- Email: [email protected]
Effect of hormonal replacement therapy on C-reactive protein and cell-adhesion molecules in postmenopausal women
Effect of Hormonal Replacement Therapy on C-Reactive Protein and Cell-Adhesion Molecules in Postmenopausal Women Stefania Lamon-Fava,
MD, PhD,
Borbala Posfai,
ecent secondary and primary prevention trials have shown no protection from coronary heart R disease in postmenopausal women using hormonal replacement therapy (HRT).1–3 It has been hypothesized that the beneficial effects of HRT on plasma lipid levels may be counteracted by an increased thrombogenicity and inflammation. Women with mutations in the prothrombin gene have a sevenfold increased risk of developing myocardial infarction when exposed to HRT than women on HRT and with the wild-type gene.4 HRT also increases plasma levels of C-reactive protein (CRP),5,6 a predictor of atherosclerosis.7,8 Although some studies have suggested that progestins can reduce CRP levels,9 other studies have not found a beneficial effect of progestins on CRP.5 HRT also decreases plasma levels of soluble adhesion molecules,10,11 but the independent effect of progestins on these parameters is not clear. To clarify the role of medroxyprogesterone acetate (MPA), the most frequently prescribed progestin, on the regulation of cell-adhesion molecules and CRP levels, we performed a randomized, double-blind, placebo-controlled, crossover study comparing the effects of conjugated equine estrogen (CEE) and the combination of CEE and MPA in postmenopausal women. •••
Healthy postmenopausal women were enrolled in a placebo-controlled, double-blind, randomized, crossover study consisting of 3 different phases: (1) placebo, (2) CEE (0.625 mg/day), and (3) CEE (0.625 mg/day) and MPA (2.5 mg/day). Both CEE and MPA tablets had a matching placebo tablet, and during each phase of the study, patients took 2 tablets/day (1 tablet as active CEE or CEE placebo, and 1 tablet as active MPA or MPA placebo). Each phase of the study lasted 8 weeks. Phases were separated by a 4-week washout period. Postmenopausal women with coronary heart disease, liver or kidney disease, thyroid dysfunction, diabetes mellitus, and women who were smoking or From the Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts. This study was supported by the National Institutes of Health Clinical Investigator Development Award HL 03209 to Dr. Lamon-Fava, ARS Grants 53-3K06-5-10, and M01 RR00054 to the New England Medical Center General Clinical Research Center, funded by the National Center for the Research Resources of the National Institutes of Health, Bethesda, Maryland. Some support for subject recruitment was provided by Grant AG08812 from the Claude D. Pepper Older Americans Independence Center, Harvard Medical School, Boston, Massachusetts. Dr. Lamon-Fava’s address is: Lipid Metabolism Laboratory, Jean Mayer USDA HNRCA, Tufts University, 711 Washington Street, Boston, Massachusetts 02111. Email: [email protected]. Manuscript received August 4, 2002; revised manuscript received and accepted September 9, 2002.
252
©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 January 15, 2003
BS,
and Ernst J. Schaefer,
MD
were taking medications known to affect lipid levels and metabolism, or with a history of clotting disorders, thromboembolism, cancer of the breast, uterus, or cervix were excluded from the study. The study protocol was approved by the Human Investigation Review Committee of New England Medical Center and Tufts University. Study subjects provided informed consent and underwent a screening visit consisting of an interview including medical history, physical examination, vital signs, electrocardiogram, and laboratory tests. In all, 14 postmenopausal women were enrolled and completed the 3 phases of the study (age 57 ⫾ 6 years, weight 69.9 ⫾ 12.3 kg, and body mass index 27.26 ⫾ 5.11 kg/m2). Subjects were asked to maintain the same lifestyle (diet, physical exercise) throughout the study. At weeks 7 and 8 of each phase, blood was drawn after a 12-hour fast in all subjects. In the first 6 subjects, an additional fasting blood draw was also obtained at week 6 of each phase. Blood was drawn in a 10-ml tube containing ethylenediaminetetraacetic acid to a final concentration of 0.15%, and in a regular 10-ml tube. Plasma and serum were separated