Journal of Postgraduate Medicine
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Year : 2010  |  Volume : 56  |  Issue : 4  |  Page : 328-331  

Selective estrogen receptor modulators promising for cardiac syndrome X

YX Chen, NS Luo, YQ Lin, WL Yuan, SL Xie, RQ Nie, JF Wang 
 Department of Cardiology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, Guangdong, China

Correspondence Address:
J F Wang
Department of Cardiology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, Guangdong
China

Abstract

Cardiac syndrome X (CSX) is defined as a typical anginal-like chest pain with a transient ischemic electrocardiogram, but without abnormal coronary angiography. It is usually accepted that endothelial dysfunction, inflammation, oxidative stress and estrogen deficiency are the main reasons of CSX. There are some methods to treat CSX including statins, b blocker, angiotensin converting enzyme inhibitors, nitrates, estrogen, and so on. The estrogen replacement therapy (ERT), in particular, has been reported by many researchers to significantly reduce the frequency of chest pain after administration of estrogen, which has been explained as estrogen acting on its receptor to improve the endothelial function. However, it has been suggested that ERT must not be used for coronary heart disease due to its adverse effects. However, some selective estrogen receptor modulators (SERMs) can inhibit inflammatory response as well as oxidative stress, and improve the endothelial function, to reduce the occurrence of chest pain. Here, we hypothesize that SERMs may be the beneficial selection for patients with CSX.



How to cite this article:
Chen Y X, Luo N S, Lin Y Q, Yuan W L, Xie S L, Nie R Q, Wang J F. Selective estrogen receptor modulators promising for cardiac syndrome X.J Postgrad Med 2010;56:328-331


How to cite this URL:
Chen Y X, Luo N S, Lin Y Q, Yuan W L, Xie S L, Nie R Q, Wang J F. Selective estrogen receptor modulators promising for cardiac syndrome X. J Postgrad Med [serial online] 2010 [cited 2019 Dec 14 ];56:328-331
Available from: http://www.jpgmonline.com/text.asp?2010/56/4/328/70936


Full Text

 Introduction



Cardiovascular disease, presently a rapidly expanding disease, is not only the leading cause of death, disability, and healthcare expense in developed countries, but also the leading cause of death worldwide: of which coronary artery disease (CAD) is the most frequent and atherosclerosis constitutes the single most important contributor to CAD.

Cardiac syndrome X (CSX) is a clinical entity characterized by typical exercise induced angina pectoris, transient ischemic ST segment depression in electrocardiogram (ECG) during exercise, or at rest, and angiographically normal coronary arteries. Although this phenomenon was recognized for more than 40 years, [1] the mediators and pathogenesis of CSX remain unclear. Currently, endothelial dysfunction, inflammation, and estrogen deficiency are usually accepted as the main etiological factors. [2],[3],[4]

The phenomenon is not infrequent at clinics, especially in some menopausal women. Despite the good prognosis, the chronic, frequent nature of persistent chest discomfort can significantly impair the quality of life of the patients and represent a substantial cost burden to the health care system. Abundant evidences that postmenopausal women represent the prevailing group among CSX patients suggest that estrogen deficiency plays a pathogenic role. Estrogen was reported to improve endothelial function by attenuating recruitment and adhesion of leukocytes to exert an anti-inflammatory effect, [5],[6] and reduce the frequency of chest pain of patients with CSX. [7],[8],[9] Therefore, estrogen replacement therapy has been a very popular method for treatment of CSX, but replacement therapy increases the risk of cardiovascular disease and breast cancer. Hence, although hormonal replacement therapy has the potential to confer cardiovascular protection, it can also cause cardiovascular harm, [10] which made estrogen replacement therapy become stagnant.

