Endothelial progenitor cell mobilization and platelet microparticle release are influenced by clopidogrel plasma levels in stable coronary artery disease.

BACKGROUND: Increased numbers of endothelial (EMP) and platelet (PMP) microparticles have been related to cardiovascular risk factors and coronary artery disease. Little is known about the early effects of statins and clopidogrel on these new biomarkers of vascular homeostasis. The aim of the present study was to evaluate pharmacokinetic interactions between atorvastatin and clopidogrel and their effects, alone or combined, on EMP, PMP, and endothelial progenitor cells (EPC). METHODS AND RESULTS: A prospective open-label study enrolled subjects with stable coronary disease (n=26). Drugs were given daily for 3 weeks (atorvastatin 80 mg, visits 1-3; clopidogrel 75 mg, visits 2-4). Counts of EPC (CD34+/CD133+/KDR+), EMP (CD51+) and PMP (CD42+/CD31+), and pharmacokinetic parameters over 24h were assessed at each visit. Atorvastatin plasma concentrations were increased by concomitant therapy with clopidogrel (maximum serum concentration [C(max)], P=0.002; area under the clopidogrel or atorvastatin plasma concentration vs. time curve from 0 to the last detectable concentration [AUC(last)], P=0.03). After atorvastatin withdrawal there was an increase in clopidogrel plasma concentrations (C(max), P=0.009; AUC(last), P=0.039). PMP were inversely correlated with clopidogrel C(max) on visit 3 (rho=-0.57, P=0.006) and on visit 4 (rho=-0.54, P=0.01), and with clopidogrel AUC(last) on visit 3 (rho=-0.44, P=0.04), and on visit 4 (rho=-0.57, P=0.005). In addition, clopidogrel C(max) was correlated with EPC (CD133+/KDR+) on visit 4 (rho=0.48, P=0.025). No correlations of atorvastatin and MP or EPC were found. CONCLUSIONS: The balance between platelet MP release and EPC mobilization seems influenced by clopidogrel plasma levels, suggesting a protective mechanism on coronary artery disease.

The role of soluble fiber intake in patients under highly effective lipid-lowering therapy.

BACKGROUND: It has been demonstrated that statins can increase intestinal sterol absorption. Augments in phytosterolemia seems related to cardiovascular disease. OBJECTIVE: We examined the role of soluble fiber intake in endogenous cholesterol synthesis and in sterol absorption among subjects under highly effective lipid-lowering therapy. DESIGN: In an open label, randomized, parallel-design study with blinded endpoints, subjects with primary hypercholesterolemia (n = 116) were assigned to receive during 12 weeks, a daily dose of 25 g of fiber (corresponding to 6 g of soluble fibers) plus rosuvastatin 40 mg (n = 28), rosuvastatin 40 mg alone (n = 30), sinvastatin 40 mg plus ezetimibe 10 mg plus 25 g of fiber (n = 28), or sinvastatin 40 mg plus ezetimibe 10 mg (n = 30) alone. RESULTS: The four assigned therapies produced similar changes in total cholesterol, LDL-cholesterol, and triglycerides (p < 0.001 vs. baseline) and did not change HDL-cholesterol. Fiber intake decreased plasma campesterol (p < 0.001 vs. baseline), particularly among those patients receiving ezetimibe (p < 0.05 vs. other groups), and ß-sitosterol (p = 0.03 vs. baseline), with a trend for lower levels in the group receiving fiber plus ezetimibe (p = 0.07). Treatment with rosuvastatin alone or combined with soluble fiber was associated with decreased levels of desmosterol (p = 0.003 vs. other groups). Compared to non-fiber supplemented individuals, those treated with fibers had weight loss (p = 0.04), reduced body mass index (p = 0.002) and blood glucose (p = 0.047). CONCLUSION: Among subjects treated with highly effective lipid-lowering therapy, the intake of 25 g of fibers added favorable effects, mainly by reducing phytosterolemia. Additional benefits include improvement in blood glucose and anthropometric parameters.

Additive effects of plant sterols supplementation in addition to different lipid-lowering regimens.

