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Journal of the American College of... Mar 2022There is a need to identify high-risk features that predict early-onset atherosclerotic cardiovascular disease (ASCVD). The authors provide insights to help clinicians... (Review)
Review
There is a need to identify high-risk features that predict early-onset atherosclerotic cardiovascular disease (ASCVD). The authors provide insights to help clinicians identify and address high-risk conditions in the 20- to 39-year age range (young adults). These include tobacco use, elevated blood pressure/hypertension, family history of premature ASCVD, primary severe hypercholesterolemia such as familial hypercholesterolemia, diabetes with diabetes-specific risk-enhancing factors, or the presence of multiple other risk-enhancing factors, including in females, a history of pre-eclampsia or menopause under age 40. The authors update current thinking on lipid risk factors such as triglycerides, non-high-density lipoprotein cholesterol, apolipoprotein B, or lipoprotein (a) that are useful in understanding an individual's long-term ASCVD risk. The authors review emerging strategies, such as coronary artery calcium and polygenic risk scores in this age group, that have potential clinical utility, but whose best use remains uncertain. Finally, the authors discuss both the obstacles and opportunities for addressing prevention in early adulthood.
Topics: Atherosclerosis; Heart Disease Risk Factors; Humans; Risk Factors; Young Adult
PubMed: 35210038
DOI: 10.1016/j.jacc.2021.12.016 -
Atherosclerosis Jun 2023In 2022, the European Atherosclerosis Society (EAS) published a new consensus statement on lipoprotein(a) [Lp(a)], summarizing current knowledge about its causal... (Review)
Review
In 2022, the European Atherosclerosis Society (EAS) published a new consensus statement on lipoprotein(a) [Lp(a)], summarizing current knowledge about its causal association with atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. One of the novelties of this statement is a new risk calculator showing how Lp(a) influences lifetime risk for ASCVD and that global risk may be underestimated substantially in individuals with high or very high Lp(a) concentration. The statement also provides practical advice on how knowledge about Lp(a) concentration can be used to modulate risk factor management, given that specific and highly effective mRNA-targeted Lp(a)-lowering therapies are still in clinical development. This advice counters the attitude: "Why should I measure Lp(a) if I can't lower it?". Subsequent to publication, questions have arisen relating to how the recommendations of this statement impact everyday clinical practice and ASCVD management. This review addresses 30 of the most frequently asked questions about Lp(a) epidemiology, its contribution to cardiovascular risk, Lp(a) measurement, risk factor management and existing therapeutic options.
Topics: Humans; Lipoprotein(a); Risk Factors; Risk Assessment; Aortic Valve Stenosis; Atherosclerosis; Cardiovascular Diseases
PubMed: 37188555
DOI: 10.1016/j.atherosclerosis.2023.04.012 -
Clinical Hemorheology and... 2021Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study has been conducted with nattokinase supplementation.
OBJECTIVE
To determine the effect of nattokinase on subclinical atherosclerosis progression and atherothrombotic biomarkers.
METHODS
In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units or matching placebo. Primary outcome was rate of change in subclinical atherosclerosis measured by serial carotid ultrasound every 6 months as carotid artery intima-media thickness (CIMT) and carotid arterial stiffness (CAS). Additional outcomes determined at least every 6 months were clinical parameters including blood pressure and laboratory measures including metabolic factors, blood rheology parameters, blood coagulation and fibrinolysis factors, inflammatory markers and monocyte/macrophage cellular activation markers.
RESULTS
After median 3 years of randomized treatment, annualized rate of change in CIMT and CAS did not significantly differ between nattokinase supplementation and placebo. Additionally, there was no significant effect of nattokinase supplementation on blood pressure or any laboratory determination.
CONCLUSIONS
Results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.
Topics: Aged; Atherosclerosis; Carotid Arteries; Carotid Artery Diseases; Carotid Intima-Media Thickness; Humans; Subtilisins
PubMed: 33843667
DOI: 10.3233/CH-211147 -
Arteriosclerosis, Thrombosis, and... Jun 2023The benefits of exercise on the cardiovascular system are widely recognized; however, the underlying mechanisms are unknown. Here, we report the effect of the long...
BACKGROUND
The benefits of exercise on the cardiovascular system are widely recognized; however, the underlying mechanisms are unknown. Here, we report the effect of the long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1), which is regulated by exercise, on atherosclerosis development after N6-methyladenosine (m6A) modifications.
METHODS
Using clinical cohorts and NEAT1 mice, we determined the exercise-mediated expression and role of NEAT1 in atherosclerosis. To investigate the mechanism of epigenetic modification of NEAT1 regulated by exercise, we identified METTL14 (methyltransferase-like 14)-a key m6A modification enzyme under exercise-and found that METTL14 alters the expression and role of NEAT1 through m6A modification and elucidated the specific mechanism of METTL14 in vitro and in vivo. Finally, the NEAT1 downstream regulatory network was investigated.
