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Estrogen Increases Hyperemic Microvascular Blood Flow Velocity in Postmenopausal Women

^a Division of Geriatrics and Gerontology, Washington University School of Medicine, St. Louis, Missouri.
^b Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri.
^c Appleton Heart Institute, Appleton, Wisconsin.

Linda R. Peterson, Cardiovascular Division, Washington University School of Medicine, Campus Box 8086, 660 S. Euclid Avenue, St. Louis, MO 63110 E-mail: lpeterso{at}imgate.wustl.edu.

Decision Editor: William B. Ershler, MD

	Abstract

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Background. Epidemiologic studies suggest that estrogen replacement therapy (ERT) is protective against vascular disease. ERT confers this benefit by lowering lipid levels and improving arterial function. However, its effect on the microvasculature in vivo is unknown. Thus the purposes of this study were to evaluate effect of estrogen status on the hyperemic response of the microvasculature in vivo in postmenopausal women and to compare the hyperemic response of the microvasculature in postmenopausal women taking ERT with that of premenopausal women.

Methods. We measured forearm microvasculature flow velocity by using a laser Doppler in a cross section of 64 healthy premenopausal and postmenopausal women 23 to 72 years old. Microvasculature blood flow velocity was measured at baseline, throughout 2 minutes of ischemia, and immediately after the ischemic period was terminated (i.e., during the peak hyperemic response).

Results. The peak of the hyperemic flow velocity (PHFV) in the postmenopausal women who were taking long-term ERT at usual doses was greater than that of postmenopausal women who were not currently taking ERT (p < .0001). Moreover, the PHFV of postmenopausal women taking ERT was similar to that of premenopausal women. Multivariate regression analysis showed estrogen status and baseline flow velocity to be independent predictors of PHFV.

Conclusions. Current, long-term ERT at usual replacement doses is associated with improved microvascular responses in postmenopausal women, which may explain some of its beneficial vascular effects.

CLINICALLY evident vascular disease rarely occurs in premenopausal women, but after menopause its incidence increases dramatically ^(1)(2)(3). This observation and additional evidence from epidemiologic studies suggest that postmenopausal estrogen replacement therapy (ERT) protects against vascular events ⁽⁴⁾. Mechanisms by which ERT may confer this protective effect in older postmenopausal women include induction of favorable changes in plasma lipoprotein levels and lipid peroxidation, and attenuation of atherogenesis ^{(5)(6)(7)(8)(9)(10)(11)}. However, these changes are modest and do not appear to account for all of the vasoprotective effects of estrogen.

Another mechanism by which ERT can protect against vascular disease is by improving vasomotor tone and enhancing blood vessel responses to various stimuli. Intra-arterial infusion of estrogen and short-term oral ERT (9 weeks) have been shown to induce a beneficial effect on the responses of medium-sized arteries to acetylcholine infusion or to the relief of temporary ischemia (i.e., the hyperemic response), in both animals and postmenopausal women ^{(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)}. However, there are very few studies that address how ERT affects the microvasculature; one of those that do is a recent in vitro study by Meyer and colleagues that shows that ERT has an effect on vasomotor responses of these vessels ⁽²³⁾.

Moreover, only a few studies have examined the vasodilator effects of long-term ERT (>9 weeks of ERT) in healthy postmenopausal women ^(24)(25). The effects of long-term oral and topical ERT on the vasculature are important because these preparations are the ones most commonly prescribed and because the American College of Physicians recommends that long-term ERT be considered for all postmenopausal women ⁽²⁶⁾. Thus more study is needed to ascertain whether the beneficial effects on the vasculature of older women seen with short-term estrogen infusions persist during long-term ERT. Finally, there has been limited investigation comparing the hyperemic response in postmenopausal women on ERT with that of premenopausal women, who have a low incidence of clinical events due to vascular disease. Thus the objectives of this study were to evaluate the effects of the estrogen status of women (i.e., those currently in long-term ERT versus those not on ERT) on the hyperemic response of the microvasculature in vivo in postmenopausal women and to compare the hyperemic response of the microvasculature in older women with that of younger, premenopausal women. To this end, we measured mean forearm capillary blood flow velocity at baseline, throughout brachial artery occlusion, followed by measurement of the peak of hyperemic flow velocity (PHFV) in three groups of women: (a) postmenopausal women not currently taking ERT, (b) postmenopausal women currently using ERT, and (c) premenopausal women. The women in the first group who had been on ERT in the past had all discontinued use of ERT at least 1 month before the study.