at 2,500 rpm for 30 minutes at 4°C, and aliquots were stored at ⫺80°C until time of assay. Soluble vascular cell-adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) levels were measured in plasma using the Parameter human soluble VCAM-1 and Parameter human soluble ICAM-1 immunoassays from R&D Systems (Minneapolis, Minnesota), which utilize a quantitative sandwich enzyme-linked immunosorbent assay. CRP in plasma was measured with an ultrasensitive assay from Wako (Richmond, Virginia) in a Hitachi 911 auto-analyzer (Roche Diagnostics, Indianapolis, Indiana). Data are expressed as mean ⫾ SD. Distribution of variables was assessed for normality. The effects of the 2 hormone replacement regimens on VCAM-1, ICAM-1, and CRP levels were assessed by repeatedmeasures analysis of variance. Post hoc comparisons were made by use of the Tukey’s post hoc test. A p value ⬍0.05 was considered statistically significant. Simple correlation analysis was performed with Pearson’s correlation coefficient. Compared with placebo, plasma levels of VCAM-1 were decreased by treatment with CEE alone and CEE and MPA (⫺8.4% and ⫺6.4%, respectively) (Table 1 and Figure 1). MPA did not have an independent effect on VCAM-1 levels (CEE ⫹ MPA relative to CEE, ⫹3%). Similarly, compared with placebo, plasma ICAM-1 levels were significantly decreased during CEE alone and the combination therapy (⫺8.4% and ⫺7.6%, respectively) (Table 1 and 0002-9149/03/$–see front matter PII S0002-9149(02)03121-1
TABLE 1 Plasma Concentration of Inflammatory Markers
VCAM-1 (ng/ml) ICAM-1 (ng/ml) CRP (g/ml)
Placebo
CEE
CEE ⫹ MPA
p Value*
p Value†
p Value‡
521 ⫾ 136 265 ⫾ 51 2.3 ⫾ 3.1
469 ⫾ 91 239 ⫾ 40 4.1 ⫾ 4.4
482 ⫾ 101 244 ⫾ 41 3.8 ⫾ 4.4
0.009 0.004 0.0001
0.058 0.007 0.003
0.703 0.925 0.652
p values, Tukey’s post hoc test: *CEE versus placebo; †CEE ⫹ MPA versus placebo; ‡CEE ⫹ MPA versus CEE. Values are expressed as mean ⫾ SD.
during the combination treatment were assessed with respect to estrogen alone, there was no association between the MPA-induced percent changes in CRP and in VCAM-1 and ICAM-1 (r ⫽ 0.136 and r ⫽ 0.390, respectively; p ⫽ NS). •••
In our study, consistent with previous observations,10 –13 CEE significantly lowered VCAM-1 and FIGURE 1. VCAM-1 (left panel) and ICAM-1 (right panel) levels at the end of the plaICAM-1 levels. Our data indicate cebo, CEE, and CEE and MPA treatment phases. Note that the treatment phases were randomized. that adding MPA to the estrogen regimen does not alter the beneficial effect of estrogen on cell-adhesion molecules. This is in contrast to the recent observation of a greater lowering effect with the combination of CEE and MPA, compared with CEE alone, on VCAM-1 and ICAM-1 levels in a randomized, parallel study of 45 postmenopausal women.9 Our data, however, rely on the study’s randomized, doubleblind, crossover, placebo-controlled design, which avoids biases introduced by the interindividual variability in response to treatment. Some individual variability in VCAM-1 and ICAM-1 responses to treatment with estrogen and estrogen and MPA was observed in our subjects (Figure 1). In our study, CRP levels after estrogen treatment were approximately twofold greater than those of placebo values, and adding MPA to the estrogen regimen did not significantly change the effect of estrogen on FIGURE 2. Individual plasma CRP levels at the end of the plaCRP levels. It has been previously suggested that cebo, CEE, and CEE and MPA treatment phases. Note that the treatment phases were randomized. MPA, due to its androgenic potential, may attenuate the increase in CRP levels caused by estrogen.9 HowFigure 1). As observed for VCAM-1, ICAM-1 levels ever, the results from our study and from the Postwere not affected by the addition of MPA to estrogen menopausal Estrogen/Progestin Intervention (PEPI) study indicate that MPA, at the 2.5 mg/day dose, does (CEE ⫹ MPA relative to CEE, ⫹1%). 