Hypertension = Htn, Essential Hypertension 1. See Also 1. Hypertension in Children 2. Hypertension in Infants 3. Hypertension in Pregnancy 4. Hypertension in Athletes 5. Hypertension in the Elderly 2. Epidemiology 1. Demographics 1. White Adults in US: 20% are hypertensive 2. Black Adults in US: 30% are hypertensive 3. Of all hypertensives, >50% are over age 65 years 2. Outcomes 1. BEST PREDICTOR TO OUTCOME VARIES BY AGE 1. Diastolic Blood Pressure best predictor <50 years 2. SBP and DBP predict outcomes equally ages 50-59 3. Pulse Pressure best predictor age >60 years 2. Coronary Artery Disease 1. Hypertension Causes 35-45% morbidity and mortality 3. Cerebrovascular Accident 1. Relative Risk increases 1.84 for each 10 mmHg DBP 2. Midlife hypertension raises longterm CVA risk 3. Seshadri (2001) Arch Intern Med 161:2343 4. Alzheimer's Disease 1. Increased SBP in middle age is predisposing factor 5. Reference 1. (1995) Lancet 346(8991):1647 2. Kivipelto (2001) BMJ 322:1447 3. Hypertension Definition 1. See Hypertension Criteria 4. Types 1. Essential Hypertension (Primary Hypertension) 1. Stage 1-2 (DBP 90-104) in 80% of cases 2. ACCELERATED MALIGNANT HYPERTENSION 1. Recent substantial Blood Pressure increase 2. Associated with retinal vessel damage 1. Retinal Hemorrhages 2. Retinal exudates 3. Papilledema 3. Diastolic Blood Pressure over 140
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GENERAL 1. Systolic pressure predicts risk better than diastolic
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4. Complications: Cardiovascular Risk 1. GENERAL 1. Systolic pressure predicts risk better than diastolic 2. Wide Pulse Pressure best predicts cardiovascular risk
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1. Doubles all cause mortality 2. Triples cardiovascular mortality 3. Increases cardiovascular morbidity 2.5 fold
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OTHER MEDICATIONS 1. Dihydropyridine Calcium Channel Blocker 2. Long Acting Nitroglycerin 3. ACE Inhibitor 4. Labetalol
Pulse pressure, widened: Excerpt
from Alarming Signs and
Symptoms: Lippincott Manual of
Nursing Practice Series
Pulse pressure is the difference between systolic and diastolic blood pressures. Normally, systolic pressure is about 40 mm Hg higher than diastolic pressure. Widened pulse pressure — a difference of more than 50 mm Hg — commonly occurs as a physiologic response to fever, hot weather, exercise, anxiety, anemia, or pregnancy. However, it can also result from certain neurologic disorders — especially life-threatening increased intracranial pressure (ICP) — or from cardiovascular disorders that cause blood backflow into the heart with each contraction such as aortic insufficiency. Widened pulse pressure can easily be identified by monitoring arterial blood pressure and is commonly detected during routine sphygmomanometric recordings.
Act Now: Ifthe patient’s level of consciousness (LOC) is decreased and you suspect that his widened pulse pressure results from increased ICP, check his vital signs. Maintain a patent airway, and prepare to hyperventilate the patient with a handheld resuscitation bag to help reduce partial pressure of carbon dioxide levels and, thus, ICP. Perform a thorough neurologic examination to serve as a baseline for assessing subsequent changes. Use the Glasgow Coma Scale to evaluate the patient’s LOC. (See Glasgow Coma Scale, page 196.) Also, check cranial nerve (CN) function — especially in CNs III, IV, and VI — and assess pupillary reactions, reflexes, and muscle tone. (See Exit points for the cranial nerves.) The patient may require an ICP monitor. If you don’t suspect increased ICP, ask about associated symptoms, such as chest pain, shortness of breath, weakness, fatigue, or syncope. Check for edema and auscultate for murmurs.
Hg higher than diastolic pressure. Widened pulse pressure — a difference of more than 50 mm Hg — commonly occurs as a physiologic response to fever, hot weather, exercise, anxiety, anemia, or pregnancy. However, it can also result from certain
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fatigue, or syncope. Check for edema and auscultate for murmurs.
Hypertension Causes
= Secondary Hypertension Causes, Hypertension Causes in
Children, Hypertension Causes in Adolescents
1. Causes: Secondary Hypertension in Adults
1. MEDICATIONS
1. See Medication Causes of Hypertension
2. PRIMARY ALDOSTERONISM 1. Most common treatable secondary cause
of Hypertension
2. Evaluate as cause in Refractory
Hypertension where Hypokalemia or
borderline low potassium
3. RENOVASCULAR OR RENAL PARENCHYMAL DISEASE
4. PHEOCHROMOCYTOMA
5. CUSHING'S DISEASE
6. HYPERPARATHYROIDISM
7. AORTIC COARCTATION
8. SLEEP APNEA
9. THYROID DISEASE
1. Hyperthyroidism causes systolic Hypertension
2. Hypothyroidism causes diastolic Hypertension
1. Dernellis (2002) Am Heart J 143:718
2. Causes: Secondary Hypertension in age <18 years old
1. SEE HYPERTENSION IN INFANTS
2. Renal parenchymal disease
1. Most common cause in children (up to 70%)
3. Renal vascular disease
4. Aortic Coarctation
5. Endocrine conditions 1. Metabolic Syndrome
2. Pheochromocytoma
3. Hyperthyroidism
6. Essential Hypertension
1. Rare in age <10 years
2. Most common cause in adolescents and
adults
7. Medications 1. See Medication Causes of Hypertension
Denis Nash; Laurence Magder; Mark Lustberg; et al.
