Effects of Statin Therapy on Endothelial Function in Asymptomatic Metabolic Syndrome

Boochi Babu Mannuva, Rajasekhar Durgaprasad, Vanajakshamma Velam, Vinod Kumar Mustyala, Latheef Kasala, Ashok Thakkar

Department of Cardiology, Sri Venkateswara Institute of Medical Sciences (SVIMS), Tirupati, India.
Department of Clinical Trials, Sahjanand Medical Technologies Pvt Ltd, Surat, India.

DOI: 10.4236/ijcm.2014.54026                

Abstract

Context: Endothelial dysfunction is an early predictor of adverse cardiovascular events. The present study evaluated asymptomatic metabolic syndrome (MS) patients with brachial artery endothelial dysfunction to determine whether a reversal of endothelial dysfunction occurs with statin treatment. Aim: To evaluate the short term effects of statins on endothelial function in asymptomatic metabolic syndrome patients. Methodology: This was a prospective, single centre, case-control study. We evaluated 50 recently diagnosed newly detected asymptomatic MS patients who underwent an assessment of endothelial function by brachial artery flow-mediated dilation (FMD) before and after treatment with 40 mg atorvastatin for one week. Results: A total of 50 MS patients, including 36 (62%) females and 14 (38%) males, were included in the study. The mean age of the patients was 49.70 ± 8.84 y. We identified a significant difference between cases and age- and sex-matched controls regarding baseline brachial artery FMD% (6.73 ± 2.55 vs. 11.03 ± 1.85, respectively; p < 0.001). Significant negative correlations were detected between FMD% and HDL-cholesterol (r = -0.34, p = 0.01), fasting blood sugar (r = -0.40, p = 0.004), and systolic blood pressure (r = -0.34, p = 0.015). Multiple linear regression analysis indicated that HDL-cholesterol was an independently associated factor for FMD. MS patients treated with 40 mg atorvastatin for one week showed a significant improvement in brachial artery FMD% (6.73 ± 2.55 before treatment vs. 10.19 ± 3.01 after treatment, p < 0.001). Conclusions: MS is associated with endothelial dysfunction and decreased brachial artery FMD compared with controls. Statin treatment for one week significantly improved brachial artery endothelial function in MS patients.

Keywords

Metabolic Syndrome; Endothelial Dysfunction; Flow-Mediated Dilation; Brachial Artery; Statin

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	“Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III),” JAMA, Vol. 285, No. 19, 2001, pp. 2486-2497. http://dx.doi.org/10.1001/jama.285.19.2486
[2]	S. M. Grundy, H. B. Brewer Jr., J. I. Cleeman, S. C. Smith Jr. and C. Lenfant, “Definition of Metabolic Syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition,” Circulation, Vol. 109, No. 3, 2004, pp. 433-438. http://dx.doi.org/10.1161/01.CIR.0000111245.75752.C6
[3]	B. Isomaa, P. Almgren, T. Tuomi, B. Forsen, K. Lahti, M. Nissen, M. R. Taskinen and L. Groop, “Cardiovascular Morbidity and Mortality Associated with the Metabolic Syndrome,” Diabetes Care, Vol. 24, No. 4, 2001, pp. 683-689. http://dx.doi.org/10.2337/diacare.24.4.683
[4]	D. S. Celermajer, K. E. Sorensen, V. M. Gooch, D. J. Spiegelhalter, O. I. Miller, I. D. Sullivan, J. K. Lloyd and J. E. Deanfield, “Non-Invasive Detection of Endothelial Dysfunction in Children and Adults at Risk of Atherosclerosis,” Lancet, Vol. 340, No. 8828, 1992, pp. 1111-1115. http://dx.doi.org/10.1016/0140-6736(92)93147-F
