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Alvarez-Jimenez L, Morales-Palomo F, Moreno-Cabañas A, Mora-Gonzalez D, Turrillas MDCM, Mora-Rodriguez R. Time-course atherogenic blood lipid response to statin discontinuation in dyslipidemic adults. Nutr Metab Cardiovasc Dis 2024; 34:2334-2343. [PMID: 39013748 DOI: 10.1016/j.numecd.2024.05.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/14/2024] [Accepted: 05/23/2024] [Indexed: 07/18/2024]
Abstract
BACKGROUND AND AIMS Half of dyslipidemic patients sometimes discontinue statin medication. It is unclear if blood atherogenic risk increases right after statin discontinuation or if there is a lingering protective effect. We sought to determine if a legacy effect prevented blood lipid increases during the first stages of statin cessation. METHODS AND RESULTS Atherogenic blood lipid profile was measured in 10 overweight (BMI 31 ± 3 kg m-2) middle-aged males (62 ± 7 years old), statin users, while fasted and postprandially. Trials were conducted before (i.e., Day 0) and after 4, 7, 15, and 30 days of statin withdrawal and 20 days after statins reloading (Day 50). Four days after statin discontinuation, blood fasting LDL-c, total cholesterol (CHOL), and triglyceride (TG) concentrations increased by 30%, 18%, and 17%, respectively (P < 0.05). The increases in LDL-c, CHOL, and TG peaked after 7-15 days at 79%, 48%, and 34% of basal levels (P < 0.001), respectively. There were no significant correlations between the increases in blood lipids and the dose or years under statin treatment (P = 0.156-0.575). Twenty days after resuming statins, blood LDL-c (2.79 ± 1.06 vs 2.20 ± 0.50 mmol L-1; P = 0.568), CHOL (4.85 ± 1.41 vs 4.25 ± 0.83 mmol L-1; P = 0.747), and TG (1.47 ± 0.60 vs 1.50 ± 0.68 mmol L-1; P = 0.782), returned to basal levels. CONCLUSIONS Our data does not support a statin lingering/legacy effect in blood lipids since they dangerously increased after only 4 days of statin withdrawal in every patient, regardless of dose and years under treatment. Reloading statins restored blood lipids, evidencing a reproducible biological effect at the whole-body level.
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Affiliation(s)
| | | | - Alfonso Moreno-Cabañas
- Exercise Physiology Lab at Toledo, University of Castilla-La Mancha, Spain; Centre for Nutrition, Exercise, and Metabolism, University of Bath, Bath, United Kingdom
| | - Diego Mora-Gonzalez
- Department of Nursing, Physiotherapy, and Occupational Therapy, University of Castilla-La Mancha, Toledo, Spain
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Kadoglou NPE, Stasinopoulou M. How to Use Statins in Secondary Prevention of Atherosclerotic Diseases: from the Beneficial Early Initiation to the Potentially Unfavorable Discontinuation. Cardiovasc Drugs Ther 2023; 37:353-362. [PMID: 34347204 DOI: 10.1007/s10557-021-07233-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/19/2021] [Indexed: 11/30/2022]
Abstract
Statins, a class of lipid-lowering drugs, reduce morbidity and mortality in patients with established atherosclerosis-related cardiovascular disease. Early initiation of statin therapy after admission for acute coronary syndromes (ACS), stroke, or transient ischemic attack (TIA) is associated with improved cardiovascular outcomes. Moreover, high-dose statin treatment prior to coronary or carotid revascularization has been shown to reduce cardiovascular events in these patients. However, many patients may be undertreated, and a residual cardiovascular risk remains in current clinical practice. Despite the beneficial role of statins, their discontinuation rate among patients is still elevated leading to severe adverse cardiovascular events due to atherosclerotic plaque destabilization. In this review, we summarized the impact of statin treatment among patients, focusing on the initiation time-points as well as the potential harm derived by their discontinuation.
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Affiliation(s)
| | - Marianna Stasinopoulou
- Center of Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation, Academy of Athens, 4, Soranou Ephesius str, 11527, Athens, Greece.
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Glycative Stress, Glycated Hemoglobin, and Atherogenic Dyslipidemia in Patients with Hyperlipidemia. Cells 2023; 12:cells12040640. [PMID: 36831307 PMCID: PMC9954063 DOI: 10.3390/cells12040640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/14/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023] Open
Abstract
(1) Background: Diabetes mellitus (DM) is a significant health problem and is associated with dyslipidemia; however, the association between glycative stress, in terms of glycated hemoglobin (HbA1c), and atherogenic dyslipidemia in hyperlipidemic patients with and without DM has rarely been reported. (2) Methods: We prospectively recruited 949 hyperlipidemic patients from the Lipid Clinic of the National Taiwan University Hospital. HbA1c and fasting serum lipids, including total cholesterol (TC), high- and low-density lipoprotein cholesterol (HDL-C and LDL-C), small dense LDL-C (sdLDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglycerides, and advanced glycation end-products (AGEs), were measured. After fasting for 10-14 h, all subjects except those with DM underwent a standard oral glucose tolerance test (OGTT) with 75 g of glucose loading. All subjects were asked to discontinue the use of lipid-lowering agents for 8 weeks before recruitment. (3) Results: Patients with DM had a higher prevalence of hypertension and higher levels of triglyceride, TC/HDL-C ratio, AGEs, VLDL-C, and sdLDL-C. Among patients with higher HbA1c, the serum VLDL-C, AGEs, and TC/HDL-C ratio were significantly higher than those with lower HbA1c. After adjustment for covariates, multiple logistic regression analyses revealed different groups of dysglycemia with higher HbA1c had a higher odds ratio for TC/HDL-C ≥ 5, sdLDL-C ≥ 75th percentile, VLDL-C ≥ 75th percentile and AGEs ≥ 75th percentile. (4) Conclusions: A higher HbA1c was associated with a significant increase in the risk of atherogenic dyslipidemia and AGEs levels in patients with hyperlipidemia. The findings can be very promising in clinical application.
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Shcheblykin DV, Bolgov AA, Pokrovskii MV, Stepenko JV, Tsuverkalova JM, Shcheblykina OV, Golubinskaya PA, Korokina LV. Endothelial dysfunction: developmental mechanisms and therapeutic strategies. RESEARCH RESULTS IN PHARMACOLOGY 2022. [DOI: 10.3897/rrpharmacology.8.80376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Introduction: Every year the importance of the normal functioning of the endothelial layer of the vascular wall in maintaining the health of the body becomes more and more obvious.
The physiological role of the endothelium: The endothelium is a metabolically active organ actively involved in the regulation of hemostasis, modulation of inflammation, maintenance of hemovascular homeostasis, regulation of angiogenesis, vascular tone, and permeability.
Risk factors for the development of endothelial dysfunction: Currently, insufficient bioavailability of nitric oxide is considered the most significant risk factor for endothelial dysfunction.