Perimenopausal and Postmenopausal WomenBlood Lead, Blood Pressure, and Hypertension in
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Contact me when new articles are published in these topic areas.Other; Hypertension Occupational and Environmental Medicine; Women's Health; Women's Health,
Related Letters
. 2003;290(4):460.JAMARobert P. Heaney. . 2003;290(4):460.JAMAHans W. Hense.
Blood Lead, Blood Pressure, andHypertension in Perimenopausaland Postmenopausal WomenDenis Nash, PhD, MPHLaurence Magder, PhD, MPHMark Lustberg, PhDRoger W. Sherwin, MDRobert J. Rubin, PhDRachel B. Kaufmann, PhDEllen K. Silbergeld, PhD
SINCE THE 1970S, CONSIDERABLE
attention has been paid to thepossibility that low levels of leadexposure among adults in the
general population can elevate bloodpressure and increase the risk for hy-pertension, a leading risk factor for car-diovascular disease morbidity and mor-tality.1-3 Evidence for this associationfrom the epidemiological literature iscompelling,4 but the exact causal na-ture of the relationship remains con-troversial.
The notion that lead exposure may in-fluence blood pressure in humans is bio-logically plausible. Lead induces hyper-tension in rats,5,6 and other animal datasuggest that lead acts at multiple siteswithin the cardiovascular system, in-cluding direct effects on the excitabilityand contractility of the heart, alterationof the compliance of the vascular smoothmuscle tissue, and direct action on partsof the central nervous system respon-sible for blood pressure regulation.2 Evi-dence in animals also suggests that leadmay affect blood pressure through the re-nin-angiotensin system.6 Lead is neph-rotoxic to humans, and alteration of
Author Affiliations: Department of Epidemiology andPreventive Medicine, University of Maryland Schoolof Medicine, Baltimore (Drs Nash, Magder, Lust-berg, Sherwin, and Silbergeld); New York City De-partment of Health and Mental Hygiene, HIV/AIDSSurveillance and Epidemiology Program, New York (DrNash); Department of Epidemiology, Tulane Univer-sity School of Public Health and Tropical Medicine, NewOrleans, La (Dr Sherwin); Department of Environ-mental Health Sciences, The Johns Hopkins Univer-sity Bloomberg School of Public Health, Baltimore, Md
(Dr Rubin); and National Center for EnvironmentalHealth, Centers for Disease Control and Prevention,Atlanta, Ga (Dr Kaufmann). Dr Silbergeld is now withthe Department of Environmental Health Sciences, TheJohns Hopkins University Bloomberg School of Pub-lic Health, Baltimore, Md.Corresponding Author and Reprints: Denis Nash, PhD,MPH, New York City Department of Health and Men-tal Hygiene, HIV/AIDS Surveillance and Epidemiol-ogy Program, 346 Broadway, Room 706, New York,NY 10013 (e-mail: [email protected]).
Context Lead exposures have been shown to be associated with increased bloodpressure and risk of hypertension in older men. In perimenopausal women, skeletallead stores are an important source of endogenous lead exposure due to increasedbone demineralization.
Objective To examine the relationship of blood lead level with blood pressure andhypertension prevalence in a population-based sample of perimenopausal and post-menopausal women in the United States.
Design, Setting, and Participants Cross-sectional sample of 2165 women aged 40to 59 years, who participated in a household interview and physical examination, fromthe Third National Health and Nutrition Examination Survey conducted from 1988 to 1994.
Main Outcome Measures Associations of blood lead with blood pressure and hy-pertension, with age, race and ethnicity, cigarette smoking status, body mass index,alcohol use, and kidney function as covariates.
Results A change in blood lead levels from the lowest (quartile 1: range, 0.5-1.6µg/dL) to the highest (quartile 4: range, 4.0-31.1 µg/dL) was associated with smallstatistically significant adjusted changes in systolic and diastolic blood pressures. Womenin quartile 4 had increased risks of diastolic (�90 mm Hg) hypertension (adjusted oddsratio [OR], 3.4; 95% confidence interval [CI], 1.3-8.7), as well as moderately in-creased risks for general hypertension (adjusted OR, 1.4; 95% CI, 0.92-2.0) and sys-tolic (�140 mm Hg) hypertension (adjusted OR, 1.5; 95% CI, 0.72-3.2). This asso-ciation was strongest in postmenopausal women, in whom adjusted ORs for diastolichypertension increased with increasing quartile of blood lead level compared with quar-tile 1 (adjusted OR, 4.6; 95% CI, 1.1-19.2 for quartile 2; adjusted OR, 5.9; 95% CI,1.5-23.1 for quartile 3; adjusted OR, 8.1; 95% CI, 2.6-24.7 for quartile 4).
Conclusions At levels well below the current US occupational exposure limit guide-lines (40 µg/dL), blood lead level is positively associated with both systolic and dias-tolic blood pressure and risks of both systolic and diastolic hypertension among womenaged 40 to 59 years. The relationship between blood lead level and systolic and dias-tolic hypertension is most pronounced in postmenopausal women. These results pro-vide support for continued efforts to reduce lead levels in the general population, es-pecially women.JAMA. 2003;289:1523-1532 www.jama.com
kidney function may precede the devel-opment of hypertension.7,8 However,whether lead affects blood pressurethrough altering kidney function in hu-mans is not known.
