Clonal haematopoiesis of indeterminate potential and mortality in coronary artery disease.

Background And Aims: Clonal haematopoiesis of indeterminate potential (CHIP) has been associated with cardiovascular risk, but its prognostic relevance and mechanistic role in coronary artery disease (CAD) remains incompletely understood. This study investigated the association between CHIP and all-cause mortality in CAD and explored the cellular and molecular mechanisms, focusing on TET2 mutations.

Methods: Targeted deep sequencing of 13 CHIP driver genes in 8612 patients with angiographically confirmed CAD was performed.

An interplay of non-coding RNAs regulates CDH13 expression and affects endothelial function and coronary artery disease risk.

Many common diseases have a polygenic architecture. The responsible alleles are thought to mediate risk by disturbing gene regulation in most cases, however, the precise mechanisms have been elucidated only for a few. Here, we investigated the genomic locus, which genome-wide significantly associates with coronary artery disease, a globally leading cause of death caused by accumulation of lipid-rich inflammatory plaques in the arterial wall.

Circulating Trimethylamine N-Oxide and Growth Rate of Abdominal Aortic Aneurysms and Surgical Risk.

Importance: Plasma levels of the gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) are associated with prevalent abdominal aortic aneurysms (AAA) in humans and fostering of AAA progression in animal models; therapeutic targeting of TMAO production blocks AAA progression and rupture in multiple mouse models. A blood biomarker that identifies individuals at risk for incident AAA development, accelerated AAA expansion, or recommendation for surgical AAA repair could be an asset for risk stratification.

Objective: To determine whether TMAO is associated with risk for AAA development, rapid AAA expansion, and risk for recommended surgical intervention.

MicroRNA-15a-5p mediates abdominal aortic aneurysm progression and serves as a potential diagnostic and prognostic circulating biomarker.

Background: MicroRNAs are post transcriptional modulators of gene expression. We explored the diagnostic and prognostic value of circulating microRNAs in abdominal aortic aneurysm (AAA) disease, for which currently no established circulating biomarker is available.

Methods: We profiled the expression of 754 human microRNAs in plasma from 187 patients with AAA and 190 matched non-diseased controls.

Comprehensive Multimodal Profiling of Atherosclerosis Reveals Bhlhe40 as a Potential Regulator of Vascular Smooth Muscle Cell Phenotypic Modulation.

Background: Vascular smooth muscle cells (VSMCs) play a central role in atherosclerosis by undergoing phenotypic modulation from a quiescent, contractile state to a range of synthetic phenotypes, including fibroblast-like, macrophage-like, and lipid-laden foam cell-like states. However, a comprehensive multimodal characterization and understanding of the transcriptional programs driving these transitions remain incomplete.

Methods: To comprehensively define the phenotypic diversity of VSMCs during atherosclerosis progression, we performed in-depth profiling using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and bulk RNA sequencing in a VSMC lineage-tracing atherosclerotic mouse model.

Abdominal aortic aneurysm histomorphology shows different inflammatory aspects among patients and is not associated with classic risk factors - the HistAAA study.

Aims: Abdominal aortic aneurysm (AAA) treatment is upon a diameter threshold. Attempts for medical growth abrogation have failed thus far. This study aims to elucidate the heterogeneity of AAA histomorphology in correlation to individual patient and aneurysm metrics.

An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis.

Atherosclerosis is the underlying cause of myocardial infarction and ischemic stroke. It is a lipid-triggered and cytokine/chemokine-driven arterial inflammatory condition. We identify D-dopachrome tautomerase/macrophage migration-inhibitory factor-2 (MIF-2), a paralog of the cytokine MIF, as an atypical chemokine promoting both atherosclerosis and hepatic lipid accumulation.

PRDM16 controls smooth muscle cell fate in atherosclerosis.

Vascular smooth muscle cells (SMCs) normally exist in a contractile state but can undergo fate switching to produce various cell phenotypes in response to pathologic stimuli. In atherosclerosis, these phenotypically modulated SMCs regulate plaque composition and influence the risk of major adverse cardiovascular events. We found that PRDM16, a transcription factor that is genetically associated with cardiovascular disease, is highly expressed in arterial SMCs and downregulated during SMC fate switching in human and mouse atherosclerosis.

Ezh2 Shapes T Cell Plasticity to Drive Atherosclerosis.

Background: The activation and polarization of T cells play a crucial role in atherosclerosis and dictate athero-inflammation. The epigenetic enzyme EZH2 (enhancer of zeste homolog 2) mediates the H3K27me3 (trimethylation of histone H3 lysine 27) and is pivotal in controlling T cell responses.

Methods: To detail the role of T cell EZH2 in atherosclerosis, we used human carotid endarterectomy specimens to reveal plaque expression and geography of EZH2.

Circular RNAs increase during vascular cell differentiation and are biomarkers for vascular disease.

