- Email: [email protected]
Changes in hemodynamics and left ventricular structure after menopause
Changes in Hemodynamics and Left Ventricular Structure After Menopause Alan L. Hinderliter, MD, Andrew Sherwood, PhD, James A. Blumenthal, PhD, Kathleen C. Light, PhD, Susan S. Girdler, PhD, Judith McFetridge, PhD, Kristy Johnson, MS, and Robert Waugh, MD To evaluate the cardiovascular changes associated with menopause, we studied hemodynamics at rest, ambulatory blood pressure, and left ventricular structure in a biracial cohort of pre- and postmenopausal women of similar age, race, weight, and blood pressure. Despite similar levels of blood pressure, postmenopausal women had a higher indexed peripheral resistance (2,722 ⴞ 757 vs 2,262 ⴞ 661 dynes·s·m2/cm5, p <0.01) and a lower cardiac index (2.64 ⴞ 0.73 vs 3.10 ⴞ 0.71 L/min·m2, p <0.01) than premenopausal women. Postmenopausal women also had less nocturnal decreases in both systolic (15 ⴞ 8 vs 19 ⴞ 8 mm Hg, p <0.01) and diastolic (12 ⴞ 6 vs 15 ⴞ 6 mm Hg, p ⴝ 0.05) pressures during ambulatory monitoring and higher levels of hematocrit (40 ⴞ 2% vs 38 ⴞ 3%, p
<0.01). In association with this greater hemodynamic load, postmenopausal women had evidence of early concentric left ventricular remodeling, manifested by a greater relative wall thickness (0.38 ⴞ 0.06 vs 0.35 ⴞ 0.06, p <0.01) than that observed in premenopausal women. Differences between pre- and postmenopausal women in hemodynamics, diurnal blood pressure variation, and left ventricular structure were observed in white and African-American subjects. These results suggest that menopause is associated with hemodynamic changes and left ventricular remodeling, which may contribute to the enhanced cardiovascular risk observed in postmenopausal women. 䊚2002 by Excerpta Medica, Inc. (Am J Cardiol 2002;89:830 – 833)
pidemiologic studies have demonstrated that cardiovascular risk in women increases dramatically E after menopause. This increased risk may be in part
prescription cardiovascular medications, and use of tobacco products. Recruitment was designed to obtain samples of pre- and postmenopausal women that were matched by age, weight, race, and blood pressure. Women were classified as premenopausal if they reported regular menstruation and as postmenopausal if they were amenorrheic for ⱖ9 months. Postmenopausal status was confirmed by measurements of follicular stimulating hormone. Demographic characteristics and the height and weight of each subject were determined at the time of recruitment. Body mass index was calculated as weight/height2. Hemodynamics at rest: Hemodynamic measurements were made between 9:00 A.M. and 12:00 P.M. After instrumentation, subjects rested for 20 minutes in a comfortable chair, with blood pressure measurements initiated every 5 minutes. During the final 5 minutes, blood pressure and cardiac output measurements were repeated every minute, and these readings were averaged to represent hemodynamics at rest. Blood pressure was measured using a Suntech 4240 monitor (Raleigh, North Carolina). Cardiac output was estimated using impedance cardiography, incorporating a standard tetrapolar band electrode configuration. Impedance signals were acquired on-line using customized software that utilizes a hybrid ensemble averaging procedure to filter respiratory and movement artifact.5 Stroke volume was derived using Kubicek et al’s equation.6 Cardiac output and peripheral vascular resistance were calculated by standard formulas and indexed by body surface area. Ambulatory blood pressure monitoring: Ambulatory blood pressure monitoring was performed for 24 hours on a typical work day using an Accutracker II monitor
1,2
due to concentric remodeling of the left ventricle associated with increased ventricular afterload.3 A previous study from our group noted a blunted nocturnal blood pressure decline in African-American and white postmenopausal women compared with premenopausal women of similar age, body size, and blood pressure.4 In the present study, we describe hemodynamic and echocardiographic findings in this same cohort of women.
METHODS The protocol was approved by the Committee on the Protection of Rights of Human Subjects and written informed consent was obtained from all subjects before participation. The study population consisted of 118 employed volunteers between 47 and 55 years of age, recruited by advertisements in local newspapers. All had casual blood pressure on screening examination of ⬍180/90 mm Hg. None were taking exogenous estrogen. Other exclusions included history of surgical menopause, diabetes mellitus, chronic renal insufficiency, overt heart disease, treatment with From the University of North Carolina, Chapel Hill; and Duke University Medical Center, Durham, North Carolina. This study was supported by grants HL-49427 and HL-53724 from the National Institutes of Health (NIH) and M01-RR-30 General Clinical Research Centers Program, National Center for Research Resources, NIH, Bethesda, Maryland. Manuscript received August 6, 2001; revised manuscript received and accepted December 10, 2001. Address for reprints: Alan L. Hinderliter, UNC Division of Cardiology, CB # 7075, Chapel Hill, North Carolina 27599-7075. E-mail: [email protected].
