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Hormone Replacement Therapy and Risk of Cardiovascular Disease: Implications of the Results of the Women’s Health Initiative
- Lewis H. Kuller
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 23, Issue 11 January 2003

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The higher rates of coronary heart disease (CHD), stroke, and venous thrombosis among women taking estrogen and progesterone (E+P) compared with placebo in the Women’s Health Initiative clinical trial have important implications for women’s health. Previous studies in both men and women have shown that estrogen therapy lowers low-density lipoprotein cholesterol and raises high-density lipoprotein cholesterol. The changes in these lipoproteins should be associated with at least a 30% decline in CHD risk. Estrogens increased very-low-density lipoprotein (VLDL) triglyceride levels and C-reactive protein. There is evidence that estrogens increase thrombin generation and fibrinolysis. The increase in VLDL triglycerides may enhance thrombotic risk as well as higher levels of atherogenic lipoproteins, such as dense low-density lipoprotein. Genetic variations in estrogen receptors and thrombosis or fibrinolysis may also be important in risks associated with E+P therapy. The increased risk of CHD and stroke with E+P therapy may be attributable to rise in VLDL triglycerides and thrombosis.
Contrasting Effects of Oral Versus Transdermal Estrogen on Serum Amyloid A (SAA) and High-Density Lipoprotein–SAA in Postmenopausal Women
- Aamer Abbas,
- Paul J. Fadel,
- Zhongyun Wang,
- Debbie Arbique,
- Ishwarlal Jialal and
- Wanpen Vongpatanasin
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 24, Issue 101 October 2004

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Objectives— Previous studies indicated that oral estrogen increased C-reactive protein by a first-pass hepatic effect. In this study, we determine whether the route of estrogen administration influences serum amyloid A (SAA), another acute-phase protein produced by the liver, and the SAA content of the high-density lipoprotein (HDL-SAA) in postmenopausal women.Methods and Results— In 29 postmenopausal women without coronary heart disease, we conducted a randomized crossover placebo-controlled study to compare effects of transdermal versus oral estrogen on SAA and HDL-SAA. SAA, apolipoprotein A-I, HDL, and HDL-SAA were measured before and after 8 weeks of transdermal estradiol (100 μg per day), oral-conjugated estrogens (0.625 mg per day), or placebo. We found that oral estrogen significantly increased levels of SAA, HDL, and HDL-SAA, whereas transdermal estrogen reduced both SAA and HDL-SAA but had no effect on HDL in the same women.Conclusions— Oral estrogen increased SAA and altered HDL composition to contain a higher level of SAA by a first-pass hepatic mechanism. Because elevated SAA levels predict adverse prognosis in healthy postmenopausal women, and elevated HDL-SAA levels have been shown to interfere with HDL function, the route of administration may be an important consideration in minimizing side effects of estrogen replacement therapy on cardiovascular outcomes.In this study, we determine whether the route of estrogen administration influences serum amyloid A (SAA), another acute-phase protein produced by the liver, and the SAA content of the high-density lipoprotein (HDL-SAA) in postmenopausal women. Oral estrogen increased SAA and altered HDL composition to contain a higher level of SAA by a first-pass hepatic mechanism. Because elevated SAA levels predict adverse prognosis in healthy postmenopausal women, and elevated HDL-SAA levels have been shown to interfere with HDL function, the administration route may be an important consideration in minimizing side effects of estrogen replacement therapy on cardiovascular outcomes.
Modulation of Estrogen Signaling by the Novel Interaction of Heat Shock Protein 27, a Biomarker for Atherosclerosis, and Estrogen Receptor β: Mechanistic Insight Into the Vascular Effects of Estrogens
- Harvey Miller,
- Stephanie Poon,
- Benjamin Hibbert,
- Katey Rayner,
- Yong-Xiang Chen and
- Edward R. O’Brien
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 25, Issue 31 March 2005

