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Continuum (Minneapolis, Minn.) Apr 2023Ischemic stroke due to large vessel atherosclerosis is a significant cause of stroke globally. With the aging population, the number of people with atherosclerotic... (Review)
Review
OBJECTIVE
Ischemic stroke due to large vessel atherosclerosis is a significant cause of stroke globally. With the aging population, the number of people with atherosclerotic stroke will increase in the coming decades. This article reviews the recent developments in the assessment and treatment of extracranial and intracranial atherosclerotic disease.
LATEST DEVELOPMENTS
More intensive dual antiplatelet therapy can now be recommended for patients with transient ischemic attack or stroke. More stringent blood pressure and lipid control is also advised. The need for carotid revascularization will likely decrease in the coming decades because of advances in multimodal medical therapy; in particular, the role of revascularization for treating asymptomatic carotid stenosis is controversial. Patients with symptomatic intracranial stenosis should receive intensive medical therapy. Interest in high-resolution carotid plaque imaging is growing.
ESSENTIAL POINTS
The prevention of stroke due to large vessel atherosclerosis has improved owing to advances in medical therapies. The role of carotid revascularization is unclear for many patient subgroups.
Topics: Humans; Aged; Risk Factors; Atherosclerosis; Stroke; Carotid Stenosis; Arteries
PubMed: 37039406
DOI: 10.1212/CON.0000000000001212 -
Frontiers in Endocrinology 2022The complications of macrovascular atherosclerosis are the leading cause of disability and mortality in patients with diabetes. It is generally believed that the... (Review)
Review
The complications of macrovascular atherosclerosis are the leading cause of disability and mortality in patients with diabetes. It is generally believed that the pathogenesis of diabetic vascular complications is initiated by the imbalance between injury and endogenous protective factors. Multiple endogenous protective factors secreted by endothelium, liver, skeletal muscle and other tissues are recognized of their importance in combating injury factors and maintaining the homeostasis of vasculatures in diabetes. Among them, glucagon-like peptide-1 based drugs were clinically proven to be effective and recommended as the first-line medicine for the treatment of type 2 diabetic patients with high risks or established arteriosclerotic cardiovascular disease (CVD). Some molecules such as irisin and lipoxins have recently been perceived as new protective factors on diabetic atherosclerosis, while the protective role of HDL has been reinterpreted since the failure of several clinical trials to raise HDL therapy on cardiovascular events. The current review aims to summarize systemic endogenous protective factors for diabetes-associated atherosclerosis and discuss their mechanisms and potential therapeutic strategy or their analogues. In particular, we focus on the existing barriers or obstacles that need to be overcome in developing new therapeutic approaches for macrovascular complications of diabetes.
Topics: Atherosclerosis; Diabetes Mellitus; Diabetic Angiopathies; Glucagon-Like Peptide 1; Humans; Protective Factors
PubMed: 35557850
DOI: 10.3389/fendo.2022.821028 -
Pharmacological Research Jan 2023Over the past few decades, the treatment of atherosclerotic cardiovascular disease has mainly been through an LDL lowering strategy and treatments targeting other... (Review)
Review
Over the past few decades, the treatment of atherosclerotic cardiovascular disease has mainly been through an LDL lowering strategy and treatments targeting other traditional risk factors for atherosclerosis, which has significantly reduced cardiovascular mortality. However, the overall benefit of targeting these risk factors has stagnated, and the discovery of new therapeutic targets for atherosclerosis remains a challenge. Accumulating evidence from clinical and animal experiments has revealed that the gut microbiome play a significant role in human health and disease, including cardiovascular diseases. The gut microbiome contribute to host health and disease through microbial composition and function. The gut microbiome function like an endocrine organ by generating bioactive metabolites that can impact atherosclerosis. In this review, we describe two gut microbial metabolites/pathways by which the gut affects atherosclerotic cardiovascular disease. On the one hand, we discuss the effects of trimethylamine oxide (TMAO), bile acids and aromatic amino acid metabolites on the development of atherosclerosis, and the protective effects of beneficial metabolites short chain amino acids and polyamines on atherosclerosis. On the other hand, we discuss novel therapeutic strategies for directly targeting gut microbial metabolites to improve cardiovascular outcomes. Reducing gut-derived TMAO levels and interfering with the bile acid receptor farnesoid X receptor (FXR) are new therapeutic strategies for atherosclerotic disease. Enzymes and receptors in gut microbiota metabolic pathways are potential new drug targets. We need solid insight into these underlying mechanisms to pave the way for therapeutic strategies targeting gut microbial metabolites/pathways for atherosclerotic cardiovascular disease.
