Korean Circ J.  2008 Mar;38(3):144-151. 10.4070/kcj.2008.38.3.144.

The Short-term Effect of Atorvastatin on Flow-Mediated Vasodilation, Pulse Wave Velocity and Carotid Intima-Media Thickness in Patients With Moderate Cholesterolemia

• Lee YS
• Kim KS

• KMID: 2225831
• DOI: http://doi.org/10.4070/kcj.2008.38.3.144

Abstract

BACKGROUND AND OBJECTIVES
The mechanism for the improved endothelial function after treatment with statins has been shown to be the increased bioavailability of nitric oxide, which is independent of the cholesterol-lowering effects of statin therapy. The aim of this study was to evaluate the short-term effect on flow-mediated vasodilation (FMD), the pulse wave velocity (PWV) and the carotid intima-media thickness (IMT) of statin treatment, as based on the dose and duration of therapy.
SUBJECTS AND METHODS
We enrolled 51 patients with moderate cholesterolemia (total cholesterol: 200-250 mg/dL). The patients were randomly divided into two groups according to the dose of atorvastatin (10 mg: 27 patients, 40 mg: 24 patients). We measured the FMD of the brachial artery, the carotid-radial PWV, the IMT of both common carotid arteries, the lipid profile and the serum C-reactive protein (CRP) at baseline, one week and eight weeks after statin treatment.
RESULTS
The total cholesterol and low density lipoprotein (LDL) cholesterol levels in both groups were significantly decreased one week and eight weeks later. However, a difference between the groups was only noted at eight weeks. The FMD for both groups was significantly increased at one and eight weeks; however, the difference was not significantly different between the two groups. The carotid-radial PWV of the 40 mg group was decreased at one and eight weeks, and the change of the PWV at eight weeks was significantly different between the two groups. However, the change in the PWV was not correlated with a change in the LDL-cholesterol.
CONCLUSION
Early improvement of the FMD and PWV following statin treatment might be related to the dose and duration of statin therapy and these effects of statin treatment may be independent of lipid lowering.

Keyword

Atherosclerosis; Hydroxymethylglutaryl coenzyme A reductase inhibitors

MeSH Terms

Atherosclerosis
Biological Availability
Brachial Artery
C-Reactive Protein
Carotid Artery, Common
Carotid Intima-Media Thickness
Cholesterol
Heptanoic Acids
Humans
Lipoproteins
Nitric Oxide
Pulse Wave Analysis
Pyrroles
Vasodilation
Atorvastatin Calcium
C-Reactive Protein
Cholesterol
Heptanoic Acids
Lipoproteins
Nitric Oxide
Pyrroles

Figure

• 

  Fig. 1 Changes of the lipid profile and C-reactive protein (CRP) after 10 mg (left panel) and 40 mg (right panel) atorvastatin treatment at one week and eight weeks later. The total cholesterol and low density lipoprotein (LDL) cholesterol were significantly decreased after 10 mg and 40 mg treatment, but not the high density lipoprotein (HDL) cholesterol and CRP. *p<0.05. NS: non-significant.

• 

  Fig. 2 Change of total cholesterol (TC) and low density cholesterol (LDL) one week and eight weeks after atorvastatin medication. The TC and LDL were significantly decreased and this was dependent on the dose of statin medication. *p<0.05.

• 

  Fig. 3 Changes of creatine kinase (CK) and alanine aminotransferase (ALT) after treatment with atorvastatin 10 mg (left panel) and 40 mg (right panel). In the 40 mg treatment group, the ALT was significantly increased over time, although none of the patients exhibited a clinical relevant increase at eight weeks. *p<0.05. NS: non-significant.

• 

  Fig. 4 Changes in flow-medicated dilatation (FMD) of the brachial artery, the carotid-radial pulse wave velocity (PWV) and intima-media thickness (IMT) of both common carotid arteries after atorvastatin 10 mg (left panel) and 40 mg (right panel). The FMD was significantly improved after atorvastatin medication one week and eight weeks later; this improvement was related to the duration of statin medication. The carotid radial PWV was significantly improved after only atorvastatin 40 mg medication at one week and eight weeks, and this improvement was related to dose of the statin medication. However, there was no significant change in the carotid IMT despite atorvastatin medication for eight weeks. *p<0.05. NS: non-significant.

• 

  Fig. 5 Changes of flow-mediated dilatation (FMD) in the brachial artery and carotid radial pulse wave velocity (PWV) one week and eight weeks after atorvastatin treatment. Improvement of the FMD was related to the duration of statin treatment; however, improvement of the carotid radial PWV was related to the statin dose eight weeks later. *p<0.05. NS: non-significant.

• 

  Fig. 6 Relationship between the change of low density lipoprotein (LDL) cholesterol and the change of the carotid radial pulse wave velocity (PWV) and flow-mediated dilatation (FMD) 8 weeks later. The changes of PWV and FMD were not related to those of LDL-cholesterol. Consequently, our findings suggested that the improvements of FMD and PWV were independent of the lipid lowering effect of statin.

Reference

1. Lüscher TF, Barton M. Biology of the endothelium. Clin Cardiol. 1997. 20:11 Suppl 2. II-3-10.

2. Simon A, Gariepy J, Chironi G, Megnien JL, Levenson J. Intima-media thickness: a new tool for diagnosis and treatment of cardiovascular risk. J Hypertens. 2002. 20:159–169.