Mechanisms of development of endothelial dysfunction: The genesis of endothelial dysfunction is a multifactorial process. Among various complex mechanisms, this review examines oxidative stress, inflammation, hyperglycemia, vitamin D deficiency, dyslipidemia, excess visceral fat, hyperhomocysteinemia, hyperuricemia, as well as primary genetic defect of endotheliocytes, as the most common causes in the population underlying the development of endothelial dysfunction.
Markers of endothelial dysfunction in various diseases: This article discusses the main biomarkers of endothelial dysfunction currently used, as well as promising biomarkers in the future for laboratory diagnosis of this pathology.
Therapeutic strategies: Therapeutic approaches to the endothelium in order to prevent or reduce a degree of damage to the vascular wall are briefly described.
Conclusion: Endothelial dysfunction is a typical pathological process involved in the pathogenesis of many diseases. Thus, pharmacological agents with endothelioprotective properties can provide more therapeutic benefits than a drug without such an effect.
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Statins in High Cardiovascular Risk Patients: Do Comorbidities and Characteristics Matter? Int J Mol Sci 2022; 23:ijms23169326. [PMID: 36012589 PMCID: PMC9409457 DOI: 10.3390/ijms23169326] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/12/2022] [Accepted: 08/15/2022] [Indexed: 11/25/2022] Open
Abstract
Atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality are decreasing in high-income countries, but ASCVD remains the leading cause of morbidity and mortality in high-income countries. Over the past few decades, major risk factors for ASCVD, including LDL cholesterol (LDL-C), have been identified. Statins are the drug of choice for patients at increased risk of ASCVD and remain one of the most commonly used and effective drugs for reducing LDL cholesterol and the risk of mortality and coronary artery disease in high-risk groups. Unfortunately, doctors tend to under-prescribe or under-dose these drugs, mostly out of fear of side effects. The latest guidelines emphasize that treatment intensity should increase with increasing cardiovascular risk and that the decision to initiate intervention remains a matter of individual consideration and shared decision-making. The purpose of this review was to analyze the indications for initiation or continuation of statin therapy in different categories of patient with high cardiovascular risk, considering their complexity and comorbidities in order to personalize treatment.
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Zinellu A, Mangoni AA. A systematic review and meta-analysis of the effect of statin treatment on sVCAM-1 and sICAM-1. Expert Rev Clin Pharmacol 2022; 15:601-620. [PMID: 35485866 DOI: 10.1080/17512433.2022.2072294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND AND AIMS Statins might prevent cell adhesion to the endothelium, a key step in atherosclerosis. We conducted a systematic review and meta-analysis of the effect of statins on soluble vascular (sVCAM-1) and intercellular (sICAM-1) adhesion molecule 1. METHODS A systematic literature search was conducted in PubMed, Web of Science, and Scopus, from inception to July 2021. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for analytical studies and GRADE, respectively. RESULTS Statins significantly reduced both sVCAM-1 (standard mean difference, SMD=-0.28, 95% CI -0.44 to -0.12, p=0.001; 46 treatment arms; low certainty of evidence) and sICAM-1 (SMD=-0.75, 95% CI -1.00 to -0.50, p<0.001; 61 treatment arms; moderate certainty of evidence) concentrations. In sensitivity analysis, the SMD values were not modified when individual studies were sequentially removed. There were significant associations between SMD and publication year and, for sICAM-1, statin-induced changes in HDL-cholesterol. In subgroup analysis, the lowering effect was significant with liphophilic, but not hydrophilic, statins, and similar, for sICAM-1, in participants with or without clinically overt atherosclerosis. CONCLUSIONS Statins significantly lower sVCAM-1/sICAM-1. Prospective studies are required to determine whether this mediates their atheroprotective effects (PROSPERO registration number: CRD42021276825).
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Affiliation(s)
- Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Arduino A Mangoni
- Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, Australia.,Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, Australia
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Ryou IS, Chang J, Son JS, Ko A, Choi S, Kim K, Kim SM, Park SM. Association between CVDs and initiation and adherence to statin treatment in patients with newly diagnosed hypercholesterolaemia: a retrospective cohort study. BMJ Open 2021; 11:e045375. [PMID: 33827840 PMCID: PMC8031030 DOI: 10.1136/bmjopen-2020-045375] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVES To evaluate the association between incident cardiovascular disease (CVD) and initiation and adherence to statin treatment for primary prevention of CVD in patients with newly diagnosed hypercholesterolaemia. DESIGN A population-based retrospective cohort study. SETTING This study used National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) from Republic of Korea. PARTICIPANTS This study included 11 320 participants without previous history of CVD aged between 40 and 79 years who had elevated total cholesterol level (more than 240 mg/dL) and had initiated statin treatment within 24 months of the national health screening from 2004 to 2012 identified in the NHIS-HEALS. PRIMARY AND SECONDARY OUTCOME MEASURES The primary outcome, CVD, was defined as first-ever admission or death due to ischaemic heart disease, acute myocardial infarction, revascularisation or stroke, or December 31 2013. The HRs of CVD according to statin adherence were calculated according to stratification by Systematic COronary Risk Evaluation. RESULTS Early statin initiation significantly lowered risk of CVD outcomes compared with late initiation (HR of late statin user, 1.24; 95% CI 1.02 to 2.51). Among early initiators, statin discontinuers had a significantly higher risk for CVD compared with persistent users (HR, 1.71; 95% CI 1.10 to 2.67), while statin reinitiators had an attenuated risk increase (HR 1.34, 95% CI 0.79 to 2.30). CONCLUSIONS Among statin users with newly diagnosed hypercholesterolaemia, early statin initiation is associated with lower CVD risk compared with late initiation. Furthermore, statin discontinuation is associated with increased risk of CVD, but reinitiation attenuated the risk.