	Methods

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Study Population
Sixty-four healthy women 23 to 72 years old were enrolled in this study between December 1995 and October 1996. Subjects were recruited by word of mouth and by posted advertisement. All subjects completed a standard questionnaire regarding their height, weight, cholesterol level, medication, smoking status, and estrogen and progesterone status. Body surface area (BSA) was calculated from patient height and weight with standard tables. Women were divided into the three groups described above. They were excluded if they had known cardiac or vascular disease, hypertension, diabetes, or hypercholesterolemia (a total cholesterol > 260 mg/dl), or were pregnant, lactating, or perimenopausal (i.e., those with vasomotor symptoms, such as hot flashes, and/or whose menstrual cycles were becoming longer and more irregular). In addition, no subject was included in this study if she was taking a cholesterol-lowering drug, an antioxidant, a vasoactive medication (such as a beta-adrenergic blocker), or an oral contraceptive. Because smoking is known to affect the hyperemic response, all current smokers were excluded ⁽²⁷⁾.

Of the women studied, 20 women were postmenopausal and not currently taking ERT (), 18 of the women were postmenopausal and currently taking ERT (), and 25 of the women () were premenopausal. Subjects were classified as postmenopausal if they had not had a menstrual period in the 12 months before their enrollment or if they had undergone a bilateral oophorectomy. None of the postmenopausal women had taken progesterone within 24 hours before the study. Of the 20 postmenopausal women not currently taking ERT, 12 had never taken it and 8 had taken it in the past (although not for at least 1 month before their participation in this study).

Sixty percent of the women on ERT (12 of 18 subjects) were taking conjugated oral equine estrogen (Premarin, 0.625 mg). The other women were taking either a different dose of conjugated equine estrogen or estradiol (orally or by topical patch). No subject was using a topical estrogen cream alone. The premenopausal women studied were at various points in their menstrual cycle. Of the premenopausal women, 4 of the 25 (15%) were menstruating on the day of the study, as would be expected from a random sampling of premenopausal women with normal menstrual cycles. All women recruited were from the St. Louis, Missouri, metropolitan area or the Fox River Valley area in Wisconsin. The study was approved by the Washington University Human Studies Committee Internal Review Board (IRB), and informed consent was obtained from each subject before she entered the study.

Measurement of Microvascular Blood Flow
Subjects were asked to refrain from consuming ethanol or caffeine-containing food or drink for 12 hours before the study. The laser Doppler study was performed after the subjects had been recumbent and supine in a quiet temperature-controlled (approximately 70°F) room for at least 15 minutes. Flow velocity and skin temperatures were measured in each subject with a DRT4 model laser Doppler instrument (Moor Instruments Ltd., Devon, England). The approximate sampling area of the laser Doppler was 1 mm³ directly below the skin surface.

Resting baseline blood pressure measurements were obtained on the dominant arm, and these were used to calculate the mean arterial pressure (MAP). The nondominant arm was used for all laser Doppler examinations: The two probes were placed on the midforearm on the volar surface at a distance of 4 cm from the elbow. All flow measurements were recorded as continuous signals, all flow and temperature measurements were made by two probes, and the results from the two were averaged. Guidelines for standardized cutaneous blood flow recording with the laser Doppler as proposed by Bircher and colleagues ⁽²⁷⁾ were applied. Baseline forearm microvascular blood flow velocity was measured after consistent readings between the two laser Doppler probes and appropriate sensing of the pulse were obtained. Mean baseline flow velocity was determined after continuous measurement over 1 minute. Brachial artery occlusion was achieved by inflating a sphygmomanometer to at least 30 mm Hg above the systolic blood pressure (SBP) for 2 minutes. The mean blood flow velocity during brachial artery occlusion was designated the biological zero; these values were not subtracted from the baseline or PHFV values. After the brachial artery occlusion was released, the reactive hyperemic blood flow velocity was recorded for one minute. The PHFV was the maximum blood flow velocity during the hyperemic response. All flow velocity values are given in arbitrary units, as recommended by Bircher and colleagues ⁽²⁷⁾.

