Direct anti-atherosclerotic therapy preventing intracellular cholesterol retention


The key initiating process in atherogenesis is the subendothelial cholesterol retention, which is both necessary and sufficient to provoke lesion initiation. Retention of cholesterol transported by low density lipoprotien (LDL) in subendothelial cells of arterial wall, is an absolute requirement for lesion development. This allows us to consider intracellular cholesterol retention as a novel target for anti-atherosclerotic therapy. In this case, the target is not the level of blood cholesterol but the level of cholesterol in vascular cells. This review summarizes the results of our basic studies shedding light on the mechanisms of intracellular cholesterol retention. We describe our cellular models to search for anti-atherosclerotic agents and demonstrate the use of these models for the development of anti-atherosclerotic drugs. We use natural products as the basis of anti-atherosclerotic drugs because anti-atherosclerotic therapy should be long-term or even lifelong. Using cellular models and natural products, we have developed an approach to prevent intracellular cholesterol retention in cultured subendothelial aortic cells. We have developed drugs that reduce intracellular cholesterol retention, namely Allicor on the basis of garlic powder, anti-inflammatory drug Inflaminat (calendula, elder, and violet) possessing anti-cytokine activity and phytoestrogen-rich drug Karinat (garlic powder, extract of grape seeds, green tea leaves, hop cones, β-carotene, α-tocopherol, and ascorbic acid). Treatment with Allicor or Inflaminat caused regression of carotid atherosclerosis in asymptomatic men. Karinat prevented the development of new atherosclerotic plaques in postmenopausal women. Thus, the main findings of our basic research have been successfully translated into clinics. As a result, this translation, a novel approach to the development of anti-atherosclerotic therapy, has been established. Our clinical trials have confirmed the suitability of innovative approach and the efficacy of novel drugs developed on the basis our methodology.

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N. Orekhov, A. (2013) Direct anti-atherosclerotic therapy preventing intracellular cholesterol retention. Health, 5, 11-18. doi: 10.4236/health.2013.57A1002.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Williams, K.J. and Tabas, I. (1995) The Response-to-retention hypothesis of early atherogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 15, 551-561. doi:10.1161/01.ATV.15.5.551
[2] Williams, K.J. and Tabas, I. (1998) The response-to-retention hypothesis of atherogenesis reinforced. Current Opinion in Lipidology, 9, 471-474. doi:10.1097/00041433-199810000-00012
[3] Tabas, I., Williams, K.J. and Borén, J. (2007) Subendothelial lipoprotein retention as the initiating process in atherosclerosis: Update and therapeutic implications. Circulation, 116, 1832-1844. doi:10.1161/CIRCULATIONAHA.106.676890
[4] Insull Jr., W. (2009) The pathology of atherosclerosis: Plaque development and plaque responses to medical treatment. The American Journal of Medicine, 122, S3-S14. doi:10.1016/j.amjmed.2008.10.013
[5] Moore, K.J. and Freeman, M.W. (2008) Targeting innate immunity for CV benefit. Drug Discovery Today Therapeutic Strategies, 5, 15-23. doi:10.1016/j.ddstr.2008.05.007
[6] Orekhov, A.N., Tertov, V.V., Kudryashov, S.A. and Smirnov, V.N. (1990) Triggerlike stimulation of cholesterol accumulation and DNA and extracellular matrix synthesis induced by atherogenic serum or low density lipoprotein in cultured cells. Circulation Research, 66, 311-320. doi:10.1161/01.RES.66.2.311