A case-control investigation of menfrom the Normative Aging Study9 re-ported significantly higher levels of leadin skeletal and blood compartmentsamong men with hypertension com-pared with normotensives. The all-male study population had mean base-line blood lead levels of 6.3 µg/dL,similar to men in the general popula-tion.10 An increase from the midpointof the lowest quintile to the highestquintile of bone lead was associatedwith an adjusted odds ratio (OR) of1.5 (95% confidence interval [CI],1.1-1.8) for hypertension, suggestingthat cumulative lead exposure, repre-sented by bone lead stores, may be anindependent risk factor for hyperten-sion in the general population.9
Evidence suggests that bone leadstores contribute to circulating levelsof lead in blood.11-13 In particular, bloodlead levels in women appear to increaseduring the menopausal transition,because of the mobilization of skeletallead stores associated with bone demin-eralization.14-18 The impactof these smallbut significant increases in blood leadin postmenopausal compared with pre-menopausal women is difficult to inter-pret, because relatively few studies haveexamined the health impacts of lead inwomen. A case-control study7 of 297women with hypertension who partici-pated in the Nurses’ Health Studyshowed that increases in bone patellalead levels from the 10th to the 90th per-centile were associated with increasedrisks of hypertension (OR, 1.86, 95%CI, 1.09-3.19). However, informationabout menopausal status was extremelylimited in this study.7
The objective of our investigation wasto examine the relationship of blood leadlevels with blood pressure and hyper-tension in a population-based sample ofperimenopausal and postmenopausalwomen in the United States. We se-lected blood pressure and hyperten-sion as outcomes because of the epide-
miological data associating relatively lowlevels of lead in the blood with cardio-vascular outcomes1,2,4,19-38 and becausehypertension is a significant health con-cern for women after menopause.39
METHODSThe study population included womenfrom the Third National Health and Nu-trition Examination Survey (NHANESIII), a cross-sectional sample obtainedthrough a complex survey design, rep-resenting the US civilian, noninstitu-tionalized population. During a 6-yearperiod (1988-1994), participants tookpart in a household interview and anin-depth physical examination withlaboratory tests. Full details of the sur-vey design have been published by theNational Center for Health Statistics ofthe Centers for Disease Control andPrevention.40
Our investigation focused on the sub-set of 2574 women aged 40 to 59 yearswho participated in the NHANES IIIsurvey interview. From this group, 409women were excluded for the follow-ing reasons: 211 did not undergo aphysical examination or blood test-ing; 77 did not have information aboutblood lead levels; and 121 women ofethnicity other than non-Hispanicblack, non-Hispanic white, and Mexi-can American were excluded becauseof small numbers in any single self-reported category. The remaining 2165women constituted the sample used.
DefinitionsBlood Pressure and Hypertension. Weused the mean of 3 systolic and dias-tolic blood pressure measurements, allof which were taken by a physician atthe end of the 4-hour physical exami-nation that occurred in the NHANESmobile examination center. Womenwere categorized as hypertensive if anyof the following criteria were met: cur-rent user of blood pressure medica-tion (self-report), a systolic blood pres-sure of 140 mm Hg or higher, or adiastolic blood pressure of 90 mm Hgor higher. We also examined separatedichotomous variables for systolic hy-pertension and diastolic hypertension
using these cutoff values, excluding per-sons who reported being treated for hy-pertension. More details on measure-ment of and outcomes related to bloodpressure and hypertension in NHANESIII have been published elsewhere.3
Blood Lead. Blood samples were ob-tained by venipuncture during thephysical examination. Blood lead con-centration was measured by graphitefurnace atomic absorption spectropho-tometry at the laboratories of the Na-tional Center for Environmental Healthat the Centers for Disease Control andPrevention in Atlanta, Georgia. The as-say detection limit was 1.0 µg/dL. Eachsample analysis was performed in du-plicate, and the mean of both measure-ments was used in these analyses. Allblood lead levels less than 1.0 µg/dLwere assigned a value of 0.5 µg/dL tobe consistent with previous analyses ofNHANES III lead data by other inves-tigators.10
Menopausal Status. Women were cat-egorized as premenopausal (ovarianfunction intact), surgically menopausal(both ovaries removed surgically be-fore cessation of menses), and naturallymenopausal (nonsurgical cessation ofovarian function). Women without his-tories of reproductive surgery were clas-sified as premenopausal if they re-ported a menstrual period during theprevious 12 months and postmeno-pausal if they did not. Women report-ing having undergone hysterectomy(without ovariectomy) within a monthof the last menstrual period were as-signed a menopausal classification basedon their age (�51 years, premeno-pausal; �51 years, naturally meno-pausal). Women who underwent bilat-eral ovariectomy within 1 month of thedate of the last menstrual period wereclassified as surgically menopausal.Women who underwent hysterectomyor ovariectomy more than 1 month af-ter the reported date of the last men-strual period were classified as natu-rally menopausal. A total of 101 womencould not be assigned a menopausal sta-tus due to missing information.
Kidney Function. Serum creatininewas measured because it is the most
BLOOD LEAD, BLOOD PRESSURE, AND HYPERTENSION IN WOMEN
specific of the 3 measures of kidneyfunction available in NHANES III (se-rum creatinine, urinary creatinine clear-ance, and blood urea nitrogen) and wasconsistent with other recent studies ofthe effects of lead on the kidney.41
Covariates. Information about raceand ethnicity (non-Hispanic black,non-Hispanic white, and MexicanAmerican), age (years), cigarette smok-ing history (current, former, or never),family income, and education was ob-tained from the household interview.Information about body mass index(BMI, calculated as weight in kilo-grams divided by the square of heightin meters) and alcohol use (amountconsumed per week) was obtained fromthe physical examination and exami-nation-associated questionnaire, re-spectively. A 4-level categorical vari-able for weekly alcohol intake wascreated with the following levels: none,less than 1, 1 to 2, or 3 or more drinksper week. The poverty income ratio, aratio of family income to the povertylevel income for a given family size ad-justed to the poverty threshold for theyear of the interview, was used to cre-ate a 3-level family income variable. Aparticipant was assigned a family in-come higher than the poverty level ifthe poverty income ratio was more than1, at or lower than poverty if the pov-erty income ratio was less than or equalto 1, and missing if the survey partici-pant did not report a family incomelevel. A 4-level education variable wascreated on the basis of the number ofyears of education reported by the sur-vey participant (0-11 years=�highschool; 12 years = completed highschool; 12-15 years=some college; and�16 years=completion of college orhigher).