Topics: Animals; Humans; Cardiovascular Diseases; Gastrointestinal Microbiome; Methylamines; Atherosclerosis
PubMed: 36460280
DOI: 10.1016/j.phrs.2022.106586 -
European Journal of Medicinal Chemistry Nov 2020Atherosclerosis (AS), an important cause of high mortality of cardiovascular disease, involves numerous pathophysiological processes, including endothelial cell damage,... (Review)
Review
Atherosclerosis (AS), an important cause of high mortality of cardiovascular disease, involves numerous pathophysiological processes, including endothelial cell damage, oxidative stress, inflammation, lipid deposition, vascular smooth muscle proliferation and migration, macrophage-derived foam cell formation, and platelet aggregation, and seriously endangers human health and safe of life. Hydrogen sulfide (HS) was discovered as the third gaseous signaling molecule following nitric oxide (NO) and carbon monoxide (CO), and has been proposed to exert potentially significant effects in many physiological processes, especially in atherosclerosis. Compelling evidence suggests that malfunction of CSE/HS pathway and downregulation of endogenous HS level contribute to the pathogenesis of atherosclerosis, whereas exogenous supplementation of HS can ameliorate many of atherogenic processes. The current knowledge on the anti-atherogenic role of HS comes from the use of HS donors and CSE or CBS inhibitors, or another more accurate genetic technology, including gene knockout and gene therapy studies. Among them HS releasing donors have vast therapeutic potential in anti-atherosclerosis and are promising as one of the clinical strategies for atherosclerosis treatment. Based on the recent studies on therapeutic effects and mechanisms of HS donors, this review focuses on the most recent advances of therapeutic potential of HS donors in anti-atherosclerosis, especially synthetic organic donors, because sulfide salts can release HS rapidly and lead to various adverse effects. In addition, the future of this domain is prospected.
Topics: Animals; Atherosclerosis; Drug Discovery; Humans; Hydrogen Sulfide; Molecular Targeted Therapy
PubMed: 32795766
DOI: 10.1016/j.ejmech.2020.112665 -
Free Radical Biology & Medicine Aug 2021Atherosclerosis develops due to lipid accumulation in the arterial wall and sclerosis as result of increased hyperlipidemia, oxidative stress, lipid oxidation, and... (Review)
Review
Atherosclerosis develops due to lipid accumulation in the arterial wall and sclerosis as result of increased hyperlipidemia, oxidative stress, lipid oxidation, and protein oxidation. However, improving antioxidant status through diet may prevent the progression of atherosclerotic cardiovascular disease. It is believed that polyphenol-rich plants contribute to the inverse relationship between fruit and vegetable intake and chronic disease. Anthocyanins are flavonoid polyphenols with antioxidant properties that have been associated with reduced risk of cardiovascular disease. The consumption of anthocyanins increases total antioxidant capacity, antioxidant defense enzymes, and HDL antioxidant properties by several measures in preclinical and clinical populations. Anthocyanins appear to impart antioxidant actions via direct antioxidant properties, as well as indirectly via inducing intracellular Nrf2 activation and antioxidant gene expression. These actions counter oxidative stress and inflammatory signaling in cells present in atherosclerotic plaques, including macrophages and endothelial cells. Overall, anthocyanins may protect against atherosclerosis and cardiovascular disease through their effects on cellular antioxidant status, oxidative stress, and inflammation; however, their underlying mechanisms of action appear to be complex and require further elucidation.