5 Treatment with CEE resulted in a significant in- not change the estrogen effect on CRP. Also, it has been shown that administration of testosterone to crease in plasma CRP levels (⫹105%) (Table 1 and healthy men in doses ranging from physiologic to Figure 2). The addition of MPA 2.5 mg/day resulted in a significant, but more modest, increase in CRP levels superphysiologic does not have any effect on CRP (⫹82%). There was no significant independent effect levels.14 However, in a recent study with cyclic cyproof MPA on this parameter (CEE ⫹ MPA compared terone acetate combined with estrogen, CRP levels were not elevated.15 Therefore, whereas our study with CEE: ⫺5%). Although the percent change in VCAM-1 observed indicates that MPA does not significantly affect CRP during the CEE treatment was significantly associated levels, the effect of other progestins needs to be furwith the percent change in ICAM-1 (r ⫽ 0.692, p ther elucidated. Although cell-adhesion molecules are expressed by ⬍0.01), there was no association between the percent change in CRP and the percent change in both adhe- endothelial and vascular cells, CRP is mainly synthesion molecules (r ⫽ ⫺0.025 and r ⫽ 0.201, respec- sized by liver cells. Therefore, it is likely that the tively; p ⫽ NS). Also, when the percent changes mechanisms regulating plasma levels of these 2 BRIEF REPORTS
253
classes of inflammatory markers are somewhat independent. In our study, there was no correlation between the HRT-induced changes in adhesion molecule levels and changes in CRP levels, supporting the hypothesis that the molecular mechanisms driving the HRT response for these 2 classes of inflammatory molecules are independent. In conclusion, estrogen replacement therapy has a differential effect on markers of inflammation in healthy postmenopausal women by decreasing plasma levels of soluble adhesion molecules and increasing plasma levels of CRP. MPA, one of the most frequently prescribed progestins in HRT, does not significantly change the effects of estrogen on these parameters. 1. Hulley SB, Grady D, Bush T, Furberg CD, Herrington DM, Riggs B, Vitting-
hoff E, for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605– 613. 2. Herrington DM, Reboussin DM, Brosnihan B, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, Givens DH, Waters D. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522–529. 3. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–333. 4. Psaty B, Smith N, Lemaitre R, Vos H, Heckbert S, LaCroix A, Rosendaal F. Hormone replacement therapy, prothrombotic mutations, and the risk of incident
nonfatal myocardial infarction in postmenopausal women. JAMA 2001;285:906 – 913. 5. Cushman M, Legault C, Barrett-Connor E, Stefanick M, Kessler G, Judd H, Sakkinen P, Tracy R. Effect of postmenopausal hormones on inflammationsensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) study. Circulation 1999;100:717–722. 6. Ridker PM, Hennekens CH, Rifai N, Buring JM, Manson JA. Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation 1999;100:713–716. 7. Ridker PM, Stampfer MI, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001;285:2481–2485. 8. Koenig W, Sund M, Frohlich M, Fischer H, Lowel H, Doring A, Hutchinson W, Pepys M. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999;99:237–242. 9. Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Effect of medroxyprogesterone acetate on vascular inflammatory markers in postmenopausal women receiving estrogen. Circulation 2002;105:1436 –1439. 10. Scarabin P, Alhene-Gelas M, Oger E, Plu-Bureau G. Hormone replacement therapy and circulating ICAM-1 in postmenopausal women. A randomized controlled trial. Thromb Haemost 1999;81:673–675. 11. Herrington DM, Brosnihan B, Pusser B, Seely E, Ridker PM, Rifai N, MacLean D. Differential effects of E and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women. J Clin Endocrinol Metab 2001;86:4216 –4222. 12. Koh K, Bui M, Mincemoyer R, Cannon R III. Effects of hormone therapy on inflammatory cell adhesion molecules in postmenopausal women. Am J Cardiol 1997;80:1505–1507. 13. Koh K, Jin D, Yang S, Lee S, Hwang H, Kang M, Kim W, Kim D, Choi I, Shin E. Vascular effects of synthetic or natural progestagen combined with conjugated equine estrogen in healthy postmenopausal women. Circulation 2001; 103:1961–1966. 14. Singh A, Hsia S, Alaupovic P, Sinha-Hikim I, Woodhouse L, Buchanan T, Shen R, Bross R, Bernam N, Bhasin S. The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men. J Clin Endocrinol Metab 2002;87:136 –143. 15. Skouby S, Gram J, Andersen L, Sidelmann J, Petersen K, Jespersen J. Hormone replacement therapy: estrogen and progestin effects on plasma C-reactive protein concentrations. Am J Obst Gyn 2002;186:969 –977.