The selective estrogen receptor modulator (SERMs), a routine drug for patients with breast cancer, is capable of binding to estrogen receptors (ER) to induce an alternative, specific profile. Due to their different molecular structures, SERMs generate ligand receptor complexes with a three dimensional conformation capable of activating cell functions, with a profile distinct from estrogens. This is the basis for the traditional concept of SERMs as agonist alternatives to estrogens. Analysis from MORE (Multiple Outcomes of Raloxifene Evaluation) trial and CORE (Continuing Outcomes Relevant to Evista) trial demonstrated that the eight year incidence of serious cardiovascular adverse events did not differ significantly between the raloxifene (5.5%) and placebo (4.7%) groups, and there was no difference in the incidence of stroke, uterine cancer, endometrial hyperplasia, ovarian cancer or postmenopausal bleeding between the raloxifene and placebo treatment groups, [11],[12] which meant that the particular agonistic actions of some SERMs might avoid the adverse effects associated with estrogens. Accordingly, we hypothesize that SERMs may be the beneficial selection for patients with CSX.

 Possible Effect Pathway of SERM on CSX



Estrogen replacement has ever been applied to treat postmenopausal women with CAD because of their estrogen deficiency and estrogen's benefits from basic studies. However, it is interesting that some differences seem to exist between the effects attributed to endogenous or exogenous estrogens. This contrast is evident in the case of CAD, where the possible protection mediated by endogenous estrogens has not been observed in postmenopausal women treated with this hormone, as confirmed by recent randomized clinical trials. [13],[14],[15] A scientific review [16] conducted for the US Preventative Services Task Force38 assessed the risks and benefits of this treatment and found the following: an increased risk of coronary events, stroke and venous thromboembolism (risk highest in the first year); an increased risk of breast cancer (associated with duration of treatment); an increased risk of endometrial cancer and cholecystitis; protection against osteoporotic complications; a decreased risk of colon cancer; and cognition improvement in women with menopausal symptoms.

With the unfavorable effects of estrogen mentioned herein, the interest for the cardiovascular potential of SERMs has emerged recently. The rationale for the attention lies in the demonstrated regulatory capacity of the estrogen-sensitive machinery on the pathogenesis of cardiovascular disease (CVD) by the paths as follows:

 Effects of SERMs on Blood Lipids



The changes observed in the lipid profile are very similar to those linked with estrogens. In the preclinical studies on rats, new SERMs such as lasofoxifene have confirmed a powerful ability to reduce up to a 68% of the increase in cholesterol associated with gonadectomy, and similar effects have been demonstrated for arzoxifene, a novel raloxifene analog. [17],[18],[19],[20] Except for the above mentioned results from animal experiments, another study in healthy non obese postmenopausal women also showed that raloxifene treatment caused a significant increase in high-density lipoprotein cholesterol and a decrease in total cholesterol as well as low density lipoprotein cholesterol. [21] HMR 3339, a new novel selective estrogen receptor modulator could also rapidly decrease total cholesterol and LDL in a dose dependent manner. [22]

 Effects of SERMs on the Endothelium



Consistent with the data obtained in investigations with estrogens, both genomic and non genomic mechanisms have been described for SERMs in the endothelium. Mixed evidences have been obtained in studies of flow changes with SERMs. A study from Greece showed that raloxifene could significantly increase the ratio of NO to endothelin-1. [23] Several other studies also showed that raloxifene could significantly improve flow-mediated endothelium dependent vasodilation in postmenopausal women to an extent similar to that of hormone replacement therapy, [24],[25],[26] which demonstrates that SERMs can significantly improve endothelial function.

 Effects of SERMs on Vascular Smooth Muscle Cells



There are only sparse data that generally support an anti proliferative effect of SERMs. Raloxifene induced an arrest and apoptosis of platelet-derived growth factor (PDGF) stimulated cultured human vascular smooth muscle cells (VSMCs). [27],[28] Consistent with this observation, raloxifene was equivalent to estradiol in limiting intimal thickening in a model of ovariectomized senile ewes. [29] Similar protective effects have been described for tamoxifen in different studies with VSMCs, in a culture [30],[31] and for idoxifene in a study including experiments with VSCMs and animal data. [32]