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Objective— We sought to discover proteins that associate with estrogen receptor beta (ERβ) and modulate estrogen signaling.Methods and Result— Using a yeast 2-hybrid screen, we identified heat shock protein 27 (HSP27) as an ERβ-associated protein. HSP27 is a recently identified biomarker of atherosclerosis that is secreted at reduced levels from atherosclerotic compared with normal arteries. In vitro protein-binding assays confirmed the specific interaction of HSP27 with ERβ and not ERα. HSP27 expression was absent in coronary arteries with complex atherosclerotic lesions. Interestingly, HSP27 expression was also absent in 60% of coronary arteries from young males and females (27±6.5 years) with normal histology or nonobstructive fatty streaks/atheromas. Moreover, the absence of HSP27 in these normal or minimally diseased arteries coincided with the loss of ERβ expression. Only 35% of arteries showed coexpression of HSP27 and ERβ. Relative to controls, estradiol-mediated transcription was reduced 20% with overexpression of HSP27 and increased 44% when HSP27 protein levels were reduced with HSP27 siRNA.Conclusions— HSP27, an ERβ-associated protein, shows attenuated expression with coronary atherosclerosis and modulates estrogen signaling.We sought to discover proteins that associate with estrogen receptor beta (ERβ) and modulate estrogen signaling. We identified heat shock protein 27 (HSP27) as an ERβ-associated protein and confirmed the specific interaction of HSP27 with ERβ and not ERα. HSP27 expression was absent in coronary arteries with complex atherosclerotic lesions. Moreover, the absence of HSP27 in these normal or minimally diseased arteries coincided with the loss of ERβ expression. HSP27, an ERβ-associated protein, shows attenuated expression with coronary atherosclerosis and modulates estrogen signaling.
Estrogen Receptor β Protects the Murine Heart Against Left Ventricular Hypertrophy
- Fawzi A. Babiker,
- Daniel Lips,
- Rainer Meyer,
- Els Delvaux,
- Pieter Zandberg,
- Ben Janssen,
- Guillaume van Eys,
- Christian Grohé and
- Pieter A. Doevendans
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 26, Issue 71 July 2006

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Background— Left ventricular hypertrophy (LVH) displays significant gender-based differences. 17β-estradiol (E2) plays an important role in this process because it can attenuate pressure overload hypertrophy via 2 distinct estrogen receptors (ERs): ERα and ERβ. However, which ER is critically involved in the modulation of LVH is poorly understood. We therefore used ERα-deficient (ERα⁻/⁻) and ERβ-deficient (ERβ⁻/⁻) mice to analyze the respective ER-mediated effects.Methods and Results— Respective ER-deficient female mice were ovariectomized and were given E2 or placebo subcutaneously using 60-day release pellets. After 2 weeks, they underwent transverse aortic constriction (TAC) or sham operation. In ERα⁻/⁻ animals, TAC led to a significant increase in ventricular mass compared with sham operation. E2 treatment reduced TAC induced cardiac hypertrophy significantly in wild-type (WT) and ERα⁻/⁻ mice but not in ERβ^−/− mice. Biochemical analysis showed that E2 blocked the increased phosphorylation of p38–mitogen-activated protein kinase observed in TAC-treated ERα⁻/⁻ mice. Moreover, E2 led to an increase of ventricular atrial natriuretic factor expression in WT and ERα⁻/⁻ mice.Conclusions— These findings demonstrate that E2, through ERβ-mediated mechanisms, protects the murine heart against LVH.E2 protects the murine heart against LVH via ERβ. Presence of E2 antagonizes the increase in heart weight with TAC. This protective effect is played by blocking the increased phosphorylation of p38-MAPK and increasing the expression of ANF. ERα appears to be involved in regulation of other processes.
Conjugated Equine Estrogen, Esterified Estrogen, Prothrombotic Variants, and the Risk of Venous Thrombosis in Postmenopausal Women
- Nicholas L. Smith,
- Susan R. Heckbert,
- Rozenn N. Lemaitre,
- Alexander P. Reiner,
- Thomas Lumley,
- Frits R. Rosendaal and
- Bruce M. Psaty
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 26, Issue 121 December 2006