Influence of Age on Assessment of Diastolic Function by Doppler Tissue Imaging Dennis A. Tighe, MD, Craig S. Vinch, MD, Jeffrey C. Hill, RDCS, Theo E. Meyer, MD, DPhil, Robert J. Goldberg, PhD, and Gerard P. Aurigemma, raditional Doppler methods for assessing left ventricular (LV) filling include transmitral and pulmoT nary vein Doppler flow recordings. These methods 1–3
are influenced by age.4 Recently, Doppler tissue imaging (DTI) has emerged as a method to assess diastolic filling,5–10 which when coupled with mitral inflow data can be used to predict LV filling pressures.6,9 However, the influence of age on DTI parameters has not been well studied. Accordingly, the purpose of this cross-sectional study was to examine the association between age and pulse-wave DTI parameters of diastolic function obtained at the lateral mitral annulus in apparently healthy subjects. From the Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts. Dr. Tighe’s address is: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, 55 Lake Avenue, North, Worcester, Massachusetts 01655. E-mail: [email protected]. Manuscript received August 9, 2002; revised manuscript received and accepted September 12, 2002.
254
©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 January 15, 2003
MD
•••
Healthy men and women (n ⫽ 103) were recruited for the present study. No subject had a history of hypertension, diabetes, coronary artery disease, angina pectoris, myocardial infarction, stroke, transient ischemic events, significant valvular heart disease, or congestive heart failure. A 12-lead electrocardiogram was obtained in each subject. All subjects gave written informed consent. Studies were performed with commercially available echocardiographs equipped with fusion frequency (2 to 4 MHz), tissue harmonic transducers, and preprogrammed DTI settings (Sonos 4500 & 5500, Agilent Technologies, Andover, Massachusetts). Standard 2-dimensional, Doppler color flow, and spectral Doppler examinations were performed and recorded to videotape for subsequent off-line analysis. Chamber dimensions and LV mass were measured using previously described methods.11–13 The apical 4-and 2-chamber views were used to calculate LV 0002-9149/03/$–see front matter PII S0002-9149(02)03122-3
MD, PhD,
Borbala Posfai,
ecent secondary and primary prevention trials have shown no protection from coronary heart R disease in postmenopausal women using hormonal replacement therapy (HRT).1–3 It has been hypothesized that the beneficial effects of HRT on plasma lipid levels may be counteracted by an increased thrombogenicity and inflammation. Women with mutations in the prothrombin gene have a sevenfold increased risk of developing myocardial infarction when exposed to HRT than women on HRT and with the wild-type gene.4 HRT also increases plasma levels of C-reactive protein (CRP),5,6 a predictor of atherosclerosis.7,8 Although some studies have suggested that progestins can reduce CRP levels,9 other studies have not found a beneficial effect of progestins on CRP.5 HRT also decreases plasma levels of soluble adhesion molecules,10,11 but the independent effect of progestins on these parameters is not clear. To clarify the role of medroxyprogesterone acetate (MPA), the most frequently prescribed progestin, on the regulation of cell-adhesion molecules and CRP levels, we performed a randomized, double-blind, placebo-controlled, crossover study comparing the effects of conjugated equine estrogen (CEE) and the combination of CEE and MPA in postmenopausal women. •••
Healthy postmenopausal women were enrolled in a placebo-controlled, double-blind, randomized, crossover study consisting of 3 different phases: (1) placebo, (2) CEE (0.625 mg/day), and (3) CEE (0.625 mg/day) and MPA (2.5 mg/day). Both CEE and MPA tablets had a matching placebo tablet, and during each phase of the study, patients took 2 tablets/day (1 tablet as active CEE or CEE placebo, and 1 tablet as active MPA or MPA placebo). Each phase of the study lasted 8 weeks. Phases were separated by a 4-week washout period. Postmenopausal women with coronary heart disease, liver or kidney disease, thyroid dysfunction, diabetes mellitus, and women who were smoking or From the Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts. This study was supported by the National Institutes of Health Clinical Investigator Development Award HL 03209 to Dr. Lamon-Fava, ARS Grants 53-3K06-5-10, and M01 RR00054 to the New England Medical Center General Clinical Research Center, funded by the National Center for the Research Resources of the National Institutes of Health, Bethesda, Maryland. Some support for subject recruitment was provided by Grant AG08812 from the Claude D. Pepper Older Americans Independence Center, Harvard Medical School, Boston, Massachusetts. Dr. Lamon-Fava’s address is: Lipid Metabolism Laboratory, Jean Mayer USDA HNRCA, Tufts University, 711 Washington Street, Boston, Massachusetts 02111. Email: [email protected]. Manuscript received August 4, 2002; revised manuscript received and accepted September 9, 2002.