RESULTS
We found that NEAT1 expression was downregulated with exercise and that downregulation of NEAT1 was an important factor in the improvement of atherosclerosis with exercise. Exercise-mediated loss of function of NEAT1 can delay atherosclerosis. Mechanistically, we showed that exercise induced a significant downregulation of m6A modification and METTL14, which binds to the m6A sites of NEAT1 and promotes NEAT1 expression through subsequent YTHDC1 (YTH domain-containing 1) recognition to promote endothelial pyroptosis. Furthermore, NEAT1 induces endothelial pyroptosis by binding KLF4 (Kruppel-like factor 4) to promote the transcriptional activation of the key pyroptotic protein NLRP3 (NOD-like receptor thermal protein domain-associated protein 3), whereas exercise can attenuate NEAT1-mediated endothelial pyroptosis to improve atherosclerosis.
CONCLUSIONS
Our study of NEAT1 provides new insights into the improvement of atherosclerosis by exercise. This finding demonstrates the role of exercise-mediated NEAT1 downregulation in atherosclerosis while expanding our understanding of the mechanisms by which exercise regulates long noncoding RNA function through epigenetic modifications.
Topics: Animals; Mice; Adenosine; Atherosclerosis; Pyroptosis; RNA, Long Noncoding
PubMed: 37078289
DOI: 10.1161/ATVBAHA.123.319251 -
BMC Biology Feb 2023Immune cells that infiltrate lesions are important for atherosclerosis progression and immunotherapies. This study was aimed at gaining important new insights into the...
BACKGROUND
Immune cells that infiltrate lesions are important for atherosclerosis progression and immunotherapies. This study was aimed at gaining important new insights into the heterogeneity of these cells by integrating the sequencing results of multiple samples and using an enhanced single-cell sequencing workflow to overcome the limitations of a single study.
RESULTS
Integrative analyses identified 28 distinct subpopulations based on gene expression profiles. Further analysis demonstrated that these cells manifested high heterogeneity at the levels of tissue preferences, genetic perturbations, functional variations, immune dynamics, transcriptional regulators, metabolic changes, and communication patterns. Of the T cells, interferon-induced CD8 T cells were involved in the progression of atherosclerosis. In contrast, proinflammatory CD4 CD28 T cells predicted a poor outcome in atherosclerosis. Notably, we identified two subpopulations of foamy macrophages that exhibit contrasting phenotypes. Among them, TREM2SPP1 foamy macrophages were preferentially distributed in the hypoxic core of plaques. These glycolytic metabolism-enriched cells, with impaired cholesterol metabolism and robust pro-angiogenic capacity, were phenotypically regulated by CSF1 secreted by co-localised mast cells. Moreover, combined with deconvolution of the bulk datasets, we revealed that these dysfunctional cells had a higher proportion of ruptured and haemorrhagic lesions and were significantly associated with poor atherosclerosis prognoses.
CONCLUSIONS
We systematically explored atherosclerotic immune heterogeneity and identified cell populations underlying atherosclerosis progression and poor prognosis, which may be valuable for developing new and precise immunotherapies.
Topics: Humans; Atherosclerosis; Biological Transport; CD8-Positive T-Lymphocytes; Immunotherapy
PubMed: 36855107
DOI: 10.1186/s12915-023-01540-2 -
Current Atherosclerosis Reports Dec 2021Chronic inflammation has been recognized as one of the most important pathophysiological mechanisms' initiation and progression of atherosclerosis. Statins belong to... (Review)
Review
PURPOSE OF REVIEW
Chronic inflammation has been recognized as one of the most important pathophysiological mechanisms' initiation and progression of atherosclerosis. Statins belong to most successful therapeutic agents in the prevention and treatment of atherothrombotic vascular disease. Their non-lipid related effects including suppression of inflammation have been repeatedly proven in both experimental and clinical settings.
RECENT FINDINGS
Recently, the importance of inflammation in the process of atherosclerosis has been confirmed by interventions targeting inflammation selectively. Clinical trial with selective inhibitor of a principal inflammatory mediator interleukin 1-beta - canakinumab - confirmed the notion of direct vasculoprotective effects of primarily targeting inflammation. This has increased interest in the non-lipid, pleiotropic and, particularly, anti-inflammatory effects of statins. Anti-inflammatory effects of statins have been proven both experimentally and in clinical settings beyond any doubt. They comprise a direct positive effect on not only many cell types and pathways that are lipid independent but, also, some that are mediated by lipid modification. Undoubtedly, suppression of inflammatory response by statins contributes to their generally positive action in atherosclerosis and represents an important part of the vasculo- and atheroprotective effect of this drug class.
