High-Dose Atorvastatin Reduces Total Plasma Levels of Oxidized Phospholipids and Immune Complexes Present on Apolipoprotein B-100 in Patients With Acute Coronary Syndromes in the MIRACL Trial

Tsimikas, Sotirios; Witztum, Joseph L.; Miller, Elizabeth R.; Sasiela, William J.; Szarek, Michael; Olsson, Anders; Schwartz, Gregory G.

doi:10.1161/01.cir.0000141728.23033.b5

Cited by 206 publications

(170 citation statements)

References 52 publications

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“…Interestingly, reductions in oxidation markers were observed at its lowest dose (10 mg) over just 12 weeks (15). In a larger study of 2341 patients, treatment with a high dose of atorvastatin (80 mg) caused a significant reduction in levels of oxidized lipids on all apoB-100 particles after just a 16-week period (14). Comparative studies into the effects of atorvastatin versus other statins on biomarkers of oxidative stress are currently underway and will provide additional insight into this potential non-LDL mechanism of action.…”

Section: Discussionmentioning

confidence: 95%

“…Unlike other statins, ATM has the same enzymatic activity as its parent. Atorvastatin treatment has been successfully used to reduce the risk and progression of cardiovascular disease (16 -18), but there is also clinical evidence that this agent has anti-inflammatory and antioxidant properties that may not be solely related to LDL reduction (12)(13)(14)(15). A small clinical study that measured protein oxidation markers (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…ATM was selected as it has potent antioxidant activity, independent of HMG-CoA reductase inhibition (10,11). In randomized clinical trials, atorvastatin treatment has been shown to have anti-inflammatory and antioxidant benefits (12)(13)(14)(15) and is associated with reduced risk and progression of cardiovascular disease (16 -18). In this study, the activity of ATM was compared with other statins (pravastatin, rosuvastatin, simvastatin) and known antioxidants (probucol, Trolox) using membranes enriched with polyunsaturated fatty acids (PUFAs) and physiologic levels of cholesterol (17-37.5 mol %) (19,20).…”

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confidence: 99%

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Active Metabolite of Atorvastatin Inhibits Membrane Cholesterol Domain Formation by an Antioxidant Mechanism

Mason

Walter²,

Day³

et al. 2006

Journal of Biological Chemistry

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The advanced atherosclerotic lesion is characterized by the formation of microscopic cholesterol crystals that contribute to mechanisms of inflammation and apoptotic cell death. These crystals develop from membrane cholesterol domains, a process that is accelerated under conditions of hyperlipidemia and oxidative stress. In this study, the comparative effects of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) on oxidative stress-induced cholesterol domain formation were tested in model membranes containing physiologic levels of cholesterol using small angle x-ray diffraction approaches. In the absence of HMG-CoA reductase, only the atorvastatin active o-hydroxy metabolite (ATM) blocked membrane cholesterol domain formation as a function of oxidative stress. This effect of ATM is attributed to electron donation and proton stabilization mechanisms associated with its phenoxy group located in the membrane hydrocarbon core. ATM inhibited lipid peroxidation in human low density lipoprotein and phospholipid vesicles in a dose-dependent manner, unlike its parent and other statins (pravastatin, rosuvastatin, simvastatin). These findings indicate an atheroprotective effect of ATM on membrane lipid organization through a potent antioxidant mechanism.The unstable atherosclerotic lesion is characterized by extracellular lipid deposits consisting of cholesterol (both free and esterified), phospholipids, and lesser amounts of triacylglycerol (1). Free cholesterol is associated with phospholipid membranes and insoluble, extracellular crystals in the lipid core of the plaque. Membrane-associated cholesterol crystals have been characterized in cell culture systems and tissue explants from animal models of atherosclerosis using electron microscopy and x-ray diffraction approaches (2, 3). Microscopic cholesterol crystalline structures have also been observed in macrophage foam cells following treatment with LDL 2 or by inhibition of acyl-coenzyme A:cholesterol acyltransferase (4 -6). These crystalline structures contribute to mechanisms of cell death and inflammation (3-5). Although non-crystalline membrane cholesterol can readily exchange from the plaque with plasma lipoprotein particles, cholesterol in the crystalline state is insoluble and does not respond to pharmacologic intervention or reverse cholesterol transport mechanisms (1).We have recently reported that oxidative stress, a pathologic process associated with cardiovascular risk factors (e.g. hypertension, diabetes, hypercholesterolemia) (7), contributes directly to the formation of cholesterol crystalline microdomains in membranes (8). Domain formation as a function of lipid peroxidation was observed in lipid vesicles containing physiologic levels of cholesterol using small angle x-ray diffraction approaches (2, 9). These observations have led to our current hypothesis that the active o-hydroxy metabolite of atorvastatin (ATM) may interfere with cholesterol domain formation without altering membrane cholesterol content. ATM was selected as it has pot...