OBJECTIVE: Plant sterol (PS) supplementation has been widely used alone or combined with lipid-lowering therapies (LLTs) to reduce low-density lipoprotein (LDL) cholesterol. The effects of PS added to high-intensity LLT are less reported, especially regarding the effects on cholesterol synthesis and absorption. METHODS: A prospective, randomized, open-label study, with parallel arms and blinded end points was designed to evaluate the effects of addition of PS to LLT on LDL cholesterol, markers of cholesterol synthesis, and absorption. Eighty-six patients of both genders were submitted to a 4-wk run-in period with atorvastatin 10 mg (baseline). Following, subjects received atorvastatin 40 mg, ezetimibe 10 mg, or combination of both drugs for another 4-wk period (phase I). In phase II, capsules containing 2.0 g of PSs were added to previous assigned treatments for 4 wk. Lipids, apolipoproteins, plasma campesterol, ß-sitosterol, and desmosterol levels were assayed at all time points. Within and between-group analyses were performed. RESULTS: Compared with baseline, atorvastatin 40 mg reduced total and LDL cholesterol (3% and 22%, respectively, P < .05), increased ß-sitosterol, campesterol/cholesterol, and ß-sitosterol/cholesterol ratios (39%, 47%, and 32%, respectively, P < .05); ezetimibe 10 mg reduced campesterol and campesterol/cholesterol ratio (67% and 70%, respectively, P < .05), and the combined therapy decreased total and LDL cholesterol (22% and 38%, respectively, P < .05), campesterol, ß-sitosterol, and campesterol/cholesterol ratio (54%, 40%, and 27%, P < .05). Addition of PS further reduced total and LDL cholesterol by ∼ 7.7 and 6.5%, respectively, in the atorvastatin therapy group and 5.0 and 4.0% in the combined therapy group (P < .05, for all), with no further effects in absorption or synthesis markers. CONCLUSIONS: PS added to LLT can further improve lipid profile, without additional effects on intestinal sterol absorption or synthesis.

Euterpe oleracea (açai) modifies sterol metabolism and attenuates experimentally-induced atherosclerosis.

AIM: Euterpe Oleracea (açai) is a fruit from the Amazon region whose chemical composition may be beneficial for individuals with atherosclerosis. We hypothesized that consumption of Euterpe Oleracea would reduce atherosclerosis development by decreasing cholesterol absorption and synthesis. METHODS: Male New Zealand rabbits were fed a cholesterol-enriched diet (0.5%) for 12 weeks, when they were randomized to receive Euterpe Oleracea extract (n = 15) or water (n = 12) plus a 0.05% cholesterol-enriched diet for an additional 12 weeks. Plasma phytosterols and desmosterol were determined by ultra-performance liquid chromatography and mass spectrometry. Atherosclerotic lesions were estimated by computerized planimetry and histomorphometry. RESULTS: At sacrifice, animals treated with Euterpe Oleracea had lower levels of total cholesterol (p =0.03), non-HDL-cholesterol (p = 0.03) and triglycerides (p = 0.02) than controls. These animals had smaller atherosclerotic plaque area in their aortas (p = 0.001) and a smaller intima/media ratio (p = 0.002) than controls, without differences in plaque composition. At the end of the study, campesterol, ß-sitosterol, and desmosterol plasma levels did not differ between groups; however, animals treated with Euterpe Oleracea showed lower desmosterol/campesterol (p = 0.026) and desmosterol/ ß-sitosterol (p =0.006) ratios than controls. CONCLUSIONS: Consumption of Euterpe Oleracea extract markedly improved the lipid profile and attenuated atherosclerosis. These effects were related in part to a better balance in the synthesis and absorption of sterols.

Phytosterols and phytosterolemia: gene-diet interactions.

Phytosterol intake is recommended as an adjunctive therapy for hypercholesterolemia, and plant sterols/stanols can reduce cholesterol absorption at the intestinal lumen through the Niemann-Pick C1 Like 1 (NPC1L1) transporter pathway by competitive solubilization in mixed micelles. Phytosterol absorption is of less magnitude than cholesterol and is preferably secreted in the intestinal lumen by ABCG5/G8 transporters. Therefore, plasma levels of plant sterols/stanols are negligible compared with cholesterol, under an ordinary diet. The mechanisms of cholesterol and plant sterols absorption and the whole-body pool of sterols are discussed in this chapter. There is controversy about treatment with statins inducing further increase in plasma non-cholesterol sterols raising concerns about the safety of supplementation of plant sterols to such drugs. In addition, increase in plant sterols has also been reported upon consumption of plant sterol-enriched foods, regardless of other treatments. Rare mutations on ABCG5/G8 transporters affecting cholesterol/non-cholesterol extrusion, causing sitosterolemia with xanthomas and premature atheroslerotic disease are now known, and cholesterol/plant sterols absorption inhibitor, ezetimibe, emerges as the drug that reduces phytosterolemia and promotes xanthoma regression. On the other hand, common polymorphisms affecting the NPC1L1 transporter can interfere with the action of ezetimibe. Gene-diet interactions participate in this intricate network modulating the expression of genetic variants on specific phenotypes and can also affect the individual response to the hypolipidemic treatment. These very interesting aspects promoted a great deal of research in the field.