252
©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 January 15, 2003
BS,
and Ernst J. Schaefer,
MD
were taking medications known to affect lipid levels and metabolism, or with a history of clotting disorders, thromboembolism, cancer of the breast, uterus, or cervix were excluded from the study. The study protocol was approved by the Human Investigation Review Committee of New England Medical Center and Tufts University. Study subjects provided informed consent and underwent a screening visit consisting of an interview including medical history, physical examination, vital signs, electrocardiogram, and laboratory tests. In all, 14 postmenopausal women were enrolled and completed the 3 phases of the study (age 57 ⫾ 6 years, weight 69.9 ⫾ 12.3 kg, and body mass index 27.26 ⫾ 5.11 kg/m2). Subjects were asked to maintain the same lifestyle (diet, physical exercise) throughout the study. At weeks 7 and 8 of each phase, blood was drawn after a 12-hour fast in all subjects. In the first 6 subjects, an additional fasting blood draw was also obtained at week 6 of each phase. Blood was drawn in a 10-ml tube containing ethylenediaminetetraacetic acid to a final concentration of 0.15%, and in a regular 10-ml tube. Plasma and serum were separated at 2,500 rpm for 30 minutes at 4°C, and aliquots were stored at ⫺80°C until time of assay. Soluble vascular cell-adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) levels were measured in plasma using the Parameter human soluble VCAM-1 and Parameter human soluble ICAM-1 immunoassays from R&D Systems (Minneapolis, Minnesota), which utilize a quantitative sandwich enzyme-linked immunosorbent assay. CRP in plasma was measured with an ultrasensitive assay from Wako (Richmond, Virginia) in a Hitachi 911 auto-analyzer (Roche Diagnostics, Indianapolis, Indiana). Data are expressed as mean ⫾ SD. Distribution of variables was assessed for normality. The effects of the 2 hormone replacement regimens on VCAM-1, ICAM-1, and CRP levels were assessed by repeatedmeasures analysis of variance. Post hoc comparisons were made by use of the Tukey’s post hoc test. A p value ⬍0.05 was considered statistically significant. Simple correlation analysis was performed with Pearson’s correlation coefficient. Compared with placebo, plasma levels of VCAM-1 were decreased by treatment with CEE alone and CEE and MPA (⫺8.4% and ⫺6.4%, respectively) (Table 1 and Figure 1). MPA did not have an independent effect on VCAM-1 levels (CEE ⫹ MPA relative to CEE, ⫹3%). Similarly, compared with placebo, plasma ICAM-1 levels were significantly decreased during CEE alone and the combination therapy (⫺8.4% and ⫺7.6%, respectively) (Table 1 and 0002-9149/03/$–see front matter PII S0002-9149(02)03121-1
TABLE 1 Plasma Concentration of Inflammatory Markers
VCAM-1 (ng/ml) ICAM-1 (ng/ml) CRP (g/ml)
Placebo
CEE
CEE ⫹ MPA
p Value*
p Value†
p Value‡
521 ⫾ 136 265 ⫾ 51 2.3 ⫾ 3.1
469 ⫾ 91 239 ⫾ 40 4.1 ⫾ 4.4
482 ⫾ 101 244 ⫾ 41 3.8 ⫾ 4.4
0.009 0.004 0.0001
0.058 0.007 0.003
0.703 0.925 0.652
p values, Tukey’s post hoc test: *CEE versus placebo; †CEE ⫹ MPA versus placebo; ‡CEE ⫹ MPA versus CEE. Values are expressed as mean ⫾ SD.