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Affiliation(s)
- In Sun Ryou
- Family Medicine, Ewha Womans University School of Medicine, Seoul, Korea (the Republic of)
| | - Jooyoung Chang
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
| | - Joung Sik Son
- Family Medicine, Seoul National University Hospital, Jongno-gu, Korea (the Republic of)
| | - Ahryoung Ko
- Family Medicine, Seoul National University Hospital, Jongno-gu, Korea (the Republic of)
| | - Seulggie Choi
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
| | - Kyuwoong Kim
- Division of Cancer Control and Policy; National Cancer Survivorship Center, National Cancer Control Institute, National Cancer Center, Gyeonggi-do, Korea (the Republic of)
| | - Sung Min Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
| | - Sang Min Park
- Department of Family Medicine, Seoul National University Hospital, Jongno-gu, Korea (the Republic of)
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Stasinopoulou M, Kadoglou NPE, Christodoulou E, Paronis E, Kostomitsopoulos NG, Valsami G, Liapis CD, Kakisis J. Statins’ Withdrawal Induces Atherosclerotic Plaque Destabilization in Animal Model—A “Rebound” Stimulation of Inflammation. J Cardiovasc Pharmacol Ther 2019; 24:377-386. [DOI: 10.1177/1074248419838499] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Marianna Stasinopoulou
- Center of Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece
| | - Nikolaos P. E. Kadoglou
- Centre for Statistics in Medicine—Botnar Research Centre, University of Oxford, Oxford, United Kingdom
| | - Eirini Christodoulou
- Department of Pharmacy, Laboratory of Biopharmaceutics-Pharmacokinetics, National and Kapodistrian University of Athens, Athens, Greece
| | - Efthymios Paronis
- Center of Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece
| | - Nikolaos G. Kostomitsopoulos
- Center of Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece
| | - Georgia Valsami
- Department of Pharmacy, Laboratory of Biopharmaceutics-Pharmacokinetics, National and Kapodistrian University of Athens, Athens, Greece
| | - Christos D. Liapis
- Department of Vascular Surgery, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - John Kakisis
- Department of Vascular Surgery, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Statin discontinuation and mortality in an older adult population with traumatic brain injury: A four-year, multi-centre, observational cohort study. Injury 2017; 48:1040-1046. [PMID: 27914661 DOI: 10.1016/j.injury.2016.11.027] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 10/28/2016] [Accepted: 11/25/2016] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Statin discontinuation has been investigated in a wide range of diseases and injuries, but there is a paucity of data in the older adult population with traumatic brain injury (TBI). The purpose of this study was to re-examine the extent to which early discontinuation of pre-injury statin (PIS) therapy increases the risk of poor patient outcomes in older adult patients suffering a TBI. METHODS This was a retrospective observational cohort study of adult trauma patients with a blunt TBI across three trauma centres over four years. Patients were excluded because of no PIS use, age <55years, or a hospital length of stay (LOS) less than three days. Patients found to be intentionally discontinued from statin therapy within 48h of hospital admission for injury-related reasons were excluded. The primary and secondary outcomes were in-hospital mortality and a hospital LOS ≥1 week. Outcomes were analysed using logistic regression. RESULTS There were 266 patients in the continuation group, and 131 in the discontinuation group. The statin discontinuation group had a significantly higher proportion of patients with a moderate or severe head injury, intubation in emergency department (ED), and disposition to the intensive care unit or operating room. Overall, 23 (6%) patients died while in the hospital. After adjusting for ED Glasgow coma scale, the odds of dying in the hospital were not significantly larger for patients having been discontinued from PIS, compared to those who were continued (OR=1.75, 95%CI=0.71-4.31, p=0.22). Among patients who received an in-hospital statin, the median (interquartile range) time between hospital admission and first administration of statin medication did not differ between patients who died and those who survived (22.8h [10.96-28.91] vs. 22.9h [11.67-39.80], p=0.94). There were no significant differences between study groups in the proportion of patients with a hospital length of stay >1 week (continuation=29% vs. discontinuation=36%, p=0.19). CONCLUSION We did not observe a significantly increased odds of in-hospital mortality following PIS discontinuation, compared to PIS continuation, in an older adult population with TBI. It remains to be seen whether statin discontinuation is a proxy variable for injury severity, or whether it exerts deleterious effects after injury.
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Pandit AK, Kumar P, Kumar A, Chakravarty K, Misra S, Prasad K. High-dose statin therapy and risk of intracerebral hemorrhage: a meta-analysis. Acta Neurol Scand 2016; 134:22-8. [PMID: 26647879 DOI: 10.1111/ane.12540] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2015] [Indexed: 11/30/2022]
Abstract
Statin plays a major role in the primary and secondary prevention of cardiovascular disease (CVD). Inconsistent findings in the studies have been observed toward the risk of intracerebral hemorrhage (ICH) using higher dose of statin. To examine this issue, we performed a meta-analysis of randomized controlled trials (RCTs) to assess the association between higher dose of various statins and risk of ICH among patients with CVD. Literature was searched for studies published before June 10, 2015, using electronic database 'PubMed', 'EMBASE', and 'Google Scholar' as well as from many trial databases. The following search terms were used: 'Statin therapy' AND 'Cardiovascular Disease', AND 'Dose' AND 'Intracerebral hemorrhage', AND 'Randomized Controlled Trials' AND 'High Dose Statin'. High dose of statins was defined as atorvastatin 80 mg, simvastatin 80 mg, pravastatin 40 mg, rosuvastatin 20 mg per day. Fixed-effect model was used to estimate the risk ratio (RR) and 95% confidence interval (CI) if heterogeneity was <50%; otherwise, random-effect model was used. Begg's funnel plot was used to assess the publication bias. Seven RCTs involving 31,099 subjects receiving high-dose statin and 31,105 subjects receiving placebo were analyzed in our meta-analysis. A significant risk of ICH was observed in subjects with higher dose of statin (RR = 1.53; 95% CI: 1.16-2.01; P = 0.002). There was no difference in all-cause mortality between the two groups (RR = 0.95; 95% CI: 0.86-1.06; P = 0.36). No publication bias was observed through Begg's funnel plot. Higher dose of statins was found to be associated with the risk of ICH. Future studies are needed to confirm these findings.
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Affiliation(s)
- A. K. Pandit
- Department of Neurology; All India Institute of Medical Sciences; New Delhi India
| | - P. Kumar
- Department of Neurology; All India Institute of Medical Sciences; New Delhi India
| | - A. Kumar
- Department of Neurology; All India Institute of Medical Sciences; New Delhi India
| | - K. Chakravarty
- Department of Neurology; All India Institute of Medical Sciences; New Delhi India
| | - S. Misra
- Department of Neurology; All India Institute of Medical Sciences; New Delhi India
| | - K. Prasad
- Department of Neurology; All India Institute of Medical Sciences; New Delhi India
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Sordillo PP, Sordillo LA, Helson L. Bifunctional role of pro-inflammatory cytokines after traumatic brain injury. Brain Inj 2016; 30:1043-53. [DOI: 10.3109/02699052.2016.1163618] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Pleiotropic effects of statins: new therapeutic targets in drug design. Naunyn Schmiedebergs Arch Pharmacol 2016; 389:695-712. [PMID: 27146293 DOI: 10.1007/s00210-016-1252-4] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 04/25/2016] [Indexed: 12/13/2022]
Abstract
The HMG Co-enzyme inhibitors and new lipid-modifying agents expand their new therapeutic target options in the field of medical profession. Statins have been described as the most effective class of drugs to reduce serum cholesterol levels. Since the discovery of the first statin nearly 30 years ago, these drugs have become the main therapeutic approach to lower cholesterol levels. The present scientific research demonstrates numerous non-lipid modifiable effects of statins termed as pleiotropic effects of statins, which could be beneficial for the treatment of various devastating disorders. The most important positive effects of statins are anti-inflammatory, anti-proliferative, antioxidant, immunomodulatory, neuroprotective, anti-diabetes, and antithrombotic, improving endothelial dysfunction and attenuating vascular remodeling besides many others which are discussed under the scope of this review. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil-containing protein kinase (ROCK), and their agonistic action on peroxisome proliferator-activated receptors (PPARs) can be viewed as the principle mechanisms underlying the pleiotropic effects of statins. With gradually increasing knowledge of new therapeutic targets of statins, their use has also been advocated in chronic inflammatory disorders for example rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE). In the scope of review, we highlight statins and their pleiotropic effects with reference to their harmful and beneficial effects as a novel approach for their use in the treatment of devastating disorders. Graphical abstract Pleiotropic effect of statins.
