simvastatin

2715

ORIGINAL ARTICLE

Effects of Rosuvastatin vs. Simvastatin/ezetimibe on ArterialWall Stiffness in Patients with Coronary Artery Disease

Ban Liu 1, Wenliang Che 1, Hongwei Yan 2, Weidong Zhu 2 and Hongbao Wang 3

Abstract

Objective Statins prevent cardiovascular events in patients with coronary artery disease (CAD). However,there is little information regarding the vascular effects of statins on arterial wall stiffness in CAD patients.Methods A total of 36 patients were randomly assigned to receive rosuvastatin (10 mg per day) or simvas-tatin/ezetimibe (10/10 mg per day) for eight weeks. The aim of the present study was to determine the effectsof rosuvastatin or simvastatin/ezetimibe on arterial wall stiffness measured according to the brachial and an-kle pulse wave velocity (baPWV) in CAD patients.Results Both treatments significantly improved the levels of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP) (p

Intern Med 52: 2715-2719, 2013 DOI: 10.2169/internalmedicine.52.0731

2716

Table1.Patients Characteristic

Variables Simvastatin/ezetimibe(n=18)

Rosuvastatin(n=18)

Age(yrs) 6513 6718Male(%) 11(61.1) 10(55.6)Body mass index (kg/m2) 24.33.1 25.13.5Waist circumstance (cm) 96.14.7 96.04.7Total cholesterol (mmol/L) 3.950.2 4.010.17Triglycerides (mmol/L) 1.420.28 1.430.29HDL-C (mmol/L) 1.110.08 1.100.12LDL-C (mmol/L) 2.400.10 2.420.15hsCRP (mg/L) 2.00.38 2.10.35Multi vessel disease, n(%) 9(50) 9(50)Hypertention, n(%) 12(66.7) 11(61.1)Diabetes, n(%) 11(61.1) 12(66.7)Smoking, n(%) 6(33.3) 6(33.3)ROCK activity, % 83.2 86.1baPWV (cm/s) 1769421 1772430HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, hsCRP: high-sensitivity C-reactive protein, baPWV: brachial and ankle pulse wave velocity. No differences were observed among the 2 treatment groups (all p>0.05).

or simvastatin/ezetimibe (10/10 mg per day). Rosuvastatinwas chosen because it has been proven to be the most effec-tive hydrophilic statin in lowering cholesterol (10). Rosuvas-tatin (10 mg/day) and simvastatin/ezetimibe (10/10 mg) areconsidered to equally decrease the LDL-C level (11). A totalof 36 CAD patients with 50% or more stenosis in at leastone major coronary artery were divided into a rosuvastatin(n=18) and simvastatin/ezetimibe (n=18) group at random.Rosuvastatin was administered at a dose of 10 mg/day andsimvastatin/ezetimibe was administered at a dose of 10/10mg/day in order to lower the LDL-C level without the useof any other lipid-lowering drugs. Patients with acute myo-cardial infarction (AMI), spastic angina pectoris, chronicdiseases of the liver or kidney (a serum creatinine level of >2.0 mg/dL or elevation of the alanine transaminase level ex-ceeding three times the upper limit of normal), anemia, neu-rological or endocrine diseases or malignancy were ex-cluded. No subjects had taken any statins before this study.All subjects were advised to continue their current medica-tions and lifestyle for the duration of the study.

Measurement of the lipid profiles, hsCRP levels andROCK activity

Blood samples were collected in citrate-treated tubes twotimes in all patients: 1) immediately before coronary angiog-raphy after an overnight fast and 2) after eight weeks oflipid-lowering treatment. The concentrations of high-sensitivity C-reactive protein (hsCRP) were measured usingan immunoturbidimetric assay on a modular system random-access analyzer (Dade Behring, Deerfield, IL, USA).To evaluate the ROCK activity, the Rho kinase-dependent

phosphorylation of the myosin binding subunit (MBS) atthreonine 853 (phospho-Thr853-MBS) was assayed in pe-ripheral blood leukocytes, as previously described (12). Theblood was collected at room temperature in heparinizedtubes (20 U/mL). The leukocytes were isolated from the pe-ripheral blood samples (15 mL), suspended and diluted, aspreviously described (13). After the proteins were precipi-tated, a Western blot analysis was performed, as previouslydescribed (13). The ROCK activity was expressed as the ra-tio of phospho-Thr853-MBS/total MBS normalized to thepositive controls.