Statistical Analysis
Data were analyzed by the software program SAS as implemented on the UNIX system of the Division of Biostatistics at Washington University. Results are expressed as mean ± standard deviation. Analysis of variance (ANOVA) was used to evaluate the difference in baseline characteristics, baseline flow, biological zero, and PHFV among the three study groups, and unpaired t tests were used to evaluate the difference in baseline characteristics, baseline flow, biological zero, and PHFV between the two groups of postmenopausal women. A subset of women (n = 40) reported their total cholesterol levels on a questionnaire or had their physicians' offices fax results of their cholesterol levels to the primary investigator. ANOVA was performed to evaluate the difference in cholesterol levels among the three study groups. A p value of <.05 was considered indicative of a statistically significant difference. A bivariate linear regression analysis was performed to assess the correlation between cholesterol level and PHFV. Pearson correlation coefficients were used to evaluate the association between PHFV and continuous variables (such as age and years since menopause). Finally, a multiple stepwise regression analysis was used to determine the independent predictors of PHFV. To allow for the possibility that years since menopause was independently associated with PHFV, the same multiple regression was repeated after data from the premenopausal women were excluded.

	Results

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Table 1 lists the baseline characteristics of the women studied. The groups of women were similar for all baseline characteristics except for the expected older age, higher (SBP), and higher total cholesterol levels in the postmenopausal women compared with the premenopausal women. The postmenopausal women who were currently taking ERT were slightly younger and had slightly lower cholesterol levels than the women who were not currently taking it. The difference in age, SBP, and total cholesterol levels among all three groups of women was statistically significant by ANOVA (p < .05, p < .05, and p < .01, respectively), but age was not a predictor of PHFV in the multivariate analysis. There was no significant difference in skin temperatures, BSA, mean or diastolic blood pressure among the three groups of subjects, and between the two groups of postmenopausal women there was no significant difference in years since onset of menopause, SBP, diastolic blood pressure, or mean arterial pressure, although there was a difference in cholesterol levels (p < .05).

	Discussion

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Information on whether ERT affects the microvasculature is important because (a) it would help support the concept that ERT protects older postmenopausal women from vascular disease; (b) ERT is a pharmacologic agent that is in widespread use among older women; (c) some diseases primarily affect the microvasculature, and ERT may prove to be an important therapeutic agent for these conditions; (d) other pharmacologic agents act primarily on either medium-sized arteries (e.g., nitroglycerin) or on the microvasculature (e.g., dipyridamole) but not both, and (e) macrovascular blood flow plays a significant role in tissue perfusion. Thus it is important to investigate the benefits of ERT on the microvasculature even though it can affect the hyperemic response of medium-sized arteries ^{(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)}. Results of this study indicate that the PHFV of the forearm cutaneous microvasculature is increased in postmenopausal women who are taking ERT and that estrogen is an independent predictor of PHFV even when age and other variables are taken into account. This suggests that ERT is associated with an increase in microvascular blood flow velocity in addition to its well-known vasodilatory effect on larger vessels ^{(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(24)(25)(28)(29)}. Hyperemic flow velocity is known to be important in medium-sized arteries because an increase in shear stress on the endothelium in these vessels causes release of nitric oxide (a potent endogenous vasodilator) and vasodilation ^(18)(30). The effect of an increase in shear stress on the endothelium of the microvasculature is less clear. However, our results show that changes in PHFV (and hence shear stress) also occur in the microvasculature. Our findings are consistent with studies that show that ERT causes an increase in total forearm tissue perfusion during hyperemia ^(16)(22). The effect of this increase in PHFV on endogenous vasodilator release in the microvasculature in vivo has yet to be determined. Our in vivo results corroborate the findings of the in vitro study by Meyer et al. ⁽²³⁾ that suggest that ERT influences the microvasculature responses to the relief of ischemia. Our findings are also consistent with those that suggest that there is a beneficial effect of ERT on the tissue perfusion of other organs such as the brain ^(31)(32)(33).