[5]	K. G. Reddy, R. N. Nair, H. M. Sheehan and J. M. Hodgson, “Evidence That Selective Endothelial Dysfunction May Occur in the Absence of Angiographic or Ultrasound Atherosclerosis in Patients with Risk Factors for Atherosclerosis,” Journal of the American College of Cardiology, Vol. 23, No. 4, 1994, pp. 833-843. http://dx.doi.org/10.1016/0735-1097(94)90627-0
[6]	M. E. Widlansky, N. Gokce, J. F. Keaney Jr. and J. A. Vita, “The Clinical Implications of Endothelial Dysfunction,” Journal of the American College of Cardiology, Vol. 42, No. 7, 2003, pp. 1149-1160. http://dx.doi.org/10.1016/S0735-1097(03)00994-X
[7]	D. S. Celermajer, “Endothelial Dysfunction: Does It Matter? Is It Reversible?” Journal of the American College of Cardiology, Vol. 30, No. 2, 1997, pp. 325-333. http://dx.doi.org/10.1016/S0735-1097(97)00189-7
[8]	E. J. Benjamin, M. G. Larson, M. J. Keyes, G. F. Mitchell, R. S. Vasan, J. F. Keaney Jr., B. T. Lehman, S. Fan, E. Osypiuk and J. A. Vita, “Clinical Correlates and Heritability of Flow-Mediated Dilation in the Community: The Framingham Heart Study,” Circulation, Vol. 109, No. 5, 2004, pp. 613-619. http://dx.doi.org/10.1161/01.CIR.0000112565.60887.1E
[9]	C. J. Rodriguez, Y. Miyake, C. Grahame-Clarke, M. R. Di Tullio, R. R. Sciacca, B. Boden-Albala, R. L. Sacco and S. Homma, “Relation of Plasma Glucose and Endothelial Function in a Population-Based Multiethnic Sample of Subjects without Diabetes Mellitus,” American Journal of Cardiology, Vol. 96, No. 9, 2005, pp. 1273-1277. http://dx.doi.org/10.1016/j.amjcard.2005.06.070
[10]	J. T. Kuvin, A. R. Patel, M. Sidhu, W. M. Rand, K. A. Sliney, N. G. Pandian and R. H. Karas, “Relation between High-Density Lipoprotein Cholesterol and Peripheral Vasomotor Function,” American Journal of Cardiology, Vol. 92, No. 3, 2003, pp. 275-279. http://dx.doi.org/10.1016/S0002-9149(03)00623-4
[11]	R. D. Brook, R. L. Bard, M. Rubenfire, P. M. Ridker and S. Rajagopalan, “Usefulness of Visceral Obesity (Waist/ Hip Ratio) in Predicting Vascular Endothelial Function in Healthy Overweight Adults,” American Journal of Cardiology, Vol. 88, No. 11, 2001, pp. 1264-1269. http://dx.doi.org/10.1016/S0002-9149(01)02088-4
[12]	J. A. Suwaidi, S. Hamasaki, S. T. Higano, R. A. Nishimura, D. R. Holmes Jr. and A. Lerman, “Long-Term Follow-Up of Patients with Mild Coronary Artery Disease and Endothelial Dysfunction,” Circulation, Vol. 101, No. 9, 2000, pp. 948-954. http://dx.doi.org/10.1161/01.CIR.101.9.948
[13]	V. Schachinger, M. B. Britten and A. M. Zeiher, “Prognostic Impact of Coronary Vasodilator Dysfunction on Adverse Long-Term Outcome of Coronary Heart Disease,” Circulation, Vol. 101, No. 16, 2000, pp. 1899-1906. http://dx.doi.org/10.1161/01.CIR.101.16.1899
[14]	J. P. Halcox, W. H. Schenke, G. Zalos, R. Mincemoyer, A. Prasad, M. A. Waclawiw, K. R. Nour and A. A. Quyyumi, “Prognostic Value of Coronary Vascular Endothelial Dysfunction,” Circulation, Vol. 106, No. 6, 2002, pp. 653-658. http://dx.doi.org/10.1161/01.CIR.0000025404.78001.D8
[15]	F. Perticone, R. Ceravolo, A. Pujia, G. Ventura, S. Iacopino, A. Scozzafava, A. Ferraro, M. Chello, P. Mastroroberto, P. Verdecchia and G. Schillaci, “Prognostic Significance of Endothelial Dysfunction in Hypertensive Patients,” Circulation, Vol. 104, No. 2, 2001, pp. 191-196. http://dx.doi.org/10.1161/01.CIR.104.2.191