Aims: The role of circular RNAs (circRNAs) and their regulation in health and disease are poorly understood. Here, we systematically investigated the temporally resolved transcriptomic expression of circRNAs during differentiation of human induced pluripotent stem cells (iPSCs) into vascular endothelial cells (ECs) and smooth muscle cells (SMCs) and explored their potential as biomarkers for human vascular disease.

Methods And Results: Using high-throughput RNA sequencing and a de novo circRNA detection pipeline, we quantified the daily levels of 31 369 circRNAs in a 2-week differentiation trajectory from human stem cells to proliferating mesoderm progenitors to quiescent, differentiated EC and SMC.

Inflammatory crosstalk impairs phagocytic receptors and aggravates atherosclerosis in clonal hematopoiesis in mice.

Clonal hematopoiesis (CH) increases inflammasome-linked atherosclerosis, but the mechanisms by which CH mutant cells transmit inflammatory signals to nonmutant cells are largely unknown. To address this question, we transplanted 1.5% Jak2V617F (Jak2VF) bone marrow (BM) cells with 98.

Red blood cells as potential materials for microRNA biomarker study: overcoming heparin-related challenges.

microRNAs (miRNAs) have been intensively studied as valuable biomarkers in cardiometabolic disease. Typically, miRNAs are detected in plasma or serum, but the use of samples collected in heparinized tubes is problematic for miRNA studies using quantitative PCR (qPCR). Heparin and its derivatives interfere with qPCR-based analysis, leading to a substantial reduction or even complete loss of detectable miRNA levels.

PIEZO1 targeting in macrophages boosts phagocytic activity and foam cell apoptosis in atherosclerosis.

The rising incidences of atherosclerosis have necessitated efforts to identify novel targets for therapeutic interventions. In the present study, we observed increased expression of the mechanosensitive calcium channel Piezo1 transcript in mouse and human atherosclerotic plaques, correlating with infiltration of PIEZO1-expressing macrophages. In vitro administration of Yoda1, a specific agonist for PIEZO1, led to increased foam cell apoptosis and enhanced phagocytosis by macrophages.

Atherosclerosis Is a Smooth Muscle Cell-Driven Tumor-Like Disease.

Background: Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation of various cell types, including immunocytes (eg, macrophages and T cells), smooth muscle cells (SMCs), and endothelial cells. Accumulating evidence suggests that transition of SMCs to other cell types, known as phenotypic switching, plays a central role in atherosclerosis development and complications. However, the characteristics of SMC-derived cells and the underlying mechanisms of SMC transition in disease pathogenesis remain poorly understood.

Mustn1 is a smooth muscle cell-secreted microprotein that modulates skeletal muscle extracellular matrix composition.

Objective: Skeletal muscle plasticity and remodeling are critical for adapting tissue function to use, disuse, and regeneration. The aim of this study was to identify genes and molecular pathways that regulate the transition from atrophy to compensatory hypertrophy or recovery from injury. Here, we have used a mouse model of hindlimb unloading and reloading, which causes skeletal muscle atrophy, and compensatory regeneration and hypertrophy, respectively.

High-Dimensional Single-Cell Multimodal Landscape of Human Carotid Atherosclerosis.

Background: Atherosclerotic plaques are complex tissues composed of a heterogeneous mixture of cells. However, our understanding of the comprehensive transcriptional and phenotypic landscape of the cells within these lesions is limited.

Methods: To characterize the landscape of human carotid atherosclerosis in greater detail, we combined cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing to classify all cell types within lesions (n=21; 13 symptomatic) to achieve a comprehensive multimodal understanding of the cellular identities of atherosclerosis and their association with clinical pathophysiology.

Suppression of IL-1β promotes beneficial accumulation of fibroblast-like cells in atherosclerotic plaques in clonal hematopoiesis.

Clonal hematopoiesis (CH) is an independent risk factor for atherosclerotic cardiovascular disease. Murine models of CH suggest a central role of inflammasomes and IL-1β in accelerated atherosclerosis and plaque destabilization. Here we show using single-cell RNA sequencing in human carotid plaques that inflammasome components are enriched in macrophages, while the receptor for IL-1β is enriched in fibroblasts and smooth muscle cells (SMCs).

Utilization of an Artery-on-a-Chip to Unravel Novel Regulators and Therapeutic Targets in Vascular Diseases.

In this study, organ-on-chip technology is used to develop an in vitro model of medium-to-large size arteries, the artery-on-a-chip (AoC), with the objective to recapitulate the structure of the arterial wall and the relevant hemodynamic forces affecting luminal cells. AoCs exposed either to in vivo-like shear stress values or kept in static conditions are assessed to generate a panel of novel genes modulated by shear stress. Considering the crucial role played by shear stress alterations in carotid arteries affected by atherosclerosis (CAD) and abdominal aortic aneurysms (AAA) disease development/progression, a patient cohort of hemodynamically relevant specimens is utilized, consisting of diseased and non-diseased (internal control) vessel regions from the same patient.