830
©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 89 April 1, 2002
0002-9149/02/$–see front matter PII S0002-9149(02)02193-8
(Suntech). Readings were obtained 4 times per hour at unpredictable intervals during waking hours, and 2 times per hour during sleep. Each measurement during waking hours was accompanied by a diary entry documenting location, posture, and activity. All readings were reviewed by an experienced staff member and artifactual values were deleted using previously described criteria.7 Averaged values were determined for awake and sleep blood pressures, with categorization of individual readings based on diary reports. Echocardiography: Echocardiograms and Doppler studies were performed with a Hewlett-Packard (Andover, Massachusetts) imaging system equipped with a 2.5-MHz phased array transducer. Images were obtained with the patient in the partial left lateral decubitus position, and were recorded on s-VHS videotape. These studies were subsequently quantified by a single experienced observer who was blinded to the subjects’ menopause status. Left ventricular end-diastolic diameter, posterior wall thickness, and interventricular septal thickness were measured at end-diastole using a leading edge to leading edge convention, and could be quantified in 91 subjects. Left ventricular mass was estimated using a cube function model with a correction factor.8 To adjust for variations in heart size due to differences in body size, indexed left ventricular mass was calculated as ventricular mass/height2.7 as described by deSimone et al.9 Relative wall thickness was calculated as twice the ratio of posterior wall thickness to the left ventricular end-diastolic diameter. Biochemical and hematologic data: Blood samples were drawn between 9:00 A.M. and 12:00 P.M. after an overnight fast with the subjects seated. Specimens were collected for lipid assays, plasma renin activity, hematocrit, creatinine, estradiol, and follicular stimulating hormone. A 24-hour urine sample collected over the previous day was analyzed for sodium content. Data analysis: Continuous variables describing demographic characteristics, resting hemodynamic measurements, ambulatory blood pressures, biochemical and hematologic parameters, and echocardiographic results were expressed as mean ⫾ SD, or mean ⫾ SE for graphs. Student’s t tests and chi-square tests were used to assess differences in demographic characteristics and biochemical and hematologic parameters between pre- and postmenopausal women. Our principle hypothesis was that postmenopausal women would exhibit left ventricular remodeling and hypertrophy, independent of ethnicity. Two-factor (menopause ⫻ ethnicity) analysis of variance tests were employed to evaluate the effects of menopause and race on measures of left ventricular structure, as well as blood pressure and hemodynamics. In addition, general linear models were used to determine if the effects of menopause were independent of age. A p value of ⬍0.05 was considered significant.
RESULTS
Demographic characteristics: The demographics of the pre- and postmenopausal women in the study
TABLE 1 Demographic Characteristics of Pre- and Postmenopausal Women Variable Age (yrs) Height (m) Weight (kg) Body mass index (kg/m2) Race (% African-American) Median education (yrs)
Premenopausal (n ⫽ 64) 49 1.64 69.1 26.1
⫾ 1* ⫾ 0.07 ⫾ 11.8 ⫾ 3.6 36 16
Postmenopausal (n ⫽ 54) 51 1.63 70.5 26.6
⫾ 2* ⫾ 0.06 ⫾ 13.1 ⫾ 4.3 29 16
*p ⬍0.01 for difference between pre- and postmenopausal women.