[7] Orekhov, A.N., Tertov, V.V., Pokrovsky, S.N., Iyu, A., Martsenyuk, O.N., Lyakishev, A.A. and Smirnov, V.N. (1988) Blood serum atherogenicity associated with coronary atherosclerosis. evidence for nonlipid factor providing atherogenicity of low-density lipoproteins and an approach to its elimination. Circulation Research, 62, 421-429. doi:10.1161/01.RES.62.3.421
[8] Kruth, H.S. (2011) Receptor-independent fluid-phase pinocytosis mechanisms for induction of foam cell formation with native low-density lipoprotein particles. Current Opinion in Lipidology, 22, 386-393. doi:10.1097/MOL.0b013e32834adadb
[9] Yuan, Y., Li, P. and Ye, J. (2012) Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis. Protein & Cell, 3, 173-181. doi:10.1007/s13238-012-2025-6
[10] Orekhov, A.N., Tertov, V.V., Mukhin, D.N. and Mikhailenko, I.A. (1989) Modification of low density lipoprotein by desialylation causes lipid accumulation in cultured cells. Discovery of desialylated lipoprotein with altered cellular metabolism in the blood of atherosclerotic patients. Biochemical and Biophysical Research Communications, 162, 206-211. doi:10.1016/0006-291X(89)91982-7
[11] Orekhov, A.N., Tertov, V.V. and Mukhin, D.N. (1991) Desialylated low density lipoprotein—Naturally occurring modified lipoprotein with atherogenic potency. Atherosclerosis, 86, 153-161. doi:10.1016/0021-9150(91)90211-K
[12] Tertov, V.V., Sobenin, I.A., Gabbasov, Z.A., Popov, E.G. and Orekhov, A.N. (1989) Lipoprotein aggregation as an essential condition of intracellular lipid accumulation caused by modified low density lipoproteins. Biochemical and Biophysical Research Communications, 163, 489-494. doi:10.1016/0006-291X(89)92163-3
[13] Tertov, V.V., Sobenin, I.A., Tonevitsky, A.G., Orekhov, A.N. and Smirnov, V.N. (1990) Isolation of atherogenic modified (desialylated) low density lipoprotein from blood of atherosclerotic patients: Separation from native lipoprotein by affinity chromatography. Biochemical and Biophysical Research Communications, 167, 1122-1127. doi:10.1016/0006-291X(90)90639-5
[14] Tertov, V.V., Sobenin, I.A., Orekhov, A.N., Jaakkola, O., Solakivi, T. and Nikkari, T. (1996) Characteristics of low density lipoprotein isolated from circulating immune complexes. Atherosclerosis, 122, 191-199. doi:10.1016/0021-9150(95)05737-4
[15] Tertov, V.V., Kaplun, V.V., Sobenin, I.A., Boytsova, E.Y., Bovin, N.V. and Orekhov, A.N. (2001) Human plasma trans-sialidase causes atherogenic modification of low density lipoprotein. Atherosclerosis, 159, 103-115. doi:10.1016/S0021-9150(01)00498-1
[16] Avogaro, P., Bittolo-Bon, G. and Cazzolato, G. (1988) Presence of a modified low density lipoprotein in humans. Arteriosclerosis, 8, 79-87. doi:10.1161/01.ATV.8.1.79
[17] Krauss R.M. and Burke, D.J. (1982) Identification of multiple subclasses of plasma low density lipoproteins in normal humans. Journal of Lipid Research, 23, 97-104.
[18] Tertov, V.V., Bittolo-Bon, G., Sobenin, I.A., Cazzolato, G., Orekhov, A.N. and Avogaro, P. (1995) Naturally occurring modified low density lipoproteins are similar if not identical: More electronegative and desialylated lipoprotein subfractions. Experimental and Molecular Pathology, 62, 166-172. doi:10.1006/exmp.1995.1018
[19] Tertov, V.V., Sobenin, I.A. and Orekhov, A.N. (1996) Similarity between naturally occurring modified desialylated, electronegative and aortic low density lipoprotein. Free Radical Research, 25, 313-319. doi:10.3109/10715769609149054
[20] La Belle, M. and Krauss, R.M. (1990) Differences in carbohydrate content of low density lipoproteins associated with low density lipoprotein subclass patterns. Journal of Lipid Research, 31, 1577-1588.
[21] Kirk, J.K., Davis, S.W., Hildebrandt, C.A., Strachan, E.N., Peechara, M.L. and Lord, R. (2011) Characteristics associated with glycemic control among family medicine patients with type 2 diabetes. North Carolina Medical Journal, 72, 345-350.