Topics: Anthocyanins; Antioxidants; Atherosclerosis; Endothelial Cells; Flavonoids; Humans; Oxidative Stress
PubMed: 34087429
DOI: 10.1016/j.freeradbiomed.2021.05.040 -
Journal of Clinical Lipidology 2020South Asian risk for atherosclerotic cardiovascular disease (ASCVD) has received special emphasis in the 2018 US AHA/ACC/Multisociety Cholesterol Guidelines. The term... (Review)
Review
South Asian risk for atherosclerotic cardiovascular disease (ASCVD) has received special emphasis in the 2018 US AHA/ACC/Multisociety Cholesterol Guidelines. The term "South Asian" refers specifically to the countries of India, Pakistan, Nepal, Bhutan, Bangladesh, Sri Lanka, and Maldives and to the worldwide diaspora of families from these countries. With this definition, approximately 25% of the world's population is South Asian, but about 50% of ASCVD occurs in this group. In this JCL Roundtable, we discuss the roles of visceral adiposity, diabetes, and features of the metabolic syndrome; lipoprotein(a); and diet and lifestyle, including the transition of both diet and lifestyle over the past 40 to 50 years. Genetic and/or hidden risk is an area of ongoing research. Individual patient assessment and intervention should recognize the earlier onset of ASCVD and the value of screening for traditional risk factors as well as waist circumference, coronary artery calcium scoring, and lipoprotein(a) assay. Culturally acceptable dietary strategies are available, although not widely implemented or evaluated as yet. In very-high-risk cases of secondary prevention, one should consider combining medications to drive low-density lipoprotein cholesterol much lower than 70 mg/dL. Our discussion concludes by insisting that the signal of alarm must be accompanied by decisive action.
Topics: Asia; Atherosclerosis; Humans; Lipid Metabolism; Risk; South Australia
PubMed: 32299606
DOI: 10.1016/j.jacl.2020.03.005 -
Journal of the American Heart... Apr 2024Pyroptosis executor GsdmD (gasdermin D) promotes atherosclerosis in mice and humans. Disulfiram was recently shown to potently inhibit GsdmD, but the in vivo efficacy...
BACKGROUND
Pyroptosis executor GsdmD (gasdermin D) promotes atherosclerosis in mice and humans. Disulfiram was recently shown to potently inhibit GsdmD, but the in vivo efficacy and mechanism of disulfiram's antiatherosclerotic activity is yet to be explored.
METHODS AND RESULTS
We used human/mouse macrophages, endothelial cells, and smooth muscle cells and a hyperlipidemic mouse model of atherosclerosis to determine disulfiram antiatherosclerotic efficacy and mechanism. The effects of disulfiram on several atheroprotective pathways such as autophagy, efferocytosis, phagocytosis, and gut microbiota were determined. Atomic force microscopy was used to determine the effects of disulfiram on the biophysical properties of the plasma membrane of macrophages. Disulfiram-fed hyperlipidemic apolipoprotein E mice showed significantly reduced interleukin-1β release upon in vivo Nlrp3 (NLR family pyrin domain containing 3) inflammasome activation. Disulfiram-fed mice showed smaller atherosclerotic lesions (~27% and 29% reduction in males and females, respectively) and necrotic core areas (~50% and 46% reduction in males and females, respectively). Disulfiram induced autophagy in macrophages, smooth muscle cells, endothelial cells, hepatocytes/liver, and atherosclerotic plaques. Disulfiram modulated other atheroprotective pathways (eg, efferocytosis, phagocytosis) and gut microbiota. Disulfiram-treated macrophages showed enhanced phagocytosis/efferocytosis, with the mechanism being a marked increase in cell-surface expression of efferocytic receptor MerTK. Atomic force microscopy analysis revealed altered biophysical properties of disulfiram-treated macrophages, showing increased order-state of plasma membrane and increased adhesion strength. Furthermore, 16sRNA sequencing of disulfiram-fed hyperlipidemic mice showed highly significant enrichment in atheroprotective gut microbiota and a reduction in atherogenic species.