cohort are listed in Table 1. Postmenopausal women were slightly older than premenopausal women, but otherwise the 2 groups were similar. The 91 subjects with interpretable echocardiograms did not differ from the cohort as a whole in any of these characteristics. Hemodynamic profile, ambulatory blood pressure, and laboratory parameters: Table 2 lists hemodynamic
parameters, ambulatory blood pressures, and biochemical and hematologic data for both the pre- and postmenopausal women. Blood pressures and heart rates at rest were virtually identical in both the pre- and postmenopausal women. Despite the similarities in blood pressure, however, postmenopausal women had a higher indexed peripheral resistance and a lower cardiac index. Postmenopausal women also exhibited less nocturnal decreases in systolic and diastolic blood pressures and higher levels of hematocrit and cholesterol. These differences remained significant after controlling for age. Echocardiographic measurements: Pre- and postmenopausal women had similar values for indexed left ventricular mass (Table 3). There were significant differences, however, in left ventricular geometry. Postmenopausal women tended to have a smaller chamber size and greater posterior wall thickness. This resulted in a significantly greater relative wall thickness, independent of age, in postmenopausal subjects. Effects of menopause in ethnic subgroups: There were no significant interactions between menopausal status and ethnicity on the magnitude of decrease in systolic or diastolic nocturnal blood pressures, indexed peripheral resistance, or relative wall thickness. Thus, the effects of menopause were apparent in African-American and white women. As illustrated in Figure 1, relative wall thickness (mean ⫾ SE) was lowest in premenopausal white women (0.35 ⫾ 0.01) and greatest in postmenopausal African-American women (0.40 ⫾ 0.01).
DISCUSSION Our study suggests that menopause is associated with concentric remodeling of the left ventricle (i.e., an increase in the ratio of left ventricular wall thickness to chamber size). In our analysis of pre- and postmenopausal women of similar ages who were
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Other potential influences on left ventricular afterload examined in our study included lipid levels, hematocrit, Premenopausal Postmenopausal p Value and plasma renin activity. In our study sample, serum total cholesterol was Hemodynamics at rest Systolic blood pressure (mm Hg) 108 ⫾ 13 108 ⫾ 12 NS lower in premenopausal women than Diastolic blood pressure (mm Hg) 71 ⫾ 8 72 ⫾ 7 NS in postmenopausal women. Elevated Heart rate (beats/min) 67 ⫾ 9 67 ⫾ 9 NS concentrations of cholesterol are asso2 3.10 ⫾ 0.71 2.64 ⫾ 0.73 ⬍0.01 Cardiac index (L/min䡠m ) ciated with impaired endothelial funcPeripheral resistance index 2262 ⫾ 661 2722 ⫾ 757 ⬍0.01 (dyne䡠s䡠m2/cm5) tion,20 and several clinical studies have Ambulatory blood pressure (mm Hg) demonstrated improved nitric oxide– Daytime systolic blood pressure 119 ⫾ 11 119 ⫾ 12 NS dependent vasodilator responses with Daytime diastolic blood pressure 74 ⫾ 7 76 ⫾ 7 NS cholesterol reduction.21,22 PostmenoSystolic blood pressure during sleep 100 ⫾ 10 104 ⫾ 13 ⬍0.05 pausal women also had high levels of Diastolic blood pressure during sleep 59 ⫾ 8 63 ⫾ 8 ⬍0.05 Systolic nocturnal decrease 19 ⫾ 8 15 ⫾ 8 ⬍0.01 hematocrit—the principle determinant Diastolic nocturnal decrease 15 ⫾ 6 12 ⫾ 6 0.05 of whole blood viscosity and a correBiochemical and hematologic data late of left ventricular mass in patients Follicular stimulating hormone 17 ⫾ 21 67 ⫾ 31 ⬍0.01 with hypertension.23 There was no sig(mIU/ml) Estradiol (pg/ml) 81 ⫾ 78 22 ⫾ 36 ⬍0.01 nificant difference between pre- and Hematocrit (%) 38 ⫾ 3 40 ⫾ 2 ⬍0.01 postmenopausal women in plasma reTotal cholesterol (mg/dl) 192 ⫾ 34 207 ⫾ 44 ⬍0.05 nin activity. Triglycerides (mg/dl) 83 ⫾ 40 94 ⫾ 69 NS Pre- and postmenopausal study Plasma renin activity (mg/ml/h) 1.92 ⫾ 4.17 2.05 ⫾ 3.62 NS participants were matched for blood Creatinine (mg/dl) 0.85 ⫾ 0.12 0.87 ⫾ 0.11 NS Urinary sodium excretion 107 ⫾ 45 110 ⫾ 47 NS pressure at rest, and had similar lev(mEq/24 h) els of arterial pressure at rest and during daily activities. As reported in a previous study,4 however, blood pressures during sleep were higher and the magnitude of the decrease in nocturnal blood pressure was smaller TABLE 3 Left Ventricular Structure in Pre- and Postmenopausal Women in our postmenopausal subjects. Premenopausal Postmenopausal p Value Schillaci et al3 noted similar differ2.7 ences in the ambulatory blood pres39.5 ⫾ 8.8 38.3 ⫾ 8.5 NS Indexed left