Author + information
- Received January 25, 2013
- Revision received April 4, 2013
- Accepted April 8, 2013
- Published online July 16, 2013.
- Karen A. Matthews, PhD∗,†,‡∗ (, )
- Carolyn J. Gibson, MPH, MS‡,
- Samar R. El Khoudary, PhD, MPH† and
- Rebecca C. Thurston, PhD∗,†,‡
- ∗Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
- †Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
- ‡Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania
Reprint requests and correspondence:
Dr. Karen A. Matthews, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, Pennsylvania 15213.
Objectives The aim of this study was to compare the changes in risk factors for cardiovascular disease (CVD) leading up to and after hysterectomy with or without bilateral oophorectomy with the changes observed up to and after natural menopause.
Background Evidence suggests that hysterectomy status with or without bilateral oophorectomy might increase risk for CVD, but most studies retrospectively assess menopausal status.
Methods Study of Women's Health across the Nation enrolled 3,302 pre-menopausal women not using hormone therapy between 42 and 52 years of age and followed them annually for over 11 years for sociodemographic characteristics, menopausal status, surgeries, body mass index, medication use, lifestyle factors, lipids, blood pressure, insulin resistance, and hemostatic and inflammatory factors. By 2008, 1,769 women had reached natural menopause, 77 women had a hysterectomy with ovarian conservation, and 106 women had a hysterectomy with bilateral oophorectomy. Piece-wise hierarchical growth models compared these groups on annual changes in CVD risk factors before and after final menstrual period or surgery.
Results Multivariable analyses showed that annual changes in CVD risk factors did not vary by group, with few exceptions, and the significant group differences that did emerge were not in the anticipated direction.
Conclusions Hysterectomy with or without ovarian conservation is not a key determinant of CVD risk factor status either before or after elective surgery in midlife. These results should provide reassurance to women and their clinicians that hysterectomy in midlife is unlikely to accelerate the CVD risk of women.
Elective hysterectomy is a common surgical procedure to improve quality of life among symptomatic women approaching menopause (1–3). The clear benefits of surgery for reducing debilitating symptoms must be considered in light of potential long-term health consequences, including cardiovascular disease (CVD). The cardiovascular risk associated with hysterectomy, especially accompanied by bilateral oophorectomy, is not yet clear. In the Framingham Heart Study, women who had a hysterectomy, especially with bilateral oophorectomy, were later at elevated risk for CVD, adjusting for age group and smoking status (4). In the Nurse's Health Study, women who had a bilateral oophorectomy, usually occurring in the fifth decade, were at greater risk for incident coronary heart disease and total mortality than women who had a hysterectomy without oophorectomy (5). By contrast, in a large registry of Swedish women, the risk for incident coronary heart disease, stroke, and heart failure during the follow-up was not confined to women with hysterectomy accompanied by bilateral oophorectomy; both surgical groups were at elevated risk (6). However, this relationship was only observed among women 50 years of age or less, and smoking was not statistically controlled. In an older cohort of women enrolled in the Women's Health Initiative, women with bilateral oophorectomy and hysterectomy did not have a greater incidence of CVD, adjusting for a large number of CVD risk factors (7), compared with women with hysterectomy alone—similar to the results from the Swedish registry. In the same study, women who had hysterectomy regardless of ovarian conservation had elevated levels of CVD risk factors and were more often diabetic and hypertensive (8), compared with post-menopausal women who had not had a hysterectomy. Furthermore, hysterectomy, regardless of ovarian conservation, was associated with incident CVD, with associations largely attenuated after introducing a wide array of cardiovascular risk factors and sociodemographic characteristics.
Taken together, the findings raise a number of important issues. Because these studies only assessed CVD risk factors years after hysterectomy and/or oophorectomy, without assessment of pre-surgery CVD risk-factor levels, it is unknown whether elevated CVD risk led to the conditions warranting a surgical menopause or whether CVD risk was accelerated post-surgery. For example, obesity in pre-menopausal women increases the likelihood of abnormal bleeding and fibroids, which are common indications for these gynecologic surgeries (9–12). It is also not clear whether hysterectomy with versus without ovarian conservation has similar or different effects on CVD risk factors, compared with not having surgery and experiencing a natural menopause.
