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Hypertension 2008 Coylewright 952 9
Hypertension 2008 Coylewright 952 9
Received December 2, 2007; first decision December 21, 2007; revision accepted January 3, 2008.
From the Department of Medicine (M.C., P.O.), Johns Hopkins University School of Medicine, Baltimore, Md; and Physiology and Biophysics (J.F.R.),
University of Mississippi Medical Center, Jackson.
This paper was sent to Ernesto L. Schiffrin, consulting editor, for review by expert referees, editorial decision, and final disposition.
Correspondence to Pamela Ouyang MBBS, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave, Baltimore, MD 21224. E-mail
pouyang@jhmi.edu
(Hypertension. 2008;51:952-959.)
2008 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.107.105742
952
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Coylewright et al Menopause and Hypertension 953
Table. Studies Describing Relationship Between Menopausal Status and Blood Pressure or Cardiovascular Events
Study Menopause
Author, Publication Year Population Status Study Design Association/Conclusion Strengths Limitations
Menopause associated with HTN
Weiss 19727 897 women; Pre- and Cross-sectional Increasing DBP is related US HES cohort. Questionnaire
age 4051 postmenopausal to menopause, for menopause.
years independent of age; no Limited
effect of time since accounting of
menopause confounders
e.g. BMI, race.
Average of only
3 BP
measurements.
Staessen 19898 462 women; Pre- and Cross-sectional After stratifying by age Stratified by 3 age Questionnaire
age 3559 postmenopausal and BMI, odds of groups and 2 strata of for menopause.
years hypertension for BMI. BP from average of
postmenopausal women 10 measurements.
compared to
premenopausal women
was 2.2 (95% CI
1.14.4, P0.03).
Relation between SBP
and age steeper in
menopausal than
premenopausal women
Owens 199379 34 women and Pre- and Cross-sectional Postmenopausal women Ambulatory BP monitor Small size of
15 men; age postmenopausal had higher and standardized mental sample
4055 years stress-induced SBP and and physical challenges
DBP rises than
premenopausal women
or men. Diastolic BP was
higher in
post-menopausal women
and men compared to
pre-menopausal women
Zanchetti 200515 18,326 women; Pre-, peri-, and Cross-sectional SBP and DBP higher in Large cohort. The 2- Three BP
age 4659 postmenopausal postmenopausal women, year span subgroups measurements
years association evident only reduce age difference in 505 general
among women in the among pre-, peri- and practitioners
younger age groups post-menopausal groups. offices
(4649 years);
P0.0001
Staessen 19979 315 women, 166 pre-, 44 Prospective SBP rose nearly Median follow-up of 5.2
matched to 315 peri-, 105 5 mm Hg per decade years. Ambulatory
men by age postmenopausal more (Por0.05) in 24-hour monitoring used
and BMI; age peri- and in the follow-up
3070 years postmenopausal than in measurement. FSH levels
premenopausal women. at follow-up
These trends were not
found in DBP in women,
or in SBP or DBP in
men.
Scuteri 200110 226 women; Pre-, peri-, and Prospective Postmenopausal women Well characterized cohort Predominantly
mean age 64 postmenopausal on HRT have a smaller within Baltimore white, educated
10 years evaluating increase in SBP over Longitudinal Study of volunteers.
association with time; most pronounced Aging (BLSA) Observational
use of HRT among older women study so there
may be
unaccounted
differences
between HRT
users and
non-users
(Continued )
Table. Continued
Study Menopause
Author, Publication Year Population Status Study Design Association/Conclusion Strengths Limitations
of calcium, or timing of menopause. Careful selection of healthy cross-sectional and longitudinal analyses are subject to con-
normotensive individuals may reduce confounding, but inclu- founding; the former because of inability to assess temporal
sion of these individuals may introduce other biases and reduce relationships and the latter because of environmental changes
the generalizability of the findings. or changes in medical management over time.