ventricular mass (g/m ) Left ventricular end-diastolic 46.7 ⫾ 3.9 45.3 ⫾ 3.5 0.06 sure profiles of pre- and postmenodiameter (mm) pausal women, and several studies Posterior wall thickness (mm) 8.1 ⫾ 1.1 8.6 ⫾ 1.3 ⬍0.05 have demonstrated that an attenuated Relative wall thickness 0.35 ⫾ 0.06 0.38 ⫾ 0.06 ⬍0.01 decrease in nocturnal blood pressure is associated with left ventricular hypertrophy.24,25 matched for body size and blood pressure at rest, Our results are consistent with several previous echocardiographic measurements of left ventricular studies that have evaluated changes in hemodynamics mass were similar in the 2 groups. Postmenopausal and left ventricular structure associated with menowomen, however, had a significantly greater relative pause. Pines et al26 described a smaller aortic flow wall thickness. This pattern of left ventricular remod- velocity interval, suggesting a lower stroke volume eling is characteristically seen in subjects with in- and cardiac output in women who were postmenocreased peripheral resistance and is associated with an pausal for ⬎1 year than in recently postmenopausal or enhanced risk of cardiovascular events.10 younger premenopausal women, despite similar levels Our data indicate that changes in systemic hemo- of blood pressure. The same investigators found dynamics may play an important role in the left ven- greater left ventricular wall thickness in postmenotricular remodeling associated with menopause. De- pausal women.27 Schillaci et al3 examined ambulatory spite nearly identical blood pressures at rest, post- blood pressure, hemodynamics, and left ventricular menopausal women had a significantly higher structure in pre- and postmenopausal women matched peripheral resistance than premenopausal subjects. for age, clinic blood pressure, and body mass index. This observation is consistent with direct effects of Menopause was associated with greater peripheral reestrogen on vasomotor tone. Estrogen stimulates nitric sistance, a blunted nocturnal decrease in ambulatory oxide synthase activity in vascular endothelial blood pressure, and concentric remodeling of the left cells,11–13 leading to dilation of resistance vessels14 ventricle. Our study extends the results of these preand conduit arteries.15 On a longer term basis, estro- vious investigations by confirming similar hemodygen increases the expression of genes for nitric oxide namic and echocardiographic changes accompanying synthase and prostaglandin synthase in vascular tis- menopause in a biracial sample, and by evaluating sues16,17 and inhibits the proliferation of vascular neurohumoral and hematologic variables that may smooth muscle cells.18,19 play an etiologic role in left ventricular remodeling. TABLE 2 Hemodynamics at Rest, Ambulatory Blood Pressure, and Laboratory Parameters in Pre- and Postmenopausal Women
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10. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left
FIGURE 1. Left ventricular wall thickness in subgroups by menopause status and ethnicity. AA ⴝ African-American; Post ⴝ postmenopausal; Pre ⴝ premenopausal. Values represent mean ⴞ SE. 1. Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH. Menopause and the risk of coronary heart disease in women. N Engl J Med 1987;316:1105–1110. 2. Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and coronary heart disease: the Framingham study. Ann Intern Med 1978;89:157– 161. 3. Schillaci G, Verdecchia P, Borgioni C, Ciucci A, Porcellati C. Early cardiac changes after menopause. Hypertension 1998;32:764 –769. 4. Sherwood A, Thurston R, Steffen P, Blumenthal JA, Waugh RA, Hinderliter A. Blunted nighttime blood pressure dipping in postmenopausal women. Am J Hypertens 2001;14:749 –754. 5. Sherwood A, Carter LS, Murphy CA. Cardiac output measurement by impedance cardiography: comparison of two alternative methodologies against thermodilution values. Aviat Space Environ Med 1991;62:116 –122. 6. Kubicek WG, Karnegis JN, Patterson RP, Witsoe DA, Mattson RH. Development and evaluation of an impedance cardiograph system. Aerosp Med 1966; 37:1208 –1212. 7. Hinderliter AL, Light KC, Willis PW. Left ventricular mass index and diastolic filling: relation to blood pressure and demographic variables in a healthy biracial sample. Am J Hypertens 1991;4:579 –585. 8. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo K, Sachs I, Peinchek N. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57:450 –458. 9. deSimone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, deDiritiis O, Alderman MH. Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol 1992;20:1251–1260.
ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114:345–352. 11. Chen Z, Yuhanna IS, Galcheva-Gargova ZI, Karas RH, Mendelsohn ME, Shaul PW. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest 1999;103:401–406. 12. Lantin-Hermoso RL, Rosenfeld CR, Yuhanna IS, German Z, Chen Z, Shaul PW. Estrogen acutely stimulates nitric oxide synthase activity in fetal pulmonary artery endothelium. Am J Physiol 1997;273:L119 –L126. 13. Caulin-Glaser T, Garcı´a-Carden˜ a G, Sarrel P, Sessa WC, Bender JR. 17estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2⫹ mobilization. Circ Res 1997;81:885–892. 14. Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Canon RO III. Acute vascular effects of estrogen in postmenopausal women. Circulation 1994;90: 786 –791. 15. Liebermann EH, Gebhard MD, Uehata A, Walsh BW, Selwyn AP, Ganz P, Yeung AC, Creager MA. Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med 1994;121:936 – 941. 16. Weiner CP, Lizasoain I, Baylis SA, Knowles RG, Charles IG, Moncada S. Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci USA 1994;91:5212–5216. 17. Binko J, Majewski H. 17-Estradiol reduces vasoconstriction in endotheliumdenuded rat aortas through inducible NOS. Am J Physiol 1998;274:H853–H859. 18. Kolodgie FD, Jacob A, Wilson PS, Carlson GC, Farb A, Verma A, Virmani R. Estradiol attenuates directed migration of vascular smooth muscle cells in vitro. Am J Pathol 1996;148:969 –976. 19. Bhalla RC, Toth TK, Bhatty RA, Thompson LP, Sharma RV. Estrogen reduces proliferation and agonist-induced calcium increase in coronary artery smooth muscle cells. Am J Physiol 1997;272:H1996 –H2003. 20. Chowienczyk PJ, Watts GF, Cockcroft JR, Ritter JM. Impaired endotheliumdependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet 1992;340:1430 –1432. 21. Stroes ESG, Koomans HA, deBruin TWA, Rabelink TJ. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication. Lancet 1995;346:467–471. 22. Vogel RA, Corretti MC, Plotnick GD. Changes in flow-mediated brachial artery vasoactivity with lowering of desirable cholesterol levels in healthy middle-aged men. Am J Cardiol 1996;77:37–40. 23. Devereux RB, Drayer JIM, Chien S, Pickering TG, Letcher RL, DeYoung JL, Sealey JE, Laragh JH. Whole blood viscosity as a determinant of cardiac hypertrophy in systemic hypertension. Am J Cardiol 1984;54:592–595. 24. Verdecchia P, Schillaci G, Guerrieri M, Gatteschi C, Benemio G, Boldrini F, Porcellati C. Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation 1990;81:528 –536. 25. Schmieder RE, Rockstroh JK, Aepfelbacher F, Schulze B, Messerli FH. Gender-specific cardiovascular adaptation due to circadian blood pressure variations in essential hypertension. Am J Hypertens 1995;8:1160 –1166. 26. Pines A, Fisman EZ, Drory Y, Levo Y, Shemesh J, Ben-Ari E, Ayalon D. Menopause-induced changes in Doppler-derived parameters of aortic flow in healthy women. Am J Cardiol 1992;69:1104 –1106. 27. Pines A, Fisman EZ, Shapira I, Drory Y, Weiss A, Eckstein N, Levo Y, Averbuch M, Motro M, Rotmensch HH, Ayalon D. Exercise echocardiography in postmenopausal hormone users with mild systemic hypertension. Am J Cardiol 1996;78:1385–1389.