[22] Orekhov, A.N., Tertov, V.V., Kabakov, A.E., Iyu, A., Pokrovsky, S.N. and Smirnov, V.N. (1991) Autoantibodies against modified low density lipoprotein. nonlipid factor of blood plasma that stimulates foam cell formation. Arteriosclerosis and Thrombosis, 11, 316-326. doi:10.1161/01.ATV.11.2.316
[23] Orekhov, A.N. and Tertov, V.V. (1991) Atherogenicity of autoantibodies against low density lipoprotein. Agents and Actions, 32, 128-129. doi:10.1007/BF01983338
[24] Lopes-Virella, M.F. and Virella, G. (2010) Clinical significance of the humoral immune response to modified LDL. Clinical Immunology, 134, 55-65. doi:10.1016/j.clim.2009.04.001
[25] Tertov, V.V., Orekhov, A.N., Sayadyan, K.S., Serebrennikov, S.G., Kacharava, A.G., Lyakishev, A.A. and Smirnov, V.N. (1990) Correlation between cholesterol content in circulating immune complexes and atherogenic properties of CHD patients’ serum manifested in cell culture. Atherosclerosis, 81, 183-189. doi:10.1016/0021-9150(90)90065-Q
[26] Kacharava, A.G., Tertov, V.V. and Orekhov, A.N. (1993) Autoantibodies against low-density lipoprotein and atherogenic potential of blood. Annals of Medicine, 25, 551-555.
[27] Tertov, V.V., Orekhov, A.N., Kacharava, A.G., Sobenin, I.A., Perova, N.V. and Smirnov, V.N. (1990) Low density lipoprotein-containing circulating immune complexes and coronary atherosclerosis. Experimental and Molecular Pathology, 52, 300-308. doi:10.1016/0014-4800(90)90071-K
[28] Orekhov, A.N., Kalenich, O.S., Tertov, V.V. and Novikov, I.D. (1991) Lipoprotein immune complexes as markers of atherosclerosis. International Journal of Tissue Reactions, 13, 233-236.
[29] Orekhov, A.N., Kalenich, O.S., Tertov, V.V., Perova, N.V., Novikov, I.D., Lyakishev, A.A., Deev, A.D. and Ruda, M.Y. (1995) Diagnostic value of immune cholesterol as a marker for atherosclerosis. Journal of Cardiovascular Risk, 2, 459-466. doi:10.1097/00043798-199510000-00011
[30] Sobenin, I.A., Karagodin, V.P., Melnichenko, A.A., Bobryshev, Y.V. and Orekhov, A.N. (2013) Diagnostic and prognostic value of low density lipoprotein-containing circulating immune complexes in atherosclerosis. Journal of Clinical Immunology, 33, 489-495. doi:10.1007/s10875-012-9819-4
[31] Sobenin, I.A., Orekhova, V.A., Melnichenko, A., Bobryshev, Y.V. and Orekhov, A.N. (2012) Low density lipoprotein-containing circulating immune complexes have better prognostic value in carotid intima-media thickness progression than other lipid parameters. International Journal of Cardiology, 163, 747-748. doi:10.1016/j.ijcard.2012.09.175
[32] Orekhov, A.N., Tertov, V.V., Mukhin, D.N., Koteliansky, V.E., Glukhova, M.A., Frid, M.G., Sukhova, G.K., Khashimov, K.A. and Smirnov, V.N. (1989) Insolubilization of low density lipoprotein induces cholesterol accumulation in cultured subendothelial cells of human aorta. Atherosclerosis, 79, 59-70. doi:10.1016/0021-9150(89)90034-8
[33] Glukhova, M.A., Kabakov, A.E., Frid, M.G., Ornatsky, O.I., Belkin, A.M., Mukhin, D.N., Orekhov, A.N., Koteliansky, V.E. and Smirnov, V.N. (1988) Modulation of human aorta smooth muscle cell phenotype: A study of muscle-specific variants of vinculin, caldesmon, and actin expression. Proceedings of the National Academy of Sciences of the United States of America, 85, 9542-9546. doi:10.1073/pnas.85.24.9542
[34] Orekhov, A.N., Tertov, V.V., Mukhin, D.N., Koteliansky, V.E., Glukhova, M.A., Khashimov, K.A. and Smirnov, V.N. (1987) Association of low-density lipoprotein with particulate connective tissue matrix components enhances cholesterol accumulation in cultured subendothelial cells of human aorta. Biochimica et Biophysica Acta, 928, 251-258. doi:10.1016/0167-4889(87)90183-2
[35] Melnichenko, A.A., Aksenov, D.V., Myasoedova, V.A., Panasenko, O.M., Yaroslavov, A.A., Sobenin, I.A., Bobryshev, Y.V. and Orekhov, A.N. (2012) Pluronic block copolymers inhibit low density lipoprotein self-association. Lipids, 47, 995-1000. doi:10.1007/s11745-012-3699-5
[36] Tertov, V.V., Orekhov, A.N., Sobenin, I.A., Gabbasov, Z.A., Popov, E.G., Yaroslavov, A.A. and Smirnov, V.N. (1992) Three types of naturally occurring modified lipoproteins induce intracellular lipid accumulation due to lipoprotein aggregation. Circulation Research, 71, 218-228. doi:10.1161/01.RES.71.1.218
[37] Rekhter, M.D., Andreeva, E.R., Mironov, A.A. and Orekhov, A.N. (1991) Three-dimensional cytoarchitecture of normal and atherosclerotic intima of human aorta. American Journal of Pathology, 138, 569-580.