One approach to addressing these issues is to describe the prospective changes in cardiovascular risk factors before and after elective hysterectomy with or without bilateral oophorectomy in relation to changes in CVD risk factors that occurred in a comparable period of time before and after final menstrual period (FMP) in women who experienced a natural menopause. This report is based on cardiovascular risk factor data from SWAN (Study of Women's Health across the Nation), a study of a multi-ethnic sample of women early in the menopausal transition who were subsequently followed annually. In a prior SWAN report, we found that the time interval around FMP due to natural menopause was associated with substantial increases in low-density lipoprotein cholesterol (LDL-C) and apolipoprotein (Apo) B (13). We address in this report whether even larger increases in lipids and other risk factors—including blood pressure, insulin resistance, and hemostatic factors—occur in women who had a hysterectomy with or without bilateral oophorectomy compared those who had a natural menopause. We also examined these patterns with and without consideration of obesity, given that body mass index (BMI) increased after bilateral oophorectomy relative to natural menopause in the present sample (14).
SWAN is a multi-site community-based prospective study designed to examine the physical and psychological health of women as they undergo the menopausal transition. Details of the SWAN design and recruitment procedures have been reported elsewhere (15). At baseline, all SWAN participants had an intact uterus and at least 1 ovary and met the additional eligibility criteria: 42 to 52 years of age, not pregnant, not using reproductive hormones, and having 1 or more menstrual cycles in the 3 months before the interview. Each site recruited non-Hispanic Caucasian women as well as women belonging to a pre-determined racial/ethnic minority group: African-American women in Pittsburgh, Pennsylvania; Boston, Massachusetts; Detroit, Michigan; and Chicago, Illinois; Japanese women in Los Angeles, California; Hispanic women in Newark, New Jersey; and Chinese women in the Oakland area of California. Participants were recruited with established sampling techniques, random digit dialing, and random sampling from lists of names or household addresses. Select sites supplemented primary sampling frames to obtain adequate numbers of racial/ethnic minority women. Seventy-three percent of the women selected were contacted and provided information to determine eligibility; 51% (n = 3,302) of eligible women enrolled.
Participants returned to their local site facility annually for interviewer- and self-administered questionnaires, a fasting blood draw, and assessments of physical measures. Data collection for this analysis spanned from 1996 to 2008. SWAN was approved by the institutional review boards at each site, and each participant provided written, informed consent. Data collection ceased at the New Jersey SWAN site after 2001 for reasons unrelated to scientific aspects of the project. Because this resulted in an average length of follow-up for this site being systematically shorter than that of any other site, data from this site were excluded from the current analysis.
Measures and procedures
Menopausal and Hysterectomy Status
Menopausal status and the occurrence of hysterectomy and/or oophorectomy were assessed annually in SWAN. Participants were asked whether they had a “hysterectomy (an operation to remove your uterus or womb)” and whether they had 1 or both ovaries removed since the last study visit. Those who indicated hysterectomy were further divided into those with and without bilateral oophorectomy, provided their hysterectomy occurred before becoming naturally post-menopausal. Medical records were sought for all women who reported hysterectomy; of the 166 obtained, all but 1 confirmed hysterectomy and/or oophorectomy. Women were categorized as naturally post-menopausal if they reported a complete absence of menstrual bleeding in the previous 12 months and no hysterectomy. The FMP date or surgery date was based on participant self-report; if FMP date was unknown, it was set as 12 months before the date of the annual visit participants were first categorized post-menopausal.
Menopausal status at the annual visit immediately before the FMP/surgery date of each participant was defined as pre-menopausal (bleeding in the last 3 months with no cycle irregularity in the previous 12 months), early peri-menopausal (bleeding in the last 3 months with some change in cycle regularity in the last 12 months), late peri-menopausal (bleeding >3 months ago but within the last 12 months), and unknown (hormone therapy [HT] or other circumstance interfering with ability to characterize bleeding patterns) and collapsed for this analysis into 4 categories: pre-menopausal (pre-menopausal and early peri-menopausal); peri-menopausal (late peri-menopausal); unknown; and missing (no menopausal status available for participant, generally due to nonattendance in the annual visit of the previous year).
By 2008, a total of 1,952 women—including 1,769 women who reached natural menopause, 77 women who had a hysterectomy with ovarian conservation, and 106 women who had a hysterectomy with bilateral oophorectomy—comprised the analytic sample. Excluded from the analytic sample were 1,097 women who did not report hysterectomy or reach natural menopause during their participation in the SWAN study; 32 who had a hysterectomy after having been categorized naturally post-menopausal; 21 who reported hysterectomy in the presence of known or suspected endometrial, uterine, or ovarian cancer; 69 without BMI data from at least 1 annual visit post-FMP/surgery (because of its importance as a covariate for all outcomes and it increased post-surgery ); and 131 women from the New Jersey site. The New Jersey site women did not complete in-person clinic visits after the sixth annual follow-up and resumed clinic visits at Follow-Up 12. Thus, this site had an average length of follow-up that is systematically shorter than that of any other site.
