Prospective association between hormone replacement therapy, heart rate, and heart rate variability

Journal of Clinical Epidemiology 56 (2003) 565–571

Prospective association between hormone replacement therapy, heart rate, and heart rate variability The Atherosclerosis Risk in Communities Study Mercedes R. Carnethona,b,*, Mary S. Anthonyc, Wayne E. Casciod, Aaron R. Folsome, Pentti M. Rautaharjuc, Duanping Liaof, Gregory W. Evansc, Gerardo Heissd a

Stanford Center for Research in Disease Prevention, Stanford University School of Medicine, 1000 Welch Road, Palo Alto, CA 94304, USA b Department of Preventive Medicine, Northwestern University, 680 North Lake Shore Drive, Suite 1102, Chicago, IL 60611 c Wake Forest University School of Medicine, Medical Center BLVD, Winston-Salem, NC 27517, USA d University of North Carolina at Chapel Hill, Bank of America Building, 137 East Franklin Street, Suite 306, Chapel Hill, NC 27514, USA e Division of Epidemiology, University of Minnesota, 1300 South Second Street, Suite 300, Minneapolis, MN 55454, USA f Pennsylvania State University Hershey Medical Center, 600 Centerview Drive, Suite 2200, PO Box 855, Hershey, PA 17033, USA Received 1 April 2002; received in revised form 14 November 2002; accepted 19 December 2002

Abstract Hormone replacement therapy is universely associated with coronary heart disease (CHD) in observational studies, but it is unknown whether this association is mediated by the autonomic nervous system. We tested the hypothesis that postmenopausal hormone replacement therapy was associated with more favorable heart rate (HR) and heart rate variability (HRV) in a population sample of women (n ⫽ 2,621). Hormone therapy use was measured at four examinations beginning in 1987. Supine HR and HRV indices were measured for 6 minutes at the final examination (1996–1998). In unadjusted linear regression models, hormone therapy was associated with lower HR (hormone use ⫽ 64.7 vs. never ⫽ 65.7 beats/min, P ⫽ .01) and higher HRV. However, following adjustment for age and CHD risk factors, both associations were eliminated. Results from this observational study suggest that hormone therapy is not associated with HR or HRV. These analyses should be replicated in a randomized trial. 쑖 2003 Elsevier Inc. All rights reserved. Keywords: Autonomic nervous system; Estrogen replacement therapy; Coronary heart disease; Gender

1. Introduction Observational studies suggest that hormone replacement therapy is positively associated with cardiovascular disease risk factors [1], coronary heart disease (CHD) morbidity, and mortality [2]. Both cross-sectional observational studies and clinical trials report a favorable effect of hormone replacement on lipids [1,3], glucose, and insulin [4]. Animal models and smaller trials also report possible effects on physiologic processes related to CHD, such as atherogenesis, vascular function, and inflammation [5]. In contrast, very little research has been conducted on the role of hormone therapy on autonomic nervous system function. Impaired autonomic nervous system function, commonly measured at the population level by heart rate variability (HRV) [6], is a risk factor for nonfatal [7,8] and fatal CHD, * Corresponding author. Current address: Northwestern University, Department of Preventive Medicine, The Feinberg School of Medicine, 680 N. Lake Shore Drive, Suite 1102, Chicago, IL 60611. Tel.: 312-908-7914; fax: 312-908-9588. E-mail address: [email protected] (M.R. Carnethon). 0895-4356/03/$ – see front matter 쑖 2003 Elsevier Inc. All rights reserved. doi: 10.1016/S0895-4356(03)00008-8

[9–11] and malignant ventricular arrhythmias [12]. Gonadal hormones, both androgens and estrogens, may influence autonomic nervous system function. Previous research reports differences in HRV by gender [13–15], most commonly finding that premenopausal women have higher HRV, indicating more favorable function. Premenopausal women are reported to have higher HRV than postmenopausal women [16], which suggests that fluctuations in endogenous hormones during the menopause may play a role in age-related differences in HRV. This has lead researchers to speculate that postmenopausal hormone replacement therapy may also influence autonomic nervous system function [17,18]. The objective of this study was to investigate whether hormone replacement therapy is prospectively associated with alterations in autonomic function, as estimated by HRV. Based on previous small studies reporting that HRV is more favorable among users of hormone replacement therapy [17,18], we hypothesized that women who used hormone replacement therapy would have higher HRV, indicating a more favorable autonomic tone. To our knowledge, this is

566

M.R. Carnethon et al. / Journal of Clinical Epidemiology 56 (2003) 565–571

the first such longitudinal assessment in a population-based sample of healthy women.