Given these inconsistencies, a cross-sectional analysis was
Relative Contribution of Menopause or Aging to done in more than 18 000 Italian women, aged 46 to 59 years,
Hypertension in PMW that found a significant, but clinically small, increase in both
Conflicting findings may result from differences among systolic and diastolic BP of 3.4/3.1 mm Hg among PMW,
cohorts, including sample size, age ranges, length of time which was independent of age, BMI, smoking, or contracep-
postmenopause, use of datasets not designed to study meno- tion or HRT, and was only evident at younger menopausal
pause, and reliance on questionnaires.11 Surgically PMW age.15 The difference in BP may be underestimated given the
were often included, without considering the hormonal dif- higher prevalence of treated hypertension in PMW (35%)
ferences in natural and surgical menopause. Finally, both compared with pre-MW (20%). However, menopausal effects
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Coylewright et al Menopause and Hypertension 955
rectomy and also natural menopause.22 However, among a thiols, consistent with less NO bioavailability, were reported
broader sample of PMW, HRT results in improved FMD only in PMW compared with pre-MW.40 However, the contribu-
among women with no cardiovascular risk factors.23,24 tion of menopause could not be distinguished from that of
age. Another oxidative stress marker is F2-isoprostane,
Arterial Stiffness produced by free radicalinduced peroxidation of arachidonic
Increased arterial stiffness coincides with menopause. In a acid and has been considered a marker of in vivo ROS.41
random sample of more than 300 women and 300 men, PMW Recently, investigators reported F2-isoprostanes were not
showed higher carotid-femoral pulse wave velocity (PWV) elevated in PMW compared with pre-MW, and, contrary to
and larger common carotid artery diameters after adjustment expectations, were positively associated with levels of me-
for age, BMI, and smoking, indicating increased arterial tabolites of estradiol.42
stiffness which may explain the greater rise in systolic Estrogens, including estradiol and estrogen metabolites,
pressure among PMW.25 A study of 3149 women, ages 21 to decrease ROS by scavenging free radicals.43,44 Whether HRT
94 years, evaluated the relationship between age, menopause, in PMW protects against oxidative stress-associated diseases
and arterial stiffness assessed by brachial-ankle PWV. is unknown.
Women, aged 45 to 56 years, who were 6 years from
menopause, were most likely to be in the highest tertile of Salt Sensitivity
PWV; this was independent of age and other cardiovascular Salt sensitivity increases with age in both sexes and is likely
risk factors.26 However, other investigators have not found mediated by impaired vasodilation of the renal circulation,
sex differences in arterial wall properties with aging.27 possibly because of reduced NO availability, increased vaso-
constriction response to angiotensin II, or attenuation of the
Renin-Angiotensin System conversion of L-arginine to NO in the renal vasculature
The renin-angiotensin (RAS) system is an important regulator endothelium.29,45,46
of BP and fluid and electrolytes. Estradiol may provide PMW appear to be more salt sensitive than pre-MW,47 and
cardiovascular protection by controlling components of the surgical menopause is associated with development of salt
RAS, including decreasing AT1 receptor expression in vessels sensitivity.48 Salt sensitivity of systolic BP in healthy PMW
and kidney28 and reducing the activity of angiotensin not receiving HRT may be related to reduced bioavailability
1-converting enzyme (ACE).29 of NO associated with increased levels of the NO synthase
The role of the RAS in hypertension in PMW is less clear antagonist, asymmetrical dimethyl-L-arginine.49 Treatment
than in animal studies. A placebo-controlled study of 2 years with transdermal estradiol in PMW was associated with a
of estrogen therapy found no correlation between BP and decrease in salt sensitivity of BP.50
plasma renin activity (PRA). PRA increased during oral, but Low sodium diets decrease BP in experimental and real-
not transdermal, estradiol administration.30 Other small stud- world settings. Thus lifestyle behaviors including low sodium
ies have shown similar results,31 though some show decreased diet and exercise are recommended for individuals with
ACE activity with oral HRT.32 hypertension.