[16]	M. C. Corretti, T. J. Anderson, E. J. Benjamin, D. Celermajer, F. Charbonneau, M. A. Creager, J. Deanfield, H. Drexler, M. Gerhard-Herman, D. Herrington, P. Vallance, J. Vita and R. Vogel, “Guidelines for the Ultrasound Assessment of Endothelial-Dependent Flow-Mediated Vasodilation of the Brachial Artery: A Report of the International Brachial Artery Reactivity Task Force,” Journal of the American College of Cardiology, Vol. 39, No. 2, 2002, pp. 257-265. http://dx.doi.org/10.1016/S0735-1097(01)01746-6
[17]	N. Gokce, J. F. Keaney Jr., L. M. Hunter, M. T. Watkins, Z. S. Nedeljkovic, J. O. Menzoian and J. A. Vita, “Predictive Value of Noninvasively Determined Endothelial Dysfunction for Long-Term Cardiovascular Events in Patients with Peripheral Vascular Disease,” Journal of the American College of Cardiology, Vol. 41, No. 10, 2003, pp. 1769-1775. http://dx.doi.org/10.1016/S0735-1097(03)00333-4
[18]	J. A. Vita and J. F. Keaney Jr., “Endothelial Function: A Barometer for Cardiovascular Risk?” Circulation, Vol. 106, No. 6, 2002, pp. 640-642. http://dx.doi.org/10.1161/01.CIR.0000028581.07992.56
[19]	“Randomised Trial of Cholesterol Lowering in 4444 Patients with Coronary Heart Disease: The Scandinavian Simvastatin Survival Study (4S),” Lancet, Vol. 344, No. 8934, 1994, pp. 1383-1389.
[20]	“Influence of Pravastatin and Plasma Lipids on Clinical Events in the West of Scotland Coronary Prevention Study (WOSCOPS),” Circulation, Vol. 97, No. 15, 1998, pp. 1440-1445. http://dx.doi.org/10.1161/01.CIR.97.15.1440
[21]	F. M. Sacks, M. A. Pfeffer, L. A. Moye, J. L. Rouleau, J. D. Rutherford, T. G. Cole, L. Brown, J. W. Warnica, J. M. Arnold, C. C. Wun, B. R. Davis and E. Braunwald, “The Effect of Pravastatin on Coronary Events after Myocardial Infarction in Patients with Average Cholesterol Levels. Cholesterol and Recurrent Events Trial Investigators,” The New England Journal of Medicine, Vol. 335, No. 14, 1996, pp. 1001-1009. http://dx.doi.org/10.1056/NEJM199610033351401
[22]	G. O’Driscoll, D. Green and R. R. Taylor, “Simvastatin, an HMG-Coenzyme A Reductase Inhibitor, Improves Endothelial Function within 1 Month,” Circulation, Vol. 95, No. 5, 1997, pp. 1126-1131. http://dx.doi.org/10.1161/01.CIR.95.5.1126
[23]	K. Iida, S. Goland, T. Akima, H. Luo, Y. Birnbaum and R. J. Siegel, “Effect of a Single 20-mg Tablet of Atorvastatin on Brachial Artery Blood Flow in Normolipidemic Male Smokers versus Nonsmokers,” American Journal of Cardiology, Vol. 100, No. 5, 2007, pp. 881-884. http://dx.doi.org/10.1016/j.amjcard.2007.04.021
[24]	E. Taneva, K. Borucki, L. Wiens, R. Makarova, C. SchmidtLucke, C. Luley and S. Westphal, “Early Effects on Endothelial Function of Atorvastatin 40 mg Twice Daily and Its Withdrawal,” American Journal of Cardiology, Vol. 97, No. 7, 2006, pp. 1002-1006. http://dx.doi.org/10.1016/j.amjcard.2005.10.032
[25]	T. Tsunekawa, T. Hayashi, H. Kano, D. Sumi, H. Matsui-Hirai, N. K. Thakur, K. Egashira and A. Iguchi, “Cerivastatin, a Hydroxymethylglutaryl Coenzyme a Reductase Inhibitor, Improves Endothelial Function in Elderly Diabetic Patients within 3 Days,” Circulation, Vol. 104, No. 4, 2001, pp. 376-379. http://dx.doi.org/10.1161/hc2901.094094