3. Lee YS, Kim SK, Nam CW, et al. Clinical implication of carotid-radial pulse wave velocity for patients with coronary artery disease. Korean Circ J. 2006. 36:565–572.

4. O'Rourke MF, Mancia G. Arterial stiffness. J Hypertens. 1999. 17:1–4.

5. Park KR, Kim KY, Yoon SM, Bae JH, Seong IW. Correlation between intima-media thickness in carotid artery and the extent of coronary atherosclerosis. Korean Circ J. 2003. 33:401–408.

6. Ray KK, Cannon CP. Intensive statin therapy in acute coronary syndromes: clinical benefits and vascular biology. Curr Opin Lipidol. 2004. 15:637–643.

7. Inoue I, Goto S, Mizotani K, et al. Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of MRNA levels for interleukin-1β, interleukin-6, cyclooxygenase -2, and p22phox by regulation of peroxisome proliferator-activated receptor (PPARα) in primary endothelial cells. Life Sci. 2000. 67:863–876.

8. Laufs U, Wassmann S, Hilgers S, Ribaudo N, Bohm M, Nickenig G. Rapid effects on vascular function after initiation and withdrawal of atorvastatin in healthy, normocholesterolemic men. Am J Cardiol. 2001. 88:1306–1307.

9. Taneva E, Borucki K, Wiens L, et al. Early effects on endothelial function of atorvastatin 40 mg twice daily and its withdrawal. Am J Cardiol. 2006. 97:1002–1006.

10. Lee YS, Kim KS, Hyun DW, et al. The change of arterial stiffness according to dialysis in patients with end-stage renal disease. Korean Circ J. 2004. 34:865–873.

11. Kablak-Ziembicka A, Tracz W, Przewlocki T, Pieniazek P, Sokolowski A, Konieczynska M. Association of increased carotid intima-media thickness with the extent of coronary artery disease. Heart. 2004. 90:1286–1290.

12. Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002. 39:257–265.

13. Edwards JE, Moore RA. Statins in hypercholesterolaemia: a dose-specific meta-analysis of lipid changes in randomised, double blind trials. BMC Fam Pract. 2003. 4:18.

14. Saito Y, Goto Y, Dane A, Strutt K, Raza A. Randomized dose-response study of rosuvasatin in Japanese patients with hypercholesterolemia. J Atheroscler Thromb. 2003. 10:329–336.

15. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004. 350:1495–1504.

16. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004. 292:1307–1316.

17. Tsunekawa T, Hayashi T, Kano H, et al. Cerivastatin, a hydroxymethylglutaryl coenzyme a reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days. Circulation. 2001. 104:376–379.

18. John S, Schneider MP, Delles C, Jacobi J, Schmieder RE. Lipid-independent effects of statins on endothelial function and bioavailability of nitric oxide in hypercholesterolemic patients. Am Heart J. 2005. 149:473.

19. Omori H, Nagashima H, Tsurumi Y, et al. Direct in vivo evidence of a vascular statin: a single dose cerivastatin increases vascular endothelial responsiveness in healthy normocholesterolemic patients. Br J Pharmacol. 2002. 54:395–399.

20. John S, Schlaich M, Langenfeld M, et al. Increased bioavailability of nitric oxide after lipid-lowering therapy in hypercholesterolemic patients: a randomized, placebo-controlled, double-blind study. Circulation. 1998. 98:211–216.

21. Kalinowski L, Dobrucki LW, Brovkovych V, Malinski T. Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin. Circulation. 2002. 105:933–938.

22. Wilkinson IB, Qasem A, McEniery CM, Webb DJ, Avolio AP, Cockcroft JR. Nitric oxide regulates local arterial distensibility in vivo. Circulation. 2002. 105:213–217.

23. Matsuo T, Iwade K, Hirata N, et al. Improvement of arterial stiffness by the antioxidant and anti-inflammatory effects of short-term statin therapy in patients with hypercholesterolemia. Heart Vessels. 2005. 20:8–12.

24. Shige H, Dart A, Nestel P. Simvastatin improves arterial compliance in the lower limb but not in the aorta. Athersoclesosis. 2001. 155:245–250.

25. Simon A, Gariepy J, Chironi G, Megnien JL, Levenson J. Intima-media thickness: a new tool for diagnosis and treatment of cardiovascular risk. J Hypertens. 2002. 20:159–169.

26. Igarashi M, Takeda Y, Mori S, et al. Suppression of neointimal thickening by a newly developed HMG-CoA reductase inhibitor, BAYw6228, and its inhibitory effect on vascular smooth muscle cell growth. Br J Pharmacol. 1997. 120:1172–1178.

27. Reid JA, Wolsley C, Lau LL, et al. The effect of pravastatin on intima media thickness of the carotid artery in patients with normal cholesterol. Eur J Vasc Endovasc Surg. 2005. 30:464–468.

28. Taylor AJ, Kent SM, Flaherty PJ, et al. A randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness (ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol). Circulation. 2002. 106:2055–2060.

29. Kawasaki T, Sasayama S, Yagi S, Asakawa T, Kirai T. Non-invasive assessment of the age related changes in stiffness of major branches of the human arteries. Cardiovasc Res. 1987. 21:678–687.