Prospective Comparison of Plasma Biomarker and Traditional Risk Factor Profiles for Incident Isolated Atherosclerotic Disease and Incident Isolated Abdominal Aortic Aneurysm

Background: Traditional risk factors for atherosclerotic disease (AD) are well-known, of which some are relevant also for abdominal aortic aneurysms (AAA). The present study compares the importance of plasma biomarkers and traditional risk factor profiles for incident AD without concomitant AAA (isolated AD) and AAA without concomitant AD (isolated AAA) during long-term follow-up.Methods: In the Malmö Diet and Cancer Study—cardiovascular cohort, 5,381 participants were free from atrial fibrillation or flutter, AD (coronary artery disease, atherothrombotic ischemic stroke, carotid artery disease, or peripheral artery disease), and AAA underwent blood sampling under standardized fasting conditions between 1991 and 1994. Cox proportional hazards regression analysis was used to calculate hazard ratios (HR) with 95% CIs.Results: During a median follow-up of 23.1 years, 1,152 participants developed isolated AD, and 44 developed isolated AAA. Adjusted HR for lipoprotein-associated phospholipase A2 (mass) (HR 1.53, 95% CI 1.14–2.04 vs. HR 1.05, 95% CI.99–1.12) was higher for incident isolated AAA compared to incident isolated AD, respectively. Mid-regional pro-adrenomedullin (MR-proADM) was associated with incident isolated AD (HR 1.17, 95% CI 1.1–1.25) and incident isolated AAA (HR 1.47, 95% CI 1.15–1.88). MR-proADM was correlated (r = 0.32; p < 0.001) to body mass index (BMI), and BMI was associated with increased risk of incident isolated AAA (HR 1.43, 95% CI 1.02–2). No participant with diabetes mellitus (DM) at baseline developed isolated AAA (0/44), whereas DM was associated with an increased risk of isolated AD (HR 2.57, 95% CI 2.08–3.18). Adjusted HR for male sex (HR 4.8, 95% CI 2.42–9.48, vs. HR 1.76, 95% CI 1.56–1.98) and current smoking (HR 4.79, 95% CI 2.42–9.47 vs. HR 1.97, 95% CI 1.73–2.23) were higher in the incident isolated AAA group compared to the incident isolated AD group, respectively.Conclusions: The data supports the view that components of vascular inflammation and cardiovascular stress drives AAA development, whereas glycated cross-links in abdominal aortic wall tissue may have a plausible role in reducing AAA risk in individuals with DM.

Intracranial atherosclerosis: Review of imaging features and advances in diagnostics

Intracranial atherosclerotic disease is one of the leading causes of ischemic strokes and poses a moderate risk of recurrence. Diagnosis is currently limited to stenosis on luminal imaging, which likely underestimates the true prevalence of the disease. Detection of non-stenosing intracranial atherosclerosis is important in order to optimize secondary stroke prevention strategies. This review collates findings from the early seminal trials and the latest studies in advanced radiological techniques that characterize symptomatic intracranial atherosclerotic disease across various imaging modalities. While computed tomography angiography (CTA) and magnetic resonance angiography (MRA) comprise diagnostic mainstays in identifying stenotic changes secondary to atherosclerosis, emerging techniques such as high-resolution MRA, quantitative MRA, and computational fluid dynamics may reveal a myriad of other underlying pathophysiological mechanisms.

Pharmacodynamic profiles of dual-pathway inhibition with or without clopidogrel vs dual antiplatelet therapy in patients with atherosclerotic disease

Aim: Inhibition of thrombin-mediated signaling processes using a vascular dose of rivaroxaban in adjunct to antiplatelet therapy, known as dual-pathway inhibition (DPI), reduces atherothrombotic events in patients with stable atherosclerotic disease. However, there are limited data on the pharmacodynamic (PD) effects of this strategy. Methods and Results: This investigation was conducted in selected cohorts of patients (n=40) with stable atherosclerotic disease enrolled within a larger prospective PD study who were treated with either aspirin plus clopidogrel (DAPT), aspirin plus rivaroxaban 2.5 mg/bid (DPI) or DAPT plus rivaroxaban 2.5 mg/bid. Multiple PD assays assessing of markers of thrombosis were used. PD endpoints included platelet-mediated global thrombogenicity measured by light transmittance aggregometry (LTA) following stimuli with CATF [collagen‐related peptide +adenosine diphosphate (ADP) +tissue factor (TF)], markers of P2Y12 reactivity, markers of platelet aggregation using LTA following several stimuli (arachidonic acid, ADP, collagen, TF, and TRAP), thrombin generation and thrombus formation. There was no difference in platelet-mediated global thrombogenicity between groups. Rivaroxaban significantly reduced thrombin generation and was associated with a trend towards reduced TF-induced platelet aggregation. Clopidogrel-based treatments reduced markers of P2Y12 signaling and TRAP‐induced platelet aggregation. There were no differences between groups on markers of cyclooxygenase‐1 mediated activity. Conclusions: Compared with DAPT, DPI does not result in any differences in platelet-mediated global thrombogenicity, but reduces thrombin generation. These PD observations support that modulating thrombin generation by means of factor Xa inhibition in adjunct to antiplatelet therapy provides effective antithrombotic effects, supporting the efficacy and safety findings of DPI observed in clinical

2021 Biomaterials Science Emerging Investigators Issue: Antioxidant Response Activating nanoParticles (ARAPas) localize to atherosclerotic plaque and locally activate the Nrf2 pathway

Atherosclerotic disease is the leading cause of death world-wide with few novel therapies available despite the ongoing health burden. Redox dysfunction is a well-established driver of atherosclerotic progression; however, the...