 Effects of SERMs on Inflammation and Oxidative Stress



There are several studies that have demonstrated that SERMs have significant anti inflammatory effects. Long time, anti inflammatory actions of raloxifene in rat aorta have been observed, [33] and inflammatory responses induced by lipopolysaccharide in mouse and rat microglial cells are weakened by SERMs. [34] Data also shows that tamoxifen is associated with reductions of C reactive protein and the other inflammatory factors. [35] Of late, increasing evidences demonstrated that SERMs such as raloxifene can protect endothelial cell function against oxidative stress and suppress oxidative stress induced endothelial cell apoptosis. [36],[37] However, the study has also shown that tamoxifen, another kind of SERMs, can induce oxidative stress and mitochondrial apoptosis via stimulating mitochondrial nitric oxide synthase, [38] which means that it acts differently when suppressing oxidative stress for different kinds of SERMs.

 Effects of SERMs on Coronary Artery Disease and Stroke



An animal study showed that raloxifene treatment could result in reduced lesion volume, enhanced mechanical stability of vascular calcification, and less inflamed lesions, characterized by less macrophage infiltration and reduced COX 2, MMP 1 and MCP 1 expression. [39]

Some clinical trials also demonstrated that SERMs gave some indirect indications favoring a protective effect on CAD or stroke. [40],[41] However, a study about the effect of raloxifene on stroke and venous thromboembolism according to subgroups in postmenopausal women, at increased risk of coronary heart disease, showed that the incidences of all strokes did not differ between raloxifene and placebo treatment groups. However, there was a higher incidence of fatal strokes and venous thromboembolic events, which should be paid attention to by clinicians.

 Conclusion



The concept that inflammation, oxidative stress, estrogen deficiency, and endothelial dysfunction are the main mechanisms of CSX, especially the significant clinical effects of ERT on CSX, further demonstrate that estrogen and its receptor play an important role in CSX. It is well known that estrogen plays a key role in regulating the risk for coronary heart disease at present. Moreover, there is a wealth of experimental data confirming the action of estrogens on several mechanisms crucial in the pathogenesis of each form of cardiovascular disease. The unfavorable profile obtained for estrogens in randomized studies has limited its usage in cardiovascular diseases, including CSX. All the above mentioned evidences about the effects of SERMs, especially raloxifene, on the cardiovascular system, including its anti inflammatory, anti oxidative stress, lipid downing effects and the effects of the improving endothelial function and limiting VSMCs proliferation, provide the basic theory that SERMs may be beneficial for CSX. The MORE trial, CORE trial and PEARL trial all demonstrate the safety of SERMs in coronary artery disease, but an increased incidence of stroke and venous thromboembolic events is noted. In a word, if more attention can be paid to its thromboembolic events, SERMs may be a promising drug for CSX, which may possess a power to enhance the quality of life of patients with CSX, especially those with recurrent attack of chest pain that cannot be effectively suppressed by other drugs such as statins, b blocker, angiotensin converting enzyme inhibitors, nitrates, and calcium channel blocker.

 Acknowledgment



This paper was partly supported by National Natural Science Foundation of China to JingFeng Wang (No.30971262)

