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Journal of Postgraduate Medicine, Vol. 56, No. 4, October-December, 2010, pp. 328-331 View Point 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, dr_wjf@hotmail.com Date of Submission: 14-Mar-2010 Code Number: jp10094 PMID: 20935411 DOI: 10.4103/0022-3859.70936 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.Keywords: Cardiac syndrome X, estrogen deficiency, endothelial function, inflammation, selective estrogen receptor modulator, oxidative stress 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
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