during the combination treatment were assessed with respect to estrogen alone, there was no association between the MPA-induced percent changes in CRP and in VCAM-1 and ICAM-1 (r ⫽ 0.136 and r ⫽ 0.390, respectively; p ⫽ NS). •••
In our study, consistent with previous observations,10 –13 CEE significantly lowered VCAM-1 and FIGURE 1. VCAM-1 (left panel) and ICAM-1 (right panel) levels at the end of the plaICAM-1 levels. Our data indicate cebo, CEE, and CEE and MPA treatment phases. Note that the treatment phases were randomized. that adding MPA to the estrogen regimen does not alter the beneficial effect of estrogen on cell-adhesion molecules. This is in contrast to the recent observation of a greater lowering effect with the combination of CEE and MPA, compared with CEE alone, on VCAM-1 and ICAM-1 levels in a randomized, parallel study of 45 postmenopausal women.9 Our data, however, rely on the study’s randomized, doubleblind, crossover, placebo-controlled design, which avoids biases introduced by the interindividual variability in response to treatment. Some individual variability in VCAM-1 and ICAM-1 responses to treatment with estrogen and estrogen and MPA was observed in our subjects (Figure 1). In our study, CRP levels after estrogen treatment were approximately twofold greater than those of placebo values, and adding MPA to the estrogen regimen did not significantly change the effect of estrogen on FIGURE 2. Individual plasma CRP levels at the end of the plaCRP levels. It has been previously suggested that cebo, CEE, and CEE and MPA treatment phases. Note that the treatment phases were randomized. MPA, due to its androgenic potential, may attenuate the increase in CRP levels caused by estrogen.9 HowFigure 1). As observed for VCAM-1, ICAM-1 levels ever, the results from our study and from the Postwere not affected by the addition of MPA to estrogen menopausal Estrogen/Progestin Intervention (PEPI) study indicate that MPA, at the 2.5 mg/day dose, does (CEE ⫹ MPA relative to CEE, ⫹1%). 5 Treatment with CEE resulted in a significant in- not change the estrogen effect on CRP. Also, it has been shown that administration of testosterone to crease in plasma CRP levels (⫹105%) (Table 1 and healthy men in doses ranging from physiologic to Figure 2). The addition of MPA 2.5 mg/day resulted in a significant, but more modest, increase in CRP levels superphysiologic does not have any effect on CRP (⫹82%). There was no significant independent effect levels.14 However, in a recent study with cyclic cyproof MPA on this parameter (CEE ⫹ MPA compared terone acetate combined with estrogen, CRP levels were not elevated.15 Therefore, whereas our study with CEE: ⫺5%). Although the percent change in VCAM-1 observed indicates that MPA does not significantly affect CRP during the CEE treatment was significantly associated levels, the effect of other progestins needs to be furwith the percent change in ICAM-1 (r ⫽ 0.692, p ther elucidated. Although cell-adhesion molecules are expressed by ⬍0.01), there was no association between the percent change in CRP and the percent change in both adhe- endothelial and vascular cells, CRP is mainly synthesion molecules (r ⫽ ⫺0.025 and r ⫽ 0.201, respec- sized by liver cells. Therefore, it is likely that the tively; p ⫽ NS). Also, when the percent changes mechanisms regulating plasma levels of these 2 BRIEF REPORTS
253
classes of inflammatory markers are somewhat independent. In our study, there was no correlation between the HRT-induced changes in adhesion molecule levels and changes in CRP levels, supporting the hypothesis that the molecular mechanisms driving the HRT response for these 2 classes of inflammatory molecules are independent. In conclusion, estrogen replacement therapy has a differential effect on markers of inflammation in healthy postmenopausal women by decreasing plasma levels of soluble adhesion molecules and increasing plasma levels of CRP. MPA, one of the most frequently prescribed progestins in HRT, does not significantly change the effects of estrogen on these parameters. 1. Hulley SB, Grady D, Bush T, Furberg CD, Herrington DM, Riggs B, Vitting-
hoff E, for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605– 613. 2. Herrington DM, Reboussin DM, Brosnihan B, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, Givens DH, Waters D. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522–529. 3. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–333. 4. Psaty B, Smith N, Lemaitre R, Vos H, Heckbert S, LaCroix A, Rosendaal F. Hormone replacement therapy, prothrombotic mutations, and the risk of incident