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Background— Joint exposure to oral conjugated equine estrogen (CEE) and prothrombotic genetic variants factor II G20210A or factor V G1601A (Leiden) increase venous thrombotic risk 6- to 16-fold in postmenopausal women. Esterified estrogen (EE), an alternative estrogenic compound, appears not to be associated with increased risk and nothing is known about the joint risk with prothrombotic genetic variants.Methods and Results— We conducted a population-based, case-control study among postmenopausal women within a health maintenance organization. Subjects included 328 cases who sustained a first venous thrombosis and 1591 controls. Current hormone use was defined using electronic pharmacy records and variants FII G20210A and FV Leiden were genotyped using blood samples. FII and FV Leiden variants were associated with 2.1-fold and 3.7-fold increases in venous thrombotic risk, respectively. Overall, CEE use was associated with a 2.5-fold increase in risk compared with no hormone use, whereas EE use was not associated with a statistically increased risk. Compared with no hormone use and no variant, joint exposure to CEE and either prothrombotic variant was associated with an odds ratio (OR) of 9.1 (95% CI: 4.5 to 18.2), whereas joint exposure to EE and either variant was associated with an OR of 2.1 (0.6 to 6.8). When analyses were restricted to hormone users with either variant, CEE use was associated with an OR of 5.3 (1.3 to 21.7) compared with EE use.Conclusions— These findings need replication and suggest EE use is associated with less risk than CEE use especially among 5% to 10% of women who are carriers of a prothrombotic variant.Joint exposure to conjugated equine estrogen (CEE) and prothrombotic genetic variants increase venous thrombotic risk. Esterified estrogen (EE) is not associated with risk and nothing is known about joint risks with prothrombotic variants. Findings suggest EE is associated with less risk than CEE especially among carriers of prothrombotic variants.
Effect of Oral Postmenopausal Hormone Replacement on Progression of Atherosclerosis : A Randomized, Controlled Trial
- Peter Angerer,
- Stefan Störk,
- Wolfgang Kothny,
- Philip Schmitt and
- Clemens von Schacky
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 21, Issue 21 February 2001

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Abstract—Postmenopausal hormone replacement therapy (HRT) is associated with low cardiovascular morbidity and mortality in epidemiological studies. Yet, no randomized trial has examined whether HRT is effective for prevention of coronary heart disease (CHD) in women with increased risk. The objective of this study was to determine whether HRT can slow progression of atherosclerosis, measured as intima-media thickness (IMT) in carotid arteries. Carotid IMT is an appropriate intermediate end point to investigate clinically relevant effects on atherogenesis. This randomized, controlled, observer-blind, clinical, single-center trial enrolled 321 healthy postmenopausal women with increased IMT in ≥1 segment of the carotid arteries. For a period of 48 weeks, subjects received either 1 mg/d 17β-estradiol continuously plus 0.025 mg gestodene for 12 days every month (standard-progestin group), or 1 mg 17β-estradiol plus 0.025 mg gestodene for 12 days every third month (low-progestin group), or no HRT. Maximum IMT in 6 carotid artery segments (common, bifurcation, and internal, both sides) was measured by B-mode ultrasound before and after intervention. HRT did not slow IMT progression in carotid arteries. Mean maximum IMT in the carotid arteries increased by 0.02±0.05 mm in the no HRT group and by 0.03±0.05 and 0.03±0.05 mm, respectively, in the HRT groups (P>0.2). HRT significantly decreased LDL cholesterol, fibrinogen, and follicle-stimulating hormone. In conclusion, 1 year of HRT was not effective in slowing progression of subclinical atherosclerosis in postmenopausal women at increased risk.
Statin Attenuates Increase in C-Reactive Protein During Estrogen Replacement Therapy in Postmenopausal Women
- Kwang Kon Koh,
- William H. Schenke,
- Myron A. Waclawiw,
- Gyorgy Csako and
- Richard O. Cannon
Circulation Volume 105, Issue 132 April 2002