Measurement of baPWV

The patients were examined using a volume plethysmog-raphic instrument (PWV/ABI; Colin Co, Komaki, Japan) inthe morning following an overnight fast at the time of en-rollment and at end of the study. The brachial and anklepulse wave velocity (baPWV) was measured after allowingthe patient to rest in the supine position for 10 minutes in a24-26 air conditioned room. The baPWV was calculatedusing a time-phase analysis of the right brachial artery pres-sure and volume waveforms at both ankles at the beginningof the study, and a repeated analysis was performed on thesame side in each patient during the study (14).

Statistical analysis

All statistical analyses were conducted using the Statisti-cal Package for Social Sciences version 17.0 software pack-age (SPSS Inc., Chicago, IL). The baseline characteristics ofthe two groups were analyzed using Students t-test or theMann-Whitney U test for continuous variables and the chi-square for discrete variables. Paired Students t-test or theWilcoxon test was performed to analyze the effects of the 8-week rosuvastatin or simvastatin/ezetimibe treatment. ThePearson correlation test was used to analyze the correlationbetween changes in baPWV and the other parameters. Thedata were expressed as the mean standard deviation (SD)or median, and p0.05).

Changes in the lipid profiles, hsCRP levels andROCK activity

The patients in both groups had similar lipid profiles andhsCRP levels at randomization (Table 1). Both treatmentsproduced similar reductions in the total cholesterol (TC), tri-glyceride (TG) and LDL-C levels compared to the baselinevalues (both p0.05) (Table 2). Both treatments


2717

Table2.Effects of Treatment on Lipid Profiles, hsCRP, and baPWV

Simvastatin/ezetimibeday0 day56

Rosuvastatinday0 day56

Total cholesterol (mmol/L) 3.950.25 2.200.32* 4.010.17 1.870.28*

Triglycerides (mmol/L) 1.420.28 1.200.22* 1.430.29 1.210.23*

HDL-C (mmol/L) 1.110.08 1.130.08 1.100.12 1.150.10

LDL-C (mmol/L) 2.400.10 1.430.17* 2.420.15 1.330.19*

hsCRP (mg/L) 1.680.38 1.020.28** 1.720.35 0.980.25**

baPWV (cm/s) 1,769421 1,722386 1,772430 1,603398*

HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, hsCRP: high-sensitivity C-reactive protein, baPWV: brachial and ankle pulse wave velocity. *p


2718

ameliorated arterial wall stiffness after eight weeks of treat-ment in correlation with a reduced ROCK activity in the pa-tients with CAD. Although rosuvastatin (10 mg) and simvas-tatin/ezetimibe (10/10 mg) have comparable lipid-loweringeffects, only the rosuvastatin group achieved a significantimprovement in arterial stiffness and inhibition of theROCK activity, compared with that observed in the simvas-tatin/ezetimibe group.Increased arterial stiffness is thought to act as a risk fac-

tor for cardiovascular events via an impaired coronary bloodflow, direct atherogenic actions, increased cardiac afterloadand microvascular damage (17-19). Epidemiologic and clini-cal studies have shown that measuring the PWV is the goldstandard for assessing impaired aortic stiffness, and reduc-ing the PWV levels is potentially beneficial in the manage-ment of patients with CAD (2, 4). BaPWV measurement isa simple and effective tool in clinical practice (20). Thebenefits of statin therapy extend beyond lipid-lowering ef-fects (21). The pleiotropic effects of statins suggest thatthe improvements in outcomes are related as much to theanti-inflammatory actions as to the LDL-C-lowering effectsof the drugs (5). Inflammatory responses in the vascularwall are thought to stiffen the arteries, both functionally andstructurally (22). Considerable evidence suggests that theCRP level is an independent predictor of future cardiovascu-lar events; however, the direct involvement of CRP in athe-rosclerosis remains controversial (21, 23). Data from the1999-2000 National Health and Nutrition Examination Sur-vey (NHANES) indicated that 47.1% of respondents 20years of age or older had a high CRP level (24). Approxi-mately one-third of the population has a CRP level above 3mg/L (25).Studies have demonstrated that ROCK is a critical con-

