287 research outputs found

    Exploring the Efficacy of miR-33 Antagonism in Promoting Regression of Intracranial Atherosclerosis in an Nonhuman Primate Model

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    Atherosclerosis, characterized by lipid accumulation and arterial inflammation, is a major contributor to global morbidity and mortality. Despite significant progress in understanding atherosclerosis in extracranial arteries, the study of intracranial atherosclerosis (ICAS) has been relatively neglected, despite its crucial role in stroke and vascular cognitive impairment. Challenges related to ICAS, including its location within the cranium and limited availability of suitable animal models, have hindered research progress in this area. Although nonhuman primates (NHPs) are commonly used for studying extracranial atherosclerosis, a comprehensive understanding of ICAS pathophysiology in these animals is lacking. By subjecting NHPs to a high-fat/cholesterol diet, we successfully induced measurable ICAS, providing a unique opportunity to investigate underlying mechanisms and potential therapeutic strategies for ICAS regression. This study presents a robust NHP model of ICAS development and explores the potential of miR-33 antagonism for promoting atherosclerosis regression. Mouse studies have shown that inhibiting miR-33a can stabilize or regress atherosclerosis in extracranial arteries, but their translatability is limited. To address this, we employed an NHP model that closely mimics human miR-33a and miR-33b expression and atherosclerosis development. Our investigation aims to assess the effectiveness of miR-33 antagonism in promoting ICAS regression in 61 NHPs, using histological characterization and digital pathology techniques to evaluate ICAS morphology and composition. Surprisingly, our results showed no histological evidence supporting the efficacy of miR-33 antagonism in improving ICAS regression measures. This study significantly contributes to our understanding of ICAS and its potential treatment strategies by establishing a reliable animal model for ICAS development. However, further investigation is required to determine the role of miR-33 antagonism in atherosclerosis regression. These findings have important implications for future research and the development of therapeutic strategies to improve brain health and function while reducing the burden of ICAS on stroke and vascular cognitive impairment

    Blood Flow Regulates Atherosclerosis Progression and Regression

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    Atherosclerosis is the most prevalent pathology of cardiovascular disease with no known cure. Despite the many systemic risk factors for atherosclerosis, plaques do not form randomly in the vasculature. Instead, they form around bifurcations and the inner curvature of highly curving arterial segments that contain so-called disturbed blood flow that is low in magnitude and multidirectional over the cardiac cycle. Conversely, straight, non-bifurcated arterial segments that contain moderate-to-high and unidirectional (i.e., normal) blood flow are protected from plaque development. Thus, blood flow is a key regulator of atherosclerosis that may be able to be leveraged to develop new therapeutics. Towards this end, we performed two studies using a mouse model of atherosclerosis where a blood flow-modifying cuff was placed around the left carotid artery to induce disturbed blood flow and, in turn, plaque development. In the first study, we evaluated the hypothesis that injected nanoparticles had different accumulation kinetics in different types of disturbed flow (low versus multidirectional). We found that the blood flow profile did not affect accumulation, but the resultant plaque phenotype did. This suggests that nanoparticles could be used to target certain plaque types. In the second study, we evaluated the hypothesis that restored normal blood flow in atherosclerotic arteries promotes plaque stabilization. Our findings supported this hypothesis and also showed that the combination of normal blood flow and atorvastatin produced additive beneficial effects that led to plaque regression. This result suggests that mechanical stimuli can be therapeutic. Since the endothelium directly senses blood flow and plays a key role in atherosclerosis development, we finally characterized how different flow profiles affect atheroprotective versus atherogenic endothelial signaling molecules. Ultimately, this work provides a foundation for the development of a new therapeutic for atherosclerosis based on the beneficial effects of normal blood flow. Advisor: Ryan M. Pedrig

    Observational study of circulating endothelial cell profiles in patients with non-ST-elevation myocardial infarction stratified by plaque erosion or rupture identified by optical coherence tomography: The Plaque Erosion Pilot Study ii (PEPSii)