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Background— HMG-CoA reductase inhibitor (statin) therapy reduces cardiovascular risk, mechanisms of which may include diminished arterial inflammation, as suggested by reduction in levels of C-reactive protein (CRP). Because oral estrogens increase CRP in postmenopausal women, with potential inflammatory and thrombotic consequences that could compromise any benefit to cardiovascular risk, we determined whether the coadministration of a statin might modify the estrogenic effect on CRP.Methods and Results— In a double-blind, 3-period crossover study, 28 postmenopausal women (average LDL cholesterol 163±36 mg/dL) were randomly assigned to daily conjugated equine estrogens (CEEs) 0.625 mg, simvastatin 10 mg, or their combination for 6 weeks, with each treatment period separated by 6 weeks. CEEs increased median CRP levels from 0.27 to 0.46 mg/dL, simvastatin decreased CRP from 0.29 to 0.28 mg/dL, and the therapies combined increased CRP from 0.28 to 0.36 mg/dL (all P≤0.02 versus respective baseline values). Post hoc testing showed that the 29% increase in CRP on the combination of CEEs with simvastatin was significantly less than the 70% increase in CRP on CEEs alone (P<0.05). The effect of combination therapy on CRP levels did not correlate with baseline CRP or with baseline or treatment-induced changes in levels of interleukin-6, lipoproteins, or flow-mediated dilation of the brachial artery as a measure of nitric oxide bioactivity.Conclusions— The combination of statin with estrogen may attenuate the potential harmful effects of estrogen therapy in postmenopausal women and maximize any benefit to cardiovascular risk.
Steroid Receptor Coactivator-3 Is Required for Inhibition of Neointima Formation by Estrogen
- Yuhui Yuan,
- Lan Liao,
- David A. Tulis and
- Jianming Xu
Circulation Volume 105, Issue 224 June 2002

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Background— The vasoprotective effects of estrogen are mediated by estrogen receptors (ERs). ERs are transcription factors that require coactivators to exert transcriptional activity. The steroid receptor coactivator-3 (SRC-3, also known as pCIP, AIB1, ACTR, and TRAM-1) interacts with estrogen-bound ERs and strongly coactivates the transcription of target genes in cultured cells. This study has characterized the expression of SRC-3 in cardiovascular tissue and the role of SRC-3 in estrogen-dependent vasoprotection from vascular injury.Methods and Results— Phenotypically normal SRC-3^+/− mice with a knock-in LacZ reporter were used to characterize SRC-3 expression by X-gal staining within the cardiovascular system. Staining signals were specifically detected in vascular smooth muscle cells and endothelial cells but not in myocardial cells. The role of SRC-3 during vascular remodeling was analyzed using a unilateral carotid ligation model. The extent of neointima formation in SRC-3^−/− mice was significantly higher than in wild-type mice, and this difference was diminished after depletion of estrogen by ovariectomy. After ovariectomy, neointimal growth in wild-type mice was almost completely inhibited by estrogen treatment but only partially inhibited in SRC-3^−/− mice. Furthermore, estrogen treatment resulted in reduced inhibition of intimal cell proliferation in SRC-3^−/− mice.Conclusions— SRC-3 is highly expressed in vascular smooth muscle cells and endothelial cells. The loss of SRC-3 function causes a decrease in sensitivity of estrogen-mediated inhibition of neointimal growth, which may be attributable to an insufficient suppression of vascular cell proliferation. These results indicate that SRC-3 largely facilitates ER-dependent vasoprotective effects under conditions of vascular trauma.
Statin Therapy, Cardiovascular Events, and Total Mortality in the Heart and Estrogen/Progestin Replacement Study (HERS)
- David M. Herrington,
- Eric Vittinghoff,
- Feng Lin,
- Josephine Fong,
- Fran Harris,
- Donald Hunninghake,
- Vera Bittner,
- Helmut G. Schrott,
- Roger S. Blumenthal,
- Robert Levy
Circulation Volume 105, Issue 2525 June 2002

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Background— Although effects of statins on cardiovascular outcomes are well established in men, fewer data exist for women. Furthermore, the effects of statins plus hormone replacement therapy (HRT) on cardiovascular outcomes are uncertain.Methods and Results— We examined statin use, cardiovascular events, and total mortality in the Heart and Estrogen/progestin Replacement Study (HERS), a randomized clinical trial of estrogen plus progestin versus placebo in postmenopausal women with heart disease (n=2763). A nonrandomized comparison of statin users and nonusers revealed lower rates of the primary outcome, nonfatal myocardial infarction or coronary heart disease death (relative hazard [RH]=0.79, 95% confidence intervals [CI] 0.63 to 0.99, P=0.04), and total mortality (RH=0.67, 95% CI 0.51 to 0.87, P=0.003). Rates of venous thromboembolic events were also lower among statin users (RH=0.45, 95% CI 0.23 to 0.88, P=0.02). HRT resulted in a significant increase in early risk for primary events in women who did not use statins (RH=1.75, 95% CI 1.02 to 3.03, P=0.04) but not in statin users (RH=1.34, 95% CI 0.63 to 2.86, P=0.45). Adjustment for postrandomization statin use showed no effect of HRT on risk for the primary outcome (RH=0.96, 95% CI 0.77 to 1.29; P=0.72).Conclusions— In HERS, statin use was associated with lower rates of cardiovascular events, venous thromboembolic events, and total mortality. These data provide strong support for statin use in eligible women with coronary disease.
Effect of Transdermal Estradiol and Oral Conjugated Estrogen on C-Reactive Protein in Retinoid-Placebo Trial in Healthy Women
- Andrea Decensi,
- Umberto Omodei,
- Chris Robertson,
- Bernardo Bonanni,
- Aliana Guerrieri-Gonzaga,
- Francesca Ramazzotto,
- Harriet Johansson,
- Serena Mora,
- Maria Teresa Sandri,
- Massimiliano Cazzaniga,
- Massimo Franchi and
- Sergio Pecorelli
Circulation Volume 106, Issue 103 September 2002