The regulation of the prorenin and renin may be affected by
gonadal hormones. Ovarian production of prorenin in re- Obesity
sponse to gonadotropins has been reported.33,34 The effect of A large cross-sectional study showed an independent associ-
estrogen on prorenin and renin appear complex. Studies in ation between BMI and hypertension in women, aged 46 to
hypertensive individuals may be complicated by antihyper- 59 years.15 In a Finnish prospective population-based study of
tensive drugs that inhibit the RAS.35 9485 perimenopausal women not on antihypertensive ther-
apy, predictors of hypertension over 5-year follow-up in-
Oxidative Stress cluded baseline weight, weight increase, and PM status at
An increase in oxidative stress can result from increased baseline.51 Overweight has a stronger association with hyper-
production of reactive oxygen species (ROS) or decreased tension in pre-MW, whereas age has a stronger association in
ability to neutralize these reactive molecules. Gender differ- PM non hormone users.52
ences in oxidative stress have been found with higher levels The mechanisms by which obesity is associated with
in males.36 Gonadectomy decreased urinary H2O2 excretion in hypertension include increased sympathetic overactivity that
male SHR and increased H2O2 excretion in females, suggest- appears closely associated with abdominal visceral fat.53
ing that testosterone increases whereas estrogen suppresses Greater sympathetic activity increases renin release and
total body oxidative stress.37 In vitro and animal models have angiotensin II formation, which in turn increases adrenal
shown that estrogen modulates prooxidant and antioxidant aldosterone production with resultant sodium retention. In-
enzyme expression and activity, including NAD(P)H oxidase creased visceral fat is associated with increased inflammatory
and superoxide dismutase, inhibiting production of ROS. It is mediators, increased oxidative stress, and decreased endothe-
postulated that the postmenopausal estrogen-deficient state is lial vasodilation.
associated with increased ROS contributing to vasoconstric- It is not clear whether menopause itself results in an
tion and hypertension.38,39 increase in BMI. Although perimenopausal women and those
Whether increased ROS is present with menopause has not with surgical menopause have been found to have higher
been unequivocally demonstrated. Increased nitrotyrosine, a BMI than pre-MW when controlling for age, physical activity
marker of endogenous peroxynitrite, and decreased nitroso- and race/ethnicity were much stronger predictors of BMI.54
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Coylewright et al Menopause and Hypertension 957
Genetic Factors Influencing Hypertension with high-normal BP (130/85 to 138/89 mm Hg) developed
Genetic factors account for 30% to 50% of interindividual hypertension within 5 years, and two-thirds progressed to
variability in BP.55,56 Hypertension is most likely a polygen- hypertension within 10 years. Women with hypertension at
etic disorder with each of the genes contributing modestly to baseline had the highest age-adjusted rate of cardiovascular
BP. It is possible that menopause might provide the environ- events (4.32/1000 person-years) followed by women with
mental trigger for the expression of certain genetic suscepti- high-normal BP (2.92/1000 person-years), compared with
bilities. Polymorphisms affecting a number of pathways normotensive women (1.62/1000 person-years).71 Diastolic
involved in hypertension have been studied. While this is not hypertension is more prevalent among younger patients, but
an exhaustive review of the literature on genetics and hyper- for those older than 50, systolic hypertension is a better risk
tension, a few pertinent studies are reviewed. predictor of cardiovascular events.72
Sex-specific determinants of genetic susceptibility that are Treatment of systolic hypertension in men and women
distinct from sex hormonemediated attenuation of sex-
reduces stroke, myocardial infarction, heart failure, and
common determinants have been found.57 Several investiga-
death.73,74 Lifestyle changes, such as low sodium diets,
tors have reported sex specific associations between human
decrease BP in experimental and real-world settings.75,76
hypertension and polymorphisms of components of the
Strategies to delay the development of hypertension among
RAS,58,59 aldosterone synthase,60 and NO synthase,61 al-
women could have a significant public health benefit. Unfor-
though not in all populations studied.62 A study evaluating the
relationship between the extremes of BP with 35 loci that tunately, women are less likely to have controlled hyperten-
have physiological roles in the regulation of BP described sion despite medication. During the 1990s, undiagnosed
several gene-by-gender interactions. In women, polymor- hypertension and poorly treated hypertension increased
phism at the 1-adrenergic receptor and 2A adrenergic among women whereas hypertension among men decreased;
receptor contributed to BP, and in men polymorphism of these differences were not explained by age. Womens
2-adrenergic receptor and angiotensinogen were associat- cardiovascular health, by survey data, may be deteriorating
ed.63 Polymorphism of genes regulating sodium reabsorption, compared with mens health.77
such as adducin-1, have been associated with BP and hyper-
tension.64 Gene-environment interactions have been shown Inadequate Recognition of Hypertension in PMW
including BMI65 and salt intake.66 Inadequate recognition and control of hypertension remain
Other studies have also focused on pathways that might be major obstacles in reducing adverse cardiovascular outcomes
implicated in sex hormonerelated associations with hyper- for women. Among the 93 676 women enrolled in the
tension.67 Gender-specific contributions of estrogen-related WHI-OS, 32% were hypertensive though with no known
genes to BP variation have been described. Inactivating cardiovascular disease. Of these, 52% were on antihyperten-
mutations in the follicle-stimulating hormone (FSH) receptor sive medications, yet only 36% were at BP goal of less than
(FSHR) gene may cause hereditary hypergonadotropic ovar- 140/90 mm Hg. Among diabetic women only 21% of patients
ian failure. Polymorphisms in the human FSHR gene have reached goal pressures. These results appear related to insuf-
been linked to essential hypertension in women.68 Other ficiently therapy, as the majority of women were only on 1
candidates in the testosterone-estradiol pathway have been antihypertensive agent.78 Multi-drug therapy may be neces-
investigated. In a case-control study of hypertension, associ- sary to control hypertension as women age and should be
ations between aromatase CYP19A1 gene variants and hy- combined with lifestyle modifications, such as a low-sodium
pertension were found only in women, and this association diet and an exercise regimen.