Statistical MethodsWe used multiple linear regression mod-els to examine the associations of bloodlead and menopausal status with sys-tolic and diastolic blood pressures.Analyses that examined systolic and di-astolic blood pressure as continuous out-come variables excluded the 368 womenwith hypertension who were treated. We
used multiple logistic regression to ex-amine the risks of hypertension (gen-eral, systolic, and diastolic) by catego-rizing blood lead in terms of quartilesand comparing those women in bloodlead quartiles 2, 3, and 4 with those inquartile 1; these analyses were strati-fied by menopausal status.
Models were constructed based onoutcomes known to be biologically as-sociated with blood pressure (age, raceand ethnicity, BMI, and serumcreatinine), including the study vari-able blood lead. Potential confound-ing variables (education, poverty in-come ratio, alcohol use, and cigarettesmoking status) were included if theywere found to be significantly associ-ated with blood pressure outcomes inany 1 of the models before the inclu-sion of blood lead. Final regression co-variates included age, race and ethnic-ity, alcohol use, cigarette smokingstatus, BMI, and kidney function.
Statistical analyses were conducted us-ing SAS version 6 (SAS Institute, Cary,NC), incorporating the examinationsampling weights of NHANES III.40 Thestatistical software package SUDAANversion 7.0 (Research Triange Insti-tute, Research Triangle Park, NC) wasused to calculate SEs for the estimates,accounting for both the weights and thecomplex survey design. Linear regres-sion coefficients reported are unstand-ardized. The significance of regressioncoefficients was evaluated using theWald �2 test. Statistical tests for trendsof categorical variables were carried outin regression models by coding levels asintegers (scores) and evaluating tests forsignificance on the slope of the regres-sion line. Statistical tests with P�.05were considered statistically signifi-cant. All estimates of proportions, re-gression coefficients, and ORs areweighted to the 1990 US Census popu-lation.
RESULTSOverall, the mean blood lead level forwomen aged 40 to 59 years was 2.9 µg/dL, and the means for the quartiles ofblood lead ranged from 1.0 µg/dL to 6.3µg/dL in the lowest and highest quar-
tile, respectively (TABLE 1). Women inthe higher quartiles of blood lead tendedto be older, current smokers, regulardrinkers, poorer, less educated, andmore likely to be non-Hispanic blackthan those in the lower quartiles. All ofthese variables were significantly asso-ciated with blood lead level.
Of the 2165 women in the sample,604 were classified as hypertensivebased on their systolic and diastolicblood pressures (n=231, untreated), aswell as whether they self-reported cur-rently taking antihypertensive medica-tions (n=373). Of those that were un-treated (n = 231), 123 had systolichypertension only, 30 had diastolic hy-pertension only, and 78 had both sys-tolic and diastolic hypertension. Ofthose who were treated for hyperten-sion (n=373), 202 had neither sys-tolic nor diastolic hypertension, 102 hadsystolic hypertension only, 14 had di-astolic hypertension only, 50 had bothsystolic and diastolic hypertension, and5 did not have a systolic or diastolicblood pressure measurement during theexamination.
In these crude analyses, blood leadquartile was significantly associatedwith systolic blood pressure (P=.03)but not diastolic blood pressure(P=.86) (TABLE 2). A significant dose-response existed between blood leadquartile andgeneralhypertensionpreva-lence,with19.4%ofwomenhavinggen-eral hypertension in the lowest quar-tile compared with 28.3% in the highestquartile. However, although dose-response trends appeared to exist, bloodlead quartile was not significantly asso-ciated specifically with systolic or dias-tolic hypertension prevalence (P=.09and P=.25, respectively).
Systolic and DiastolicBlood PressureIn multivariate analyses, blood lead wassignificantly associated with both sys-tolic and diastolic blood pressures(TABLE 3). In these regression mod-els, a difference in blood lead levels be-tween the lowest and highest quartileswas associated with a difference of 1.7mm Hg in systolic blood pressure and
BLOOD LEAD, BLOOD PRESSURE, AND HYPERTENSION IN WOMEN
1.4 mm Hg in diastolic blood pres-sure, after adjustment for age, race andethnicity, cigarette smoking, BMI, al-cohol use, and kidney function. Omis-sion of the serum creatinine variable inthe multivariable models for blood leadand blood pressure (both systolic and
diastolic) did not alter the signifi-cance of the blood lead variable.
General HypertensionBefore incorporating blood lead level inthe multiple logistic regression model(TABLE 4), the most important factors
independently increasing the ORs ofgeneral hypertension in women in-cluded increasing age, being non-Hispanic black, having an alcohol in-take of less than 1 drink per week, andincreasing BMI. Adding blood lead levelto the model did not greatly alter any of
Table 1. Weighted Descriptive Characteristics of Adult Women Aged 40 to 59 Years Participating in the Third National Health and NutritionExamination Survey*
CharacteristicTotal
(N = 2165)
Blood Lead Quartile
PValue
Quartile 1(n = 568)
Quartile 2(n = 498)
Quartile 3(n = 556)
Quartile 4(n = 543)
Blood lead level, mean (range), µg/dL 2.9 (0.50-31.1) 1.0 (0.5-1.6) 2.1 (1.7-2.5) 3.2 (2.6-3.9) 6.4 (4.0-31.1)
Race and ethnicity, %Non-Hispanic white 83.9 87.4 86.5 83.4 76.3
Non-Hispanic black 11.7 8.1 9.3 12.6 18.5 �.001
Mexican American 4.4 4.5 4.2 4.1 5.2
Age, mean (SE), y 48.2 (0.2) 46 (0.32) 48 (0.44) 49 (0.34) 50.4 (0.39) �.001
Body mass index, mean (SE) 27.6 (0.25) 28.4 (0.58) 27.5 (0.31) 27.6 (0.34) 26.9 (0.29) .04
Completed high school 40.0 40.0 43.1 38.2 38.5�.001
Some college 19.9 18.4 21.9 21.0 18.5
College or higher 21.1 28.6 18.3 18.2 17.5
*Body mass index is calculated as weight in kilograms divided by the square of height in meters. P values obtained from �2 test (categorical variables) or analysis of variance(continuous variables) based on an overall test across quartiles.