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Background— The increase in C-reactive protein (CRP) during oral conjugated equine estrogen (CEE) may explain the initial excess of cardiovascular disease observed in clinical studies. Because the effect of transdermal estradiol (E2) on CRP is unclear, we compared CRP changes after 6 and 12 months of transdermal E2 and oral CEE in a randomized 2×2 retinoid-placebo trial.Methods and Results— A total of 189 postmenopausal women were randomized to 50 μg/d transdermal E2 and 100 mg BID of the retinoid fenretinide (n=45), 50 μg/d transdermal E2 and placebo (n=49), 0.625 mg/d oral CEE and 100 mg BID fenretinide (n=46), or 0.625 mg/d oral CEE and placebo (n=49) for 1 year. Sequential medroxyprogesterone acetate was added in each group. Relative to baseline, CRP increased by 10% (95% CI −9% to 33%) and by 48% (95% CI 22% to 78%) after 6 months of transdermal E2 and oral CEE, respectively. The corresponding figures at 12 months were 3% (95% CI −14% to 23%) for transdermal E2 and 64% (95% CI 38% to 96%) for oral CEE. Fenretinide did not change CRP levels at 6 and 12 months relative to placebo. Relative to oral CEE, the mean change in CRP after 12 months of transdermal E2 was −48% (95% CI −85% to −7%, P=0.012), whereas fenretinide was associated with a mean change of −1% (95% CI −34% to 40%, P=0.79) compared with placebo.Conclusions— In contrast to oral CEE, transdermal E2 does not elevate CRP levels up to 12 months of treatment. The implications for early risk of coronary heart disease require further studies.
Different Effects of Oral Conjugated Equine Estrogen and Transdermal Estrogen Replacement Therapy on Size and Oxidative Susceptibility of Low-Density Lipoprotein Particles in Postmenopausal Women
- Akihiko Wakatsuki,
- Yuji Okatani,
- Nobuo Ikenoue and
- Takao Fukaya
Circulation Volume 106, Issue 141 October 2002

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Background— Postmenopausal estrogen replacement therapy (ERT) has an antioxidant effect that opposes the oxidation of LDL particles. Oral ERT-induced increases in plasma triglyceride, however, decrease LDL particle size, which may counteract this antioxidant effect. Because transdermal ERT decreases plasma triglyceride, it may not decrease LDL particle size and may preserve estrogen’s antioxidant effect. The present study investigates whether transdermal ERT can eliminate the adverse effects of oral ERT on the size and oxidative susceptibility of LDL in postmenopausal women.Methods and Results— Postmenopausal women received no treatment (n=12) or were treated with either 0.625 mg oral conjugated equine estrogen daily (n=16) or with transdermal estradiol (50 μg/d, n=16) for 3 months. Plasma lipids and the diameter of LDL particles were determined. Susceptibility of LDL to oxidation was analyzed by incubation with CuSO₄ and subsequent measurement of thiobarbituric acid reactive substance (TBARS) concentrations. Oral ERT significantly increased plasma triglyceride and decreased LDL diameter but did not affect LDL-derived TBARS concentrations. In contrast, transdermal ERT significantly decreased the concentrations of plasma triglyceride and LDL-derived TBARS and significantly increased LDL diameter. Estrogen-induced changes in LDL diameter correlated negatively with changes in plasma triglyceride (r=−0.51, P<0.001) and LDL-derived TBARS (r=−0.50, P<0.001).Conclusions— Because transdermal, but not oral ERT, decreases plasma triglyceride and produces larger LDL particles that are resistant to oxidation, the antioxidant effect of estrogen can be preserved.
Testosterone Diminishes the Proarrhythmic Effects of Dofetilide in Normal Female Rabbits
- Thai V. Pham,
- Eugene A. Sosunov,
- Evgeny P. Anyukhovsky,
- Peter Danilo and
- Michael R. Rosen
Circulation Volume 106, Issue 1615 October 2002