tributor to many steps of the inflammatory atheroscleroticprocess (6-8). Treatment with the ROCK inhibitor fasudilcauses a decrease in arterial intima medial thickness, maxi-mum flow velocity and macrophage accumulation in athero-sclerotic lesions (26). Statins prevent the synthesis of impor-tant isoprenoid intermediates of the cholesterol biosyntheticpathway that serve as important lipid attachments for theposttranslational modification of small GTPases, such asRho, Ras and Rac (27). By inhibiting mevalonate synthesis,statins prevent the membrane targeting of Rho and its down-stream effector ROCK (27). It is difficult to separate thecholesterol-lowering effects of statins from their pleiotropiceffects. Ezetimibe, which inhibits intestinal cholesterol ab-sorption, was introduced in this study. Treatment withezetimibe combined with a statin did not alter the progres-sion of carotid artery intima-media thickening, despite a fur-ther reduction in the LDL-C and hsCRP levels, comparedwith that achieved with statins alone (28). Despite achievingequivalent reductions in the LDL-C and hsCRP levels withboth treatments, rosuvastatin, not simvastatin/ezetimibe, wasshown to improve arterial wall stiffness and reduce theROCK activity in the present study. Our data also indicatethat the ROCK activity may provide further predictive infor-

mation regarding arterial wall stiffness in patients withCAD. In this study, we found that the hsCRP level is notthe best predictor of vascular stiffness. We also found nosignificant correlations between arterial wall stiffness as-sessed according to the baPWV and aging, obesity, diabetesmellitus, hypertension and lipid profile abnormalities.Several limitations remain in this study. This study was a

single-center study with a small number of patients. A pla-cebo group was not included due to the ethical implicationsof withdrawing statin therapy in patients with CAD. Statinsmay exert their anti-inflammatory effects via the Ras super-family of small GTPases, including Ras, Rac and Cdc-42,which may also play a role in mediating vascular abnormali-ties (29). This study did not assess the effects of rosuvasta-tin on other members of the Ras superfamily. The mecha-nism underlying the improvement of arterial stiffness due tothe inhibition of the ROCK activity by rosuvastatin is in-triguing and requires further study.

Conclusion

This study demonstrates that rosuvastatin inhibits theROCK activity in patients with CAD, independent of cho-lesterol reduction, and that rosuvastatin therapy has signifi-cant vascular benefits, likely due to the suppression of theROCK pathway in the arterial wall.

The authors state that they have no Conflict of Interest (COI).

Ban Liu, Wenliang Che, and Hongwei Yan contributed equallyto this work.

References

1. La Rosa JC, Hunninghake D, Bush D, et al. The cholesterol facts.A summary of the evidence relating dietary fats, serum choles-terol, and coronary heart disease. A joint statement by the Ameri-can Heart Association and the National Heart, Lung, and BloodInstitute. The TaskForce on Cholesterol Issues, American HeartAssociation. Circulation 81: 1721-1733, 1990.

2. Teramoto T, Ohashi Y, Nakaya N, et al. Practical risk predictiontools for coronary heart disease in mild to moderate hypercholes-terolemia in Japan: originated from the MEGA study data. Circ J72: 1569-1575, 2008.

3. Prevention of cardiovascular events and death with pravastatin inpatients with coronary heart disease and a broad range of initialcholesterol levels: the Long-Term Intervention With Pravastatin inIschaemic Disease (LIPID) Study Group. N Engl J Med 339:1349-1357, 1998.

4. MRC/BHF Heart Protection Study of cholesterol lowering withsimvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360: 7-22, 2002.

5. Maron DJ, Fazio S, Linton MF. Current perspectives on statins.Circulation 101: 207-213, 2000.

6. Nunes KP, Rigsby CS, Webb RC. RhoA/Rho-kinase and vasculardiseases: what is the link? Cell Mol Life Sci 67: 3823-3836, 2010.

7. Zhou Q, Gensch C, Liao JK. Rho-associated coiled-coil-formingkinases (ROCKs): potential targets for the treatment of atheroscle-rosis and vascular disease. Trends Pharmacol 32: 167-173, 2011.