Cardiovascular risk factors
At each annual visit, blood was drawn in the morning after fasting. All lipid and lipoproteins were analyzed on ethylenediaminetetraacetic acid–treated plasma. Total cholesterol and triglycerides were analyzed by enzymatic methods on a Hitachi 747 analyzer (Boehringer Mannheim Diagnostics, Indianapolis, Indiana), and high-density lipoprotein cholesterol (HDL-C) was isolated with heparin-2M manganese chloride. The LDL-C was calculated with the Friedewald equation (16–18). Triglyceride levels and insulin resistance estimated by homeostasis model of assessment–insulin resistance (HOMA-IR) scores were logged before analysis. Serum insulin was measured with radioimmunoassay (DPC Coat-a-count, Los Angeles, California) procedure and monitored as part of the monthly quality assurance program by the Diabetes Diagnostic Laboratory at the University of Missouri. Glucose was measured with a hexokinase-coupled reaction on a Hitachi 747-200 (Boehringer Mannheim Diagnostics). Fibrinogen and Factor VII were measured in frozen citrated plasma with a clot-based turbidometric detection system, with Factor VII assay with Factor VII deficient plasma in preparing the standard curve. Tissue plasminogen activator antigen (tPA-ag) was measured in plasma with a double antibody in an enzyme-linked immunoadsorbent assay (American Diagnostica, Greenwich, Connecticut), with a human single chain tPA-ag as a standard calibrated against an international standard (Hertfordshire, England). Plasminogen activator inhibitor (PAI)-1 was measured with a solid phased monoclonal antibody and an enzyme-labeled goal second antiserum for detection (American Diagnostica). High-sensitivity C-reactive protein (CRP) was measured with an ultra-sensitive rate immunonephelometry (Dade-Behring, Marburg, Germany).
Systolic blood pressure (SBP) was manually measured twice with a minimum 2-min rest period between measures, with readings taken on the right arm, with the respondent seated and feet flat on the floor for at least 5 min before the measurement. Respondents had not smoked or consumed any caffeinated beverage within 30 min of blood pressure measurement. Appropriate cuff size was determined on the basis of arm circumference. The 2 sequential blood pressure values were averaged.
Covariates included race/ethnicity, educational attainment, menopausal status, and age the year before FMP or surgery as well as annual measurements of physical activity, smoking status, self-rated health, myocardial infarction, stroke, HT use, BMI, and antidepressant, insulin, antihypertensive, lipid-lowering, and heart medication use. Race/ethnicity and educational level were self-reported in the screening interview. Age was calculated from participant date of birth and date of FMP or surgery. Physical activity was assessed with the Kaiser Physical Activity Survey (19), an adaptation of the Baecke physical activity questionnaire (20) at baseline and annual Follow-Up Visits 3, 5, and 6. A sum score was derived from responses to questions about physical activity during sports/exercise, household/caregiving tasks, and daily routine in the previous year. Current smoking status was self-reported at each annual visit. Self-rated health was assessed at each annual visit by response to the following question: “In general, would you say your health is excellent, very good, good, fair, or poor?” (21). Responses were categorized into 2 categories, with responses of “excellent” and “very good” collapsed into 1 category, and “good,” “fair,” and “poor” collapsed into another category. Medication use and new medical diagnoses were self-reported at each annual visit. The BMI was measured at each visit by a trained technician.
Site, race/ethnicity, age at FMP/surgery, educational attainment, menopausal status the year before FMP/surgery, and reported myocardial infarction or stroke were included as covariates in final models on the basis of a priori decisions. Annual insulin use for outcomes related to glucose metabolism, annual hypertensive medication use for outcomes related to blood pressure, annual lipid-lowering medication use for outcomes related to dyslipidemia, and annual heart medications related to hemostatic and inflammatory factors and blood pressure were also included a priori. Preliminary analyses were conducted to assess independent associations between annual observations of antidepressant use, HT use, self-rated health, smoking status, and physical activity with outcomes with hierarchical linear regression. These time-varying covariates were retained in final models if they were associated with the outcomes in otherwise unadjusted models at p < 0.05.
Baseline characteristics of women with natural menopause, women with hysterectomy with ovarian conservation, and women with hysterectomy with bilateral oophorectomy were compared with chi-square or Fisher exact test for categorical variables and analysis of variance for continuous variables (without covariates) with SPSS (version 17 for Windows, Rel 17.0.0, 2008, SPSS, Chicago, Illinois).
