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Biomedicine & Pharmacotherapy =... Sep 2020The ease of breeding, low cost of maintenance, and relatively short period for developing atherosclerosis make rodents ideal for atherosclerosis research. However, none... (Review)
Review
The ease of breeding, low cost of maintenance, and relatively short period for developing atherosclerosis make rodents ideal for atherosclerosis research. However, none of the current models accurately model human lipoprotein profile or atherosclerosis progression since each has its advantages and disadvantages. The advent of transgenic technologies much supports animal models' establishment. Notably, two classic transgenic mouse models, apoE-/- and Ldlr-/-, constitute the primary platforms for studying underlying mechanisms and development of pharmaceutical approaches. However, there exist crucial differences between mice and humans, such as the unhumanized lipoprotein profile, and the different plaque progression and characteristics. Among rodents, hamsters and guinea pigs might be the more realistic models in atherosclerosis research based on the similarities in lipoprotein metabolism to humans. Studies involving rat models, a rodent with natural resistance to atherosclerosis, have revealed evidence of atherosclerotic plaques under dietary induction and genetic manipulation by novel technologies, notably CRISPR-Cas9. Ldlr-/- hamster models were established in recent years with severe hyperlipidemia and atherosclerotic lesion formation, which could offer an alternative to classic transgenic mouse models. In this review, we provide an overview of classic and innovative small rodent models in atherosclerosis researches, including mice, rats, hamsters, and guinea pigs, focusing on their lipoprotein metabolism and histopathological changes.
Topics: Animals; Atherosclerosis; Cricetinae; Diet, High-Fat; Disease Models, Animal; Disease Progression; Genetic Predisposition to Disease; Guinea Pigs; Hypercholesterolemia; Lipoproteins; Mice, Knockout, ApoE; Phenotype; Plaque, Atherosclerotic; Rats, Transgenic; Receptors, LDL; Species Specificity
PubMed: 32574973
DOI: 10.1016/j.biopha.2020.110426 -
Medicina (Kaunas, Lithuania) May 2021Cardiovascular disease (CVD) is the leading cause of death globally and hypercholesterolemia is one of the major risk factors associated with CVD. Due to a growing body... (Meta-Analysis)
Meta-Analysis Review
Cardiovascular disease (CVD) is the leading cause of death globally and hypercholesterolemia is one of the major risk factors associated with CVD. Due to a growing body of research on side effects and long-term impacts of conventional CVD treatments, focus is shifting towards exploring alternative treatment approaches such as Ayurveda. However, because of a lack of strong scientific evidence, the safety and efficacy profiles of such interventions have not been well established. The current study aims to conduct a systematic review and meta-analyses to explore the strength of evidence on efficacy and safety of Ayurvedic herbs for hypercholesterolemia. : Literature searches were conducted using databases including Medline, Cochrane Database, AMED, Embase, AYUSH research portal, and many others. All randomized controlled trials on individuals with hypercholesterolemia using Ayurvedic herbs (alone or in combination) with an exposure period of ≥ 3 weeks were included, with primary outcomes being total cholesterol levels, adverse events, and other cardiovascular events. The search strategy was determined with the help of the Cochrane Metabolic and Endocrine Disorders Group. Two researchers assessed the risk of each study individually and discrepancies were resolved by consensus or consultation with a third researcher. Meta-analysis was conducted using the inverse variance method and results are presented as forest plots and data summary tables using Revman v5.3. A systematic review of 32 studies with 1386 participants found randomized controlled trials of three Ayurvedic herbs, (garlic), (guggulu), and (black cumin) on hypercholesterolemia that met inclusion criteria. The average duration of intervention was 12 weeks. Meta-analysis of the trials showed that guggulu reduced total cholesterol and low-density lipoprotein levels by 16.78 mg/dL (95% C.I. 13.96 to 2.61; -value = 0.02) and 18.78 mg/dL (95% C.I. 34.07 to 3.48; = 0.02), respectively. Garlic reduced LDL-C by 10.37 mg/dL (95% C.I. -17.58 to -3.16; -value = 0.005). Black cumin lowered total cholesterol by 9.28 mg/dL (95% C.I. -17.36, to -1.19, -value = 0.02). Reported adverse side effects were minimal. There is moderate to high level of evidence from randomized controlled trials that the Ayurvedic herbs guggulu, garlic, and black cumin are moderately effective for reducing hypercholesterolemia. In addition, minimal evidence was found for any side effects associated with these herbs, positioning them as safe adjuvants to conventional treatments.