2. Methods 2.1. Study population and design Participants in this study were selected from the Atherosclerosis Risk in Communities cohort, a longitudinal investigation of clinical and subclinical atherosclerotic disease. A probability sample of white and black adults aged 45–64 were recruited from the Minneapolis suburbs, MN, Forsyth County, NC, and Washington County, MD; Black adults were oversampled in Forsyth County, NC, and sampled exclusively from a fourth community—Jackson, MS. A detailed description of the study design, response rates, and methods is published [19]. At baseline (1987–1989), 8,730 women were recruited and followed through 1998. For this study, we included women who at baseline were free of prevalent CHD, peri- or postmenopausal (naturally or surgically), attended all visits, and had valid HRV data. This analysis includes 2,621 women. 2.2. Data collection Women were examined at 3-year intervals during the study (exam 2: 1990–1992; exam 3: 1993–1995; exam 4: 1996–1998). Menopausal status was ascertained by selfreport at each examination and classified according to the frequency of menstrual periods in the 2 years prior to each examination. Women reporting regular menstrual periods were classified as premenopausal, women with irregular but still present menstrual periods, or who reported hysterectomy without bilateral oopherectomy were classified as perimenopausal. Women who ceased menstrual periods naturally or reported undergoing bilateral oopherectomy were classified as postmenopausal. 2.2.1. Hormone replacement therapy At each examination, women were asked whether they used hormone replacement therapies during the previous examination interval and the type of therapy used, estrogen replacement therapy (ERT), progestin plus estrogen therapy (PERT), or other. Women who reported current or former hormone therapy at any time during the study were classified as “ever” users and compared to women who did not use any hormones. Additionally, women were classified into groups based on hormone therapy at the final examination: (1) current ERT, (2) current PERT, (3) former (started and stopped therapy during the study interval or reported former use at baseline) ERT or PERT, and (4) never. Neither dose nor composition of hormone therapy was available. 2.2.2. Heart rate and HRV Following a 10-minute rest period at the final examination, HRV was measured for 6 minute from participants in the

supine position using three standard Ag/AgCl electrodes. A dedicated computer with PREDICT II HRVECG software (Arrhythmia Research Technology, Inc., Austin, TX) was used for continuous detection of electrocardiographic R waves at a sampling frequency of 1,000 Hz. Artifacts were identified by a single trained operator, and records were excluded for any of the following reasons: ⭓ 20% of QRS waves affected with artifacts, a record length of ⭐ 150 s, and use of an implanted pacemaker. Heart rate was derived from the RR interval record (heart rate ⫽ 1/R-R interval length, ms), and converted to beats/min. The standard deviation of all normal R-R intervals (SDNN) was used to estimate the overall modulation of autonomic tone. A fast Fourier transformation was used to calculate the power spectral density curve [6]. High (HF, 0.15–0.40 Hz) and low (LF, 0.04–0.15 Hz) frequency power was used to estimate parasympathetic and sympathetic modulation of variability, respectively [20]. 2.2.3. Other measurements Demographic characteristics and CHD risk factors were measured according to standardized protocols common to all study sites and subject to regular quality control checks [21,22]. Prevalent CHD was defined as a history of coronary artery bypass surgery, balloon angioplasty, or myocardial infarction based on electrocardiograph or self-report. Age, race/ethnicity, gender, education level, and smoking history were self-reported. Education was dichotomized to compared participants with less than a high school education to those with equal to or greater than a high school education. Smoking status was dichotomized to compare current to never or former smokers. Medication use was identified and defined by coding all reported medications, vitamins, and supplements used in the 2 weeks prior to the clinical examination. Medications classified as potentially influencing the autonomic nervous system included β-blockers, angiotensin converting enzyme (ACE)-inhibitors, calcium channel blockers, antianginals, antihypertensives (excluding diuretics), vasodilators, and digoxin. The Baecke questionnaire was used to assess participation in sports-related (e.g., jogging) physical activity on a five-point scale from one (low) to five (high) [23]. Participants were asked to fast for 12 hours prior to the clinical examination. Blood was drawn from seated participants and shipped to a central laboratory for assay. Total cholesterol, triglycerides, and high-density lipoprotein cholesterol were measured enzymatically [24]. Glucose was measured by a hexokinase/glucose-6-phosphate dehydrogenase method on a Coulter DACOS device. Diabetes was defined as fasting serum glucose ⭓ 126 mg/dL, nonfasting glucose ⭓ 200 mg/dL, or self-reported current use of medications for diabetes or a self-reported previous diagnosis. Seated blood pressure was measured three times using a random zero sphygmomanometer after a 5-minute rest; the average of the last two measurements was used in this study. Hypertension was defined as any of the following: (1) systolic blood pressure ⭓ 140 mmHg; (2) diastolic blood