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<0.01). In association with this greater hemodynamic load, postmenopausal women had evidence of early concentric left ventricular remodeling, manifested by a greater relative wall thickness (0.38 ⴞ 0.06 vs 0.35 ⴞ 0.06, p <0.01) than that observed in premenopausal women. Differences between pre- and postmenopausal women in hemodynamics, diurnal blood pressure variation, and left ventricular structure were observed in white and African-American subjects. These results suggest that menopause is associated with hemodynamic changes and left ventricular remodeling, which may contribute to the enhanced cardiovascular risk observed in postmenopausal women. 䊚2002 by Excerpta Medica, Inc. (Am J Cardiol 2002;89:830 – 833)
pidemiologic studies have demonstrated that cardiovascular risk in women increases dramatically E after menopause. This increased risk may be in part
prescription cardiovascular medications, and use of tobacco products. Recruitment was designed to obtain samples of pre- and postmenopausal women that were matched by age, weight, race, and blood pressure. Women were classified as premenopausal if they reported regular menstruation and as postmenopausal if they were amenorrheic for ⱖ9 months. Postmenopausal status was confirmed by measurements of follicular stimulating hormone. Demographic characteristics and the height and weight of each subject were determined at the time of recruitment. Body mass index was calculated as weight/height2. Hemodynamics at rest: Hemodynamic measurements were made between 9:00 A.M. and 12:00 P.M. After instrumentation, subjects rested for 20 minutes in a comfortable chair, with blood pressure measurements initiated every 5 minutes. During the final 5 minutes, blood pressure and cardiac output measurements were repeated every minute, and these readings were averaged to represent hemodynamics at rest. Blood pressure was measured using a Suntech 4240 monitor (Raleigh, North Carolina). Cardiac output was estimated using impedance cardiography, incorporating a standard tetrapolar band electrode configuration. Impedance signals were acquired on-line using customized software that utilizes a hybrid ensemble averaging procedure to filter respiratory and movement artifact.5 Stroke volume was derived using Kubicek et al’s equation.6 Cardiac output and peripheral vascular resistance were calculated by standard formulas and indexed by body surface area. Ambulatory blood pressure monitoring: Ambulatory blood pressure monitoring was performed for 24 hours on a typical work day using an Accutracker II monitor
1,2
due to concentric remodeling of the left ventricle associated with increased ventricular afterload.3 A previous study from our group noted a blunted nocturnal blood pressure decline in African-American and white postmenopausal women compared with premenopausal women of similar age, body size, and blood pressure.4 In the present study, we describe hemodynamic and echocardiographic findings in this same cohort of women.
METHODS The protocol was approved by the Committee on the Protection of Rights of Human Subjects and written informed consent was obtained from all subjects before participation. The study population consisted of 118 employed volunteers between 47 and 55 years of age, recruited by advertisements in local newspapers. All had casual blood pressure on screening examination of ⬍180/90 mm Hg. None were taking exogenous estrogen. Other exclusions included history of surgical menopause, diabetes mellitus, chronic renal insufficiency, overt heart disease, treatment with From the University of North Carolina, Chapel Hill; and Duke University Medical Center, Durham, North Carolina. This study was supported by grants HL-49427 and HL-53724 from the National Institutes of Health (NIH) and M01-RR-30 General Clinical Research Centers Program, National Center for Research Resources, NIH, Bethesda, Maryland. Manuscript received August 6, 2001; revised manuscript received and accepted December 10, 2001. Address for reprints: Alan L. Hinderliter, UNC Division of Cardiology, CB # 7075, Chapel Hill, North Carolina 27599-7075. E-mail: [email protected].
830
©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 89 April 1, 2002
0002-9149/02/$–see front matter PII S0002-9149(02)02193-8
(Suntech). Readings were obtained 4 times per hour at unpredictable intervals during waking hours, and 2 times per hour during sleep. Each measurement during waking hours was accompanied by a diary entry documenting location, posture, and activity. All readings were reviewed by an experienced staff member and artifactual values were deleted using previously described criteria.7 Averaged values were determined for awake and sleep blood pressures, with categorization of individual readings based on diary reports. Echocardiography: Echocardiograms and Doppler studies were performed with a Hewlett-Packard (Andover, Massachusetts) imaging system equipped with a 2.5-MHz phased array transducer. Images were obtained with the patient in the partial left lateral decubitus position, and were recorded on s-VHS videotape. These studies were subsequently quantified by a single experienced observer who was blinded to the subjects’ menopause status. Left ventricular end-diastolic diameter, posterior wall thickness, and interventricular septal thickness were measured at end-diastole using a leading edge to leading edge convention, and could be quantified in 91 subjects. Left ventricular mass was estimated using a cube function model with a correction factor.8 To adjust for variations in heart size due to differences in body size, indexed left ventricular mass was calculated as ventricular mass/height2.7 as described by deSimone et al.9 Relative wall thickness was calculated as twice the ratio of posterior wall thickness to the left ventricular end-diastolic diameter. Biochemical and hematologic data: Blood samples were drawn between 9:00 A.M. and 12:00 P.M. after an overnight fast with the subjects seated. Specimens were collected for lipid assays, plasma renin activity, hematocrit, creatinine, estradiol, and follicular stimulating hormone. A 24-hour urine sample collected over the previous day was analyzed for sodium content. Data analysis: Continuous variables describing demographic characteristics, resting hemodynamic measurements, ambulatory blood pressures, biochemical and hematologic parameters, and echocardiographic results were expressed as mean ⫾ SD, or mean ⫾ SE for graphs. Student’s t tests and chi-square tests were used to assess differences in demographic characteristics and biochemical and hematologic parameters between pre- and postmenopausal women. Our principle hypothesis was that postmenopausal women would exhibit left ventricular remodeling and hypertrophy, independent of ethnicity. Two-factor (menopause ⫻ ethnicity) analysis of variance tests were employed to evaluate the effects of menopause and race on measures of left ventricular structure, as well as blood pressure and hemodynamics. In addition, general linear models were used to determine if the effects of menopause were independent of age. A p value of ⬍0.05 was considered significant.