Topics: Cardiovascular Diseases; Garlic; Humans; Hypercholesterolemia; Hyperlipidemias; Medicine, Ayurvedic
PubMed: 34071454
DOI: 10.3390/medicina57060546 -
Cell Metabolism Oct 2021High levels of cholesterol are generally considered to be associated with atherosclerosis. In the past two decades, however, a number of studies have shown that excess... (Review)
Review
High levels of cholesterol are generally considered to be associated with atherosclerosis. In the past two decades, however, a number of studies have shown that excess cholesterol accumulation in various tissues and organs plays a critical role in the pathogenesis of multiple diseases. Here, we summarize the effects of excess cholesterol on disease pathogenesis, including liver diseases, diabetes, chronic kidney disease, Alzheimer's disease, osteoporosis, osteoarthritis, pituitary-thyroid axis dysfunction, immune disorders, and COVID-19, while proposing that excess cholesterol-induced toxicity is ubiquitous. We believe this concept will help broaden the appreciation of the toxic effect of excess cholesterol, and thus potentially expand the therapeutic use of cholesterol-lowering medications.
Topics: Animals; Anticholesteremic Agents; Atherosclerosis; Biomarkers; COVID-19; Cholesterol; Humans; Hypercholesterolemia; Prognosis; Risk Factors; COVID-19 Drug Treatment
PubMed: 34562355
DOI: 10.1016/j.cmet.2021.09.001 -
Clinica E Investigacion En... 2021During pregnancy there is a physiological increase in total cholesterol (TC) and triglycerides (TG) plasma concentrations, due to increased insulin resistance,...
During pregnancy there is a physiological increase in total cholesterol (TC) and triglycerides (TG) plasma concentrations, due to increased insulin resistance, oestrogens, progesterone, and placental lactogen, although their reference values are not exactly known, TG levels can increase up to 300mg/dL, and TC can go as high as 350mg/dL. When the cholesterol concentration exceeds the 95 percentile (familial hypercholesterolaemia (FH) and transient maternal hypercholesterolaemia), there is a predisposition to oxidative stress in foetal vessels, exposing the newborn to a greater fatty streaks formation and a higher risk of atherosclerosis. However, the current treatment of pregnant women with hyperlipidaemia consists of a diet and suspension of lipid-lowering drugs. The most prevalent maternal hypertriglyceridaemia (HTG) is due to secondary causes, like diabetes, obesity, drugs, etc. The case of severe HTG due to genetic causes is less prevalent, and can be a higher risk of maternal-foetal complications, such as, acute pancreatitis (AP), pre-eclampsia, preterm labour, and gestational diabetes. Severe HTG-AP is a rare but potentially lethal pregnancy complication, for the mother and the foetus, usually occurs during the third trimester or in the immediate postpartum period, and there are no specific protocols for its diagnosis and treatment. In conclusion, it is crucial that dyslipidaemia during pregnancy must be carefully evaluated, not just because of the acute complications, but also because of the future cardiovascular morbidity and mortality of the newborn child. That is why the establishment of consensus protocols or guidelines is essential for its management.
Topics: Cholesterol; Dyslipidemias; Female; Humans; Hypercholesterolemia; Hypertriglyceridemia; Infant, Newborn; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Triglycerides
PubMed: 33309071
DOI: 10.1016/j.arteri.2020.10.002 -
Nutrients Jun 2023Atherosclerotic cardiovascular disease (ASCVD) remains the major mortality cause in developed countries with hypercholesterolaemia being one of the primary modifiable... (Review)
Review
Atherosclerotic cardiovascular disease (ASCVD) remains the major mortality cause in developed countries with hypercholesterolaemia being one of the primary modifiable causes. Lifestyle intervention constitutes the first step in cholesterol management and includes dietary modifications along with the use of functional foods and supplements. Functional foods enriched with plant sterols/stanols have become the most widely used nonprescription cholesterol-lowering approach, despite the lack of randomized trials investigating their long-term safety and cardiovascular efficacy. The cholesterol-lowering effect of plant-sterol supplementation is well-established and a potential beneficial impact on other lipoproteins and glucose homeostasis has been described. Nevertheless, experimental and human observational studies investigating the association of phytosterol supplementation or circulating plant sterols with various markers of atherosclerosis and ASCVD events have demonstrated controversial results. Compelling evidence from recent genetic studies have also linked elevated plasma concentrations of circulating plant sterols with ASCVD presence, thus raising concerns about the safety of phytosterol supplementation. Thus, the aim of this review is to provide up-to-date data on the effect of plant sterols/stanols on lipid-modification and cardiovascular outcomes, as well as to discuss any safety issues and practical concerns.