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Pantan R, Tocharus J, Suksamrarn A, Tocharus C. Synergistic effect of atorvastatin and Cyanidin-3-glucoside on angiotensin II-induced inflammation in vascular smooth muscle cells. Exp Cell Res 2016; 342:104-12. [PMID: 26957227 DOI: 10.1016/j.yexcr.2016.02.017] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Revised: 02/03/2016] [Accepted: 02/24/2016] [Indexed: 12/21/2022]
Abstract
Statins have often been used in atherosclerosis treatment because of its pleiotropic effects on inflammation. However, some adverse effects of high doses of statin show reverse effects after withdrawal. Cyanidin-3-glucoside (C3G) is a powerful anti-inflammation and antioxidant that has been of interest for use in combination with low doses of statin, which may be alternative treatment for atherosclerosis. The objective is to investigate the synergistic effect of atorvastatin and C3G in angiotensin II (Ang II)-induced inflammation in vascular smooth muscle cells. Human aortic smooth muscle cells (HASMCs) were exposed to Ang II with or without atorvastatin and C3G alone, or in combination. The results revealed that the combination of atorvastatin and C3G produces synergism against inflammation and oxidative stress. The mechanism of the combination of atorvastatin and C3G suppressed the translocation of the p65 subunit of NF-κB from cytosol to nucleus, and attenuated the expression of proteins including inducible nitric oxide synthase, intracellular adhesion molecule 1(ICAM-1), and vascular cell adhesion molecule 1(VCAM-1), in addition to nitric oxide (NO) production. Moreover, C3G exerts the antioxidative properties of atorvastatin through down-regulating NOX1 and promoting the activity of the Nrf2(-)ARE signaling pathway and downstream proteins including heme oxygenase (HO-1), NAD(P)H:quinoneoxidoreductase 1 (NQO-1), and glutamate-cysteine ligase catalytic subunit (γ-GCLC), besides increasing the activity of superoxide dismutase (SOD) enzymes. Taken together, these results suggest that a combination of low dose statins and C3G might serve as a potential regulator of the atherosclerosis process which is mediated by attenuating oxidative stress, thereby inhibiting NF-κB and activating Nrf2 signaling pathways induced by Ang II.
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Affiliation(s)
- Rungusa Pantan
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Jiraporn Tocharus
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Apichart Suksamrarn
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok 10240, Thailand
| | - Chainarong Tocharus
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
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Hong H, He J, Yang S, Wang H, Zhou X, Shang W, Liao H. WITHDRAWN: Effects of atorvastatin treatment and withdrawal on blood brain barrier in focal cerebral ischemia-reperfusion injury. Life Sci 2015:S0024-3205(15)30138-7. [PMID: 26743953 DOI: 10.1016/j.lfs.2015.12.045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 10/09/2015] [Accepted: 12/28/2015] [Indexed: 11/16/2022]
Abstract
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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Affiliation(s)
- Hua Hong
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou 510080, PR China.
| | - Juanjuan He
- Department of Rehabilitation, The Third Affiliated Hospital, Sun Yat-sen University, No. 600, Tianhe Road, Guangzhou 510630, PR China
| | - Shiliang Yang
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou 510080, PR China
| | - Hongxuan Wang
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yanjiang Road West, Guangzhou 510120, PR China
| | - Xiaoming Zhou
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou 510080, PR China
| | - Wenjin Shang
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou 510080, PR China
| | - Huanquan Liao
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou 510080, PR China
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Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol 2015; 7:719-741. [PMID: 26635921 PMCID: PMC4660468 DOI: 10.4330/wjc.v7.i11.719] [Citation(s) in RCA: 145] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/23/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.
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Tong LS, Hu HT, Zhang S, Yan SQ, Lou M. Statin withdrawal beyond acute phase affected outcome of thrombolytic stroke patients: an observational retrospective study. Medicine (Baltimore) 2015; 94:e779. [PMID: 25929921 PMCID: PMC4603028 DOI: 10.1097/md.0000000000000779] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Statin withdrawal is associated with deleterious outcome on stroke patients. Whether risk changes over time, depends on concomitant treatment of intravenous thrombolysis, or both remains to be clarified. We assessed the influence of statin withdrawal within 3 weeks while initiated in acute phase (72 hours) among patients receiving intravenous thrombolysis.This was a monocentered retrospective observational study enrolling intravenous thrombolytic stroke patients from June 2009 to May 2014. Consecutive patients were distinguished into 3 groups according to the initiation and withdrawal of statin: the reference group (not received statin in 72 hours after stroke onset); the continued group (initiated statin therapy in 72 hours and continued for at least 3 weeks); the withdrawal group (initiated statin in 72 hours and discontinued within 3 weeks). All reasons for cessation were recorded. The effects of statin withdrawal on short-, mid-, and long-term outcomes were evaluated as neurologic improvement (NIH Stroke Scale [NIHSS] score improvement ≥4 from baseline or later NIHSS = 0), death or poor outcome (modified Rankin Scale [mRS] ≥4), and favorable outcome (mRS ≤2). We further evaluate statin withdrawal effects in cardioembolic stroke patients for these outcomes.Among 443 IVT patients enrolled, 367 were included in the final study population. There were 88, 188, and 91 patients in the reference, continued, and withdrawal groups, respectively. Multivariable logistic regression showed that statin withdrawal compared with the reference was related to a lower possibility of long-term favorable outcome (OR = 0.45, 95% CI [0.22, 0.90], P = 0.024). Compared with the continued group, the adjusted OR of statin withdrawal was 0.40 (95% CI [0.22, 0.72], P = 0.002) and 2.52 (95% CI [1.34, 4.75], P = 0.004) for long-term favorable and poor/death outcomes, respectively. Also, results were similar for cardioembolic stroke patients (OR = 0.35, 95% CI [0.14, 0.89], P = 0.027 of favorable outcome and OR = 3.62, 95% CI [1.37, 9.62], P = 0.010 of poor/death outcome).In a real-world setting, for stroke patients receiving intravenous thrombolysis, statin withdrawal within 3 weeks initiating in 72 hours may have a harmful effect on the long-term neurologic outcome, even in cardioembolic stroke patients.