was dependent on BMI. No association with menopause was
found, suggesting that the effect of CYP19A1 variants on BP
may be mainly related to aromatase activity in adipose Future Directions
tissue.69 Hypertension in PMW is a major medical problem. Further
Gene-gender and gene-environment interactions impact understanding of the basic mechanisms leading to hyperten-
hypertension in women. Menopause may provide an impor- sion in postmenopausal women may promote or guide more
tant environmental trigger resulting in genetic influences that effective and rational choices of antihypertensive treatment.
mediate hypertension in women. These findings also raise the Future research should focus on strategies to increase public
potential that antihypertensives may have different efficacy awareness of the association of hypertension with age among
based on the gender and genetic background.70 both women and men, including high risk minority groups, to
educate about and improve adherence to lifestyle modifica-
Current Clinical Issues tions and to implement evidence-based medical practice.
Most women will develop hypertension in their lifetime, and
women who develop hypertension at a younger age are at Sources of Funding
higher risk of adverse cardiovascular events. The prevalence J.F.R. is funded by the National Institutes of Health HL51971,
of hypertension rises more steeply in women than men after HL69194, and HL66072. P.O. is funded by National Institutes of
middle age. A study of women aged 45 years or older and Health RR023561, HL074406, and DK062368.
initially free of cardiovascular disease showed that one third
of women who were normotensive at baseline developed Disclosures
hypertension during the 10 year follow-up. Half the women None.
43. Martin C, Barturen K, Martinez R, Lacort M, Ruiz-Larrea MB. In vitro 64. Ylitalo A, Airaksinen KE, Hautanen A, Kupari M, Carson M, Virolainen
inhibition by estrogens of the oxidative modifications of human J, Savolainen M, Kauma H, Kesaniemi YA, White PC, Huikuri HV.
lipoproteins. J Physiol Biochem. 1998;54:195202. Baroreflex sensitivity and variants of the renin angiotensin system genes.
44. Ruiz-Larrea MB, Martin C, Martinez R, Navarro R, Lacort M, Miller NJ. J Am Coll Cardiol. 2000;35:194 200.
Antioxidant activities of estrogens against aqueous and lipophilic rad- 65. Fava C, Montagnana M, Almgren P, Rosberg L, Guidi GC, Berglund G,
icals; differences between phenol and catechol estrogens. Chem Phys Melander O. Association between adducin-1 G460W variant and blood
Lipids. 2000;105:179 188. pressure in Swedes is dependent on interaction with body mass index and
45. Higashi Y, Oshima T, Watanabe M, Matsuura H, Kajiyama G. Renal gender. Am J Hypertens. 2007;20:981989.
response to L-arginine in salt-sensitive patients with essential hyper- 66. Kuznetsova T, Staessen JA, Brand E, Cwynar M, Stolarz K, Thijs L,
tension. Hypertension. 1996;27:643 648. Tikhonoff V, Wojciechowska W, Babeanu S, Brand-Herrmann SM,
46. Hernandez Schulman I, Raij L. Salt sensitivity and hypertension after Casiglia E, Filipovsky J, Grodzicki T, Nikitin Y, Peleska J, Struijker-Boudier
menopause: role of nitric oxide and angiotensin II. Am J Nephrol. 2006; H, Bianchi G, Kawecka-Jaszcz K. Sodium excretion as a modulator of
26:170 180. genetic associations with cardiovascular phenotypes in the European Project
47. Tominaga T, Suzuki H, Ogata Y, Matsukawa S, Saruta T. The role of sex on Genes in Hypertension. J Hypertens. 2006;24:235242.