M.R. Carnethon et al. / Journal of Clinical Epidemiology 56 (2003) 565–571

pressure ⭓ 90 mmHg; or (3) reported use of hypertension lowering medications at least 2 weeks prior to the clinic examination. Body mass index was calculated as the ratio of weight (kg) to standing height in meters squared (kg/m2). With participants standing erect, waist girth was measured at the umbilicus, and hip girth was measured as the largest diameter around the gluteal muscles. 2.3. Statistical methods Age-adjusted means (standard errors) and proportions of baseline covariates were compared by hormone therapy using t-tests (means) and χ2 tests (proportions). Multivariable linear regression models were used to compare mean HRV indices by hormone therapy. Separate models compared the following groups to never users: (1) “ever” use of ERT or PERT during follow-up; (2) ERT and PERT users at the final examination and former users who discontinued therapy; (3) ERT and PERT users (separately) at the final examination. Because of the well-known “healthy user” bias in observational studies of postmenopausal hormones and health outcomes [25], we present results adjusted statistically for characteristics that differ between hormone users and nonusers. Adjusted models include terms for age, race and study center, heart rate, body mass index, current alcohol drinking, current cigarette smoking, previous oral contraceptive use, medications know to affect the autonomic nervous system, hypertension, and diabetes. Statistical significance is denoted at P ⬍ .05. All statistical computations were performed using SAS software (The SAS Institute, Cary, NC).

3. Results Over the course of the study, 60% of all women (n ⫽ 1,485) used hormone therapy. Of those, 961 were using hormones at the final examination. Women who used hormone therapy at any time during the study were, on average, 2.5 years younger than never users, so all baseline characteristics were adjusted for age and compared by hormone therapy use (Table 1). Following age adjustment, hormone users were less likely to be Black, more likely to have achieved at least a high school education, more likely to have previously used oral contraceptives, more likely report current alcohol use, and less physically active than never users. Women who used hormone therapy during the study were leaner at baseline, had lower total and low-density lipoprotein cholesterol, and the prevalence of diabetes and hypertension was lower. This pattern of association was similar by hormone therapy at the final examination. Table 2 displays the distribution of heart rate and HRV indices in the sample. Mean heart rate was 65.1 beats/min (SD ⫽ 9.5) and mean SDNN was 34.7 ms (SD ⫽ 18.7). The distributions of HF and LF power were highly skewed, so values were log-transformed for all modeling. The relationship between hormone therapy use, heart rate, and HRV is displayed in Table 3. In unadjusted models,

567

Table 1 Age-adjusted baseline (1987–1989) characteristics by HRT use Covariate (units)

HRTa

Never

P valueb

n Age (years), Mean, SEc Race (% Black) Education (% ⭓High School) Previous oral contraceptive use (%) Medication Use (%)d Physical Activity, mean (SE)e Current smokers (%) Current drinkers (%) Body mass index (kg/m2) mean, SE Waist/Hip Ratio (cm), mean, SE Total Cholesterol (mmol/L), mean, SE LDL CHolesterol (mmol/L), mean, SE Diabetes (%) Hypertension (%)