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Affiliation(s)
- Lu-Sha Tong
- From the Department of Neurology, The 2nd Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China
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Lee SH, Kwon HS, Park YM, Ko SH, Choi YH, Yoon KH, Ahn YB. Statin Discontinuation after Achieving a Target Low Density Lipoprotein Cholesterol Level in Type 2 Diabetic Patients without Cardiovascular Disease: A Randomized Controlled Study. Diabetes Metab J 2014; 38:64-73. [PMID: 24627830 PMCID: PMC3950197 DOI: 10.4093/dmj.2014.38.1.64] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Accepted: 08/06/2013] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND This study investigated the rate of relapse of dyslipidemia and the factors which could predict relapse following a short-term statin discontinuation after achieving a target low density lipoprotein cholesterol (LDL-C) level in type 2 diabetic patients without cardiovascular disease (CVD). METHODS Ninety-nine subjects on rosuvastatin treatment and whose LDL-C level was lower than 100 mg/dL were randomly assigned to discontinue or maintain statin treatment at a 2:1 ratio. The subjects were followed-up after 10 weeks. A relapse of dyslipidemia was defined as a reascent of LDL-C level to greater than 100 mg/dL. RESULTS The statin discontinuation group had a significant rate of relapse compared to the maintenance group (79% vs. 3%, respectively). Pretreatment and baseline lipid levels, their ratios, and hemoglobin A1c level were significantly different between the relapse and nonrelapse groups. The pretreatment and baseline lipid profiles and their ratios were independently associated with relapse. The pretreatment LDL-C level was the most useful parameter for predicting a relapse, with a cutoff of 123 mg/dL. During the follow-up period, no CVD event was noted. CONCLUSION The relapse rate of dyslipidemia was high when statins were discontinued in type 2 diabetic patients without CVD. Statin discontinuation should be considered carefully based on the pretreatment lipid profiles of patients.
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Affiliation(s)
- Seung-Hwan Lee
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea College of Medicine, Suwon, Korea
| | - Hyuk-Sang Kwon
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Yong-Moon Park
- Department of Preventive Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Seung-Hyun Ko
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea College of Medicine, Suwon, Korea
| | - Yoon-Hee Choi
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Kun-Ho Yoon
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Yu-Bae Ahn
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea College of Medicine, Suwon, Korea
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Orlando A, Bar-Or D, Salottolo K, Levy AS, Mains CW, Slone DS, Offner PJ. Unintentional discontinuation of statins may increase mortality after traumatic brain injury in elderly patients: a preliminary observation. J Clin Med Res 2013; 5:168-73. [PMID: 23671542 PMCID: PMC3651067 DOI: 10.4021/jocmr1333w] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2013] [Indexed: 11/23/2022] Open
Abstract
Background The abrupt discontinuation of statin therapy has been suggested as being deleterious to patient outcomes. Although pre-injury statin (PIS) therapy has been shown to have a protective effect in elderly trauma patients, no study has examined how this population is affected by its abrupt discontinuation. This study examined the effects of in-hospital statin discontinuation on patient outcomes in elderly traumatic brain injury (TBI) patients. Methods This was a multicenter, retrospective cohort study on consecutively admitted elderly (≥ 55) PIS patients who were diagnosed with a blunt TBI and who had a hospital length of stay (LOS) ≥ 3 days. Patients who received an in-hospital statin within 48 hours of admission were considered continued, and patients who never received an in-hospital statin were considered discontinued. Differences in in-hospital mortality, having at least one complication, and LOS > 1 week were examined between those who continued and discontinued PIS. Results Of 93 PIS patients, 46 continued and 15 discontinued statin therapy. The two groups were equivalent vis-a-vis demographic and clinical characteristics. Those who discontinued statin therapy had a 4-fold higher mortality rate than those who continued (n = 4, 27% vs. n = 3, 7%, P = 0.055). Statin discontinuation did not have a higher complication rate, compared to statin continuation (n = 3, 20% vs. n = 7, 15%, P = 0.70), and no difference was seen in the proportion with a hospital LOS > 1 week (P > 0.99). Conclusions Though our study is not definitive, it does suggest that the abrupt, unintended discontinuation of statin therapy is associated with increased mortality in the elderly TBI population. Continuing in-hospital statin therapy in PIS users may be an important factor in the prevention of in-hospital mortality in this elderly TBI population.
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Affiliation(s)
- Alessandro Orlando
- Trauma Research Department, St. Anthony Hospital, Lakewood, CO, USA ; Trauma Research Department, Swedish Medical Center, Englewood, CO, USA
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Antonopoulos AS, Margaritis M, Lee R, Channon K, Antoniades C. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des 2012; 18:1519-30. [PMID: 22364136 PMCID: PMC3394171 DOI: 10.2174/138161212799504803] [Citation(s) in RCA: 329] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2011] [Accepted: 01/10/2012] [Indexed: 12/18/2022]
Abstract
Ample evidence exists in support of the potent anti-inflammatory properties of statins. In cell studies and animal models statins exert beneficial cardiovascular effects. By inhibiting intracellular isoprenoids formation, statins suppress vascular and myocardial inflammation, favorably modulate vascular and myocardial redox state and improve nitric oxide bioavailability. Randomized clinical trials have demonstrated that further to their lipid lowering effects, statins are useful in the primary and secondary prevention of coronary heart disease (CHD) due to their anti-inflammatory potential. The landmark JUPITER trial suggested that in subjects without CHD, suppression of low-grade inflammation by statins improves clinical outcome. However, recent trials have failed to document any clinical benefit with statins in high risk groups, such in heart failure or chronic kidney disease patients. In this review, we aim to summarize the existing evidence on statins as an anti-inflammatory agent in atherogenesis. We describe the molecular mechanisms responsible for the anti-inflammatory effects of statins, as well as clinical data on the non lipid-lowering, anti-inflammatory effects of statins on cardiovascular outcomes. Lastly, the controversy of the recent large randomized clinical trials and the issue of statin withdrawal are also discussed.
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Affiliation(s)
- Alexios S Antonopoulos
- Department of Cardiovascular Medicine, University of Oxford, West Wing Level 6, John Radcliffe Hospital, Headley Way, OX3 9DU, Oxford UK
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Jasińska-Stroschein M, Owczarek J, Wejman I, Orszulak-Michalak D. Novel mechanistic and clinical implications concerning the safety of statin discontinuation. Pharmacol Rep 2011; 63:867-79. [DOI: 10.1016/s1734-1140(11)70602-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Revised: 02/16/2011] [Indexed: 12/29/2022]
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Westover MB, Bianchi MT, Eckman MH, Greenberg SM. Statin use following intracerebral hemorrhage: a decision analysis. ACTA ACUST UNITED AC 2011; 68:573-9. [PMID: 21220650 DOI: 10.1001/archneurol.2010.356] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
CONTEXT Statins are widely prescribed for primary and secondary prevention of ischemic cardiac and cerebrovascular disease. Although serious adverse effects are uncommon, results from a recent clinical trial suggested increased risk of intracerebral hemorrhage (ICH) associated with statin use. For patients with baseline elevated risk of ICH, it is not known whether this potential adverse effect offsets the cardiovascular and cerebrovascular benefits. OBJECTIVE To address the following clinical question: Given a history of prior ICH, should statin therapy be avoided? DESIGN A Markov decision model was used to evaluate the risks and benefits of statin therapy in patients with prior ICH. MAIN OUTCOME MEASURE Life expectancy, measured as quality-adjusted life-years. We investigated how statin use affects this outcome measure while varying a range of clinical parameters, including hemorrhage location (deep vs lobar), ischemic cardiac and cerebrovascular risks, and magnitude of ICH risk associated with statins. RESULTS Avoiding statins was favored over a wide range of values for many clinical parameters, particularly in survivors of lobar ICH who are at highest risk of ICH recurrence. In survivors of lobar ICH without prior cardiovascular events, avoiding statins yielded a life expectancy gain of 2.2 quality-adjusted life-years compared with statin use. This net benefit persisted even at the lower 95% confidence interval of the relative risk of statin-associated ICH. In patients with lobar ICH who had prior cardiovascular events, the annual recurrence risk of myocardial infarction would have to exceed 90% to favor statin therapy. Avoiding statin therapy was also favored, although by a smaller margin, in both primary and secondary prevention settings for survivors of deep ICH. CONCLUSIONS Avoiding statins should be considered for patients with a history of ICH, particularly those cases with a lobar location.