RESULTS
Demographic characteristics: The demographics of the pre- and postmenopausal women in the study
TABLE 1 Demographic Characteristics of Pre- and Postmenopausal Women Variable Age (yrs) Height (m) Weight (kg) Body mass index (kg/m2) Race (% African-American) Median education (yrs)
Premenopausal (n ⫽ 64) 49 1.64 69.1 26.1
⫾ 1* ⫾ 0.07 ⫾ 11.8 ⫾ 3.6 36 16
Postmenopausal (n ⫽ 54) 51 1.63 70.5 26.6
⫾ 2* ⫾ 0.06 ⫾ 13.1 ⫾ 4.3 29 16
*p ⬍0.01 for difference between pre- and postmenopausal women.
cohort are listed in Table 1. Postmenopausal women were slightly older than premenopausal women, but otherwise the 2 groups were similar. The 91 subjects with interpretable echocardiograms did not differ from the cohort as a whole in any of these characteristics. Hemodynamic profile, ambulatory blood pressure, and laboratory parameters: Table 2 lists hemodynamic
parameters, ambulatory blood pressures, and biochemical and hematologic data for both the pre- and postmenopausal women. Blood pressures and heart rates at rest were virtually identical in both the pre- and postmenopausal women. Despite the similarities in blood pressure, however, postmenopausal women had a higher indexed peripheral resistance and a lower cardiac index. Postmenopausal women also exhibited less nocturnal decreases in systolic and diastolic blood pressures and higher levels of hematocrit and cholesterol. These differences remained significant after controlling for age. Echocardiographic measurements: Pre- and postmenopausal women had similar values for indexed left ventricular mass (Table 3). There were significant differences, however, in left ventricular geometry. Postmenopausal women tended to have a smaller chamber size and greater posterior wall thickness. This resulted in a significantly greater relative wall thickness, independent of age, in postmenopausal subjects. Effects of menopause in ethnic subgroups: There were no significant interactions between menopausal status and ethnicity on the magnitude of decrease in systolic or diastolic nocturnal blood pressures, indexed peripheral resistance, or relative wall thickness. Thus, the effects of menopause were apparent in African-American and white women. As illustrated in Figure 1, relative wall thickness (mean ⫾ SE) was lowest in premenopausal white women (0.35 ⫾ 0.01) and greatest in postmenopausal African-American women (0.40 ⫾ 0.01).
DISCUSSION Our study suggests that menopause is associated with concentric remodeling of the left ventricle (i.e., an increase in the ratio of left ventricular wall thickness to chamber size). In our analysis of pre- and postmenopausal women of similar ages who were
PREVENTIVE CARDIOLOGY/CARDIOVASCULAR CHANGES AFTER MENOPAUSE
831
Other potential influences on left ventricular afterload examined in our study included lipid levels, hematocrit, Premenopausal Postmenopausal p Value and plasma renin activity. In our study sample, serum total cholesterol was Hemodynamics at rest Systolic blood pressure (mm Hg) 108 ⫾ 13 108 ⫾ 12 NS lower in premenopausal women than Diastolic blood pressure (mm Hg) 71 ⫾ 8 72 ⫾ 7 NS in postmenopausal women. Elevated Heart rate (beats/min) 67 ⫾ 9 67 ⫾ 9 NS concentrations of cholesterol are asso2 3.10 ⫾ 0.71 2.64 ⫾ 0.73 ⬍0.01 Cardiac index (L/min䡠m ) ciated with impaired endothelial funcPeripheral resistance index 2262 ⫾ 661 2722 ⫾ 757 ⬍0.01 (dyne䡠s䡠m2/cm5) tion,20 and several clinical studies have Ambulatory blood pressure (mm Hg) demonstrated improved nitric oxide– Daytime systolic blood pressure 119 ⫾ 11 119 ⫾ 12 NS dependent vasodilator responses with Daytime diastolic blood pressure 74 ⫾ 7 76 ⫾ 7 NS cholesterol reduction.21,22 PostmenoSystolic blood pressure during sleep 100 ⫾ 10 104 ⫾ 13 ⬍0.05 pausal women also had high levels of Diastolic blood pressure during sleep 59 ⫾ 8 63 ⫾ 8 ⬍0.05 Systolic nocturnal decrease 19 ⫾ 8 15 ⫾ 8 ⬍0.01 hematocrit—the principle determinant Diastolic nocturnal decrease 15 ⫾ 6 12 ⫾ 6 0.05 of whole blood viscosity and a correBiochemical and hematologic data late