References

1Likoff W, Segal BL, Kasparian H. Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease. N Engl J Med 1967;276:1063-6.
2Gil-Ortega I, Marzoa Rivas R, Ríos Vázquez R, Kaski JC. Role of inflammation and endothelial dysfunction in the pathogenesis of cardiac syndrome X. Future Cardiol 2006;2:63-73.
3Hurst T, Olson TH, Olson LE, Appleton CP. Cardiac syndrome X and endothelial dysfunction: new concepts in prognosis and treatment. Am J Med 2006;119:560-6.
4Kaski JC. Cardiac syndrome X in women: the role of oestrogen deficiency. Heart 2006;92:5-9.
5Nilsson BO. Modulation of the inflammatory response by estrogens with focus on the endothelium and its interactions with leukocytes. Inflamm Res 2007;56:269-73.
6Colacurci N, Manzella D, Fornaro F, Carbonella M, Paolisso G. Endothelial function and menopause: effects of raloxifene administration. J Clin Endocrinol Metab 2003;88:2135-40.
7Rosano GM, Peters NS, Lefroy D, Lindsay DC, Sarrel PM, Collins P, et al. 17_beta_estradiol therapy lessens angina in postmenopausal women with syndrome X. J Am Coll Cardiol 1996;28:1500-5.
8Albertsson PA, Emanuelsson H, Milsom I. Beneficial effect of treatment with transdermal estradiol-17-beta on exercise-induced angina and ST segment depression in syndrome X. Int J Cardiol 1996;54:13-20.
9Adamson DL, Webb CM, Collins P. Esterified estrogens combined with methyltestosterone improve emotional well_being in postmenopausal women with chest pain and normal coronary angiograms. Menopause 2001;8:233-8.
10Paoletti R, Wenger NK. Review of the international position on women's health and menopause: a comprehensive approach. Circulation 2003;107:1336-9.
11Martino S, Disch D, Dowsett SA, Keech CA, Mershon JL. Safety assessment of raloxifene over eight years in a clinical trial setting. Curr Med Res Opin 2005;21:1441-52.
12Ensrud K, Genazzani AR, Geiger MJ, McNabb M, Dowsett SA, Cox DA, et al. Effect of raloxifene on cardiovascular adverse events in postmenopausal women with osteoporosis. Am J Cardiol 2006;97:520-7.
13Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-13.
14Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-33.
15Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-12.
16Paoletti R, Wenger NK. Review of the international position on women's health and menopause: a comprehensive approach. Circulation 2003;107:1336-9.
17Armamento Villareal R, Sheikh S, Nawaz A, Napoli N, Mueller C, Halstead LR, et al. A new selective estrogen receptor modulator, CHF 4227.01, preserves bone mass and microarchitecture in ovariectomized rats. J Bone Miner Res 2005;20:2178-88.
18Ke HZ, Qi H, Chidsey Frink KL, Crawford DT, Thompson DD. Lasofoxifene (CP-336,156) protects against the age related changes in bone mass, bone strength, and total serum cholesterol in intact aged male rats. J Bone Miner Res 2001;16:765-73.
19Ke HZ, Qi H, Crawford DT, Chidsey Frink KL, Simmons HA, Thompson DD. Lasofoxifene (CP-336,156), a selective estrogen receptor modulator, prevents bone loss induced by aging and orchidectomy in the adult rat. Endocrinology 2000;141:1338-44.
20Ma YL, Bryant HU, Zeng Q, Palkowitz A, Jee WS, Turner CH, et al.Long term dosing of arzoxifene lowers cholesterol, reduces bone turnover, and preserves bone quality in ovariectomized rats. J Bone Miner Res 2002;17:2256-64.
21Nanetti L, Camilletti A, Francucci CM, Vignini A, Raffaelli F, Mazzanti L, et al. Role of raloxifene on platelet metabolism and plasma lipids. Eur J Clin Invest 2008;38:117-25.
22Vogelvang TE, Mijatovic V, Kenemans P, Teerlink T, van der Mooren MJ. HMR 3339, a novel selective estrogen receptor modulator, reduces total cholesterol, lowdensity lipoprotein cholesterol, and homocysteine in healthy postmenopausal women. Fertil Steril 2004;82:1540-9.
23Christodoulakos G, Panoulis C, Kouskouni E, Chondros C, Dendrinos S, Creatsas G. Effects of estrogen-progestin and raloxifene therapy on nitric oxide, prostacyclin and endothelin-1 synthesis. Gynecol Endocrinol 2002;16:9-17.