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Affiliation(s)
- M Brandon Westover
- Massachusetts General Hospital Stroke Research Center, 175 Cambridge Street, Boston, MA 02114, USA
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Skrlin S, Hou V. A review of perioperative statin therapy for noncardiac surgery. Semin Cardiothorac Vasc Anesth 2010; 14:283-90. [PMID: 21041202 DOI: 10.1177/1089253210386387] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The leading cause of perioperative morbidity and mortality after major noncardiac surgery is cardiovascular complications. Clinical trials of lipid-lowering 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have shown improved cardiovascular outcomes; therefore, statins have become a mainstay in the prevention of cardiovascular disease. Retrospective trials and a small number of prospective randomized trials indicate that statin use may be beneficial during the perioperative period. In addition to the effects on serum lipid levels, statins influence inflammatory, thrombotic, and vasodilatory cellular pathways; and thus, their beneficial effects are not limited to patients with hypercholesterolemia. This review will (1) examine the evidence for using perioperative statin therapy in the noncardiac surgical patient (2) explore the possible consequences of statin withdrawal, and (3) revisit the evidence for the safety of statin use. Further studies are still needed to establish the optimal dosage as well as timing and length of statin therapy perioperatively.
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Affiliation(s)
- Sara Skrlin
- Oregon Health and Science University, Portland, OR, USA
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Chen YX, Wang XQ, Fu Y, Yao YJ, Kong MY, Nie RQ, Wang JF. Pivotal role of inflammation in vascular endothelial dysfunction of hyperlipidemic rabbit and effects by atorvastatin. Int J Cardiol 2009; 146:140-4. [PMID: 19570586 DOI: 10.1016/j.ijcard.2009.06.019] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2009] [Revised: 04/30/2009] [Accepted: 06/06/2009] [Indexed: 10/20/2022]
Abstract
AIMS To evaluate the role of inflammation in vascular endothelial function of hyperlipidemic rabbits and atorvastatin's effects on it. METHODS 22 rabbits were divided into high-fat diet and atorvastatin plus high-fat diet group. Basic levels of total and low-density lipoprotein cholesterol, triglyceride, C-reactive protein (CRP), interleukin-6 (IL-6), nitric oxide (NO), endothelin-1 (ET-1), fasting blood glucose (FBG), insulin and endothelial function were measured when grouping. Eight weeks later, all above parameters were remeasured and repeated again at days 1, 4 and 7 after atorvastatin withdrawal. RESULTS Eight-week high-fat diet could not cause the changes of FBG and insulin, but significantly induce increased blood lipids as well as inflammatory markers, imbalance between ET-1 and NO, and direct endothelial dysfunction, which could be significantly improved by atorvastatin therapy but could not be well controlled to near baseline. Abrupt withdrawal of atorvastatin caused sharp increase of inflammatory markers and endothelial dysfunction at days 4 and 7 after atorvastatin withdrawal independent of the changes of blood lipids. CONCLUSIONS High-fat diet could cause endothelial dysfunction associated with inflammation, and atorvastatin could counter-regulate it. Sudden withdrawal of statins could induce rebound of inflammatory response and endothelial dysfunction independent of changes of lipids, which may be responsible for increased cardiovascular events in patients with coronary artery disease after withdrawing statins.
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Affiliation(s)
- Yang Xin Chen
- Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120 China
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Rebound inflammatory response during the acute phase of myocardial infarction after simvastatin withdrawal. Atherosclerosis 2009; 207:191-4. [PMID: 19464010 DOI: 10.1016/j.atherosclerosis.2009.04.008] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2009] [Revised: 04/06/2009] [Accepted: 04/09/2009] [Indexed: 11/22/2022]
Abstract
OBJECTIVE The present study aimed to verify the existence of a rebound inflammatory effect after statin withdrawal in the acute phase of myocardial infarction (MI). METHODS In a prospective observational cohort, changes in C-reactive protein (CRP) between the first and the fifth day after MI were evaluated in 249 consecutive patients who were using statins prior to and during MI (SS), statins prior to but not during MI (SN), no statin prior to but during MI (NS), and no statin prior to nor during MI (NN). Data are presented as median (interquartile range). RESULTS At baseline, statin users presented a trend to lower CRP values as compared with those without this treatment before the MI (NN: 1.0(0.4-1.5)mg/dL vs. NS: 1.0(0.3-2.8)mg/dL vs. SS: 0.5(0.3-1.0)mg/dL vs. SN: 0.6(0.4-1.0)mg/dL; p=0.08). By the fifth day, median CRP was significantly higher in the SN (18.1(16.1-23.2)mg/dL) group as compared with other groups (NN: 10.5(9.3-13.2)mg/dL vs. NS: 2.9(1.5-4.5)mg/dL vs. SS: 1.1(0.8-2.4)mg/dL; p<0.0001). At the fifth day, the median CRP in the NN group was lower than in the SN group (p<0.0001), but higher than the NS and SS groups (p<0.0001). There was no significant correlation between CRP change and the change of LDL-cholesterol, HDL-cholesterol or triglycerides. CONCLUSION The present study has, for the first time, provided evidence for the existence of a rebound inflammatory effect after statin cessation. This rebound reaction may contribute for the adverse outcome of patients who stop statin treatment during MI.