1,485 53,5 (0.1) 20 87

1,136 56.0 (0.02) 33 74

⬍ .0001 ⬍ .0001 ⬍ .0001

50 15

37 13

⬍ .0001 .13

2.42 (0.02) 20 59

2.34 (0.02) 21 44

0.0043 0.42 ⬍ .0001

26.8 (0.2)

28.8 (0.2)

⬍ .0001

0.88 (0.00)

0.90 (0.00)

⬍ .0001

5.58 (0.03)

5.75 (0.03)

⬍ .0001

3.39 (0.03) 6 30

3.67 (0.03) 13 37

⬍ .0001 ⬍ .0001 .0006

a Ever used hormone replacement therapy ([HRT] estrogen or progestin plus estrogen replacement therapy) during the study. b P values from χ2 test of proportions, and adjusted F-statistics from ANOVA models for Least-Squares Means. c Unadjusted. d β-Blockers, angiotensin converting enzyme (ACE)-inhibitors, calcium channel blockers, antianginals, antihypertensives, vasodilators, digoxin. e Baecke sport index: 1 ⫽ low; 5 ⫽ high.

women who used hormones at any time during the study, including the final examination (current ERT only) had mean heart rates approximately 1 beat/min lower than women who never used hormone therapy. Following adjustment for demographic characteristics, this association attenuated to nonsignificance for all women, except those currently using ERT. However, adjusting for all possible covariates that differed between hormone users and nonusers completely eliminated the association. SDNN was not associated with hormone therapy use. HF and LF power demonstrate a pattern similar to that of heart rate; hormone users had higher HF and LF in unadjusted models, but these differences are eliminated in models adjusted for demographic characteristics and other covariates. Only among current users of PERT does HF retain a modest elevation (4.64 vs. 4.47, P ⫽ .02). Table 2 Distribution of HRV at the final examination (1996–1998) Heart rate variability index Mean heart rate (beats/min) SDNNa (ms) High frequency power (ms2) Low frequency power (ms2) a

Mean

SD

65.1

Median 9.5

34.7 250.9

18.7 2,860.60

298

2,670.50

SD of normal R-R intervals.

Interquartile range

64.2

12.3

30.3 87.5

177.4 148.5

123

198.7

1 2 3 1 2 3 1 2 3 1 2 3

Heart rate, bpm

64.7 64.9 65.0 35.2 35.0 35.0 4.56 4.54 4.55 4.89 4.84 4.84

(0.3) (0.2) (0.3) (0.5) (0.5) (0.5) (0.03) (0.03) (0.03) (0.03) (0.03) (0.03)

64.5 64.6 64.9 34.6 34.2 34.0 4.56 4.53 4.53 4.90 4.83 4.82

(0.3) (0.3) (0.3) (0.6) (0.6) (0.4) (0.04) (0.04) (0.04) (0.04) (0.04) (0.04)

64.3 64.3 64.6 34.3 33.8 33.4 4.54 4.49 4.48 4.89 4.83 4.80

(0.4) (0.4) (0.4) (0.7) (0.7) (0.7) (0.05) (0.05) (0.04) (0.05) (0.05) (0.04)

Hormone replacement therapy Current Current Ever HRT ERT 64.9 65.5 65.5 35.2 35.0 35.5 4.60 4.62 4.64 4.92 4.84 4.85

(0.5) (0.6) (0.6) (1.1) (1.1) (1.0) (0.07) (0.07) (0.07) (0.07) (0.07) (0.07)

Current PERT 65.4 65.4 65.4 36.4 36.3 36.7 4.56 4.57 4.58 4.87 4.87 4.89

(0.4) (0.4) (0.4) (0.8) (0.8) (0.8) (0.05) (0.05) (0.05) (0.05) (0.05) (0.05)

Former 65.7 65.5 64.9 34.1 34.4 34.8 4.43 4.45 4.47 4.74 4.80 4.83

(0.3) (0.3) (0.3) (0.6) (0.6) (0.5) (0.04) (0.04) (0.03) (0.03) (0.04) (0.03)