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Background— Recent clinical and experimental data suggest that testosterone may protect males against the deleterious effects of repolarization-prolonging drugs. This study tests the hypothesis that 5α-dihydrotestosterone (DHT) protects normal females against drug-induced excessive prolongation of repolarization.Methods and Results— We used microelectrode techniques to study isolated preparations of rabbit ventricular endocardium from age-matched normal control female rabbits and female rabbits treated with DHT for 4 weeks. Serum 17β-estradiol levels were identical in the control and DHT-treated animals, whereas DHT levels were high (equaling those in normal males) only in the DHT-treated animals. Basal action potential duration to 90% repolarization (APD₉₀) was significantly shorter in DHT-treated (155±7.4 ms, n=32) than control females (178±6.7 ms, n=29; P<0.05) at cycle length=1000 ms. The increase in APD₉₀ induced by 10⁻⁸ mol/L dofetilide at cycle length=1000 ms was significantly less in DHT-treated females than normal females (ΔAPD₉₀=8±7 and 29±5 ms, respectively, P<0.05). At 10⁻⁶ mol/L dofetilide, the incidence of early afterdepolarizations was 28% in DHT-treated and 55% in normal female rabbits (P<0.05).Conclusions— Elevating DHT levels diminishes the effects of dofetilide to increase APD and induce early afterdepolarizations in females. Moreover, treatment of females with DHT results in prolongation of APD and an incidence of early afterdepolarization equal to values previously reported by us for dofetilide-treated normal males. That serum levels of 17β-estradiol were the same in DHT-treated and untreated females suggests that estradiol is not involved in the response to dofetilide. Thus, these data suggest that DHT and perhaps other androgenic hormones may protect normal females against the risk of dofetilide-induced arrhythmia.
Does Leptin Cause Vascular Disease?
- John P. Cooke and
- Roberta K. Oka
Circulation Volume 106, Issue 158 October 2002

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Current Use of Unopposed Estrogen and Estrogen Plus Progestin and the Risk of Acute Myocardial Infarction Among Women With Diabetes: The Northern California Kaiser Permanente Diabetes Registry, 1995–1998
Circulation Volume 107, Issue 17 January 2003

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Background— Little is known about hormone replacement therapy (HRT) and risk for myocardial infarction (MI) in diabetic women. We examined associations of current HRT, estrogen dosage, and time since HRT initiation with risk of acute MI in diabetic women.Methods and Results— Cox proportional hazards models, with current HRT modeled as a time-dependent covariate, were used to assess the 3-year risk of MI. Among 24 420 women without a recent MI (mean age 64.9 years), 1110 incident MIs were identified. After adjustment for cardiovascular risk factors, current HRT was associated with reduced MI risk (relative hazard [RH] 0.84, 95% CI 0.72 to 0.98). The RH for MI associated with current estrogen plus progestin use was 0.77 (95% CI 0.61 to 0.97), and the RH for MI associated with current unopposed estrogen use was 0.88 (95% CI 0.73 to 1.05). Women were at reduced MI risk if they were taking a low or medium dose of estrogen (equivalent to <0.625 or 0.625 mg of conjugated estrogen, respectively) but not a high dose (>0.625 mg of conjugated estrogen or its equivalent). Among those whose current use of HRT was <1 year, the RH for MI was 1.03 (95% CI 0.74 to 1.44), whereas among users for ≥1 year, the RH was 0.81 (95% CI 0.66 to 1.00). Among 580 women with a recent MI (mean age 69.2 years), 89 recurrent MIs were identified. An increased risk of recurrent MI was observed among current HRT users (RH 1.78, 95% CI 1.06 to 2.98), which was higher among those with current use for <1 year (RH 3.84, 95% CI 1.60 to 9.20).Conclusions— In women without a recent MI, use of estrogen plus progestin was associated with decreased risk of MI. However, HRT was associated with increased risk of MI in women with history of a recent MI. Data from clinical trials in diabetic women are needed.
Myocardial Production of C-Type Natriuretic Peptide in Chronic Heart Failure
- Paul R. Kalra,
- Jonathon R. Clague,
- Aidan P. Bolger,
- Stefan D. Anker,
- Phillip A. Poole-Wilson,
- Allan D. Struthers and
- Andrew J. Coats
Circulation Volume 107, Issue 44 February 2003