Topics: Humans; Phytosterols; Hypercholesterolemia; Anticholesteremic Agents; Cholesterol; Atherosclerosis; Cardiovascular Diseases
PubMed: 37447172
DOI: 10.3390/nu15132845 -
Journal of Cardiovascular Pharmacology Aug 2021Hypercholesterolemia is a leading cause of cardiovascular morbidity and mortality. Accordingly, efforts to lower apolipoprotein B-containing lipoproteins in plasma are... (Review)
Review
Hypercholesterolemia is a leading cause of cardiovascular morbidity and mortality. Accordingly, efforts to lower apolipoprotein B-containing lipoproteins in plasma are the centerpiece of strategies for cardiovascular prevention and treatment in primary and secondary management. Despite the importance of this endeavor, many patients do not achieve appropriate low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) goals, even among those who have experienced atherosclerotic cardiovascular disease. The development of new LDL-C-lowering medications with alternative mechanisms of action will facilitate improved goal achievement in high-risk patients. Inclisiran is a novel small interfering RNA-based drug that is experimental in the United States and approved for clinical use in the European Union. It lowers LDL-C and other apolipoprotein B-containing lipoproteins by reducing production of proprotein convertase subtilisin/kexin Type 9 (PCSK9), a protein that normally contributes to LDL-receptor degradation, thereby increasing LDL-receptor density and recycling in hepatocytes. Although the lipid-lowering efficacy of inclisiran is comparable with results achieved with PCSK9-blocking monoclonal antibodies (alirocumab and evolocumab), there are several important differences between the 2 drug classes. First, inclisiran reduces levels of PCSK9 both intracellularly and extracellularly by blocking translation of and degrading PCSK9 messenger RNA. Second, the long biological half-life of inclisiran produces sustained LDL-C lowering with twice yearly dosing. Third, although PCSK9-blocking monoclonal antibodies drugs are proven to reduce atherosclerotic cardiovascular disease events, clinical outcomes trials with inclisiran are still in progress. In this article, we review the clinical development of inclisiran, its mechanism of action, lipid-lowering efficacy, safety and tolerability, and potential clinical role of this promising new agent.
Topics: Animals; Apolipoprotein B-100; Biomarkers; Cholesterol, LDL; Down-Regulation; Humans; Hypercholesterolemia; PCSK9 Inhibitors; Proprotein Convertase 9; RNA Interference; RNA, Small Interfering; Treatment Outcome
PubMed: 33990512
DOI: 10.1097/FJC.0000000000001053 -
Nature Communications Jul 2023Hypercholesterolemia and vascular inflammation are key interconnected contributors to the pathogenesis of atherosclerosis. How hypercholesterolemia initiates vascular...
Hypercholesterolemia and vascular inflammation are key interconnected contributors to the pathogenesis of atherosclerosis. How hypercholesterolemia initiates vascular inflammation is poorly understood. Here we show in male mice that hypercholesterolemia-driven endothelial activation, monocyte recruitment and atherosclerotic lesion formation are promoted by a crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol (27HC). The pro-atherogenic actions of macrophage-derived 27HC require endothelial estrogen receptor alpha (ERα) and disassociation of the cytoplasmic scaffolding protein septin 11 from ERα, leading to extranuclear ERα- and septin 11-dependent activation of NF-κB. Furthermore, pharmacologic inhibition of cyp27a1, which generates 27HC, affords atheroprotection by reducing endothelial activation and monocyte recruitment. These findings demonstrate cell-to-cell communication by 27HC, and identify a major causal linkage between the hypercholesterolemia and vascular inflammation that partner to promote atherosclerosis. Interventions interrupting this linkage may provide the means to blunt vascular inflammation without impairing host defense to combat the risk of atherosclerotic cardiovascular disease that remains despite lipid-lowering therapies.
Topics: Male; Mice; Animals; Estrogen Receptor alpha; Hypercholesterolemia; Endothelial Cells; Septins; Cholesterol; Atherosclerosis; Macrophages; Signal Transduction; Inflammation
PubMed: 37491347
DOI: 10.1038/s41467-023-39586-z -
The New England Journal of Medicine Oct 2019
Review
Topics: Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol, LDL; Decision Making; Healthy Lifestyle; Humans; Hypercholesterolemia; Lipid Metabolism; Lipids; Practice Guidelines as Topic; Risk Assessment
PubMed: 31618541
DOI: 10.1056/NEJMra1806939 -
Endocrinology and Metabolism Clinics of... Sep 2022Inherited hypercholesterolemias include monogenic and polygenic disorders, which can be very rare (eg, cerebrotendinous xanthomatosis (CTX)) or relatively common (eg,... (Review)
Review
Inherited hypercholesterolemias include monogenic and polygenic disorders, which can be very rare (eg, cerebrotendinous xanthomatosis (CTX)) or relatively common (eg, familial combined hyperlipidemia [FCH]). In this review, we discuss familial hypercholesterolemia (FH), FH-mimics (eg, polygenic hypercholesterolemia [PH], FCH, sitosterolemia), and other inherited forms of hypercholesterolemia (eg, hyper-lipoprotein(a) levels [hyper-Lp(a)]). The prevalence, genetics, and management of inherited hypercholesterolemias are described and selected guidelines summarized.
Topics: Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Phytosterols
PubMed: 35963626
DOI: 10.1016/j.ecl.2022.02.006 -
Journal of Atherosclerosis and... Dec 2022
Topics: Humans; Temperature; Hypercholesterolemia
PubMed: 36031359
DOI: 10.5551/jat.ED214