[26]	E. Karatzis, J. Lekakis, C. Papamichael, I. Andreadou, A. Cimponeriu, K. Aznaouridis, T. G. Papaioannou, A. Protogerou and M. Mavrikakis, “Rapid Effect of Pravastatin on Endothelial Function and Lipid Peroxidation in Unstable Angina,” International Journal of Cardiology, Vol. 101, No. 1, 2005, pp. 65-70. http://dx.doi.org/10.1016/j.ijcard.2004.03.060
[27]	H. Omori, H. Nagashima, Y. Tsurumi, A. Takagi, N. Ishizuka, N. Hagiwara, M. Kawana and H. Kasanuki, “Direct in Vivo Evidence of a Vascular Statin: A Single Dose of Cerivastatin Rapidly Increases Vascular Endothelial Responsiveness in Healthy Normocholesterolaemic Subjects,” British Journal of Clinical Pharmacology, Vol. 54, No. 4, 2002, pp. 395-399. http://dx.doi.org/10.1046/j.1365-2125.2002.01677.x
[28]	A. V. Chobanian, G. L. Bakris, H. R. Black, W. C. Cushman, L. A. Green, J. L. Izzo Jr., D. W. Jones, B. J. Materson, S. Oparil, J. T. Wright Jr. and E. J. Roccella, “The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report,” JAMA, Vol. 289, No. 19, 2003, pp. 2560-2572. http://dx.doi.org/10.1001/jama.289.19.2560
[29]	W. T. Friedewald, R. I. Levy and D. S. Fredrickson, “Estimation of the Concentration of Low-Density Lipoprotein Cholesterol in Plasma, without Use of the Preparative Ultracentrifuge,” Clinical Chemistry, Vol. 18, No. 6, 1972, pp. 499-502.
[30]	American Diabetes Association, “Diagnosis and Classification of Diabetes Mellitus,” Diabetes Care, Vol. 30, No. 1, pp. S42-S47. http://dx.doi.org/10.2337/dc07-S042
[31]	N. Sattar, A. Gaw, O. Scherbakova, I. Ford, D. S. O’Reilly, S. M. Haffner, C. Isles, P. W. Macfarlane, C. J. Packard, S. M. Cobbe and J. Shepherd, “Metabolic Syndrome with and without C-Reactive Protein as a Predictor of Coronary Heart Disease and Diabetes in the West of Scotland Coronary Prevention Study,” Circulation, Vol. 108, No. 4, 2003, pp. 414-419. http://dx.doi.org/10.1161/01.CIR.0000080897.52664.94
[32]	H. M. Lakka, D. E. Laaksonen, T. A. Lakka, L. K. Niskanen, E. Kumpusalo, J. Tuomilehto and J. T. Salonen, “The Metabolic Syndrome and Total and Cardiovascular Disease Mortality in Middle-Aged Men,” JAMA, Vol. 288, No. 21, 2002, pp. 2709-2716. http://dx.doi.org/10.1001/jama.288.21.2709
[33]	P. Libby, “Current Concepts of the Pathogenesis of the Acute Coronary Syndromes,” Circulation, Vol. 104, No. 3, 2001, pp. 365-372. http://dx.doi.org/10.1161/01.CIR.104.3.365
[34]	K. Egashira, Y. Hirooka, H. Kai, M. Sugimachi, S. Suzuki, T. Inou and A. Takeshita, “Reduction in Serum Cholesterol with Pravastatin Improves Endothelium-Dependent Coronary Vasomotion in Patients with Hypercholesterolemia,” Circulation, Vol. 89, No. 6, 1994, pp. 2519-2524. http://dx.doi.org/10.1161/01.CIR.89.6.2519
[35]	N. Gokce, J. F. Keaney Jr., L. M. Hunter, M. T. Watkins, J. O. Menzoian and J. A. Vita, “Risk Stratification for Postoperative Cardiovascular Events via Noninvasive Assessment of Endothelial Function: A Prospective Study,” Circulation, Vol. 105, No. 13, 2002, pp. 1567-1572. http://dx.doi.org/10.1161/01.CIR.0000012543.55874.47
[36]	G. Brevetti, A. Silvestro, V. Schiano and M. Chiariello, “Endothelial Dysfunction and Cardiovascular Risk Prediction in Peripheral Arterial Disease: Additive Value of Flow-Mediated Dilation to Ankle-Brachial Pressure Index,” Circulation, Vol. 108, No. 17, 2003, pp. 2093-2098. http://dx.doi.org/10.1161/01.CIR.0000095273.92468.D9