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Background— C-type natriuretic peptide (CNP) is a vasodilator produced by the vascular endothelium. It shares structural and physiological properties with the cardiac hormones atrial natriuretic peptide and brain natriuretic peptide (BNP), but little is known about its pathophysiological role in chronic heart failure (CHF). We assessed the hypothesis that CNP is produced by the heart in patients with CHF.Methods and Results— Myocardial CNP production was determined (difference in plasma levels between the aortic root and coronary sinus [CS]) in 9 patients undergoing right and left heart catheterization as part of their CHF assessment (all male, age 59±9 years; New York Heart Association class 2.2±0.1; left ventricular ejection fraction 29±5%; creatinine 105±8 μmol/L [all values mean±SEM]). BNP, established as originating from myocardium, was assessed from the same samples as a positive control. Analyses were performed by a blinded operator using a standard competitive radioimmunoassay kit (Peninsula Laboratories, Bachem Ltd UK). A step-up (29%) in plasma CNP concentration was found from the aorta to the CS (3.55±1.53 versus 4.59±1.54 pg/mL, respectively; P=0.035). The mean increase in CNP was 0.90±0.35 pg/mL (range 0.05 to 2.80 pg/mL). BNP levels increased by 57% from aorta to CS (86.0±20.5 versus 135.0±42.2 pg/mL; P=0.01). CS CNP levels correlated with mean pulmonary capillary wedge pressure (r=0.82, P=0.007).Conclusions— We have shown that CNP is produced by the heart in patients with CHF. Although further evaluation is required to define its full pathophysiological role in this condition, CNP may represent an important new local mediator in the heart.
Hormone Replacement Therapy and Heart Disease: Replacing Dogma With Data
- David M. Herrington
Circulation Volume 107, Issue 17 January 2003

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Review of the International Position Paper on Women’s Health and Menopause: A Comprehensive Approach
- Rodolfo Paoletti and
- Nanette K. Wenger
Circulation Volume 107, Issue 911 March 2003

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Inhibitory Effect of Natriuretic Peptides on Aldosterone Synthase Gene Expression in Cultured Neonatal Rat Cardiocytes
- Teruhiko Ito,
- Michihiro Yoshimura,
- Shota Nakamura,
- Masafumi Nakayama,
- Yukio Shimasaki,
- Eisaku Harada,
- Yuji Mizuno,
- Megumi Yamamuro,
- Masaki Harada,
- Yoshihiko Saito,
- Kazuwa Nakao,
- Hiroki Kurihara,
- Hirofumi Yasue and
- Hisao Ogawa
Circulation Volume 107, Issue 618 February 2003

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Background— Although previously thought to be synthesized solely in adrenal cortex, we have recently showed that aldosterone is also produced in and the expression of CYP11B2 mRNA was induced in the failing or hypertensive human ventricle. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones with wide biological effects, including inhibition of renin and aldosterone production. We hypothesized that natriuretic peptides reduce the expression of CYP11B2 mRNA in the heart.Methods and Results— To test this hypothesis, we examined whether endogenous or exogenous natriuretic peptides reduce the expression of CYP11B2 mRNA using real-time reverse transcription-polymerase chain reaction. By using HS 142–1, a functional guanylyl cyclase-A type receptor antagonist, we showed that angiotensin II (AngII) pretreated with HS 142–1 increased CYP11B2 mRNA expression (1.62±0.12-fold, HS 142–1+AngII 10⁻⁷ mol/L versus AngII 10⁻⁷ mol/L alone, P<0.0001). The treatment with exogenous (10⁻⁶ mol/L) ANP and BNP reduced CYP11B2 mRNA expression (ANP, P=0.0042; BNP, P=0.0012).Conclusions— We showed that endogenous and exogenous natriuretic peptides reduced CYP11B2 mRNA expression in cultured neonatal rat cardiocytes. This may inhibit the cardiac renin-angiotensin-aldosterone system by suppressing the gene expression of CYP11B2 and restraining cardiac hypertrophy and fibrosis.
Vasopressin V₂-Receptor Blockade With Tolvaptan in Patients With Chronic Heart Failure: Results From a Double-Blind, Randomized Trial
- Mihai Gheorghiade,
- Imran Niazi,
- John Ouyang,
- Frank Czerwiec,
- Jun-ichi Kambayashi,
- Manuela Zampino,
- Cesare Orlandi
Circulation Volume 107, Issue 213 June 2003