Table 2. Weighted Distributions of Blood Pressure–Related Variables Among Adult Women Aged 40 to 59 Years Participating in the ThirdNational Health and Nutrition Examination Survey
CharacteristicTotal
(N = 2165)
Blood Lead Quartile
PValue*
P forTrend
Quartile 1(n = 568)
Quartile 2(n = 498)
Quartile 3(n = 556)
Quartile 4(n = 543)
Blood lead level, mean (range), µg/dL 2.9 (0.50-31.1) 1.0 (0.5-1.6) 2.1 (1.7-2.5) 3.2 (2.6-3.9) 6.4 (4.0-31.1)
Blood pressure, mean (SE), mm HgSystolic 118.7 (0.48) 117.2 (0.95) 117.7 (0.83) 119.3 (1.10) 121.2 (0.92) .03 �.001
*P values obtained from �2 test (categorical variables) or analysis of variance (continuous variables) based on an overall test across quartiles.†General hypertension defined as systolic blood pressure of 140 mm Hg or higher, diastolic blood pressure of 90 mm Hg or higher, or self-report of prescription antihypertensive
treatment.‡Excludes women who reported being currently treated for hypertension.
BLOOD LEAD, BLOOD PRESSURE, AND HYPERTENSION IN WOMEN
the existing associations between age,race and ethnicity, alcohol intake, andBMI. For women in the highest 2 quar-tiles of blood lead level relative to thelowest quartile, the adjusted ORs of hy-pertension were elevated but not sig-nificantly (OR, 1.3; 95% CI, 0.90-2.0 andOR, 1.4; 95% CI, 0.90-2.0, for quartiles3 and 4, respectively). Separate modelsof these associations for premeno-pausal women and postmenopausalwomen yielded similar results, with theexception that serum creatinine was
strongly associated with general hyper-tension in premenopausal women.
Systolic and Diastolic HypertensionAfter similar adjustment, a weak asso-ciation existed for untreated systolic hy-pertension. For women in the fourthquartile of blood lead, the ORs were thehighest (OR, 1.55; 95% CI, 0.72-3.20)(TABLE 5). The adjusted ORs of dias-tolic hypertension relative to women inthe lowest quartile of blood lead level in-creased with a clear dose-response (quar-
Stratification by menopausal status re-vealed a weak dose-response relation-ship between blood lead level and sys-tolic hypertension in premenopausalwomen, and a significantly elevated ORof systolic hypertension in postmeno-pausal women in the second and thirdquartiles of blood lead relative to womenin the lowest quartile (quartile 2: OR, 3.0;95% CI, 1.3-6.9 and quartile 3: OR, 2.7;
Table 3. Unstandardized Regression Coefficients for Blood Lead and Systolic Blood Pressure and Diastolic Blood Pressure in Women Aged 40to 59 Years Not Treated for Hypertension*
*Body mass index is calculated as weight in kilograms divided by the square of height in meters. A total of 69 women could not be assigned a menopausal status due to missingdata.
BLOOD LEAD, BLOOD PRESSURE, AND HYPERTENSION IN WOMEN
95% CI, 1.2-6.2). A dose-response re-lationship was apparent for blood leadquartile and diastolic hypertension,which was particularly striking for post-menopausal women.
COMMENTTo our knowledge, this is the first studyto examine the effects of blood lead andblood pressure in perimenopausalwomen. After accounting for age, raceand ethnicity, alcohol intake, ciga-rette smoking status, BMI, and kidneyfunction, we found a significant asso-ciation between blood lead and sys-tolic and diastolic hypertension preva-lence among women aged 40 to 59 yearsin the US population. We selected thispopulation to analyze the role of meno-pausal status, which we and others haveshown can influence blood lead levelsin women.14-17,42,43 Furthermore, this isthe age range at which the risks for hy-
pertension increase markedly in wom-en.39,44 The highest quartile of blood lead(mean, 6.3 µg/dL) was associated witha 3.4-fold increase in the risks of dias-tolic hypertension (95% CI, 1.3-8.7)relative to those in the lowest blood leadquartile (mean, 1.0 µg/dL). These riskswere considerably higher for postmeno-pausal women. In addition, blood leadwas a significant, positive predictor ofboth elevated systolic and diastolicblood pressure in these women. A dif-ference in blood lead levels between thelowest quartile and the highest quar-tile was associated with a difference of1.7 mm Hg in systolic blood pressureand 1.4 mm Hg in diastolic blood pres-sure. Blood lead is among the few pre-dictors of both systolic and diastolicblood pressures in perimenopausal USwomen. Per unit change, blood lead wasa stronger predictor of diastolic bloodpressure than age.
The results are consistent with thoseof Korrick et al,7 who found an asso-ciation between self-reported hyper-tension and bone lead in older women.In a study of 45-year-old women liv-ing in Copenhagen County, Den-mark, higher blood lead levels were as-sociated with elevated diastolic bloodpressure.29 Neither study accounted formenopausal status in either blood leadlevel or hypertension analyses.