[38] Orekhov, A.N., Andreeva, E.R., Krushinsky, A.V. and Smirnov, V.N. (1984) Primary cultures of enzyme-isolated cells from normal and atherosclerotic human aorta. Medical Biology, 62, 255-259.
[39] Orekhov, A.N., Tertov, V.V., Novikov, I.D., Krushinsky, A.V., Andreeva, E.R., Lankin V.Z. and Smirnov, V.N. (1985) Lipids in cells of atherosclerotic and uninvolved human aorta: I. lipid composition of aortic tissue and enzyme isolated and cultured cells. Experimental and Molecular Pathology, 42, 117-137. doi:10.1016/0014-4800(85)90022-X
[40] Orekhov, A.N., Krushinsky, A.V., Andreeva, E.R., Repin V.S. and Smirnov, V.N. (1986) Adult human aortic cells in primary culture: Heterogeneity in shape. Heart and Vessels, 2, 193-201. doi:10.1007/BF02059968
[41] Yamada, S., Guo, X., Yoshizawa, M., Li, Z., Matsuyama, A., Hashimoto, H. and Sasaguri, Y. (2011) Primary desmoplastic cutaneous leiomyosarcoma associated with high MIB-1 labeling index: A teaching case giving rise to diagnostic difficulties on a small biopsy specimen. Pathology, Research and Practice, 207, 728-732. doi:10.1016/j.prp.2011.08.008
[42] Orekhov, A.N., Kosykh, V.A., Repin, V.S. and Smirnov, V.N. (1983) Cell proliferation in normal and atherosclerotic human aorta. II. Autoradiographic observation on deoxyribonucleic acid synthesis in primary cell culture. Laboratory Investigation, 48, 749-754.
[43] Orekhov, A.N., Tertov, V.V., Kudryashov, S.A., Khashimov, Kh.A. and Smirnov, V.N. (1986) Primary culture of human aortic intima cells as a model for testing anti-atherosclerotic drugs. Effects of cyclic AMP, prostaglandins, calcium antagonists, antioxidants, and lipid-lowering agents. Atherosclerosis, 60, 101-110. doi:10.1016/0021-9150(86)90002-X
[44] Chazov, E.I., Tertov, V.V., Orekhov, A.N., Lyakishev, A.A., Perova, N.V., Kurdanov, Kh.A., Khashimov, Kh.A., Novikov, I.D. and Smirnov, V.N. (1986) Atherogenicity of blood serum from patients with coronary heart disease. Lancet, 2, 595-598. doi:10.1016/S0140-6736(86)92426-8
[45] Tertov, V.V., Orekhov, A.N., Ryong, Li.Hwa. and Smirnov, V.N. (1988) Intracellular cholesterol accumulation is accompanied by enhanced proliferative activity of human aortic intimal cells. Tissue & Cell, 20, 849-854. doi:10.1016/0040-8166(88)90026-2
[46] Tertov, V.V., Orekhov, A.N., Martsenyuk, O.N., Perova, N.V. and Smirnov, V.N. (1989) Low density lipoproteins isolated from the blood of patients with coronary heart disease induce the accumulation of lipids in human aortic cells. Experimental and Molecular Pathology, 50, 337-347. doi:10.1016/0014-4800(89)90043-9
[47] Orekhov, A.N. (1990) In vitro models of antiatherosclerotic effects of cardiovascular drugs. The American Journal of Cardiology, 66, 23I-28I. doi:10.1016/0002-9149(90)91260-D
[48] Palatini, P. (2009) Elevated heart rate in cardiovascular diseases: A target for treatment? Progress in Cardiovascular Diseases, 52, 46-60. doi:10.1016/j.pcad.2009.05.005
[49] Schulman, I.H., Zachariah, M. and Raij, L. (2005) Calcium channel blockers, endothelial dysfunction, and combination therapy. Aging Clinical and Experimental Research, 17, 40-45.