8. Dong M, Yan BP, Yu CM. Current status of Rho-associatedkinases (ROCKs) in coronary atherosclerosis and vasospasm. Car-


2719

diovasc Hematol Agents Med Chem 7: 322-330, 2009.9. Mallat Z, Gojova A, Sauzeau V, et al. Rho-associated protein

kinase contributes to early atherosclerotic lesion formation inmice. Circ Res 93: 884-888, 2003.

10. Jones PH, Davidson MH, Stein EA, et al. Comparison of the effi-cacy and safety of rosuvastatin versus atorvastatin, simvastatin,and pravastatin across doses (STELLAR* Trial). Am J Cardiol 92:152-160, 2003.

11. Moutzouri E, Liberopoulos E, Mikhailidis DP, et al. Comparisonof the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance. Int J Clin Pract 65:1141-1148, 2011.

12. Kawano Y, Fukata Y, Oshiro N, et al. Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase invivo. J Cell Biol 147: 1023-1038, 1999.

13. Nohria A, Prsic A, Liu PY, et al. Statins inhibit Rho kinase activ-ity in patients with atherosclerosis. Atherosclerosis 205: 517-521,2009.

14. Imanishi R, Seto S, Toda G, et al. High brachialankle pulse wavevelocity is an independent predictor of the presence of coronaryartery disease in men. Hypertens Res 27: 71-78, 2004.

15. Lunder M, JaniM, Jug B, et al. The effects of low-dose fluvasta-tin and valsartan combination on arterial function: A randomizedclinical trial. Eur J Intern Med 23: 261-266, 2012.

16. Raison J, Rudnichi A, Safar ME. Effects of atorvastatin on aorticpulse wave velocity in patients with hypertension and hypercho-lesterolaemia: a preliminary study. J Hum Hyperten 16: 705-710,2002.

17. McEniery C, Cockcroft J. Does Arterial Stiffness Predict Athero-sclerotic Coronary Events? Adv Cardiol 44: 160-172, 2007.

18. Laurent S, Cockcroft J, Van Bortel L, et al. European Network forNon-invasive Investigation of Large Arteries. Expert consensusdocument on arterial stiffness: Methodological issues and clinicalapplications. Eur Heart J 27: 2588-2605, 2006.

19. ORourke MF, Hashimoto J. Mechanical factors in arterial aging:A clinical perspective. J Am Coll Cardiol 50: 1-13, 2007.

20. Sugawara J, Hayashi K, Yokoi T, et al. Brachial-ankle pulse wavevelocity: An index of central arterial stiffness? J Hum Hypertens19: 401-406, 2005.

21. Liu PY, Liu YW, Lin LJ, et al. Evidence for statin pleiotropy inhumans: differential effects of statins and ezetimibe on rho-associated coiled-coil containing protein kinase activity, endothe-lial function, and inflammation. Circulation 119: 131-138, 2009.

22. Goligorsky MS. Endothelial cell dysfunction: Cant live with it,how to live without it. Am J Physiol Renal Physiol 288: F871-F880, 2005.

23. Kones R. Rosuvastatin, inflammation, C-reactive protein,JUPITER, and primary prevention of cardiovascular disease-a per-spective. Drug Des Devel Ther 4: 383-413, 2010.

24. Ford ES, Giles WH, Myers GL, et al. Population distribution ofhigh-sensitivity C-reactive protein among US men: findings fromnational health and nutrition examination survey 1999-2000. ClinChem 49: 686-690, 2003.

25. Rifai N, Ridker PM. Population distributions of C-reactive proteinin apparently healthy men and women in the United States: impli-cation for clinical interpretation. Clin Chem 49: 666-669, 2003.

26. Wu DJ, Xu JZ, Wu YJ, et al. Effects of fasudil on early athero-sclerotic plaque formation and established lesion progression inapolipoprotein E-knockout mice. Atherosclerosis 207: 68-73,2009.

27. Hall A. G proteins and small GTPases: distant relatives keep intouch. Science 280: 2074-2075, 1998.

28. Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with orwithout ezetimibe in familial hypercholesterolemia. N Engl J Med358: 1431-1443, 2008.

29. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. ArteriosclerThromb Vasc Biol 21: 1712-1719, 2001.

2013 The Japanese Society of Internal Medicinehttp://www.naika.or.jp/imonline/index.html

simvastatin

Documents