Topics: Atherosclerosis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation
PubMed: 34851454
DOI: 10.1007/s11883-021-00977-6 -
Recenti Progressi in Medicina 2020The atherosclerotic cardiovascular disease (ASCVD) represents the leading cause of death and disability not only in countries with a high degree of socio-economic... (Review)
Review
The atherosclerotic cardiovascular disease (ASCVD) represents the leading cause of death and disability not only in countries with a high degree of socio-economic development but also in low- middle-income countries. The study of atherosclerosis and the strategies to control ASCVD are evolving. All strategies emphasize the need to lower LDL cholesterol through an appropriate lifestyle and the use of lipid-lowering drugs. A therapy with statin with or without other lipid lowering drugs is recommended in secondary prevention. In primary prevention, the use of the lipid-lowering drug should instead take into account the cost-benefit ratio. Available evidence coming from clinical trials is useful to inform clinical choices but must be associated with a shared decision-making process between doctor and patient.
Topics: Atherosclerosis; Cardiovascular Diseases; Cholesterol, LDL; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Life Style; Secondary Prevention
PubMed: 32658882
DOI: 10.1701/3407.33925 -
Circulation Research Jun 2022miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to...
BACKGROUND
miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to correct the imbalance of gene expression found in human diseases such as obesity, metabolic syndrome, and atherosclerosis. The in vivo efficacy of current anti-miRNA technologies hindered by physiological and cellular barriers to delivery into targeted cells and the nature of miRNAs that allows one to target an entire pathway that may lead to deleterious off-target effects. For these reasons, novel targeted delivery systems to inhibit miRNAs in specific tissues will be important for developing effective therapeutic strategies for numerous diseases including atherosclerosis.
METHODS
We used pH low-insertion peptide (pHLIP) constructs as vehicles to deliver microRNA-33-5p (miR-33) antisense oligonucleotides to atherosclerotic plaques. Immunohistochemistry and histology analysis was performed to assess the efficacy of miR-33 silencing in atherosclerotic lesions. We also assessed how miR-33 inhibition affects gene expression in monocytes/macrophages by single-cell RNA transcriptomics.
RESULTS
The anti-miR-33 conjugated pHLIP constructs are preferentially delivered to atherosclerotic plaque macrophages. The inhibition of miR-33 using pHLIP-directed macrophage targeting improves atherosclerosis regression by increasing collagen content and decreased lipid accumulation within vascular lesions. Single-cell RNA sequencing analysis revealed higher expression of fibrotic genes (, etc) and tissue inhibitor of metalloproteinase 3 () and downregulation of in macrophages from atherosclerotic lesions targeted by pHLIP-anti-miR-33.
CONCLUSIONS
This study provides proof of principle for the application of pHLIP for treating advanced atherosclerosis via pharmacological inhibition of miR-33 in macrophages that avoid the deleterious effects in other metabolic tissues. This may open new therapeutic opportunities for atherosclerosis-associated cardiovascular diseases via selective delivery of other protective miRNAs.
Topics: Antagomirs; Atherosclerosis; Humans; Macrophages; MicroRNAs; Plaque, Atherosclerotic
PubMed: 35534923
DOI: 10.1161/CIRCRESAHA.121.320296 -
Atherosclerosis Apr 2020
Topics: Atherosclerosis; Biomarkers; Biomedical Research; Editorial Policies; Genetic Predisposition to Disease; Humans; Periodicals as Topic; Phenotype; Prognosis; Risk Assessment; Risk Factors
PubMed: 32248950
DOI: 10.1016/j.atherosclerosis.2020.03.018 -
International Journal of Molecular... Feb 2022Atherosclerosis has been known in medicine for several centuries. As early as 1755, the Swedish anatomist Albrecht von Haller used the term "atheroma" to describe... (Review)
Review
Atherosclerosis has been known in medicine for several centuries. As early as 1755, the Swedish anatomist Albrecht von Haller used the term "atheroma" to describe vascular lesions. Atherosclerosis may originate from an unbalanced diet or bad habits, and is mainly found in developed countries. Clinical trials have been conducted to establish the causes of atherosclerosis, and also to develop treatments for this disease. However, prevention of the disease has always been better than treatment, so vaccination may be the key to saving thousands of lives. The creation of a vaccine may be directly related to the study of autoimmune processes occurring in the body, immunity. This review considers the issues related to the involvement of the immune response in the development of atherosclerotic lesions. Modern concepts of atherogenesis, immune inflammation in atherosclerosis, and potential vaccine targets are also discussed. There is a particular focus on experimental and clinical data supporting the development of immune therapies to reduce cardiovascular risk.
Topics: Adaptive Immunity; Atherosclerosis; Drug Development; Humans; Vaccination
PubMed: 35269559
DOI: 10.3390/ijms23052417