hormones and sodium intake in postmenopausal hypertension. J Hum 67. Peter I, Shearman AM, Zucker DR, Schmid CH, Demissie S, Cupples
Hypertens. 1991;5:495500. LA, Larson MG, Vasan RS, DAgostino RB, Karas RH, Mendelsohn ME,
48. Schulman IH, Aranda P, Raij L, Veronesi M, Aranda FJ, Martin R. Surgical Housman DE, Levy D. Variation in estrogen-related genes and cross-
menopause increases salt sensitivity of blood pressure. Hypertension. 2006; sectional and longitudinal blood pressure in the Framingham Heart Study.
47:11681174. J Hypertens. 2005;23:21932200.
49. Scuteri A, Stuehlinger MC, Cooke JP, Wright JG, Lakatta EG, Anderson 68. Nakayama T, Kuroi N, Sano M, Tabara Y, Katsuya T, Ogihara T, Makita
DE, Fleg JL. Nitric oxide inhibition as a mechanism for blood pressure Y, Hata A, Yamada M, Takahashi N, Hirawa N, Umemura S, Miki T, Soma
increase during salt loading in normotensive postmenopausal women. M. Mutation of the follicle-stimulating hormone receptor gene
J Hypertens. 2003;21:1339 1346. 5-untranslated region associated with female hypertension. Hypertension.
50. Scuteri A, Lakatta EG, Anderson DE, Fleg JL. Transdermal 17 beta- 2006;48:512518.
oestradiol reduces salt sensitivity of blood pressure in postmenopausal 69. Ramirez-Lorca R, Grilo A, Martinez-Larrad MT, Manzano L, Serrano-
women. J Hypertens. 2003;21:2419 2420. Hernando FJ, Moron FJ, Perez-Gonzalez V, Gonzalez-Sanchez JL,
51. Juntunen M, Niskanen L, Saarelainen J, Tuppurainen M, Saarikoski S, Fresneda J, Fernandez-Parrilla R, Monux G, Molero E, Sanchez E,
Honkanen R. Changes in body weight and onset of hypertension in Martinez-Calatrava MJ, Saban-Ruiz J, Ruiz A, Saez ME, Serrano-Rios
perimenopausal women. J Hum Hypertens. 2003;17:775779. M. Sex and body mass index specific regulation of blood pressure by
52. Kaufer-Horwitz M, Pelaez-Robles K, Lazzeri-Arteaga P, Goti-Rodriguez CYP19A1 gene variants. Hypertension. 2007;50:884 890.
LM, Avila-Rosas H. Hypertension, overweight and abdominal adiposity 70. Davis BR, Arnett DK, Boerwinkle E, Ford CE, Leiendecker-Foster C,
in women. An analytical perspective. Arch Med Res. 2005;36:404 411. Miller MB, Black H, Eckfeldt JH. Antihypertensive therapy, the alpha-
53. Alvarez GE, Beske SD, Ballard TP, Davy KP. Sympathetic neural acti- adducin polymorphism, and cardiovascular disease in high-risk hyper-
vation in visceral obesity. Circulation. 2002;106:25332536. tensive persons: the Genetics of Hypertension-Associated Treatment
54. Matthews KA, Abrams B, Crawford S, Miles T, Neer R, Powell LH, Study. Pharmacogenomics J. 2007;7:112122.
Wesley D. Body mass index in mid-life women: relative influence of 71. Conen D, Ridker PM, Buring JE, Glynn RJ. Risk of cardiovascular events
menopause, hormone use, and ethnicity. Int J Obes Relat Metab Disord. among women with high normal blood pressure or blood pressure pro-
2001;25:863 873. gression: prospective cohort study. BMJ. 2007;335:432.