CONCLUSIONS
Taken together, our data show that disulfiram can simultaneously modulate several atheroprotective pathways in a GsdmD-dependent as well as GsdmD-independent manner.
Topics: Male; Female; Mice; Humans; Animals; Disulfiram; Efferocytosis; Endothelial Cells; Gastrointestinal Microbiome; Atherosclerosis; Autophagy
PubMed: 38563369
DOI: 10.1161/JAHA.123.033881 -
Trends in Cardiovascular Medicine Apr 2023Fixed-dose combination (FDC) therapies (also known as polypills) remain underutilized in clinical practice despite over two decades of evidence from randomized... (Review)
Review
Fixed-dose combination (FDC) therapies (also known as polypills) remain underutilized in clinical practice despite over two decades of evidence from randomized controlled trials demonstrating increased adherence to multidrug therapy, improved cardiovascular disease (CVD) risk factor control, and lower incidence of cardiovascular events. Evidence demonstrates that FDC-based implementation strategies can substantially complement and augment current strategies for CVD risk prevention globally. The next decade is likely to extend the frontier of cardiovascular FDC therapies, particularly given expected advances in FDC manufacturing technology and accessibility. FDC-based anti-hypertensive therapies are emerging as integral components of a pragmatic blood pressure lowering strategy. Cardiovascular FDCs are rapidly approaching its coming of age, transforming from heavily hyped research tools to pragmatic clinical instruments. This review evaluates the current evidence for cardiovascular FDCs, barriers to current use, and potential next generation advances.
Topics: Humans; Platelet Aggregation Inhibitors; Cardiovascular Diseases; Drug Therapy, Combination; Drug Combinations; Leprostatic Agents; Antihypertensive Agents; Atherosclerosis
PubMed: 34973412
DOI: 10.1016/j.tcm.2021.12.013 -
Atherosclerosis Jun 2023As the global burden of atherosclerotic cardiovascular disease continues to rise, there is an increased demand for improved imaging techniques for earlier detection of... (Review)
Review
As the global burden of atherosclerotic cardiovascular disease continues to rise, there is an increased demand for improved imaging techniques for earlier detection of atherosclerotic plaques and new therapeutic targets. Plaque lesions, vulnerable to rupture and thrombosis, are thought to be responsible for the majority of cardiovascular events, and are characterized by a large lipid core, a thin fibrous cap, and neovascularization. In addition to supplying the plaque core with increased inflammatory factors, these pathological neovessels are tortuous and leaky, further increasing the risk of intraplaque hemorrhage. Clinically, plaque neovascularization has been shown to be a significant and independent predictor of adverse cardiovascular outcomes. Microvessels can be detected through contrast-enhanced ultrasound (CEUS) imaging, however, clinical assessment in vivo is generally limited to qualitative measures of plaque neovascularization. There is no validated standard for quantitative assessment of the microvessel networks found in plaques. Advances in our understanding of the pathological mechanisms underlying plaque neovascularization and its significant role in the morbidity and mortality associated with atherosclerosis have made it an attractive area of research in translational medicine. Current areas of research include the development of novel therapeutic and diagnostic agents to target plaque neovascularization stabilization. With recent progress in nanotechnology, nanoparticles have been investigated for their ability to specifically target neovascularization. Contrast microbubbles have been similarly engineered to carry loads of therapeutic agents and can be visualized using CEUS. This review summarizes the pathogenesis, diagnosis, clinical significance of neovascularization, and importantly the emerging areas of theranostic tool development.
Topics: Humans; Plaque, Atherosclerotic; Precision Medicine; Atherosclerosis; Neovascularization, Pathologic; Ultrasonography
PubMed: 37149970
DOI: 10.1016/j.atherosclerosis.2023.04.008 -
Aging Dec 2019
Topics: Aged; Anticholesteremic Agents; Atherosclerosis; Biomarkers; Humans; PCSK9 Inhibitors
PubMed: 31829977
DOI: 10.18632/aging.102621