Never 0.01 0.13 0.81 0.13 0.43 0.76 0.01 0.05 0.10 0.001 0.34 0.89

Ever vs. never

P valuesb

0.01 0.06 0.94 0.58 0.77 0.35 0.01 0.15 0.27 0.002 0.54 0.77

Current HRT vs. never 0.59 0.97 0.34 0.03 0.06 0.05 0.04 0.07 0.07 0.04 0.26 0.37

Former vs. never

0.003 0.01 0.52 0.87 0.51 0.11 0.05 0.49 0.87 0.01 0.63 0.60

Current ERT vs. never

0.25 0.98 0.35 0.36 0.62 0.51 0.03 0.04 0.02 0.02 0.58 0.79

Current PERT vs. never

0.59 0.98 0.17 0.46 0.34 0.07 0.50 0.13 0.04 0.69 0.86 0.52

Current ERT vs. PERT

Abbreviations: BPM, beats/minute; ERT, estrogen replacement therapy; HF, high frequency power; HRT, hormone replacement therapy; HRV, heart rate variability; SDNN, standard deviation of normal R-R intervals; LF, low frequency power; PERT, progestin ⫹ estrogen replacement therapy. a Model 1: unadjusted. Model 2: adjusted age, race, education. Model 3: model 2 + heart rate, previous birth control pill use, β-blockers, angiotensin converting enzyme (ACE)-inhibitors, calcium channel blockers, antianginals, antithypertensive, vasodilators, digoxin, body mass index, current smoking, current drinking, diabetes, hypertension, physical activity (Baecke index 1 ⫽ low, 5 ⫽ high). b P values based on F-tests.

Log LF, ms2

Log HF, ms2

SDNN, ms

Modela

HRV index

Table 3 Heart rate and HRV by HRT

568 M.R. Carnethon et al. / Journal of Clinical Epidemiology 56 (2003) 565–571

M.R. Carnethon et al. / Journal of Clinical Epidemiology 56 (2003) 565–571

4. Discussion In this population sample of women, hormone replacement therapy use may be associated with a slightly lower heart rate and higher HF and LF power, a marker of parasympathetic modulation of autonomic nervous system variability. However, given the marked attenuation in statistical significance following adjustment, this relationship may be explained in large part by differences in age and the prevalence of other cardiovascular risk factors between hormone users and nonusers. Our data indicate that there may be differences in effect by hormone formulation, as ERT use was most strongly associated with lower heart rates, and PERT use was associated with higher HF power. Three previous small trials [17,18,26] and two crosssectional studies [13,27] reported improvements in autonomic function with the use of hormone therapy. Our finding that women using combination estrogen/progestin therapy had slightly higher HF power than their counterparts was consistent with a report based on a randomized trial of 43 women followed for 3 months [26]. Results in this trial were adjusted for age and mean arterial pressure, but no lifestyle factors. Rosano et al. [17] compared HRV parameters after 4 months between 18 postmenopausal women who agreed to use ERT patches and 12 women who refused (mean age ⫽ 56). In this nonrandomized trial, the ratio of LF and HF power (an estimate of sympathetic input) decreased, and mean R-R length (the inverse of heart rate) and SDNN increased after 4 months in women who used ERT patches, which was opposite to our findings. Similarly, Yildirir et al. [18] followed 46 women (mean age ⫽ 48) who used PERT or ERT (for women without a uterus) for 6 months, and report that LF/HF decreased and HF power and SDNN increased. Lipsitz et al. [27] studied HRV in response to postural tilt and meal ingestion (established sympathetic nervous system stimulants) in 20 healthy women (aged 60 to 75), 10 of whom had previously used oral estrogen. They reported that women who used hormone therapy had smaller sympathetic responses (LF power) and higher heart rates in response to tilt and meal ingestion. In a population based cross-sectional investigation, Huikuri et al. [13] reported that women (mean age ⫽ 51 years) who used ERT (n ⫽ 46) had higher HRV (lower LF and higher HF) than age-matched nonusers (n ⫽ 140). In each study, the authors concluded that hormone replacement had a favorable impact on autonomic nervous system activity. Unadjusted results in our observational study were similar; however, we found that age and other known cardiovascular risk factors explained the differences in heart rate and HF power by hormone therapy. With the exception of the studies by Huikuri et al. [13] and Farag et al. [26], earlier research did not adjust for age or the prevalence of cardiovascular disease risk factors. Previous research indicates that age is a major determinant of HRV, and that HRV decreases with increasing age [14,15]. Further, lower HRV is also associated with elevated blood pressure, diabetes, cigarette