The results of our study suggest that the beneficial effects of intra-arterial or other short-term ERT on vasomotor function that have been demonstrated in previous studies are also seen with long-term therapy ^{(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)}. These findings support the theories that long-term use of usual doses of ERT improve vasomotor function in healthy postmenopausal women. Our findings also suggest that the microvasculature responses of healthy postmenopausal women on ERT to various stimuli are similar to those of the premenopausal women who are known to be at low risk for vascular disease, as evidenced by the finding that PHFV in premenopausal women and in the postmenopausal women on ERT were not significantly different.

Multiple stepwise regression analysis showed that current estrogen use was one of the most important predictors of an increased hyperemic response, which is consistent with and extends the findings of Bungum's group, which found that estrogen levels in premenopausal women correlated with PHFV ⁽³⁴⁾. In our study, age was not an independent predictor of the hyperemic response, which is consistent with findings of other studies in which the effect of age on microvascular flow was examined ⁽²⁷⁾. In contrast, studies of the coronary and brachial arteries have shown that the vasomotor response of these arteries (to various stimuli such as the relief of temporary ischemia as measured by ultrasound) is age dependent ^(35)(36). Thus vessels of different sizes may be affected differently by aging. Our finding that baseline flow was independently associated with PHFV also confirms the findings of previous studies describing the importance of the influence of baseline flow on the hyperemic response ^(37)(38)(39).

Study Limitations
The limitations of our study include the fact that it was a cross-sectional, not longitudinal, study. The different groups of women studied were, however, similar in almost all of the baseline clinical characteristics. All were healthy nonsmokers who had none of the aforementioned conditions that are known to affect blood flow ^{(27)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)}. Nevertheless, as is the case with any cross-sectional study, it is impossible to exclude fully the potentially confounding healthy user bias, i.e., that the women on ERT were healthier than those not on ERT. Also, the doses of ERT were not the same in all women. Although this lack of uniformity may be a limitation, it is also a strength because this situation is representative of that in the general population of postmenopausal women who are taking ERT. Because there were only a small number of women who were not Caucasian, this study's conclusions may not be extended to the minorities.

Our results focused on the effects of ERT on the forearm cutaneous microvasculature, which may have different vasomotor responses from the microvasculature of other tissues. However, our findings were consistent with those of Meyer and colleagues, who examined the in vitro responses of mesenteric arterioles to ERT ⁽²³⁾.

Clinical Implications
The implications of the results of this study showing that long-term ERT is associated with an increase in the PHFV of the microvasculature of healthy postmenopausal women are several. First, they suggest that the salutary effect of ERT is not limited to the conduit vessels such as the brachial of coronary arteries but extends to an increased hyperemic flow velocity in the microvasculature. Thus ERT may have a therapeutic role in the treatment of diseases of tissue perfusion. Future studies on the effects of ERT in other groups of women, such as those with peripheral vascular disease, would further enhance our understanding of ERT's effects. Also, supporting the theory that the increase in PHFV in the microvasculature may translate into a beneficial effect is the finding that postmenopausal women currently using ERT preparations appear to have a PHFV that is not different from that of premenopausal women (who are known to be at low risk of vascular disease and diseases of tissue perfusion).

