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Abstract
Statins are a family of drugs that are used for treating hyperlipidaemia with a recognized
capacity to prevent cardiovascular disease events. They inhibit β‐hydroxy β‐methylglutaryl‐coenzyme
A reductase, i.e. the rate‐limiting enzyme in mevalonate pathway, reduce endogenous
cholesterol synthesis, and increase low‐density lipoprotein clearance by promoting
low‐density lipoprotein receptor expression mainly in the hepatocytes. Statins have
pleiotropic effects including stabilization of atherosclerotic plaques, immunomodulation,
anti‐inflammatory properties, improvement of endothelial function, antioxidant, and
anti‐thrombotic action. Despite all beneficial effects, statins may elicit adverse
reactions such as myopathy. Studies have shown that mitochondria play an important
role in statin‐induced myopathies. In this review, we aim to report the mechanisms
of action of statins on mitochondrial function. Results have shown that statins have
several effects on mitochondria including reduction of coenzyme Q10 level, inhibition
of respiratory chain complexes, induction of mitochondrial apoptosis, dysregulation
of Ca
2+ metabolism, and carnitine palmitoyltransferase‐2 expression. The use of statins has
been associated with the onset of additional pathological conditions like diabetes
and dementia as a result of interference with mitochondrial pathways by various mechanisms,
such as reduction in mitochondrial oxidative phosphorylation, increase in oxidative
stress, decrease in uncoupling protein 3 concentration, and interference in amyloid‐β
metabolism.
Overall, data reported in this review suggest that statins may have major effects
on mitochondrial function, and some of their adverse effects might be mediated through
mitochondrial pathways.
Summary Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation.
Abstract Aims To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). Methods and results We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. Conclusion Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.
Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment. We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes. In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.) 2008 Massachusetts Medical Society
Journal ID (iso-abbrev): J Cachexia Sarcopenia Muscle
Journal ID (doi): 10.1007/13539.2190-6009
Journal ID (publisher-id): JCSM
Title:
Journal of Cachexia, Sarcopenia and Muscle
Publisher:
John Wiley and Sons Inc.
(Hoboken
)
ISSN
(Print):
2190-5991
ISSN
(Electronic):
2190-6009
Publication date
(Electronic):
29
January
2021
Publication date
(Print):
April
2021
Volume: 12
Issue: 2
(
doiID:
10.1002/jcsm.v12.2
)
Pages: 237-251
Affiliations
[1]Department of Physiology and Pharmacology, Faculty of Medicine
North Khorasan University of Medical Sciences
Bojnurd
Iran
[2]Natural Products and Medicinal Plants Research Center
North Khorasan University of Medical Sciences
Bojnurd
Iran
[3]Student Research Committee, School of Medicine
North Khorasan University of Medical Sciences
Bojnurd
Iran
[4]Department of Medical Sciences
University of Turin
Turin
Italy
[5]Department of Medical Sciences, AOU Città della Salute e della Scienza di Torino
University of Turin
Turin
Italy
[6]Department of Hypertension
WAM University Hospital in Lodz
Medical University of Lodz, Lodz
Poland
[7]
Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz
Poland
[8]Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of
Medicine
University of Perugia
Perugia
Italy
[9]Department of Cardiology and Pneumology
University Medical Center Göttingen
Göttingen
Germany
[10]
German Center for Cardiovascular Research (DZHK), partner site Göttingen
Göttingen
Germany
[11]Department of Food Science and Technology
Islamic Azad University
Quchan
Quchan
Iran
[12]Department of Nutrition, Faculty of Medicine
Mashhad University of Medical Sciences
Mashhad
Iran
[13]Biotechnology Research Center, Pharmaceutical Technology Institute
Mashhad University of Medical Sciences
Mashhad
Iran
[14]Neurogenic Inflammation Research Center
Mashhad University of Medical Sciences
Mashhad
Iran
[15]Halal Research Center of IRI
FDA
Tehran
Iran
Author notes
[*][*
]
Correspondence to: Amirhossein Sahebkar, Department of Medical Biotechnology, School
of Medicine, Mashhad University of Medical Sciences, PO Box: 91779‐48564, Mashhad,
Iran. Phone: 985138002288, Fax: 985138002287, Email:
amir_saheb2000@
123456yahoo.com
;
sahebkara@
123456mums.ac.ir
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