569

smoking, physical inactivity, a history of CHD, and the use of β-blockers [15,28–30], all of which are behaviors and health conditions that are more prevalent among women who choose not use hormones [25]. Therefore, it is likely that the positive association detected in these smaller nonrandomized studies may be attributable to study design flaws that resulted in incomplete adjustment. In contrast to these favorable reports of the effect of hormone therapy on HRV and our null results, one crosssectional study reported an attenuation of HRV following the use of hormone therapy. Christ et al. [31] found that 21 women who used hormone replacement therapy had significantly lower markers of parasympathetic tone than 24 nonusers, and this association was restricted to the 13 women who used PERT. The authors suggested, and we agree with the need for, randomized trials to study the relationship. Despite the mixed findings, the biological plausibility of a relationship between hormone therapy and HRV is convincing [32]. The hormone, noradrenaline, is released during sympathetic nerve stimulation, and is thus used as a marker of sympathetic nervous system activation. According to one study, postmenopausal women (n ⫽ 26) have higher levels of plasma noradrenaline and an exaggerated noradrenaline response to stress testing compared to premenopausal women (n ⫽ 13) [33]. Following 6 weeks of estrogen therapy, the exaggerated stress response was blunted. This same effect was observed in a double-blind crossover study of 20 men who were exposed to estrogen [34]. An animal study demonstrated that heart rates increased following ovarectomy female rats and castration in male rats, which suggests a role for either estrogen or testosterone on parasympathetic stimulation [35]. Support for the role of estrogen was provided in another animal study that showed that parasympathetic activity, as estimated by heart period variability, which was suppressed following ovarectomy in rats was restored with estrogen replacement [36]. Our results must be interpreted in light of some limitations. First, the choice to use hormone replacement therapy is associated with characteristics related to favorable health status [37,38]. Thus, the potential for bias in this observational study cannot be ruled out. We attempted to statistically control for an extensive set of possible confounding variables to try to reduce this bias. However, because this is not a randomized trial, all differences may not have been eliminated. Information about the specific hormone formulation and dose was not available, which may obscure associations. However, during the time period of this study (1987–1996) one of the most commonly used estrogens was a 0.625 mg daily dose of conjugated equine estrogen (trade name, Premarin). Commonly, a synthetic progestin, medroxyprogesterone acetate (trade names, Provera, Cycrin, Amen, Curretab), was added at 5–0 mg (cyclic dose) or 2.5–5 (continuous daily dose) [39] for women with a uterus. It is not known whether hormone therapy has a lasting effect on HRV, so women using hormones at the end of the

570

M.R. Carnethon et al. / Journal of Clinical Epidemiology 56 (2003) 565–571

study were examined separately from women who discontinued therapy by the study end. Another option was to categorize hormone use at the baseline examination. We feel the latter option is more problematic because of the inability to capture changes in hormone use. If the estimated effect of hormone use on HRV is restricted to women currently using hormones, this could not be captured with baseline measures of hormone use. Despite these limitations and those intrinsic to observational studies of hormone replacement therapy, this is the largest observational study of postmenopausal women with the longest follow-up to evaluate the effects of hormone therapy on HRV. Our findings suggest that the potential benefits of hormone therapy on cardiovascular morbidity as seen in observational studies are not attributable to improved HRV. However, future studies should replicate these analyses in randomized trials. Further research is needed to explore possible mechanisms to explain the relationship between hormone therapy and cardiovascular risk.

Acknowledgments Support for this article was provided by the National Heart, Lung, and Blood Institute, ARIC Contracts: N01-HC55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022; and HRV Grant: 5 R01 HL55669; and also by NIH/NHLBI NRSA Training Grant: 5T32HL07034-26. The authors thank the staff and participants in the ARIC study for their important contributions.