[50] Orekhov, A.N., Baldenkov, G.N., Tertov, V.V., Ryong, Li.Hwa., Kozlov, S.G., Lyakishev, A.A., Tkachuk, V.A., Ruda, M.Ya. and Smirnov, V.N. (1988) Cardiovascular drugs and atherosclerosis: Effects of calcium antagonists, beta-blockers, and nitrates on atherosclerotic characteristics of human aortic cells. Journal of Cardiovascular Pharmacology, 12, S66-S68. doi:10.1097/00005344-198812006-00017
[51] Loaldi, A., Polese, A., Montorsi, P., Cesare, N.De., Fabbiocchi, F., Ravagnani, P. and Guazzi, M.D. (1989) Comparison of nifedipine, propranolol and isosorbide dinitrate on angiographic progression and regression of coronary arterial narrowings in angina pectoris. The American Journal of Cardiology, 64, 433-439. doi:10.1016/0002-9149(89)90417-7
[52] Orekhov, A.N., Baldenkov, G.N., Tertov, V.V., Ruda, M.Ya., Khashimov, Kh.A., Kudryashov, S.A., Li, H.R., Kozlov, S.G., Lyakishev, A.A., Tkachuk V.A. and Smirnov, V.N. (1990) Antiatherosclerotic effects of calcium antagonists. Study in human aortic cell culture. Herz, 15, 139-145.
[53] Orekhov, A.N. and Tertov, V.V. (1997) In vitro effect of garlic powder extract on lipid content in normal and atherosclerotic human aortic cells. Lipids, 32, 1055-1060. doi:10.1007/s11745-997-0136-7
[54] Orekhov, A.N. and Grünwald, J. (1997) Effects of garlic on atherosclerosis. Nutrition, 13, 656-663. doi:10.1016/S0899-9007(97)83010-9
[55] Orekhov, A.N., Sobenin, I.A., Korneev, N.V., Kirichenko, T.V., Myasoedova, V.A., Melnichenko, A.A., Balcells, M., Edelman, E.R. and Bobryshev, Y.V. (2012) Anti-atherosclerotic therapy based on botanicals. Recent Patents on Cardiovascular Drug Discovery.
[56] Koscielny, J., Klüssendorf, D., Latza, R., Schmitt, R., Radtke, H., Siegel, G. and Kiesewetter, H. (1999) The antiatherosclerotic effect of Allium sativum. Atherosclerosis, 144, 237-249. doi:10.1016/S0021-9150(99)00060-X
[57] Crouse 3rd, J.R., Byington, R.P., Bond, M.G., Espeland, M.A., Craven, T.E., Sprinkle, J.W., McGovern, M.E. and Furberg, C.D. (1995) Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II). American Journal of Cardiology, 75, 455-459. doi:10.1016/S0002-9149(99)80580-3
[58] Salonen, R., Nyyssonen, K., Porkkala, E., Rummukainen, J., Belder, R., Park, J.S. and Salonen, J.T. (1995) Kuopio atherosclerosis prevention study (KAPS). A populationbased primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation, 92, 1758-1764. doi:10.1161/01.CIR.92.7.1758
[59] Smilde, T.J., van Wissen, S., Wollersheim, H., Trip, M.D., Kastelein, J. and Stalenhoef, A.F. (2001) Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): A prospective, randomised, double-blind trial. Lancet, 357, 577-581. doi:10.1016/S0140-6736(00)04053-8
[60] Pitt, B., Byington, R.P., Furberg, C.D., Hunninghake, D.B., Mancini, G.B., Miller, M.E. and Riley, W. (2000) Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Prevent investigators. Circulation, 102, 1503-1510. doi:10.1161/01.CIR.102.13.1503
[61] Blankenhorn, D.H., Selzer, R.H., Crawford, D.W., Barth, J.D., Liu, C.R., Liu, C.H., Mack W.J. and Alaupovic, P. (1993) Beneficial effects of colestipol-niacin therapy on the common carotid artery. Two-and four-year reduction of intima-media thickness Measured by ultrasound. Circulation, 88, 20-28. doi:10.1161/01.CIR.88.1.20
[62] Hodis, H.N. (1995) Reversibility of atherosclerosis-evolving perspectives from two arterial imaging clinical trials: The cholesterol lowering atherosclerosis regression study and the monitored atherosclerosis regression study. Journal of Cardiovascular Pharmacology, 25, S25-S31.