Intersecting single-cell transcriptomics and genome-wide association studies identifies crucial cell populations and candidate genes for atherosclerosis

Aim GWASs have discovered hundreds of common genetic variants for atherosclerotic disease and cardiovascular risk factors. The translation of susceptibility loci into biological mechanisms and targets for drug discovery remains challenging. Intersecting genetic and gene expression data has led to the identification of candidate genes. However, previously studied tissues are often non-diseased and heterogeneous in cell composition, hindering accurate candidate prioritization. Therefore, we analyzed single-cell transcriptomics from atherosclerotic plaques for cell-type-specific expression to identify atherosclerosis-associated candidate gene-cell pairs. Methods and Results We applied gene-based analyses using GWAS summary statistics from 46 atherosclerotic and cardiovascular disease, risk factors, and other traits. We then intersected these candidates with scRNA-seq data to identify genes specific for individual cell (sub)populations in atherosclerotic plaques. The coronary artery disease loci demonstrated a prominent signal in plaque smooth muscle cells (SKI, KANK2, SORT1) p-adj. = 0.0012, and endothelial cells (SLC44A1, ATP2B1) p-adj. = 0.0011. Finally, we used liver-derived scRNA-seq data and showed hepatocyte-specific enrichment of genes involved in serum lipid levels. Conclusion We discovered novel and known gene-cell pairs pointing to new biological mechanisms of atherosclerotic disease. We highlight that loci associated with coronary artery disease reveal prominent association levels in mainly plaque smooth muscle cell and endothelial cell populations. We present an intuitive single-cell transcriptomics-driven workflow rooted in human large-scale genetic studies to identify putative candidate genes and affected cells associated with cardiovascular traits. Collectively, our workflow allows for the identification of cell-specific targets relevant for atherosclerosis and can be universally applied to other complex genetic diseases and traits. Translational perspective GWAS identified a large number of genomic loci associated with atherosclerotic disease. The translation of these results into drug development and faster diagnostics remains challenging. With our approach, we cross-reference the GWAS findings for atherosclerotic disease with scRNA-seq data of disease-relevant tissue and bring the GWAS findings closer to the functional and mechanistic studies.

Epigenome-Wide Histone Acetylation Changes in Peripheral Blood Mononuclear Cells in Patients with Type 2 Diabetes and Atherosclerotic Disease

There is emerging evidence of an association between epigenetic modifications, glycemic control and atherosclerosis risk. In this study, we mapped genome-wide epigenetic changes in patients with type 2 diabetes (T2D) and advanced atherosclerotic disease. We performed chromatin immunoprecipitation sequencing (ChIP-seq) using a histone 3 lysine 9 acetylation (H3K9ac) mark in peripheral blood mononuclear cells from patients with atherosclerosis with T2D (n = 8) or without T2D (ND, n = 10). We mapped epigenome changes and identified 23,394 and 13,133 peaks in ND and T2D individuals, respectively. Out of all the peaks, 753 domains near the transcription start site (TSS) were unique to T2D. We found that T2D in atherosclerosis leads to an H3K9ac increase in 118, and loss in 63 genomic regions. Furthermore, we discovered an association between the genomic locations of significant H3K9ac changes with genetic variants identified in previous T2D GWAS. The transcription factor 7-like 2 (TCF7L2) rs7903146, together with several human leukocyte antigen (HLA) variants, were among the domains with the most dramatic changes of H3K9ac enrichments. Pathway analysis revealed multiple activated pathways involved in immunity, including type 1 diabetes. Our results present novel evidence on the interaction between genetics and epigenetics, as well as epigenetic changes related to immunity in patients with T2D and advanced atherosclerotic disease.

Genome sequencing reveals the role of rare genomic variants in Chinese patients with symptomatic intracranial atherosclerotic disease

ObjectivesThe predisposition of intracranial atherosclerotic disease (ICAD) to East Asians over Caucasians infers a genetic basis which, however, remains largely unknown. Higher prevalence of vascular risk factors (VRFs) in Chinese over Caucasian patients who had a stroke, and shared risk factors of ICAD with other stroke subtypes indicate genes related to VRFs and/or other stroke subtypes may also contribute to ICAD.MethodsUnrelated symptomatic patients with ICAD were recruited for genome sequencing (GS, 60-fold). Rare and potentially deleterious single-nucleotide variants (SNVs) and small insertions/deletions (InDels) were detected in genome-wide and correlated to genes related to VRFs and/or other stroke subtypes. Rare aneuploidies, copy number variants (CNVs) and chromosomal structural rearrangements were also investigated. Lastly, candidate genes were used for pathway and gene ontology enrichment analysis.ResultsAmong 92 patients (mean age at stroke onset 61.0±9.3 years), GS identified likely ICAD-associated rare genomic variants in 54.3% (50/92) of patients. Forty-eight patients (52.2%, 48/92) had 59 rare SNVs/InDels reported or predicted to be deleterious in genes related to VRFs and/or other stroke subtypes. None of the 59 rare variants were identified in local subjects without ICAD (n=126). 31 SNVs/InDels were related to conventional VRFs, and 28 were discovered in genes related to other stroke subtypes. Our study also showed that rare CNVs (n=7) and structural rearrangement (a balanced translocation) were potentially related to ICAD in 8.7% (8/92) of patients. Lastly, candidate genes were significantly enriched in pathways related to lipoprotein metabolism and cellular lipid catabolic process.ConclusionsOur GS study suggests a role of rare genomic variants with various variant types contributing to the development of ICAD in Chinese patients.

Frank's sign with acute aortic dissection

A 59-year-old man with a long smoking history presented with sudden back pain. Frank’s sign was noticed in his bilateral ears, and computed tomography revealed Stanford type A acute aortic dissection. If young patients have Frank’s sign, attention should be paid to atherosclerotic disease including aortic disease.