In analyses of systolic and diastolicblood pressures, the relationship be-tween blood lead and blood pressure wasnot stronger for blacks than for whites,nor did blood lead levels explain racialdifferences in hypertension preva-lence. In fact, the blood lead and hyper-tension relationships reported ap-peared to be less pronounced amongblacks compared with the cohort as awhole. However, stratification of the co-hort by race and ethnicity resulted insmall sample sizes in each blood leadquartile, limiting precision.
The associations of blood lead withsystolic and diastolic hypertension weremuch more pronounced for postmeno-pausal women than for premenopausalwomen. The reasons for this associa-tion are unclear. Postmenopausalwomen may be more sensitive to the hy-pertensive effects of lead because of lossof estrogen at menopause.44 Estrogen hasbeen postulated to protect women fromage-related increases in blood pres-sure,44 although results from a largerandomized clinical trial have not sup-ported this hypothesis.45 This observa-tion also may reflect complex relation-ships between bone lead and blood lead,which are altered by the changes in bonemineral metabolism that accompany themenopausal transition.
Whether lead affects blood pressurethrough altering kidney function in hu-mans is not known. Lead is nephro-toxic to humans, and alteration ofkidney function may precede the devel-opment of hypertension.7,8 Kidney func-tion, as measured by serum creatinine,was found to be significantly positivelyassociated with both systolic and dias-tolic blood pressures in premeno-pausal women who are untreated for
Table 4. Adjusted Odds Ratio of General Hypertension, Stratified by Menopausal Status*
Odds Ratio (95% Confidence Interval)
All Women(N = 2165)
Adjusted†
All Women(N = 2165)
PremenopausalWomen
(n = 1214)
PostmenopausalWomen(n = 850)
Blood lead quartile1 1.0 1.0 1.0
2 1.0 (0.63-1.6) 0.78 (0.38-1.6) 0.73 (0.40-1.3)
3 1.3 (0.87-2.0) 1.4 (0.82-2.4) 1.3 (0.75-2.2)
4 1.4 (0.92-2.0) 1.5 (0.78-2.8) 1.3 (0.68-2.3)
Age, y 1.1 (1.1-1.1) 1.1 (1.1-1.1) 1.1 (1.0-1.1) 1.1 (1.0-1.2)
Race and ethnicityNon-Hispanic black 2.3 (1.7-3.1) 2.2 (1.7-2.9) 2.4 (1.5-3.7) 2.2 (1.5-3.2)
Mexican American 0.90 (0.60-1.4) 0.90 (0.60-1.3) 1.1 (0.60-1.7) 0.80 (0.40-1.5)
*Body mass index is calculated as weight in kilograms divided by the square of height in meters. General hypertensiondefined as systolic blood pressure of 140 mm Hg or higher, diastolic blood pressure of 90 mm Hg or higher, orself-report of prescription antihypertensive treatment. A total of 101 women could not be assigned a menopausalstatus due to missing data. For every unit change in each of these variables (age, body mass index, serum creati-nine), the regression coefficient represents the increase in odds of hypertension for each covariate.
†Adjusted for age, race, alcohol intake, cigarette smoking status, body mass index, and serum creatinine clearance.
BLOOD LEAD, BLOOD PRESSURE, AND HYPERTENSION IN WOMEN
hypertension. Perhaps this reflects thatthe kidney can be a common pathwayfor blood pressure regulation, and theeffect of lead on the kidney is only partof the relationship between kidney func-tion and blood pressure. However, con-trolling for kidney function did not re-duce the association of blood lead withblood pressure and hypertension, aswould be expected if kidney functionwere along the causal pathway. In thepresent investigation, serum creatininewas both a sensitive and significant pre-dictor of general hypertension in pre-menopausal women. For every unit in-crease in serum creatinine, the risks ofhypertension increased more than 7-fold(OR, 7.4; 95% CI, 1.7-32.7). However,
a significant association between leadand general hypertension was not found.
The mechanisms of lead-induced hy-pertension are not well-characterized,even in animal models. One hypoth-esis is that lead induces hypertensionthrough direct effects on the kidney. Arecent retrospective study of 509 healthyparticipants of the Normative AgingStudy found blood lead levels to be sig-nificantly positively correlated with se-rum creatinine levels.41 A study of lead-exposed workers, with high blood leadlevels (mean, 37 µg/dL), reported in-creases in diastolic blood pressure andin levels of urinary biomarkers for re-nal function.7 Batuman et al46 reportedthat patients with essential hyperten-
sion who had reduced renal function hadsignificantly more chelatable lead thanthose with essential hypertension withnormal renal function.
In the present study, kidney func-tion measured by serum creatinine didnot appear to mediate the associationsbetween blood lead and blood pres-sure. Thus, lead may act on blood pres-sure through effects on the vasculatureor central nervous system, or more sen-sitive measures of renal function maybe required to test mechanistic hypoth-eses. However, Staessen47 reported no as-sociation between renal markers of leadtoxicity and blood pressure in a largecohort study of women. The magni-tude of the effects of blood lead on blood
Table 5. Adjusted Odds Ratios for Hypertension, Systolic Hypertension, and Diastolic Hypertension by Blood Lead Quartile*
Systolic hypertension �140 mm Hg, OR (95% CI)‡ 1.0 3.0 (1.3-6.9) 2.7 (1.2-6.2) 2.6 (0.89-7.5)
Diastolic hypertension �90 mm Hg, OR (95% CI)‡ 1.0 4.6 (1.1-19.2) 5.9 (1.5-23.1) 8.1 (2.6-24.7)Abbreviations: OR, odds ratio; CI, confidence interval.*Adjusted for age, race, alcohol intake, cigarette smoking status, body mass index (calculated as weight in kilograms divided by the square of height in meters), and serum cre-
atinine.†General hypertension defined as systolic blood pressure of 140 mm Hg or higher, diastolic blood pressure of 90 mm Hg or higher, or self-report of prescription antihypertensive
treatment.‡Excludes women who reported currently receiving antihypertensive treatment.
