Evidence for Statin Pleiotropy in Humans

Abstract

Background-By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins not only reduce cholesterol biosynthesis but also decrease the formation of isoprenoids, which are important for mediating signaling through the Rho-associated coiled-coil containing protein kinase (ROCK) pathway. Increased ROCK activity has been implicated in endothelial dysfunction and vascular inflammation. We hypothesize that ezetimibe, which inhibits intestinal cholesterol absorption, may not exert similar cholesterol-independent or pleiotropic effects of statins and, when used with a lower dose of statin, have less effect on ROCK activity than a higher dose of statin. Methods and Results-In a prospective, randomized, observer-blinded study, we treated 60 dyslipidemic subjects without cardiovascular disease with simvastatin 40 mg/d, simvastatin/ezetimibe 10/10 mg/d, or placebo tablets for 28 days (nϭ20 in each arm). We evaluated baseline demographics and lipid levels, ROCK activity, C-reactive protein, and flow-mediated dilation before and after treatment. Compared with the placebo group, both treatment regimens decreased low-density lipoprotein cholesterol by 38% and C-reactive protein by 38% to 40% after 28 days (PϽ0.01 for both compared with placebo). Although the low-density lipoprotein cholesterol and C-reactive protein reductions were comparable with either lipid-lowering regimen, only simvastatin 40 mg reduced ROCK activity and improved flow-mediated dilation (PϽ0.01 for both compared with baseline). Reduction in ROCK activity with simvastatin 40 mg remained significant even after controlling for changes in low-density lipoprotein cholesterol (Pϭ0.01) and correlated with improvement in flow-mediated dilation (R 2 ϭϪ0.78, PϽ0.01). No correlation was found between changes in flow-mediated dilation and changes in low-density lipoprotein cholesterol or C-reactive protein. Conclusion-These

Vascular Permeability in Cerebral Cavernous Malformations

“…Another ongoing exploratory and developmental research study (R21NS087328) is seeking to correlate brain and lesional permeability in CCM subjects with ROCK activity measured in peripheral blood leukocytes. 9 Results from these various projects will complement preliminary observations reported herein, and generate further information on this topic, with potential clinical interest.…”

“…There was greater brain permeability in familial CCM patients compared with sporadic cases (excluding patients on statin medications due to its potential pleiotropic effects on vascular permeability [9][10][11] ). The difference was significant in WMN, GMF, and WMF regions (Po 0.01, P o0.01, and P o 0.001, respectively).…”

Comparative study between high-dose fluvastatin and low-dose fluvastatin and ezetimibe with regard to the effect on endothelial function in diabetic patients

“…Thus, the RLP lowering effect of ezetimibe might at least partly contribute to improvement in endothelial function. Considering that the patients in the study by Liu et al [5] had a low cardiovascular risk, were not all naive to statin treatment, and did not include patients with diabetes mellitus, RLP levels in these patients were probably lower than those in the study by Settergren et al [4].…”

“…In addition to these studies, a number of other studies have investigated the pleiotropic effects of statins with varying results [4][5][6][7]. These results stress the need for mechanistic study of an individual statin and multicenter study examining whether there is a clinical benefit of a particular statin beyond its lipid-lowering effect.…”

“…Likewise, similar reductions in LDL-C were observed among the two groups (45% to 50%), suggesting that the lipid-lowering effect of therapy might be a more important mediator of flowmediated dilation than pleiotropic effects. In another study, Liu et al [5] compared the effect of simvastatin 40 mg daily, and a combination of simvastatin 10 mg and ezetimibe 10 mg daily, with placebo in three groups of patients with low-density lipoprotein cholesterol readings >130 mg/dL and less than two cardiovascular risk factors. The groups were compared based on relative changes in Rho-associated coiled-coil containing protein kinase activity as the primary endpoint, and endothelial function as a secondary endpoint.…”