[37]	D. Shimbo, C. Grahame-Clarke, Y. Miyake, C. Rodriguez, R. Sciacca, M. Di Tullio, B. Boden-Albala, R. Sacco and S. Homma, “The Association between Endothelial Dysfunction and Cardiovascular Outcomes in a PopulationBased Multi-Ethnic Cohort,” Atherosclerosis, Vol. 192, No. 1, 2007, pp. 197-203. http://dx.doi.org/10.1016/j.atherosclerosis.2006.05.005
[38]	M. Frick, A. Suessenbacher, H. F. Alber, W. Dichtl, H. Ulmer, O. Pachinger and F. Weidinger, “Prognostic Value of Brachial Artery Endothelial Function and Wall Thickness,” Journal of the American College of Cardiology, Vol. 46, No. 6, 2005, pp. 1006-1010. http://dx.doi.org/10.1016/j.jacc.2005.05.070
[39]	S. Y. Chan, G. B. Mancini, L. Kuramoto, M. Schulzer, J. Frohlich and A. Ignaszewski, “The Prognostic Importance of Endothelial Dysfunction and Carotid Atheroma Burden in Patients with Coronary Artery Disease,” Journal of the American College of Cardiology, Vol. 42, No. 6, 2003, pp. 1037-1043. http://dx.doi.org/10.1016/S0735-1097(03)00927-6
[40]	T. D. Wang, W. J. Chen, J. W. Lin, M. F. Chen and Y. T. Lee, “Effects of Rosiglitazone on Endothelial Function, C-Reactive Protein, and Components of the Metabolic Syndrome in Nondiabetic Patients with the Metabolic Syndrome,” American Journal of Cardiology, Vol. 93, No. 3, 2004, pp. 362-365. http://dx.doi.org/10.1016/j.amjcard.2003.10.022
[41]	R. D. Brook, R. L. Bard, M. Rubenfire, P. M. Ridker and S. Rajagopalan, “Usefulness of Visceral Obesity (Waist/ Hip Ratio) in Predicting Vascular Endothelial Function in Healthy Overweight Adults,” American Journal of Cardiology, Vol. 88, No. 11, 2001, pp. 1264-1269. http://dx.doi.org/10.1016/S0002-9149(01)02088-4
[42]	L. Lind, “Endothelium-Dependent Vasodilation, Insulin Resistance and the Metabolic Syndrome in an Elderly Cohort: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study,” Atherosclerosis, Vol. 196, No. 2, 2008, pp. 795-802. http://dx.doi.org/10.1016/j.atherosclerosis.2007.01.014
[43]	A. Lteif, K. Han and K. J. Mather, “Obesity, Insulin Resistance, and the Metabolic Syndrome: Determinants of Endothelial Dysfunction in Whites and Blacks,” Circulation, Vol. 112, No. 1, 2005, pp. 32-38. http://dx.doi.org/10.1161/CIRCULATIONAHA.104.520130
[44]	G. Dell’Omo, G. Penno, L. Pucci, M. Mariani, S. Del Prato and R. Pedrinelli, “Abnormal Capillary Permeability and Endothelial Dysfunction in Hypertension with Comorbid Metabolic Syndrome,” Atherosclerosis, Vol. 172, No. 2, 2004, pp. 383-389. http://dx.doi.org/10.1016/j.atherosclerosis.2003.11.013
[45]	N. M. Hamburg, M. G. Larson, J. A. Vita, R. S. Vasan, M. J. Keyes, M. E. Widlansky, C. S. Fox, G. F. Mitchell, D. Levy, J. B. Meigs and E. J. Benjamin, “Metabolic Syndrome, Insulin Resistance, and Brachial Artery Vasodilator Function in Framingham Offspring Participants without Clinical Evidence of Cardiovascular Disease,” American Journal of Cardiology, Vol. 101, No. 1, 2008, pp. 82-88. http://dx.doi.org/10.1016/j.amjcard.2007.07.053
[46]	N. Melikian, P. Chowienczyk, P. A. MacCarthy, I. L. Williams, S. B. Wheatcroft, R. Sherwood, C. Gale, A. M. Shah and M. T. Kearney, “Determinants of Endothelial Function in Asymptomatic Subjects with and without the Metabolic Syndrome,” Atherosclerosis, Vol. 197, No. 1, 2008, pp. 375-382. http://dx.doi.org/10.1016/j.atherosclerosis.2007.06.009