BLOOD LEAD, BLOOD PRESSURE, AND HYPERTENSION IN WOMEN
pressure observed in this study are simi-lar to previous investigations, includ-ing 1 study of women.29
Several cross-sectional21-24,29-31,33,48 andprospective29,31,35 population-based stud-ies on the association of lead with sys-tolic and diastolic blood pressures havebeen performed from the mid-1980s.The results of these studies have beenmixed, but there is considerable con-cordance with the directionality of theobserved associations, with most con-sistently finding a weak-positive asso-ciation between blood lead and both sys-tolic and diastolic blood pressure in men,women, blacks, and whites.4 A meta-analysis by Schwartz38 of 15 studies oflead and systolic blood pressure in menestimated that a change in blood leadfrom 5 to 10 µg/dL was associated withan increase of 1.5 mm Hg in systolicblood pressure (95% CI, 0.87-1.63mm Hg), which compares well with thecorresponding estimate from our study(1.6 mm Hg; 95% CI, 0.97-2.20). Theadjusted ORs from multiple logistic re-gression models performed separately forpremenopausal and postmenopausalwomen (Table 5) show a consistent, al-though not always significant, dose-response relationship between bloodlead quartile and risks of hypertension.These subgroup analyses resulted insmaller numbers of women in the mod-els, and this is reflected in the wide CIsin some of the estimates.
The conventional predictors of bloodlead in the current US population havebeen published in a previous NHANESIII analysis by Brody et al.10 Other non-bone density–related exposures that canresult in elevated blood lead levels inthe United States include residential ex-posure to lead paint, residential prox-imity to a lead smeltering facility, oc-cupational exposure (lead smelter,battery manufacturing, welding, orbridge painting), cigarette smoking, andalcohol intake.15 Those variables asso-ciated with lead and also known to beassociated with blood pressure and hy-pertension (ie, potential confound-ers) were adjusted for in the blood leadand blood pressure and hypertensionanalyses of our study.
The human skeleton is a dynamicphysiological compartment of min-eral metabolism. Women lose as muchas 50% of trabecular bone and 30% ofcortical bone during their lifetime, and30% to 50% of this bone loss occurs inthe early postmenopausal years.49-53 Es-trogen deficiency appears to play a sig-nificant role in bone loss.51,54
Observational evidence suggests thatlead may be mobilized from the skel-eton during periods of increased bonedemineralization, such as during preg-nancy and lactation,12,55-57 very old age,58
and menopause.14-16,59 Two cross-sectional studies14,15 of US women thatwere performed using data from the sec-ond NHANES (NHANES II, 1976-1980) and the Hispanic HANES (1982-1984) documented that postmenopausalwomen have significantly higher bloodlead levels than premenopausal women,controlling for age and other factors re-lated to exogenous lead exposure. An-other study59 also identified meno-pausal status as an independentpredictor of blood lead levels in a ran-dom sample of Scandinavian women.
Hu et al60 noted that bone lead maybe a more appropriate marker of leadexposure for chronic disease out-comes such as hypertension. The pres-ent study is a cross-sectional study inthat the exposures and the outcomeswere measured simultaneously. The rel-evant exposures affecting blood pres-sure and hypertension may occurmonths or years before the observedeffect. For example, the average BMIduring the 5 years preceding the bloodpressure measurement may have moreexplanatory power than BMI mea-sured on the same day as the blood pres-sure. Likewise, cumulative lead expo-sure during the preceding decade, bonelead burden, or serum creatinine maybe more predictive of blood pressurethan blood lead level measured on thesame day as blood pressure. Evidencesuggests that bone lead stores can con-tribute to circulating levels of lead inblood.11-13
The findings of our study are incon-sistent with the notion of a latency pe-riod of months to years between the on-
set of perimenopausal bone loss resultingin increased endogenous lead expo-sure, followed by a chronic effect of leadon blood pressure. A study by Cake etal61 suggests that bone lead released intothe blood may be more bioavailable thanlead resulting from environmental ex-posure. Therefore, if blood lead in peri-menopausal women is more driven bybone lead levels, it is possible that bloodlead levels may be a more sensitive pre-dictor of blood pressure outcomes in thispopulation, because it represents liber-ated skeletal lead stores.
Important methodological chal-lenges exist in observational studies oflead exposure and blood pressure andhypertension. First, if an association be-tween lead exposure and blood pres-sure exists, lead is most likely respon-sible for a relatively small effect onblood pressure, and thus, this associa-tion may be difficult to consistently as-certain in different populations. Sec-ond, when examining small effects, theissue of residual confounding, beyondthat which is controlled in the analy-sis, becomes extremely important. Insuch cases, what may be interpreted asa small effect of blood lead on bloodpressure may actually be due to inad-equate control of confounding fac-tors. However, the restricted age rangechosen for this investigation helps tominimize the effect of confounding byage, which is strongly related to bloodlead, blood pressure, and hyperten-sion. Third, because the mechanisms bywhich lead may act on blood pressurein humans are not well understood, in-vestigators may tend to include morecovariates than necessary in their mod-els or use mechanical, stepwise ap-proaches to modeling. The true size ofthe effect may be decreased by over-controlling. This is a particular prob-lem in studies of environmental lead ex-posure, because blood lead levels arehighly correlated with race and ethnic-ity, income, and education,10 which alsomay be risk factors for outcomes suchas hypertension.49
Whether bone or blood is the appro-priate biomarker for lead exposure instudies of chronic disease outcomes is
BLOOD LEAD, BLOOD PRESSURE, AND HYPERTENSION IN WOMEN
uncertain.60 Blood lead is a marker ofrelatively recent exposures to lead.Hypertension in adults that may be asso-ciated with past exposures to lead is con-sistent with a follow-up study of lead-poisoned children in whom the risks forhypertension were significantly higherthan they were in controls matched byage, sex, race and ethnicity, and neigh-borhood.50 Bone lead is a more appro-priate marker for chronic exposure;however, its interpretation depends onan understanding of bone physiologyand events such as pregnancy andmenopause.11 Future studies of bloodpressure and hypertension should con-sider blood lead and bone lead as inde-pendent factors influencing the risk forhypertension.