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Meier N, Nedeltchev K, Brekenfeld C, Galimanis A, Fischer U, Findling O, Remonda L, Schroth G, Mattle HP, Arnold M. Prior statin use, intracranial hemorrhage, and outcome after intra-arterial thrombolysis for acute ischemic stroke. Stroke 2009; 40:1729-37. [PMID: 19265056 DOI: 10.1161/strokeaha.108.532473] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND PURPOSE There are only limited data on whether prior statin use and/or cholesterol levels are associated with intracranial hemorrhage (ICH) and outcome after intra-arterial thrombolysis. The purpose of this study was to evaluate the association of statin pretreatment and cholesterol levels with the overall frequency of ICH, the frequency of symptomatic ICH, and clinical outcome at 3 months. METHODS We analyzed 311 consecutive patients (mean age, 63 years; 43% women) who received intra-arterial thrombolysis. RESULTS Statin pretreatment was present in 18%. The frequency of any ICH was 20.6% and of symptomatic ICH 4.8%. Patients with any ICH were more often taking statins (30% versus 15%, P=0.005), more often had atrial fibrillation (45% versus 30%, P=0.016), had more severe strokes (mean National Institute of Health Stroke Scale score 16.5 versus 14.7, P=0.022), and less often good collaterals (16% versus 24%, P=0.001). Patients with symptomatic ICH were more often taking statins (40% versus 15%, P=0.009) and had less often good collaterals (0% versus 24%, P<0.001). Any ICH or symptomatic ICH were not associated with cholesterol levels. After multivariate analysis, the frequency of any ICH remained independently associated with previous statin use (OR, 3.1; 95% CI, 1.53 to 6.39; P=0.004), atrial fibrillation (OR, 2.5; CI, 1.35 to 4.75; P=0.004), National Institutes of Health Stroke Scale score (OR, 1.1; CI, 1.00 to 1.10; P=0.037), and worse collaterals (OR, 1.7; CI, 1.19 to 2.42; P=0.004). There was no association of outcome with prior statin use, total cholesterol level, or low-density lipoprotein cholesterol level. CONCLUSIONS Prior statin use, but not cholesterol levels on admission, is associated with a higher frequency of any ICH after intra-arterial thrombolysis without impact on outcome.
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Affiliation(s)
- Niklaus Meier
- Department of Neurology, Inselspital, University Hospital Bern and University of Bern, Bern, Switzerland
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Abstract
Statin treatment is essential for the prevention of vascular disease. Despite the established benefits of statins, discontinuation of these agents is frequent. Whether statin discontinuation leads to adverse outcomes is still debated and the most convincing evidence is mainly restricted to patients who experienced an acute vascular event. It is important to establish if this phenomenon extends to other populations, like those without vascular disease but with a high calculated risk. Overall, it appears that even a brief discontinuation of statins might be harmful. Therefore, statin treatment should not be interrupted except if there is a very good reason. Moreover, patients should be instructed as to why they must adhere to their medication. Adherence should be monitored regularly.
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Howard-Alpe G, Foëx P, Biccard B. Cardiovascular protection by anti-inflammatory statin therapy. Best Pract Res Clin Anaesthesiol 2008; 22:111-33. [DOI: 10.1016/j.bpa.2007.08.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Levin AI. Till death us do part? Postoperative statin discontinuation. SOUTHERN AFRICAN JOURNAL OF ANAESTHESIA AND ANALGESIA 2008. [DOI: 10.1080/22201173.2008.10872514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Biccard BM. A peri-operative statin update for non-cardiac surgery. Part I: The effects of statin therapy on atherosclerotic disease and lessons learnt from statin therapy in medical (non-surgical) patients. Anaesthesia 2007; 63:52-64. [DOI: 10.1111/j.1365-2044.2007.05264.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Abstract
BACKGROUND AND PURPOSE Statins reduce the risk for myocardial infarctions and stroke which may in part depend on cholesterol-independent (pleiotropic) vasoprotective effects. Here, we review evidence to suggest that the abrupt discontinuation of statin medication exerts negative vascular effects in patients with acute vascular events. SUMMARY OF REVIEW It is increasingly recognized that statins (HMG-CoA reductase inhibitors) exert rapid cholesterol-independent effects. Cessation of statin treatment confers overshoot activation of heterotrimeric G-proteins Rho and Rac causing production of reactive oxygen species and suppression of NO bioavailability. In humans, discontinuation of statin therapy leads to a proinflammatory, prothrombotic state with impaired endothelium function. In patients with acute coronary syndromes, abrupt discontinuation of statin therapy significantly increases morbidity and mortality, whereas in stable vascular patients discontinuation may be safe. Recent prospective data indicated that the cessation of statin medication in acute ischemic stroke patients confers a significantly higher likelihood of early neurological deterioration and poor outcome. CONCLUSIONS We propose that in all acute ischemic stroke patients chronically treated with statins before the event, treatment should be continued and the patient should receive medication at the day of the stroke.
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Affiliation(s)
- Matthias Endres
- Klinik und Polikinik für Neurologie, Charité Universitätsmedizin Berlin, Charité Campus Mitte, D-10117 Berlin, Germany.
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Hu CL, Li YB, Tang YH, Chen JB, Liu J, Tang QZ, Zhang QH, Huang CX. Effects of Withdrawal of Xuezhikang, an Extract of Cholestin, on Lipid Profile and C-reactive Protein: A Short-Term Time Course Study in Patients with Coronary Artery Disease. Cardiovasc Drugs Ther 2006; 20:185-91. [PMID: 16775668 DOI: 10.1007/s10557-006-7947-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
OBJECTIVE C-reactive protein (CRP) is considered a risk factor for coronary artery disease. In addition to its lipid-lowering properties, statin decreases the level of CRP. Abrupt cessation of statin therapy during treatment could increase CRP level independently of the elevation of serum lipids and the incidence of cardiac events in patients with atherosclerotic heart disease. Xuezhikang (XZK), an extract of cholestin, has a marked modulating effect on lipid and CRP concentrations in different study time course. However, no attention has been paid to the changes of lipid profile and CRP concentrations after withdrawal of XZK treatment. This study was designed to explore short-term time course effects on lipid profile and CRP concentrations after withdrawal of XZK treatment in coronary heart disease patients. MATERIALS AND METHODS Seventy-five consecutive patients with documented coronary heart disease were randomly divided into three groups: 1. Pretreatment with XZK 1,200 mg daily for 6 weeks and then replaced by placebo (XZK discontinued group; n = 25); 2. Treatment with XZK 1,200 mg daily throughout the study (XZK continued group; n = 25); or 3. Placebo (no XZK group; n = 25). Lipid levels (total cholesterol, HDL-C, LDL-C and triglycerides) and CRP were assessed before receiving the XZK therapy, 1 day before discontinuation of XZK, and on days 1, 2, 3, 7 and 14 after discontinuation of XZK, respectively. RESULTS After 6-week XZK treatment, the fasting total cholesterol, LDL-C, triglyceride and median hs-CRP concentrations decreased, whereas HDL-C concentration increased significantly (p < 0.001, respectively). At day 14 after discontinuation of XZK therapy, total cholesterol (15%), LDL-C (17%) and triglyceride (20%) significantly increased (p < 0.001, respectively), whereas HDL-C level (15%) significantly decreased (p < 0.05). The median level of CRP increased by 11, 65, 128, 103 and 101% on the first, second, third, seventh, and fourteenth day after withdrawal of XZK therapy (p > 0.05, <0.05, <0.001, <0.001, <0.001, compared with 1 day before withdrawal of XZK therapy, respectively). There was a prominent rebound of CRP concentration 3 days after discontinuation of XZK therapy. At this time point, hs-CRP concentration was higher than in the placebo group (p < 0.05). Seven to 14 days after discontinuation of XZK therapy, the hs-CRP concentration declined to a similar level as in the placebo group. No significant correlation was seen between the changes in hs-CRP and lipid profile at all time points. CONCLUSIONS The level of hs-CRP increases on the second day after withdrawal of XZK and there is a prominent rebound 3 days after discontinuation of XZK therapy. The increase of CRP ends within 7 days, where lipids increase at 14 days after discontinuation of XZK therapy. The results may be clinically important for patients with coronary artery disease.