	Acknowledgments

 
This research was supported in part by a grant from the National Institutes of Health (ROI-AG-12235) to R.J. Spina and a Minority Investigator Research Award from the American Heart Association to V.G. Dávila-Román. We gratefully acknowledge the support and assistance of Jean Lehndorf, RN, and the staff of Appleton Heart Institute, and Jane Miller, RN, and the staff at the Center for Digestive Diseases at Barnes-Jewish Hospital. We also acknowledge the technical assistance of Timothy Lee, B. Eng of Moor Instruments, the editorial assistance of Beth Engeszer, and the statistical analysis of Ken Schechtman, Ph.D.

Received January 4, 1999

Accepted August 29, 1999

	References

Top Abstract Methods Results Discussion References

 

1. Kannel WB, Hjortland MC, McNamara PM, Gordon T, 1976. Menopause and risk of cardiovascular disease: the Framingham Study. Ann Intern Med. 85:447-452.
2. Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speitzer FE, Hennekens CH, 1987. Menopause and the risk of coronary heart disease in women. N Engl J Med. 316:1105-1110. [Abstract]
3. Wuest JH, Jr Dry TJ, Edwards JE, 1953. The degree of coronary atherosclerosis in bilaterally oophorectomized women. Circulation. 7:801-809. [Medline]
4. Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster V, Cummings SR, 1992. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 117:1016-1037.
5. Miller VT, La Rosa JC, 1990. Sex steroids and lipoprotein. Redmond GP, , ed.Lipids and Women's Health 48-65. Springer-Verlag, New York.
6. Haines C, Chung T, Chang A, Maseri J, Tomlinson B, Wong E, 1996. Effect of oral estradiol on Lp(a) and other lipoprotein in postmenopausal women: a randomized double-blind, placebo-controlled, cross-over study. Arch Intern Med. 156:866-872. [Abstract/Free Full Text]
7. Barrett-Conner E, Bush TL, 1991. Estrogen and coronary heart disease. JAMA. 265:1861-1867. [Abstract/Free Full Text]
8. Peterson LR, 1997. Estrogen and cardiovascular disease. Becker RC, , ed.The Textbook of Coronary Thrombosis and Thrombolysis 585-610. Kluwer, Worcester, MA.
9. Sack MN, Rader DJ, Cannon RO, 1994. Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women. Lancet. 343:269-270. [Medline]
10. Subbiah MTR, Kessel B, Agrawal M, Raghunandan R, Abplanalp W, Rymaszewski Z, 1993. Antioxidant potential of specific estrogen on lipid peroxidation. J Clin Endocrinol Metab. 77:1095-1097. [Abstract]
11. Adams MR, Kaplan JR, Manuck SB, Koritnik DR, Parks JS, Wolfe MS, Clarkson TB, 1990. Inhibition of coronary atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Arteriosclerosis. 10:1051-1057. [Abstract/Free Full Text]
12. Keaney JF, Shwaery GT, Xu A, Nicolosi RJ, Loscalzo J, Foxall TL, Vita JA, 1994. 17-ß-estradiol preserves endothelial vasodilator function and limits low-density lipoprotein oxidation in hypercholesterolemia swine. Circulation. 89:2251-2259. [Abstract/Free Full Text]
13. Williams JK, Adams MR, Klopfenstein HS, 1990. Estrogen modulates responses of atherosclerotic coronary arteries. Circulation. 81:1680-1687. [Abstract/Free Full Text]
14. Williams JK, Adams MR, Herrington DM, Clarkson TB, 1992. Short-term administration of estrogen and vascular responses of atherosclerotic coronary arteries. J Am Coll Cardiol. 20:452-457. [Abstract]
15. Sudhir K, Chou TM, Mullen WL, Hausmann D, Collins P, Yock PG, Chattergee K, 1995. Mechanisms of estrogen-induced vasodilation: in vivo studies in canine coronary conductance and resistance arteries. J Am Coll Cardiol. 26:807-814. [Abstract]
16. Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon RO, 1996. Acute vascular effects of estrogen in postmenopausal women. Circulation. 93:1928-1937. [Free Full Text]