of left ventricular mass in patients Follicular stimulating hormone 17 ⫾ 21 67 ⫾ 31 ⬍0.01 with hypertension.23 There was no sig(mIU/ml) Estradiol (pg/ml) 81 ⫾ 78 22 ⫾ 36 ⬍0.01 nificant difference between pre- and Hematocrit (%) 38 ⫾ 3 40 ⫾ 2 ⬍0.01 postmenopausal women in plasma reTotal cholesterol (mg/dl) 192 ⫾ 34 207 ⫾ 44 ⬍0.05 nin activity. Triglycerides (mg/dl) 83 ⫾ 40 94 ⫾ 69 NS Pre- and postmenopausal study Plasma renin activity (mg/ml/h) 1.92 ⫾ 4.17 2.05 ⫾ 3.62 NS participants were matched for blood Creatinine (mg/dl) 0.85 ⫾ 0.12 0.87 ⫾ 0.11 NS Urinary sodium excretion 107 ⫾ 45 110 ⫾ 47 NS pressure at rest, and had similar lev(mEq/24 h) els of arterial pressure at rest and during daily activities. As reported in a previous study,4 however, blood pressures during sleep were higher and the magnitude of the decrease in nocturnal blood pressure was smaller TABLE 3 Left Ventricular Structure in Pre- and Postmenopausal Women in our postmenopausal subjects. Premenopausal Postmenopausal p Value Schillaci et al3 noted similar differ2.7 ences in the ambulatory blood pres39.5 ⫾ 8.8 38.3 ⫾ 8.5 NS Indexed left ventricular mass (g/m ) Left ventricular end-diastolic 46.7 ⫾ 3.9 45.3 ⫾ 3.5 0.06 sure profiles of pre- and postmenodiameter (mm) pausal women, and several studies Posterior wall thickness (mm) 8.1 ⫾ 1.1 8.6 ⫾ 1.3 ⬍0.05 have demonstrated that an attenuated Relative wall thickness 0.35 ⫾ 0.06 0.38 ⫾ 0.06 ⬍0.01 decrease in nocturnal blood pressure is associated with left ventricular hypertrophy.24,25 matched for body size and blood pressure at rest, Our results are consistent with several previous echocardiographic measurements of left ventricular studies that have evaluated changes in hemodynamics mass were similar in the 2 groups. Postmenopausal and left ventricular structure associated with menowomen, however, had a significantly greater relative pause. Pines et al26 described a smaller aortic flow wall thickness. This pattern of left ventricular remod- velocity interval, suggesting a lower stroke volume eling is characteristically seen in subjects with in- and cardiac output in women who were postmenocreased peripheral resistance and is associated with an pausal for ⬎1 year than in recently postmenopausal or enhanced risk of cardiovascular events.10 younger premenopausal women, despite similar levels Our data indicate that changes in systemic hemo- of blood pressure. The same investigators found dynamics may play an important role in the left ven- greater left ventricular wall thickness in postmenotricular remodeling associated with menopause. De- pausal women.27 Schillaci et al3 examined ambulatory spite nearly identical blood pressures at rest, post- blood pressure, hemodynamics, and left ventricular menopausal women had a significantly higher structure in pre- and postmenopausal women matched peripheral resistance than premenopausal subjects. for age, clinic blood pressure, and body mass index. This observation is consistent with direct effects of Menopause was associated with greater peripheral reestrogen on vasomotor tone. Estrogen stimulates nitric sistance, a blunted nocturnal decrease in ambulatory oxide synthase activity in vascular endothelial blood pressure, and concentric remodeling of the left cells,11–13 leading to dilation of resistance vessels14 ventricle. Our study extends the results of these preand conduit arteries.15 On a longer term basis, estro- vious investigations by confirming similar hemodygen increases the expression of genes for nitric oxide namic and echocardiographic changes accompanying synthase and prostaglandin synthase in vascular tis- menopause in a biracial sample, and by evaluating sues16,17 and inhibits the proliferation of vascular neurohumoral and hematologic variables that may smooth muscle cells.18,19 play an etiologic role in left ventricular remodeling. TABLE 2 Hemodynamics at Rest, Ambulatory Blood Pressure, and Laboratory Parameters in Pre- and Postmenopausal Women
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