55. Lalouel JM. Large-scale search for genes predisposing to essential hyper- 72. Franklin SS, Larson MG, Khan SA, Wong ND, Leip EP, Kannel WB,
tension. Am J Hypertens. 2003;16:163166. Levy D. Does the relation of blood pressure to coronary heart disease risk
56. Levy D, DeStefano AL, Larson MG, ODonnell CJ, Lifton RP, Gavras H, change with aging? The Framingham Heart Study. Circulation. 2001;
Cupples LA, Myers RH. Evidence for a gene influencing blood pressure 103:12451249.
on chromosome 17. Genome scan linkage results for longitudinal blood 73. Prevention of stroke by antihypertensive drug treatment in older persons
pressure phenotypes in subjects from the Framingham Heart study. with isolated systolic hypertension. Final results of the Systolic Hyper-
Hypertension. 2000;36:477 483. tension in the Elderly Program (SHEP). SHEP Cooperative Research
57. Poulsen P, Vaag A, Kyvik K, Beck-Nielsen H. Genetic versus environ- Group. JAMA. 1991;265:32553264.
mental aetiology of the metabolic syndrome among male and female 74. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH,
twins. Diabetologia. 2001;44:537543. Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G,
58. Sagnella GA, Rothwell MJ, Onipinla AK, Wicks PD, Cook DG, Cappuccio Nachev C, OBrien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A.
FP. A population study of ethnic variations in the angiotensin-converting Randomised double-blind comparison of placebo and active treatment for
enzyme I/D polymorphism: relationships with gender, hypertension and older patients with isolated systolic hypertension. The Systolic Hypertension
impaired glucose metabolism. J Hypertens. 1999;17:657664. in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350:757764.
59. Sethi AA, Nordestgaard BG, Agerholm-Larsen B, Frandsen E, Jensen G, 75. Myers J, TM. The effect of sodium intake on the blood pressure related
Tybjaerg-Hansen A. Angiotensinogen polymorphisms and elevated blood to age and sex. Clin Exp Hypertens A. 1983;5:99 118.
pressure in the general population: the Copenhagen City Heart Study. 76. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D,
Hypertension. 2001;37:875 881. Obarzanek E, Conlin PR, Miller ER, 3rd, Simons-Morton DG, Karanja N,
60. Russo P, Loguercio M, Lauria F, Barba G, Arnout J, Cappuccio FP, Lin PH. Effects on blood pressure of reduced dietary sodium and the
Iacoviello L, Siani A. Age- and gender-dependent association of the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium
-344C/T polymorphism of CYP11B2 with blood pressure in European Collaborative Research Group. N Engl J Med. 2001;344:310.
populations. J Hum Hypertens. 2007;21:333336. 77. Kim JK, Alley D, Seeman T, Karlamangla A, Crimmins E. Recent
61. Chen W, Srinivasan SR, Li S, Boerwinkle E, Berenson GS. Gender- changes in cardiovascular risk factors among women and men. J Womens
specific influence of NO synthase gene on blood pressure since Health (Larchmt). 2006;15:734 746.
childhood: the Bogalusa Heart Study. Hypertension. 2004;44:668 673. 78. Oparil S. Women and hypertension. What did we learn from the
62. Pereira AC, Mota GF, Cunha RS, Herbenhoff FL, Mill JG, Krieger JE. Womens Health Initiative. Cardiol Rev. 2006;14:267275.
Angiotensinogen 235T allele dosage is associated with blood pressure 79. Owens JF, Stoney CM, Matthews KA. Menopausal status influences
phenotypes. Hypertension. 2003;41:2530. ambulatory blood pressure levels and blood pressure changes during
63. Rana BK, Insel PA, Payne SH, Abel K, Beutler E, Ziegler MG, Schork mental stress. Circulation. 1993;88:2794 2802.
NJ, OConnor DT. Population-based sample reveals gene-gender inter- 80. Pearson JD, Morrell CH, Brant LJ, Landis PK, Fleg JL. Age-associated
actions in blood pressure in White Americans. Hypertension. 2007;49: changes in blood pressure in a longitudinal study of healthy men and
96 106. women. J Gerontol A Biol Sci Med Sci. 1997;52:M177183.
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