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Active Metabolite of Atorvastatin Inhibits Membrane Cholesterol Domain Formation by an Antioxidant Mechanism

Mason

Walter²,

Day³

et al. 2006

Journal of Biological Chemistry

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“…The only practical approach at this time is to reduce the antigenic load, either by dietary modification, or by pharmacological means. Statins have been shown to reduce the levels of circulating modified LDL-IC in two studies [97,98], and have also anti-inflammatory and antioxidant effects [99][100][101]. Their effects on modified LDL-IC levels should be investigated in a well designed trial with sufficient numbers of patients and methodological rigor, designed to determine how much of the benefits attributed to statins can be correlated with the reduction of the major pro-inflammatory insult that mLDL-IC appear to represent.…”

Section: Discussionmentioning

confidence: 99%

Atherogenesis and the humoral immune response to modified lipoproteins

Virella¹,

Lopes‐Virella²

2008

Atherosclerosis

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Modified forms of LDL are immunogenic and activate both cell-mediated and humoral immune responses. Both types of responses are pro-inflammatory and are probably primary players in the perpetuation of the chronic inflammatory reaction characteristic of atherosclerosis. The immunologic response to modified LDL can be directed to MHC-II-associated peptides in the case of T helper cells, and to a variety of epitopes -modified lysine groups, modified phospholipids, proteins that become associated with oxidized LDL (such as β2GP1) -in the case of B cell responses. T cell activation is likely to play a major role through cross-activation of macrophages. Humoral responses to modified LDL are pathogenic as a consequence of the formation of antigen-antibody complexes containing modified LDL and IgG antibodies. Those immune complexes induce cholesterol ester accumulation in macrophages and macrophage-like cells, and induce the release of proinflammatory cytokines, chemokines, oxygen active radicals, and matrix metalloproteinases from those cells. There is no conclusive evidence supporting a protective role for IgM antibodies in humans, possibly because autoantibodies to modified lipoproteins are predominantly of the IgG isotype.

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“…A recent meta-analysis also found that atorvastatin modestly decreased the Lp (a) levels (17). However, other studies didn't find the statins' beneficial effects on the Lp (a) reductions (18)(19)(20). We think that it's reasonable the statins exhibit beneficial effects in reducing the Lp (a) levels given that the statins can deplete apolipoprotein B100 (apo B), which is indispensable to assemble the Lp (a).…”

Section: Introductionmentioning

confidence: 99%

Long-term statin therapy could be efficacious in reducing the lipoprotein (a) levels in patients with coronary artery disease modified by some traditional risk factors

Xu¹,

Liu²,

He³

et al. 2017

J. Thorac. Dis.

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Background: Lipoprotein (a) [Lp (a)] is a well-established risk factor for coronary artery disease (CAD).However, up till now, treatment of patients with higher Lp (a) levels is challenging. This current study aimed to investigate the therapeutic effects of short-, medium and long-term statin use on the Lp (a) reduction and its modifying factors. Methods: The therapeutic duration was categorized into short-term (median, 39 days), medium term (median, 219 days) and long-term (median, 677 days). The lipid profiles before therapy served as baselines.Patients at short-, medium or long-term exactly matched with those at baseline. Every patient's lipid profiles during the follow-ups were compared to his own ones at baselines. Results: The current study demonstrated that long-term statin therapy significantly decreased the Lp (a) levels in CAD patients while short-term or medium term statin therapy didn't. When grouped by statin use, only long-term simvastatin use significantly decreased the Lp (a) levels while long-term atorvastatin use insignificantly decreased the Lp (a) levels. Primary hypertension (PH), DM, low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) could modify the therapeutic effects of statin use on the Lp (a) levels in CAD patients. Conclusions: The long-term statin therapy could be efficacious in reducing the Lp (a) levels in CAD patients, which has been modified by some traditional risk factors. In the era of commercial unavailability of more reliable Lp (a) lowering drugs, our findings will bolster confidence in fighting higher Lp (a) abnormalities both for patients and for doctors.

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High-Dose Atorvastatin Reduces Total Plasma Levels of Oxidized Phospholipids and Immune Complexes Present on Apolipoprotein B-100 in Patients With Acute Coronary Syndromes in the MIRACL Trial

Cited by 206 publications

References 52 publications

Active Metabolite of Atorvastatin Inhibits Membrane Cholesterol Domain Formation by an Antioxidant Mechanism

Active Metabolite of Atorvastatin Inhibits Membrane Cholesterol Domain Formation by an Antioxidant Mechanism

Atherogenesis and the humoral immune response to modified lipoproteins

Long-term statin therapy could be efficacious in reducing the lipoprotein (a) levels in patients with coronary artery disease modified by some traditional risk factors

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