[63] Blankenhorn, D.H., Azen, S.P., Kramsch, D.M., Mack, W.J., Cashin-Hemphill, L., Hodis, H.N., DeBoer, L.W., Mahrer, P.R., Masteller, M.J., Vailas, L.I., Alaupovic, P., Hirsch L.J., MARS Research Group (1993) Coronary angiographic changes with lovastatin therapy. The monitored atherosclerosis regression study (MARS). Annals of Internal Medicine, 119, 969-976. doi:10.7326/0003-4819-119-10-199311150-00002
[64] Zanchetti, A., Rosei, E.A., Dal Palù, C., Leonetti, G., Magnani, B. and Pessina, A. (1998) The verapamil in hypertension and atherosclerosis study (VHAS): Results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness. Journal of Hypertension, 16, 1667-1676. doi:10.1097/00004872-199816110-00014
[65] Libby, P. (2006) Inflammation and cardiovascular disease mechanisms. The American Journal of Clinical Nutrition, 83, 456S-460S.
[66] Aidinian, G., Weiswasser, J.M. and Arora, S. (2006) Carotid plaque morphologic characteristics. Perspectives in Vascular Surgery and Endovascular Therapy, 18, 63-70. doi:10.1177/153100350601800124
[67] Daugherty, A., Webb, N.R., Rateri, D.L. and King, V.L. (2005) The immune system and atherogenesis. Cytokine regulation of macrophage functions in atherogenesis. Journal of Lipid Research, 46, 1812-1822. doi:10.1194/jlr.R500009-JLR200
[68] Burger, H.G., Maclennan, A.H., Huang, K.E. and Castelo-Branco, C. (2012) Evidence-based assessment of the impact of the WHI on women’s health. Climacteric, 15, 281-287. doi:10.3109/13697137.2012.655564
[69] de Villiers, T.J. and Stevenson, J.C. (2012) The WHI: The effect of hormone replacement therapy on fracture prevention. Climacteric, 15, 263-266. doi:10.3109/13697137.2012.659975
[70] Ellis, M.J., Suman, V.J., Hoog, J., Lin, L., Snider, J., Prat, A., Parker, J.S., Luo, J., DeSchryver, K., Allred, D.C., Esserman, L.J., Unzeitig, G.W., Margenthaler, J., Babiera, G.V., Marcom, P.K., Guenther, J.M., Watson, M.A., Leitch, M., Hunt, K. and Olson, J.A. (2011) Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: Clinical and biomarker outcomes and predictive value of the baseline pam50-based intrinsic subtype-ACOSOG Z1031. Journal of Clinical Oncology, 29, 2342-2349. doi:10.1200/JCO.2010.31.6950
[71] Smith, N.L., Wiley, J.R., Legault, C., Rice, K.M., Heckbert, S.R., Psaty, B.M., Tracy, R.P. and Cushman, M. (2008) Effect of progestogen and progestogen type on hemostasis measures in postmenopausal women: The postmenopausal estrogen/progestin intervention (pepi) study. Menopause, 15, 1145-1150. doi:10.1097/gme.0b013e3181775eca
[72] Masood, D.E., Roach, E.C., Beauregard, K.G. and Khalil, R.A. (2010) Impact of sex hormone metabolism on the vascular effects of menopausal hormone therapy in cardiovascular disease. Current Drug Metabolism, 11, 693-714. doi:10.2174/138920010794233477
[73] Pellegrini, C.N., Vittinghoff, E., Lin, F., Hulley, S.B. and Marcus, G.M. (2009) Statin use is associated with lower risk of atrial fibrillation in women with coronary disease: The HERS trial. Heart, 95, 704-708. doi:10.1136/hrt.2008.154054
[74] Slevin, M., Ahmed, N., Wang, Q., McDowell, G. and Badimon, L. (2012) Unique vascular protective properties of natural products: Supplements or future main-line drugs with significant anti-atherosclerotic potential?. Vascular Cell, 4, 9. doi:10.1186/2045-824X-4-9

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