the role of mimecan in human atherosclerotic disease remains unknown., Methods: 196 human atherosclerotic carotid plaques were immunostained for mimecan. Smooth muscle cells, macrophages and intraplaque haemorrhage were also measured with immunohistochemistry. Neutral lipids were stained with Oil Red O and calcium deposits were quantified. Plaque homogenate levels of MCP-1, IL-6 and MIP-1β were measured using a Proximity Extension Assay and MMP-9 levels were measured using Mesoscale. Glycosaminoglycans, collagen and elastin were assessed by colorimetric assays and TGF-β1, β2 and β3 were measured using a multiplex assay. Mimecan gene expression in THP-1 derived macrophages was quantified by qPCR and protein expression in vitro was visualized with immunofluorescence. Cardiovascular events were registered using medical charts and national registers during follow-up., Results: Mimecan correlated positively with plaque area of lipids, macrophages, intraplaque haemorrhage and inversely with smooth muscle cell staining. Mimecan also correlated positively with plaque levels of MMP-9 and MCP-1. Mimecan was upregulated in THP-1 derived macrophages upon stimulation with MCP-1. Patients with high levels of mimecan (above median) had higher risk for cardiovascular death., Conclusions: This study indicates that mimecan is associated with a vulnerable plaque phenotype, possibly regulated by plaque inflammation. In line, plaque levels of mimecan independently predict future cardiovascular death., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Galectin-3 (Gal-3) has been suggested to have both pro- and anti-atherogenic properties. High plasma Gal-3 levels are associated with increased risk for cardiovascular (CV) death. However, it has so far not been investigated if plasma Gal-3 levels can predict the risk for future stroke in patients suffering from carotid atherosclerosis. The aim of this study was to investigate whether Gal-3 could be used as a marker to predict postoperative cerebrovascular ischemic events among patients who underwent carotid endarterectomy (CEA)., Methods: Plasma samples were obtained from 558 CEA patients and Gal-3 levels were analyzed by the proximity extension assay technique. The Swedish national in-patient health register was used to identify postoperative cerebrovascular events during the follow-up period (42.6 ± 26.2 months)., Results: Plasma Gal-3 was increased in patients treated for a symptomatic carotid stenosis (p = 0.013). Patients with Gal-3 levels above the median value had an increased incidence of stroke as shown by Kaplan-Meier curves of event-free survival (p = 0.007). Gal-3 was a predictor of postoperative stroke among women (hazard ratio 15.1, 95% CI 1.3-172.2; p = 0.028) even after correction for traditional CV risk factors., Conclusions: This study is the first to show that increased plasma levels of Gal-3 can help in predicting the occurrence of postoperative strokes among female subjects who undergo CEA, independently of traditional risk factors for cerebrovascular disease. This finding suggests that Gal-3 could be used as a marker to identify patients in need of intensified postoperative medical care., (© 2016 S. Karger AG, Basel.)

Objectives: Atherosclerotic plaques with a low content of connective tissue proteins are believed to have an increased risk of rupture and to give rise to clinical events. The aim of the present study was to investigate if the content of elastin, collagen and of the matrix metalloproteinase (MMP) -1, -3, -9 and -12 in plaques removed at surgery can be associated with the occurrence of ipsilateral symptoms., Methods: The atherosclerotic plaques of 221 patients undergoing carotid endarterectomy were analyzed and their composition was related to the incidence of preoperative, intraoperative and postoperative neurological events., Results: Elastin, collagen and MMP-12 contents were lower in males and diabetic patients. Elastin (P .010), MMP-3 (P .008) and MMP-9 (P < .0001) were lower, while MMP-1 (P .004) and MMP-9 (P .002) were higher in plaques of patients with preoperative symptoms, even after correction for the time between the occurrence of symptoms and surgery. Elastin and MMP-12 decreased (r = -0.17, P .009 and r = -.288, P <.0001 respectively) while MMP-1 (r = 0.17, P .012) and MMP-9 (r = .21 P <.0001) increased with age. After a mean follow-up time of 39.6 ± 16.6 months, 7.7% of patients had suffered one or multiple ipsilateral neurological events. Patients with plaque elastin levels lower than the median (52 mg/g) had increased post-operative incidence of ipsilateral stroke (P for trend 0.009 using Log Rank Chi-square test). This finding was confirmed when controlling for age, gender, hypertension, diabetes, smoking, pre-operative symptoms and statin usage in a Cox Proportional Hazard model (hazard ratio 7.38, 95% C.I. 1.50-36.31)., Conclusions: These observations support the concept that elastin may be important for plaque stability, and suggest that a low plaque content of elastin is associated with a higher risk for ipsilateral stroke.