17. Guetta V, Cannon RO, 1996. Cardiovascular effects of estrogen and lipid-lowering therapies in postmenopausal women. Circulation. 93:1928-1937.
18. Lieberman EH, Gerhard MD, Uehata A, Walsh VW, Selwyn AP, Ganz P, Yeung AC, Creager MA, 1994. Estrogen improves endothelium-dependent flow-mediated vasodilation in postmenopausal women. Ann Intern Med. 121:936-941. [Abstract/Free Full Text]
19. Gilligan DM, Quyyami AA, Cannon RO, 1994. Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women. Circulation. 89:2545-2551. [Abstract/Free Full Text]
20. Collins P, Rosano G, Sarrel P, Ulrich L, Adamopolis S, Beale CM, McNeill JG, Poole-Wilson PA, 1995. 17-ß estrodiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation. 92:24-30. [Abstract/Free Full Text]
21. Reis SE, Gloth ST, Blumenthal RS, Resar JR, Zacur HA, Gerstenblith G, Brinker JA, 1994. Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. Circulation. 89:52-60. [Abstract/Free Full Text]
22. Volteranni M, Rosano G, Coats A, Beale C, Collins P, 1995. Estrogen acutely increases peripheral blood flow in postmenopausal women. Am J Med. 99:119-122. [Medline]
23. Meyer MC, Cummings K, Osol G, 1997. Estrogen replacement attenuates resistance artery adrenergic sensitivity via endothelial vasodilators. Am J Physiol. 272:H2264-H2270. [Abstract/Free Full Text]
24. Gangar KF, Vyas S, Whitehead M, Crook D, Meire H, Campbell S, 1991. Pulsatility index in internal carotid artery in relation to transdermal estrogen oestradiol and time since menopause. Lancet. 338:839-842. [Medline]
25. Herrington DM, Braden GA, Williams JK, Morgan TM, 1994. Endothelial-dependent coronary vasomotor responsiveness in postmenopausal women with and without estrogen replacement therapy. Am J Cardiol. 73:951-952. [Medline]
26. American College of Physicians1992. Guidelines for counseling postmenopausal women about preventive hormone therapy. Ann Intern Med. 117:1038-1041.
27. Bircher A, de Boer EM, Agner T, Wahlberg JE, Serup J, 1993. Guidelines for measurement of cutaneous blood flow by laser Doppler flowmetry: a report from the standardization group of the European Society of Contact Dermatitis. Contact Dermatitis. 28:1-8. [Medline]
28. Chester AH, Jiang C, Borland JA, Yacoub MJ, Collins P, 1995. Oestrogen relaxes human epicardial coronary arteries through non-endothelium-dependent mechanisms. Coron Artery Dis. 6:417-422. [Medline]
29. Jiang C, Sarrel PM, Lindsay DC, Poole-Wilson PA, Collins P, 1991. Endothelium-independent relaxation of rabbit coronary artery by 17-ß oestradiol in vitro. Br J Pharmacol. 104:1033-1037. [Medline]
30. Nichols WW, O'Rourke MF, eds. McDonald's Blood Flow in Arteries. The Coronary Circulation. Philadelphia: Lea & Febiger; 1990:364–368.
31. Greene RA, Boone K, Lewis D, et al. Improvements in neuropsychological performance correlate with regionally specific increases in cerebral blood flow during estrogen replacement therapy in menopausal women (Abstr). Presented at: Annual Meeting of the Pacific Coast Fertility Society, April 17, 1996; Indian Wells, CA.
32. Shaw TG, Mortel KF, Meyer JS, Rogers RL, Hardenberg J, Cutaia MM, 1984. Cerebral blood flow changes in benign aging and cerebrovascular disease. Neurology. 34:855-862. [Abstract/Free Full Text]
33. Funk JL, Mortel KF, Meyer JS, 1991. Effects of estrogen replacement therapy on cerebral perfusion and cognition among postmenopausal women. Dementia. 2:268-272.
34. Bungum L, Kvernebo K, Øian P, Maltau JM, 1996. Laser Doppler-recorded reactive hyperaemia in the forearm skin during the menstrual cycle. Br J Obstet Gynaecol. 103:70-75. [Medline]