[47]	C. Mineo, H. Deguchi, J. H. Griffin and P. W. Shaul, “Endothelial and Antithrombotic Actions of HDL,” Circulation Research, Vol. 98, No. 11, 2006, pp. 1352-1364. http://dx.doi.org/10.1161/01.RES.0000225982.01988.93
[48]	I. S. Yuhanna, Y. Zhu, B. E. Cox, L. D. Hahner, S. Osborne-Lawrence, P. Lu, Y. L. Marcel, R. G. Anderson, M. E. Mendelsohn, H. H. Hobbs and P. W. Shaul, “High-Density Lipoprotein Binding to Scavenger Receptor-BI Activates Endothelial Nitric Oxide Synthase,” Nature Medicine, Vol. 7, No. 7, 2001, pp. 853-857. http://dx.doi.org/10.1038/89986
[49]	Z. Ou, J. Ou, A. W. Ackerman, K. T. Oldham and K. A. Pritchard Jr., “L-4F, an Apolipoprotein A-1 Mimetic, Restores Nitric Oxide and Superoxide Anion Balance in Low-Density Lipoprotein-Treated Endothelial Cells,” Circulation, Vol. 107, No. 11, 2003, pp. 1520-1524. http://dx.doi.org/10.1161/01.CIR.0000061949.17174.B6
[50]	J. Ou, J. Wang, H. Xu, Z. Ou, M. G. Sorci-Thomas, D. W. Jones, P. Signorino, J. C. Densmore, S. Kaul, K. T. Oldham and K. A. Pritchard Jr., “Effects of D-4F on Vasodilation and Vessel Wall Thickness in Hypercholesterolemic LDL Receptor-Null and LDL Receptor/Apolipoprotein A-I Double-Knockout Mice on Western Diet,” Circulation Research, Vol. 97, No. 11, 2005, pp. 1190-1197. http://dx.doi.org/10.1161/01.RES.0000190634.60042.cb
[51]	T. Kimura, K. Sato, E. Malchinkhuu, H. Tomura, K. Tamama, A. Kuwabara, M. Murakami and F. Okajima, “High-Density Lipoprotein Stimulates Endothelial Cell Migration and Survival through Sphingosine 1-Phosphate and Its Receptors,” Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 23, No. 7, 2003, pp. 1283-1288. http://dx.doi.org/10.1161/01.ATV.0000079011.67194.5A
[52]	J. R. Nofer, B. Levkau, I. Wolinska, R. Junker, M. Fobker, A. von Eckardstein, U. Seedorf and G. Assmann, “Suppression of Endothelial Cell Apoptosis by High Density Lipoproteins (HDL) and HDL-Associated Lysosphingolipids,” The Journal of Biological Chemistry, Vol. 276, No. 37, 2001, pp. 34480-34485. http://dx.doi.org/10.1074/jbc.M103782200
[53]	T. J. Anderson, I. T. Meredith, A. C. Yeung, B. Frei, A. P. Selwyn and P. Ganz, “The Effect of Cholesterol-Lowering and Antioxidant Therapy on Endothelium-Dependent Coronary Vasomotion,” The New England Journal of Medicine, Vol. 332, No. 8, 1995, pp. 488-493. http://dx.doi.org/10.1056/NEJM199502233320802
[54]	C. B. Treasure, J. L. Klein, W. S. Weintraub, J. D. Talley, M. E. Stillabower, A. S. Kosinski, J. Zhang, S. J. Boccuzzi, J. C. Cedarholm and R. W. Alexander, “Beneficial Effects of Cholesterol-Lowering Therapy on the Coronary Endothelium in Patients with Coronary Artery Disease,” The New England Journal of Medicine, Vol. 332, No. 8, 1995, pp. 481-487. http://dx.doi.org/10.1056/NEJM199502233320801
[55]	J. A. Beckman and M. A. Creager, “The Nonlipid Effects of Statins on Endothelial Function,” Trends in Cardiovascular Medicine, Vol. 16, No. 5, 2006, pp. 156-162. http://dx.doi.org/10.1016/j.tcm.2006.03.003
[56]	J. A. Beckman, J. K. Liao, S. Hurley, L. A. Garrett, D. Chui, D. Mitra and M. A. Creager, “Atorvastatin Restores Endothelial Function in Normocholesterolemic Smokers Independent of Changes in Low-Density Lipoprotein,” Circulation Research, Vol. 95, No. 2, 2004, pp. 217-223. http://dx.doi.org/10.1161/01.RES.0000134628.96682.9b