References [1] Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu KK, Szklo M. Association of hormone replacement therapy with various cardiovascular risk factors in postmenopausal women. N Engl J Med 1993;328:1069–75. [2] Grodstein F, Stampfer MJ, Colditz GA, Willett WC, Manson JE, Joffe M, Rosner B, Fuchs C, Hankinson SE, Hunter DJ, Hennekens CH, Speizer FE. Postmenopausal hormone therapy and mortality. N Engl J Med 1997;336:1769–76. [3] The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/ progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Intervension (PEPI) trial. JAMA 1995;273:199–208. [4] Espeland MA, Hogan PE, Fineberg SE, Howard G, Schrott H, Waclawiw MA, Bush TL. Effect of postmenopausal hormone therapy on glucose and insulin concentrations. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions [see comments]. Diabetes Care 1998;21:1589–95. [5] Mosca L. The role of hormone replacement therapy in the prevention of postmenopausal heart disease. Arch Intern Med 2000;160:2263–72. [6] Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation 1996;93:1043–65. [7] Liao D, Cai J, Rosamond WD, Barnes RW, Hutchinson RG, Whitsel EA, Rautaharju P, Heiss G. Cardiac autonomic function and incident

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16] [17]

[18]

[19] [20]

[21]

[22]

[23]

[24]

[25]

coronary heart disease: a population-based case cohort study: The ARIC study. Am J Epidemiol 1997;145:696–706. Tsuji H, Larson MG, Venditti FJ Jr, Manders ES, Evans JC, Feldman CL, Levy D. Impact of reduced heart rate variability on risk for cardiac events: The Framingham Heart study. Circulation 1996;94:2850–5. Dekker JM, Crow RS, Folsom AR, Hannan PJ, Liao D, Swenne CA, Schouten EG. Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortablity from several causes. The ARIC study. Circulation 2000;102:1239–44. Dekker J, Schouten E, Klootwijk P, Pool J, Sweene C, Kromhout D. Heart rate variability from short electrocardiographic recordings predicts mortality from all cuases in middle-aged and elderly men. The Zutphen study. Am J Epidemiol 1997;145:899–908. Fei L, Anderson MH, Katritsis D, Sneedon J, Statters DJ, Malik M, Camm AJ. Decreased heart rate variability in survivors of sudden cardiac death not associated with coronary artery disease. Br Heart J 1994;71:16–21. Farrell TG, Bashir Y, Cripps T, Malik M, Poloniecki J, Bennett ED, Ward DE, Camm AJ. Risk stratification for arrhythmic events in postinfarction patients based on heart rate variability, ambulatory electrocardiographic variables and the signal-averaged electrocardiogram. J Am Coll Cardiol 1991;18:687–97. Huikuri HV, Pikkujamsa SM, Airaksinen KEJ, Ikaheimo MJ, Rantala AO, Kauma H, Lilja M, Kesaniemi YA. Sex-related differences in autonomic modulation of heart rate in middle-aged subjects. Circulation 1996;94:122–5. Liao D, Barnes RW, Chambless LE, Simpson RJ, Sorlie P, Heiss G. Age, race, and sex differences in autonomic cardiac function measured by spectral analysis of heart rate variability—The ARIC study. Am J Cardiol 1995;76:906–12. Tsuji H, Ferdinand J, Venditti J, Manders ES, Evans JC, Larson MG, Feldman CL, Leavy D. Determinants of heart rate variability. J Am Coll Cadiol 1996;28:1539–46. Brockbank CL, Chatterjee F, Bruce SA, Woledge RC. Heart rate and its variability change after the menopause. Exp Physiol 2000;85:327–30. Rosano GMC, Patrizi R, Leonardo F, Ponikowski P, Collins P, Sarrel PM, Chierchia SL. Effect of estrogen replacement therapy on heart rate variability and heart rate in healthy postmenopausal women. Am J Cardiol 1997;80:815–7. Yildirir A, Kabakci G, Yarali H, Aybar F, Akgul E, Bukulmez O, Tokgozoglu L, Gurgan T, Oto A. Effects of hormone replacement therapy on heart rate variability in postmenopausal women. Ann Non-Invasive Electrocardiol 2001;6:280–4. ARIC Investigators. The Atherosclerosis Risk in Communities (ARIC) study: design and objectives. Am J Epidemiol 1989;129:687–99. Akselrod S. Components of heart rate variability: basic studies. In: Malik M, Camm AJ, editors. Heart rate variability. Armonk, NY: Futura Publishing Company, Inc.; 1995. National Heart Lung and Blood Institute. Manual 1: general description and study management. In: Atherosclerosis risk in communities study protocol. Chapel Hill, NC: University of North Carolina at Chapel Hill, ARIC Coordinating Center (CSCC); 1997. National Heart Lung and Blood Institute. Manual 12: quality assurance and quality control. Atherosclerosis Risk in Communities Study protocol. Chapel Hill, NC: University of North Carolina at Chapel Hill; 1997. Baecke J, Burema J, Frijters J. A short questionnaire for the measurement of habitual physical activity in epidemiologic studies. Am J Clin Nutr 1982;36:936–42. Warnick GR, Mayfield C, Benderson J, Chen JS, Albers JJ. HDL cholesterol quantitation by phosphotungstate-Mg2⫹ and by dextran sulfate-Mn2⫹-polyethylene glycol precipitation, both with enzymic cholsterol assay compared with the lipid research method. Am J Clin Pathol 1982;78:718–23. Grodstein F. Can selection bias explain the cardiovascular benefits of estrogen replacement therapy? Am J Epidemiol 1996;143:979–82.