nonfatal myocardial infarction in postmenopausal women. JAMA 2001;285:906 – 913. 5. Cushman M, Legault C, Barrett-Connor E, Stefanick M, Kessler G, Judd H, Sakkinen P, Tracy R. Effect of postmenopausal hormones on inflammationsensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) study. Circulation 1999;100:717–722. 6. Ridker PM, Hennekens CH, Rifai N, Buring JM, Manson JA. Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation 1999;100:713–716. 7. Ridker PM, Stampfer MI, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001;285:2481–2485. 8. Koenig W, Sund M, Frohlich M, Fischer H, Lowel H, Doring A, Hutchinson W, Pepys M. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999;99:237–242. 9. Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Effect of medroxyprogesterone acetate on vascular inflammatory markers in postmenopausal women receiving estrogen. Circulation 2002;105:1436 –1439. 10. Scarabin P, Alhene-Gelas M, Oger E, Plu-Bureau G. Hormone replacement therapy and circulating ICAM-1 in postmenopausal women. A randomized controlled trial. Thromb Haemost 1999;81:673–675. 11. Herrington DM, Brosnihan B, Pusser B, Seely E, Ridker PM, Rifai N, MacLean D. Differential effects of E and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women. J Clin Endocrinol Metab 2001;86:4216 –4222. 12. Koh K, Bui M, Mincemoyer R, Cannon R III. Effects of hormone therapy on inflammatory cell adhesion molecules in postmenopausal women. Am J Cardiol 1997;80:1505–1507. 13. Koh K, Jin D, Yang S, Lee S, Hwang H, Kang M, Kim W, Kim D, Choi I, Shin E. Vascular effects of synthetic or natural progestagen combined with conjugated equine estrogen in healthy postmenopausal women. Circulation 2001; 103:1961–1966. 14. Singh A, Hsia S, Alaupovic P, Sinha-Hikim I, Woodhouse L, Buchanan T, Shen R, Bross R, Bernam N, Bhasin S. The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men. J Clin Endocrinol Metab 2002;87:136 –143. 15. Skouby S, Gram J, Andersen L, Sidelmann J, Petersen K, Jespersen J. Hormone replacement therapy: estrogen and progestin effects on plasma C-reactive protein concentrations. Am J Obst Gyn 2002;186:969 –977.
Influence of Age on Assessment of Diastolic Function by Doppler Tissue Imaging Dennis A. Tighe, MD, Craig S. Vinch, MD, Jeffrey C. Hill, RDCS, Theo E. Meyer, MD, DPhil, Robert J. Goldberg, PhD, and Gerard P. Aurigemma, raditional Doppler methods for assessing left ventricular (LV) filling include transmitral and pulmoT nary vein Doppler flow recordings. These methods 1–3
are influenced by age.4 Recently, Doppler tissue imaging (DTI) has emerged as a method to assess diastolic filling,5–10 which when coupled with mitral inflow data can be used to predict LV filling pressures.6,9 However, the influence of age on DTI parameters has not been well studied. Accordingly, the purpose of this cross-sectional study was to examine the association between age and pulse-wave DTI parameters of diastolic function obtained at the lateral mitral annulus in apparently healthy subjects. From the Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts. Dr. Tighe’s address is: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, 55 Lake Avenue, North, Worcester, Massachusetts 01655. E-mail: [email protected]. Manuscript received August 9, 2002; revised manuscript received and accepted September 12, 2002.
254
©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 January 15, 2003
MD
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Healthy men and women (n ⫽ 103) were recruited for the present study. No subject had a history of hypertension, diabetes, coronary artery disease, angina pectoris, myocardial infarction, stroke, transient ischemic events, significant valvular heart disease, or congestive heart failure. A 12-lead electrocardiogram was obtained in each subject. All subjects gave written informed consent. Studies were performed with commercially available echocardiographs equipped with fusion frequency (2 to 4 MHz), tissue harmonic transducers, and preprogrammed DTI settings (Sonos 4500 & 5500, Agilent Technologies, Andover, Massachusetts). Standard 2-dimensional, Doppler color flow, and spectral Doppler examinations were performed and recorded to videotape for subsequent off-line analysis. Chamber dimensions and LV mass were measured using previously described methods.11–13 The apical 4-and 2-chamber views were used to calculate LV 0002-9149/03/$–see front matter PII S0002-9149(02)03122-3