24Katz DL, Evans MA, Njike VY, Hoxley ML, Nawaz H, Comerford BP, et al. Raloxifene, soy phytoestrogens and endothelial function in postmenopausal women. Climacteric 2007;10:500-7.
25Saitta A, Altavilla D, Cucinotta D, Morabito N, Frisina N, Corrado F, et al. Randomized, double blind, placebo controlled study on effects of raloxifene and hormone replacement therapy on plasma NO concentrations, endothelin 1 levels, and endothelium dependent vasodilation in postmenopausal women. Arterioscler Thromb Vasc Biol 2000;21:1512-9.
26Takahashi K, Mori-Abe A, Takata K, Ohta T, Kawagoe J, Tsutsumi S, et al. Raloxifene improves the ovariectomy induced impairment in endothelium-dependent vasodilation. Menopause 2007;14:656-61.
27Takahashi K, Ohmichi M, Yoshida M, Hisamoto K, Mabuchi S, Arimoto-Ishida E, et al. Both estrogen and raloxifene cause G1 arrest of vascular smooth muscle cells. J Endocrinol 2003;178:319-29.
28Mori Abe A, Tsutsumi S, Takahashi K, Toya M, Yoshida M, Du B, et al. Estrogen and raloxifene induce apoptosis by activating p38 mitogen activated protein kinase cascade in synthetic vascular smooth muscle cells. J Endocrinol 2003;178:417-26.
29Selzman CH, Turner AS, Gaynor JS, Miller SA, Monnet E, Harken AH. Inhibition of intimal hyperplasia using the selective estrogen receptor modulator raloxifene. Arch Surg 2002;137:333-6.
30Somjen D, Kohen F, Jaffe A, Amir Zaltsman Y, Knoll E, Stern N. Effects of gonadal steroids and their antagonists on DNA synthesis in human vascular cells. Hypertension 1998;32:39-45.
31Dubey RK, Tyurina YY, Tyurin VA, Gillespie DG, Branch RA, Jackson EK, et al. Estrogen and tamoxifen metabolites protect smooth muscle cell membrane phospholipids against peroxidation and inhibit cell growth. Circ Res 1999;84:229- 39.
32Yue TL, Vickery Clark L, Louden CS, Gu JL, Ma XL, Narayanan PK, et al. Selective estrogen receptor modulator idoxifene inhibits smooth muscle cell proliferation, enhances reendothelialization, and inhibits neointimal formation in vivo after vascular injury. Circulation 2000;102:281-8.
33Pinna C, Bolego C, Sanvito P, Pelosi V, Baetta R, Corsini A, et al. Raloxifene elicits combined rapid vasorelaxation and long-term anti-inflammatory actions in rat aorta. J Pharmacol Exp Ther 2006;319:1444-51.
34Suuronen T, Nuutinen T, Huuskonen J, Ojala J, Thornell A, Salminen A. Anti inflammatory effect of selective estrogen receptor modulators (SERMs) in microglial cells. Inflamm Res 2005;54:194-203.
35Eilertsen AL, Sandvik L, Steinsvik B, Sandset PM. Differential impact of conventional dose and low dose postmenopausal hormone therapy, tibolone and raloxifene on C reactive protein and other inflammatory markers. J Thromb Haemost 2008;6:928-34.
36Yu J, Eto M, Kozaki K, Akishita M, Okabe T, Ouchi Y. Raloxifene analogue LY117018 suppresses oxidative stress induced endothelial cell apoptosis through activation of ERK1/2 signaling pathway. Eur J Pharmacol 2008;589:32-6.
37Wong CM, Yung LM, Leung FP, Tsang SY, Au CL, Chen ZY, et al. Raloxifene protects endothelial cell function against oxidative stress. Br J Pharmacol 2008;155:326-34.
38Nazarewicz RR, Zenebe WJ, Parihar A, Larson SK, Alidema E, Choi J, et al. Tamoxifen induces oxidative stress and mitochondrial apoptosis via stimulating mitochondrial nitric oxide synthase. Cancer Res 2007;67:1282-90.
39Choi BG, Vilahur G, Zafar MU, Cardoso L, Yadegar D, Ibanez B, et al. Selective estrogen receptor modulation influences atherosclerotic plaque composition in a rabbit menopause model. Atherosclerosis 2008;201:76-84.
40Barrett Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, et al. MORE Investigators (Multiple Outcomes of Raloxifene Evaluation): Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 2002;287:847-57.
41Cummings SR, Ensrud K, Delmas PD, LaCroix AZ, Vukicevic S, Reid DM, et al; PEARL Study Investigators. Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med 2010;362:686-96.

 
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