The R2 values in Table 3 suggest thatthe models explain 22% and 14% of thevariation in systolic and diastolic bloodpressure, respectively. We interpret thisto mean that much of the variation inblood pressure is random or due to un-known or immeasurable factors. Be-cause blood pressure has been so wellstudied, it is unlikely that there are un-discovered factors responsible for theremaining unexplained variation.
Other factors that contribute to thevariation in blood lead levels observedin our study include measured and un-measured aspects of conventional andbone density–related predictors of bloodlead, as well as other variables that werenot measured by NHANES. However,we controlled for all of the known fac-tors associated with blood pressure andhypertention,3 including alcohol in-take. This approach presumably mini-mizes residual confounding of our es-timate of the associations of blood leadwith blood pressure and hypertension.
Vital status data are not yet avail-able on the NHANES III cohort. How-ever, a recent analysis of men andwomen from the NHANES II cohort byLustberg and Silbergeld62 found el-evated blood lead levels to be associ-ated with a dose-related increase indeaths due to hypertension-relatedcoronary heart disease and stroke forboth men and women. Although thetiming of NHANES II resulted in higher
blood lead levels than our data in ourpopulation, the effects observed in ourstudy also suggest that lead acts on thecardiovascular system and much lowerlevels in the blood.
From a public health perspective, themost important and troubling implica-tion of these findings is that lead ap-pears to increase blood pressure inwomen at very small increments above1.0 µg/dL, well below what is consid-ered deleterious in adults. The meanblood lead level in this sample ofwomen was 2.9 µg/dL. These resultsdemonstrate effects of lead at levels lessthan the US occupational blood lead ex-posure limits (40 µg/dL) and even lessthan the current Centers for DiseaseControl and Prevention level of con-cern for preventing lead poisoning inchildren (10 µg/dL). Finally, the find-ings from our study of associations ofblood lead with systolic and diastolichypertension and blood pressure amongwomen in the general population lendsupport for further studies on the healtheffects of bone lead mobilization dur-ing the menopausal transition. Theseresults provide support for continuedefforts to reduce lead levels in the gen-eral population, especially women.
Author Contributions: Study concept and design:Nash, Magder, Lustberg, Sherwin, Rubin, Kaufmann,Silbergeld.Acquisition of data: Nash.Analysis and interpretation of data: Nash, Magder,Lustberg, Rubin, Kaufmann, Silbergeld.Drafting of the manuscript: Nash, Sherwin, Rubin,Kaufmann, Silbergeld.Critical revision of the manuscript for important in-tellectual content: Nash, Magder, Lustberg, Sherwin,Rubin, Kaufmann, Silbergeld.Statistical expertise: Magder.Obtained funding: Nash, Silbergeld.Administrative, technical, or material support:Lustberg, Silbergeld.Study supervision: Nash, Sherwin, Rubin, Kaufmann,Silbergeld.Funding/Support: This study was supported with anaward from the Centers for Disease Control and Pre-vention/Association of Teacher’s of Preventive Medi-cine cooperative agreement TS 288-14/14 and by agrant from the Heinz Family Foundation.
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2. Vitals 1. BP Examination 2. Pulse 3. Assess for Obesity 1. Weight and Height 2. Ideal body weight or BMI 3. Waist Circumference (assess for Metabolic Syndrome)
Labs: General for All Patients Urinalysis Complete Blood Count (Hemoglobin or Hematocrit minimum) Fasting lipid profile
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INDICATIONS 1. Hypertension Onset under age 30 or over age 60 2. Hypertension refractory to aggressive treatment 3. Previously controlled Hypertension now refractory 4. Accelerated Hypertension or Malignant Hypertension 5. Signs OR symptoms of secondary Hypertension
6. PRIMARY ALDOSTERONISM (STRONGLY CONSIDER IF HYPOKALEMIA)
Chlorthalidone (may be preferred) 1. Longer half-life (better 24 hour control) 2. Approaches twice the potency of Hydrochlorothiazide
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Non-Dihydropyridine Calcium Channel Blocker (e.g. Verapamil, Diltiazem) or 1. Do not use with Beta Blocker
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Caution should be exercised when patients receiving a beta blocker are administered a calcium-channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial contractility or atrioventricular conduction. There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta-blockers. Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high-degree heart block, and heart failure.
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7. Step 5: Add additional antihypertensive 1. Central Adrenergic Agonist (e.g. Clonidine) 2. Alpha Adrenergic Antagonist (e.g. Hytrin) 3. Reserpine (very effective per JNC7, but review drug interactions)
4. Family History 1. CAD, Hyperlipidemia or htn: Essential Hypertension 2. Kidney disease or deafness: Renovascular disease 3. Diabetes, Thyroid or adrenal disease: Endocrinopathy
6. Examination: Secondary Hypertension clues 1. General
1. Growth delay (Chronic Kidney Disease)
2. Eyes 1. Fundoscopic exam
3. Throat 1. Tonsil or adenoid hypertrophy (Sleep Apnea)