Relation of baseline forearm vasodilator reserve to vascular endothelial response to estrogen replacement therapy in healthy postmenopausal women

Abstract

E replacement therapy (ERT) may be protective against cardiovascular disease in postmenopausal women without established coronary heart disease, possibly by improving endothelial-dependent arterial dilation (EDAD). However, vascular endothelial function as evaluated by flow-mediated dilation (FMD) varies considerably among postmenopausal women not receiving hormone replacement therapy, and the effects of ERT are inconsistent in this patient population. Whether variability in baseline vascular endothelial function is in part responsible for the inconsistent response to ERT in postmenopausal women is currently unknown. Accordingly, the present study was undertaken to evaluate whether baseline FMD affects the vascular endothelial response to physiologic ERT in healthy postmenopausal women. • • • Seventeen women (age 49 to 68 years; range 56 1), postmenopausal for 2 years, were prospectively studied. Exclusion criteria were use of hormone replacement therapy within 3 months of enrollment, body mass index 32 kg/m, or history of coronary artery disease, congestive heart failure, diabetes, hypertension, stroke, breast or endometrial cancer, deep vein thrombosis, renal failure, or use of lipid-lowering medications. Baseline clinical, laboratory, and echocardiographic findings are listed in Table 1. The Institutional Review Board approved the study and all participants signed informed consent. Laboratory tests and ultrasound examinations were performed at baseline and at the end of a 6-week treatment period with estrogen. Estrogen preparations included transdermal estradiol 0.1 mg (13 of 17 women, 76%) or oral conjugated equine estrogen (Premarin, Wyeth-Ayerst, Philadelphia, Pennsylvania) 0.625 mg/day (4 of 17 women, 24%). The left brachial artery (BA) was imaged using a 12-MHz linear array transducer as previously reported. Reactive hyperemia was produced following release of upper arm cuff occlusion at 50 mm Hg above systolic blood pressure for 5 minutes. After cuff release, pulsewave Doppler was performed immediately and blood flow velocity was measured as early as possible within the initial 30 seconds as an average of 3 consecutive cardiac cycles. Subsequent 2-dimensional and M-mode imaging of the artery for measurement of diameter were performed between 30 and 90 seconds after cuff release. BA systolic blood flow was calculated as: (BA diameter/2) flow VTI , where VTI is the velocity time integral of the Doppler spectral signal. BA FMD was calculated as: (100 [BA diameter postcuff release BA diameter pre cuff release]/BA diameter precuff release) . The degree of reactive hyperemia was calculated as: (100 [BA flow postcuff release BA flow precuff release]/BA flow precuff release) . All data were recorded on super-VHS videotape and selected frames stored on optical disk. Data are expressed as mean SEM, numbers or percentages. Continuous variables were compared using a 2-tailed Student’s t test. A 2-tailed bivariate Pearson’s correlation coefficient was used to assess the relation of baseline FMD to its change following estrogen therapy. A p value of 0.05 was considered significant. Baseline BA diameter increased from 2.88 0.01 to 3.09 0.01 mm after reactive hyperemia, corresponding to a FMD of 7.6 1.4% (range 0% to 17.2%). Following ERT, BA diameter increased from 3.01 0.01 to 3.28 0.01 mm after reactive hyperemia, corresponding to a FMD of 9.2 0.9% (range 2.0% to 12.9%) (Figure 1). Both resting and posthyperemic BA diameters were significantly larger on ERT compared with pretreatment values. However, FMD did not increase significantly with ERT. Baseline BA flow VTI increased from 18 1 to 35 3 cm following reactive hyperemia, corresponding to resting and posthyperemic BA systolic blood flows of 1.14 0.08 and 2.68 0.24 ml/cycle (p 0.001). Following ERT, BA VTI increased from 17 1 to 45 4 cm following reactive hyperemia (Figure 2), corresponding to resting and posthyperemic BA systolic blood flows of 1.17 0.09 and 3.89 0.36 ml/cycle (p 0.001). Thus, resting BA VTI and systolic blood flow were similar before and after ERT. However, posthyperemic BA VTI and systolic blood flow increased significantly following ERT (p 0.001 for both). Reactive hyperemia increased from the baseline value after ERT (162 35% to 243 29%, p 0.05). A strong negative correlation was found between baseline BA FMD and its change from baseline following ERT (r 0.83, p 0.0001). There was no significant correlation between the change in FMD following From the Divisions of Cardiology and Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York. Dr. Ilercil’s address is: Division of Cardiology, The Jack D. Weiler Hospital of the Albert Einstein College of Medicine, 1825 Eastchester Road, Room W1-70, Bronx, New York 10461-2373. E-mail: ailercil@ montefiore.org. Manuscript received October 9, 2001; revised manuscript received and accepted January 24, 2002.