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Affiliation(s)
- Cheng-Lin Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang District, Wuhan 430060, PR China.
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Li JJ, Li YS, Chu JM, Zhang CY, Wang Y, Huang Y, Chen J, Yuan JQ, Huang YL. Changes of plasma inflammatory markers after withdrawal of statin therapy in patients with hyperlipidemia. Clin Chim Acta 2006; 366:269-273. [PMID: 16343471 DOI: 10.1016/j.cca.2005.10.021] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2005] [Revised: 10/23/2005] [Accepted: 10/25/2005] [Indexed: 11/26/2022]
Abstract
BACKGROUND Atherosclerosis has been considered to be an inflammatory process. In addition to its lipid-lowering properties, statin has been shown to decrease the concentrations of inflammatory markers resulting in reduction of cardiovascular events. Emerging data suggest that withdrawal of statin might be associated with increased cardiac events. The mechanism for this phenomenon, however, is still unclear. We investigated whether acute termination of statin treatment could result in rebound of inflammatory markers, such as C-reactive protein (CRP) and interleukin-6 (IL-6), in patients with hyperlipidemia. METHODS Seventeen patients (11 men and 6 women, mean age 51+/-7 years) with hyperlipidemia were given 40 mg/day of pravastatin for 6 weeks. The concentrations of plasma CRP and IL-6 were evaluated before receiving the statin therapy, immediately after 6 weeks of pravastatin therapy, and at days 1, 3 and 7 after withdrawal of pravastatin therapy. The lipid profile was also evaluated at baseline, 6 weeks of therapy, and at day 7 after terminating pravastatin. RESULTS Pravastatin therapy induced significant reductions in total cholesterol (TC, 6.88+/-0.36 vs. 5.27+/-0.23 mmol/l, p<0.01), low-density lipoprotein (LDL) cholesterol (4.28+/-0.25 vs. 3.06+/-0.14 mmol/l, p<0.01), CRP (0.28+/-0.16 vs. 0.20+/-0.08 mg/l, p<0.01), and IL-6 (8.4+/-0.6 vs. 6.7+/-0.4 pg/dl, p<0.01). Although the TC and LDL-cholesterol did not change during the 7-day period after withdrawal of pravastatin therapy, the concentrations of CRP and IL-6 increased at day 3 (CRP: 0.20+/-0.08 vs. 0.27+/-0.12 mg/l, and IL-6: 6.7+/-0.4 vs. 7.7+/-0.6 pg/dl, p<0.05 respectively) and at day 7 (CRP: 0.20+/-0.08 vs. 0.30+/-0.14 mg/l, and IL-6: 6.7+/-0.4 vs. 8.7+/-0.8 pg/dl, p<0.01 respectively) after withdrawal of pravastatin therapy. No correlation between increase of CRP as well as IL-6 and small changes of LDL-cholesterol concentrations was found after withdrawal of pravastatin therapy at day 7 (r=-0.021 and r=-0.044 respectively, p>0.05 respectively). CONCLUSIONS 6 weeks after pravastatin therapy could significant modify the lipid profile and decrease the inflammatory markers including CRP and IL-6 in patients with hyperlididemia. Moreover, statin therapy discontinuation could induce a rebound phenomenon of inflammatory response representing an increase in some inflammatory markers, which is independent of changes of lipid parameters.
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Affiliation(s)
- Jian-Jun Li
- Department of Cardiology, Fu Wai Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beilishi Road 167, Beijing 100037, People's Republic of China.
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Li JJ, Li YS, Chen J, Yang JQ. Rebound phenomenon of inflammatory response may be a major mechanism responsible for increased cardiovascular events after abrupt cessation of statin therapy. Med Hypotheses 2006; 66:1199-1204. [PMID: 16413682 DOI: 10.1016/j.mehy.2005.06.035] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2005] [Accepted: 06/28/2005] [Indexed: 11/26/2022]
Abstract
Inflammation has been recognized as having an important role in the development and progression of atherosclerosis. Statins reduce cardiovascular events mainly by cholesterol lowering. A large number of investigations have demonstrated that administration of statin could modify inflammatory response with a concurrent fall in cardiovascular events. Despite the known benefit of statin therapy, many cardiac patients abruptly discontinue therapy because of financial constraints, forgetfulness, or side effects. More recently, several studies have shown that abrupt cessation of statin therapy during treatment could increase the incidence of cardiac events in patients with atherosclerotic heart disease. However, the mechanisms of the increased incidence of cardiovascular events after abruptly stopping statin therapy are still unknown. A few data suggest that abrupt withdrawal of statin therapy deteriorates endothelial function, result in expression of pro-inflammatory gene involved in the development and progression of atherosclerosis. We hypothesis that rebound phenomenon of inflammatory response may be a major mechanism responsible for increased cardiovascular events after abrupt cessation of statin therapy. Our very recent data showed that abrupt termination of statin therapy resulted in a rapid increased C-reactive protein (CRP) and interleukin-6 (IL-6) levels in patients with hypercholesterolemia. This finding may be of important interest in the connection between inflammatory response and abrupt withdrawal of statin therapy in patients with coronary artery disease.
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Affiliation(s)
- Jian-Jun Li
- Department of Cardiology, Fu Wai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China.
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Chu CS, Kou HS, Lee CJ, Lee KT, Chen SH, Voon WC, Sheu SH, Lai WT. Effect of atorvastatin withdrawal on circulating coenzyme Q10 concentration in patients with hypercholesterolemia. Biofactors 2006; 28:177-84. [PMID: 17473378 DOI: 10.1002/biof.5520280304] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Statin therapy can reduce the biosynthesis of both cholesterol and coenzyme Q10 by blocking the common upstream mevalonate pathway. Coenzyme Q10 depletion has been speculated to play a potential role in statin-related adverse events, and withdrawal of statin is the choice in patients developing myotoxicity or liver toxicity. However, the effect of statin withdrawal on circulating levels of coenzyme Q10 remains unknown. Twenty-six patients with hypercholesterolemia received atorvastatin at 10 mg/day for 3 months. Serum lipid profiles and coenzyme Q10 were assessed before and immediately after 3 months and were also measured 2 and 3 days after the last day on the statin. After 3 months' atorvastatin therapy, serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and coenzyme Q10 (0.43 +/- 0.23 to 0.16 +/- 0.10 microg/mL) were all significantly reduced (all p<0.001). On day 2 after the last atorvastatin, the coenzyme Q10 level was significantly elevated (0.37 +/- 0.16 microg/mL) and maintained the same levels on day 3 (0.39 +/- 0.18 microg/mL) compared with those on month 3 (both p< 0.001), while TC and LDL-C did not significantly change within the same 3 days. These results suggest that statin inhibition of coenzyme Q10 synthesis is less strict than inhibition of cholesterol biosynthesis.
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Affiliation(s)
- Chih-Sheng Chu
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
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