M.R. Carnethon et al. / Journal of Clinical Epidemiology 56 (2003) 565–571 [26] Farag NH, Nelesen RA, Parry BL, Loredo JS, Dimsdale JE, Mills PJ. Autonomic and cardiovascular function in postmenopausal women: the effects of estrogen versus combination therapy. Am J Obset Gynecol 2002;186:954–61. [27] Lipsitz LA, Connelly CM, Kelley-Gagnon M, Kiely DK, Morin RJ. Effects of chronic estrogen replacementn therapy on beat-to-beat blood pressure dynamics in health postmenopausal women. Hypertension 1995;26:711–5. [28] Liao D, Cai J, Brancati FL, Folsom A, Barnes RW, Tyroler HA, Heiss G. Association of vagal tone with serum insulin, glucose, and diabetesmellitus—The ARIC study. Diabetes Res Clin Pract 1995;30:211–21. [29] Liao D, Cai J, Barnes RW, Tyroler HA, Rautaharju P, Holme I, Heiss G. Association of cardiac autonomic function and the development of hypertension: The ARIC study. Am J Hypterens 1996;9:1147–56. [30] Ito H, Ohshima A, Tsuzuki M, Ohto N, Yanagawa M, Maruyama T, Kaji Y, Kanaya S, Nishioka K. Effects of increased physical activity and mild calorie restriction on heart rate variability in obese women. Jpn Heart J 2001;42:459–69. [31] Christ M, Seyffart K, Wehling M. Attenuation of heart-rate variability in postmenopausal women on progestin-containing hormone replacement therapy. Lancet 1999;353:1939–40.

571

[32] Du X-J, Riemersma RA, Dart AM. Cardiovascular protection by ostrogen is partly mediated through modulation of autnomoic nervous function. Cardiovasc Res 1995;30:161–5. [33] Lindheim SR, Legro RS, Bernstein L. Behavioral stress responses in premenopausal and postmenopausal women and the effects of strogen. Am J Obstet Gynecol 1992;167:1831–6. [34] Del Rio G, Velardo A, Zizzo G. Effect of estradiol on the sympathoadrenal response to mental stress in normal men. J Clin Endocrinol Metab 1994;79:836–40. [35] Du XJ, Dart AM, Riemersma RA. Sex differences in the parasympathetic nerve control of rat heart. Clin Exp Pharmacol Physiol 1994; 21:485–93. [36] McCabe PM, Porges SW, Carter CS. Heart period variability during estrogen exposure and withdrawal in female rats. Physiol Behav 1981;26:535–8. [37] Goldstein IB, Shapiro D. The cardiovascular response to postural change as a function of race. Biol Psychol 1995;39:173–86. [38] Keating NL, Cleary PD, Rossi AS, Zaslavsky AM, Ayanian JZ. Use of hormone replacement therpay in the United States. Ann Intern Med 1999;130:545–53. [39] Greendale GA, Lee NP, Arriola ER. The menopause. Lancet 1999; 353:571–80.