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    Introduction Myocardial infarction (MI) remains a leading global cause of death and disability. There is growing evidence that about 40% of MI cases have plaque erosion due to mass endothelial cell apoptosis and exposure of pro-thrombotic underlying extracellular matrix, in contrast to shearing of endothelial cells during more conventional plaque rupture events. This hypothesis suggests that circulating endothelial cells (CEC) would be higher in MI cases of plaque erosion compared to plaque rupture. Accordingly, I set up a study to measure levels of CEC in patients with non-ST elevation MI (NSTEMI) who underwent plaque morphology evaluation to stratify cases into plaque erosion or rupture. Methods This was an observational study which enrolled patients undergoing elective percutaneous coronary intervention (PCI), a feasibility group to establish and refine research methods, and NSTEMI undergoing PCI (cases). Peripheral venous blood samples were obtained to assess CEC and platelet-leukocyte aggregates (PLAs) using flow cytometry. Culprit plaques were imaged using optical coherence tomography (OCT) and independently classified as plaque rupture or erosion. CEC levels in NSTEMI patients were compared between plaque erosion and plaque rupture cases. Results Overall, 22 NSTEMI patients and 11 feasibility patients were recruited. Of the NSTEMI patients, 7 did not have plaque morphology, either due to missing data, or inability to agree on a classification. CEC levels, as a percent CD45-ve PBMCs, were significantly higher in the plaque erosion group (17.4%; n=7) compared to the plaque rupture group (9%; n=8: p=0.0012). PLA analysis showed no significant differences between erosion and rupture (p=0.8665). Conclusion Higher levels of CEC in the plaque erosion group compared to rupture supports the hypothesis of mass endothelial cell denudation as a causative mechanism. Further research is needed to investigate trigger factors for erosion and to understand if specific therapeutic strategies are needed for these patients

    Pacing with restoration of respiratory sinus arrhythmia improved cardiac contractility and the left ventricular output: a translational study

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    Introduction: Respiratory sinus arrhythmia (RSA) is a prognostic value for patients with heart failure and is defined as a beat-to-beat variation of the timing between the heart beats. Patients with heart failure or patients with permanent cardiac pacing might benefit from restoration of RSA. The aim of this translational, proof-of-principle study was to evaluate the effect of pacing with or without restored RSAon parameters of LV cardiac contractility and the cardiac output

    Local Hemodynamic Microenvironment in Bioresorbable Scaffolds

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    Vascular Implications of COVID-19: Role of Radiological Imaging, Artificial Intelligence, and Tissue Characterization: A Special Report

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    The SARS-CoV-2 virus has caused a pandemic, infecting nearly 80 million people worldwide, with mortality exceeding six million. The average survival span is just 14 days from the time the symptoms become aggressive. The present study delineates the deep-driven vascular damage in the pulmonary, renal, coronary, and carotid vessels due to SARS-CoV-2. This special report addresses an important gap in the literature in understanding (i) the pathophysiology of vascular damage and the role of medical imaging in the visualization of the damage caused by SARS-CoV-2, and (ii) further understanding the severity of COVID-19 using artificial intelligence (AI)-based tissue characterization (TC). PRISMA was used to select 296 studies for AI-based TC. Radiological imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound were selected for imaging of the vasculature infected by COVID-19. Four kinds of hypotheses are presented for showing the vascular damage in radiological images due to COVID-19. Three kinds of AI models, namely, machine learning, deep learning, and transfer learning, are used for TC. Further, the study presents recommendations for improving AI-based architectures for vascular studies. We conclude that the process of vascular damage due to COVID-19 has similarities across vessel types, even though it results in multi-organ dysfunction. Although the mortality rate is ~2% of those infected, the long-term effect of COVID-19 needs monitoring to avoid deaths. AI seems to be penetrating the health care industry at warp speed, and we expect to see an emerging role in patient care, reduce the mortality and morbidity rate
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