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Background— In this study, we evaluated the effects of tolvaptan (OPC-41061), a novel, oral, nonpeptide vasopressin V₂-receptor antagonist in patients with chronic heart failure (CHF).Methods and Results— This was a double-blind study investigating the effects of three doses of tolvaptan and placebo in patients with CHF. After a run-in period, 254 patients were randomly assigned to placebo (n=63) or tolvaptan [30 mg (n=64), 45 mg (n=64), or 60 mg (n=63)] once daily for 25 days. Patients were not fluid-restricted and were maintained on stable doses of furosemide. At day 1, when compared with baseline, a decrease in body weight of −0.79±0.99, −0.96±0.93, and −0.84±0.02 kg was observed in the 30-, 45-, and 60-mg tolvaptan groups, respectively, and a body weight increase of +0.32±0.46 kg in the placebo group (P<0.001 for all treatment groups versus placebo). Although the initial decrease in body weight was maintained during the study, no further reduction was observed beyond the first day. An increase in urine volume was observed with tolvaptan when compared with placebo (3.9±0.6, 4.2±0.9, 4.6±0.4, and 2.3±0.2 L/24 hours at day 1 for 30-, 45-, and 60-mg tolvaptan groups, and placebo, respectively; P<0.001). A decrease in edema and a normalization of serum sodium in patients with hyponatremia were observed in the tolvaptan group but not in the placebo group. No significant changes in heart rate, blood pressure, serum potassium, or renal function were observed.Conclusions— In patients with CHF, tolvaptan was well tolerated; it reduced body weight and edema and normalized serum sodium in the hyponatremic patients.
Diabetes Undermines Estrogen Control of Inducible Nitric Oxide Synthase Function in Rat Aortic Smooth Muscle Cells Through Overexpression of Estrogen Receptor-β
- Adriana Maggi,
- Andrea Cignarella,
- Alessia Brusadelli,
- Chiara Bolego,
- Christian Pinna and
- Lina Puglisi
Circulation Volume 108, Issue 215 July 2003

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Background— Previous reports from our group have shown that 17β-estradiol reduces the synthesis and activity of inducible nitric oxide synthase (iNOS) in rat aortic smooth muscle cells (SMC) in response to inflammatory mediators. In this study, we investigated the effect of 17β-estradiol on iNOS function in aortic SMC from streptozotocin-diabetic rats.Methods and Results— Comparative analysis of NO release and of iNOS mRNA and protein content after 24-hour stimulation with a cytokine mixture revealed milder iNOS activation in diabetic than in control SMC. Furthermore, 17β-estradiol dose-dependently blocked iNOS synthesis and activity in control but not in diabetic SMC. The defective estrogen response in diabetic SMC at 24 hours could not be attributed to reduced expression of estrogen receptors (ER). In fact, mRNA and protein levels of ERα and, to a greater extent, of ERβ, were increased in diabetic compared with nondiabetic SMC. Cytokines decreased ERα and ERβ expression in both groups. However, 17β-estradiol dose-dependently restored the expression of ERα but further downregulated that of ERβ, indicating a differential regulation of ER isoforms.Conclusions— Estrogenic control of iNOS was impaired in diabetic SMC. This was associated with a larger increase of ERβ than of ERα protein, whereas 17β-estradiol regulated the two isoforms in an opposite fashion. Thus, modifications in the estrogen modulation of iNOS and in the expression pattern of ER may be involved in diabetic vascular dysfunction.

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