35. Egashira K, Inou T, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Kuga T, Urabe Y, Takeshita A, 1993. Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation. 88:77-81. [Abstract/Free Full Text]
36. Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopolis D, Robinson J, Deanfield JE, 1994. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol. 24:471-476. [Abstract]
37. Schächinger V, Zeiher AM, 1995. Quantitative assessment of coronary vasoreactivity in humans in vivo: importance of baseline vasomotor tone in atherosclerosis. Circulation. 91:1314-1319. [Abstract/Free Full Text]
38. Joannides R, Haefeli WE, Lindaer L, et al. 1995. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation. 91:1314-1319.
39. Sorensen JE, Celermajer DS, Spiegelhalter DJ, et al. 1995. Non-invasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility. Br Heart J. 74:247-253. [Abstract/Free Full Text]
40. Celermajer DS, Sorensen KE, Georgakopolis D, et al. 1993. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 88:2149-2155. [Abstract/Free Full Text]
41. Egashira K, Hirooka Y, Kai H, et al. 1994. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation. 89:2519-2524. [Abstract/Free Full Text]
42. Treasure CB, Klein JL, Weintraub WS, et al. 1995. Beneficial effects of cholesterol-lowering therapy on coronary endothelium in patients with coronary artery disease. N Engl J Med. 332:481-487. [Abstract/Free Full Text]
43. Goode GK, Heagerty AM, 1995. In vitro responses of human peripheral small arteries in hypercholesterolemia and effects of therapy. Circulation. 91:2898-2903. [Abstract/Free Full Text]
44. Zeiher AM, Krause T, Schächinger V, Minners J, Moser E, 1995. Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise induced myocardial ischemia. Circulation. 91:2345-2352. [Abstract/Free Full Text]
45. Casino PR, Kilyone CM, Cannon RO, Quyyumi AA, Panza J, 1995. Impaired endothelium-dependent vascular relaxation in patients with hypercholesterolemia extends beyond the muscarinic receptor. Am J Cardiol. 75:40-44. [Medline]
46. Gilligan DM, Guetta V, Panza J, García CE, Quyyumi AA, Cannon RO, 1994. Selective loss of microvascular endothelial function in human hypercholesterolemia. Circulation. 90:35-41. [Abstract/Free Full Text]
47. Panza JA, Casino PR, Kilyone CM, Quyyumi A, 1993. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation. 87:1468-1474. [Abstract/Free Full Text]
48. Linder L, Kiowski W, Bühler FR, Lüscher T, 1990. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Circulation. 81:1762-1767. [Abstract/Free Full Text]
49. Cesarone MR, Laurora G, Belcaro G, 1992. Microcirculation in systemic hypertension. Angiology. 43:899-903.
50. Frielingsdorf J, Seiler C, Kaufmann P, Vassalli G, Suter T, Hess OM, 1996. Normalization of abnormal coronary vasomotion by calcium antagonists in patients with hypertension. Circulation. 93:1380-1387. [Abstract/Free Full Text]
51. Levine GN, Frei B, Koulouris SN, Gerhard MD, Keaney JF, Vita JA, 1996. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation. 93:1107-1113. [Abstract/Free Full Text]
52. Meredith IT, Yeung AC, Weidinger FF, et al. 1993. Role of impaired endothelium-dependent vasodilation in ischemic manifestation of coronary disease. Circulation. 87: (suppl V) V56-V66.
53. Cohen RA, 1993. Dysfunction of vascular endothelium in diabetes mellitus. Circulation. 87: (suppl V) V67-V76.
54. Gilligan DM, Sack MN, Guetta V, et al. 1994. Effect of antioxidant vitamins on low density lipoprotein oxidation and impaired endothelium-dependent vasodilation in patients with hypercholesterolemia. J Am Coll Cardiol. 24:1611-1617. [Abstract]
55. Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med. 332:488–493.

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