Statin treatment

The antiinflammatory effects of statins likely result from their ability to inhibit the formation of mevalonic acid. Downstream products of this molecule include not only the end product, cholesterol, but also several isoprenoid intermediates that covalently modify ( pre-nylate ) certain key intracellular signaling molecules. Statin treatment reduces leukocyte adhesion, accumulation of macrophages, MMPs, tissue factor, and other proinflammatory mediators. By acting on the MHC class II transactivator (CIITA), statins also interfere with antigen presentation and subsequent T-cell activation. Statin treatment can also limit platelet activation in some assays as well. All these results support the concept that in addition to their favorable effect on the lipid profile, statins can also exert an array of antiinflammatory and immunomodulatory actions. 

Gertz K, Laufs U, Lindauer U, Nickenig G, Bohm M, Dirnagl U, Endres M. Withdrawal of statin treatment abrogates stroke protection in mice. Stroke 2003 34 551-557. 

It would be very interesting to go back into the other cohorts, in which no difference in cholesterol reduction between the genotypes has been seen and to examine, whether the statin treatment also abolished excess mortality of apo E4 carriers. 

Q80 Statins may be recommended to a 60-year-old asymptomatic male who is overweight, has a family history of coronary heart disease and is a smoker. The patient has a 10-year cardiovascular risk of 10% or more and is likely to benefit from statin treatment. 

Stenestrand U. Early statin treatment following acute myocardial infarction and 1-year survival. JAMA 2001 285 430-6. 

Co-enzyme Q10 concentrations were measured in blood from hypercholesterolemic subjects before and after exposure to atorvastatin 80 mg/day for 14 and 30 days in 34 subjects eligible for statin treatment (11). The mean blood concentration of co-enzyme Q10 was 1.26 pg/ml at baseline, and fell to 0.62 after 30 days of atorvastatin therapy. There was a statistically significant fall detectable after 14 days of treatment. The authors concluded that widespread inhibition of co-enzyme Q10 synthesis could explain the exercise intolerance, myalgia, and myoglobinuria that are observed with statin treatment. 

In a series of seven cases of neuropathy, all were axonal peripheral neuropathies and both thick and thin nerve fibers were affected (10). No cause of peripheral neuropathy other than statin treatment could be identified. In this series at least four of the cases were irreversible, probably due to long exposure to statins (4—7 years versus 1-2 years in previous reports). Besides an effect on ubiquinone, interference with cholesterol synthesis may alter nerve membrane function, since cholesterol is a ubiquitous component of human cell membranes. Neuropathy has not been observed in extensive long-term trials of lipid-lowering drugs. It could be due to patient selection, a low frequency of the adverse effect, or lack of attention to symptoms of peripheral neuropathy. The observed association may also not be causal. 

This case suggests that acute polyradiculoneuropathy may represent a rare but serious adverse effect of statin treatment. The pathophysiology of acute neuropathy on statin exposure is unknown a hypersensitivity reaction resulting in an immune-mediated process has been suggested. It is possible that this patient had relapsing Guillain-Barre syndrome unrelated to the use of statins. 

The term transaminitis has been coined to describe a rise in the activities of serum transaminases without clinical symptoms. One author has suggested that in such cases one should switch from one statin to another, thereby preventing unnecessary withdrawal of statin treatment in dyslipidemic patients at high cardiovascular risk (25). 

Sundram F, Roberts P, Kennedy B, Pavord S. Thrombotic thrombocytopenic purpura associated with statin treatment. Postgrad Med J 2004 80(947) 551-2. 

Ross SD, Allen IE, Connelly JE, et al. Clinical outcomes in statin treatment trials a meta-analysis. Arch Intern Med. 1999 159 1793-1802. 

I 10 Solem J, Levin M, Karlsson T, Grip L, Albertsson R Wiklund O. Composition of coronary plaques obtained by directional atherectomy in stable angina its relation to serum lipids and statin treatment. J Intern Med 2006 259 267-275. 

Okazaki S, Yakoyama T, Miyauchi K, et al. Early statin treatment in patients with acute coronary syndrome demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event the ESTABLISH Study, Circulation 2004 I 10 1061-1068. 

Fig. 4.11 Plasma levels of (a) LDL-C, (b) HDL-C and (c) triglycerides after statin treatment in human subjects.

The authors estimated that 5 years of statin treatment will prevent 100 major vascular events in every 1000 patients with previous myocardial infarction, or 70-80 events in patients with other forms of coronary heart disease or diabetes. There was no upper age limit to this benefit, and no lower limit to the level of LDL at which benefit was seen. Heart Protection Study Collaborative Group 2002 MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals. Lancet 360 7-22. 

In a series of seven cases of neuropathy, all were axonal peripheral neuropathies and both thick and thin nerve fibers were affected (6). No cause of peripheral neuropathy other than statin treatment could be identified. In this... 

Yamada M, Huang Z, Dalkara T, Endres M, Laufs U, et al. 2000. Endothelial nitric oxide synthase-dependent cerebral blood flow augmentation by L-arginine after chronic statin treatment. J. Cereb. Blood Flow Metab. 20 709-17... 

The reports of observably lower incidence of SAD among the patients prescribed statins (56), the differentiated cholesterol response to statin treatment dependent on the allele present (57), and the surprising response of e4 carriers with CVD to statin in a myocardial infarction survival study (58) emphasize the need for large enrollment studies of these links. An additional link between the ApoE allele and AD comes from the increased CSF cortisol as a function of ApoE genotype (59). The highest levels of cortisol that may contribute to neuronal degeneration were observed in e4/e4 individuals with AD. 

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