Piecewise hierarchical linear growth models were used to estimate the mean annual rate of change in CVD risk factors from baseline to the index visit, which was the first annual visit after FMP or surgery, and from the index visit to end of follow-up, with annual observations nested within women (HLM for Windows, version 6.08, 2010, Scientific Software International, Lincolnwood, Illinois). Note that the time between FMP or surgery and the index visit was a covariate. Hierarchical linear modeling was used, due to its utility in accounting for the dependence of repeated, correlated observations within individuals. Piecewise hierarchical linear growth models allowed for the possibility of different mean growth trajectories before and after FMP or surgery (22). The intercept was set at the index visit and modeled as a function of group status with covariates: site; race/ethnicity; educational attainment; age at FMP or surgery; menopausal status at the visit before FMP or surgery; and elapsed time between FMP or surgery and index visit and elapsed time between index visit and end of observations. An interaction between hysterectomy status (hysterectomy with ovarian conservation or hysterectomy with bilateral oophorectomy, with natural menopause set as the referent) and each time variable examined whether either hysterectomy status group differed significantly from the natural menopause group at the index visit or the annual changes before or after. For the referent group, the estimate refers to whether the level differs from 0. All predictors and covariates were entered simultaneously in the final multivariable models presented in the tables. For all analyses, p values <0.05 (2-tailed) were considered statistically significant. Tables present the results without adjustment for BMI. When adjustments for BMI changed the pattern of results, it is noted in the Results section.
To assess potential interactions between hysterectomy status and race/ethnicity, a secondary analysis was performed in a sample restricted to only African-American and Caucasian women to determine whether potential increases in these CVD risk factors after hysterectomy with or without oophorectomy were greater among African-American compared with Caucasian women. Other groups represented in the SWAN study were not included, due to their very low numbers of hysterectomy with or without bilateral oophorectomy. The sample for this secondary analysis included 1,422 African-American and Caucasian women who reached natural menopause, 71 women who had a hysterectomy with ovarian conservation, and 88 women who had a hysterectomy with bilateral oophorectomy. Models were otherwise identical to those described in the preceding text.
Characteristics of analytic sample
Compared with the women who were excluded from the analysis, women in the analytic sample were older (46.3 ± 2.6 years vs. mean 45.2 ± 2.7 years, p < 0.001), more educated (46.5% vs. 37.3% college or post-college, p < 0.001), reported better self-rated health (61.3% vs. 52.6% excellent/very good health, p < 0.001), had higher HDL-C (61.0 ± 16.5 vs. mean 54.7 ± 16.0, p < 0.001), and had lower BMI (28.0 ± 7.3 vs. 28.8 ± 7.1, p < 0.01), HOMA-IR scores (3.3 ± 4.0 vs. 5.0 ± 7.0, p < 0.01 on the basis of logged values), and SBP (117.8 ± 17.3 vs. 124.0 ± 15.6, p < 0.001) at baseline. Of the 183 women in the 2 surgery groups, 140 had documented medical records with regard to diagnosis. The most common preoperative symptoms and diagnoses in the available medical records were suspected or diagnosed uterine fibroids (75.7%), suspected or diagnosed menorrhagia (58.6%), and chronic pelvic pain (25.7%). Suspected or diagnosed fibroids accompanied the presentation of menorrhagia (85.4%) and chronic pelvic pain (83.3%) in this sample.
Participants were followed for up to 11 years after study entry, with observations from up to 9 years before and after FMP or surgery and a mean ± SD number of exams/woman being 10.78 ± 0.90, with 4.71 ± 2.33 on average after FMP or surgery. On average women reported HT use after FMP or surgery at 0.72 ± 1.58, 1.22 ± 1.75, and 3.42 ± 2.97 visits for natural menopause, hysterectomy with ovarian conservation, and hysterectomy with bilateral oophorectomy groups, respectively (p < 0.001). The proportion of visits on HT throughout the study before and after FMP or surgery for these groups were, on average, 0.14 ± 0.34, 0.22 ± 0.29, and 0.57 ± 0.36, p < 0.001.
Women who subsequently reported hysterectomy with or without oophorectomy were more likely to be African-American and younger (Table 1). The tPA-ag levels were elevated at study entry among women who later had hysterectomy with bilateral oophorectomy, whereas BMI, Factor VIIc levels, and use of lipid-lowering medications were higher at study entry among women who later had hysterectomy with ovarian conservation, as compared with women with naturally occurring menopause. No other risk factors differed by FMP/surgery status.
At the time of the index visit, women with hysterectomy with ovarian conservation had higher LDL-C and tended to have higher ApoB levels (which was significant when adjusted for BMI), whereas women with hysterectomy with bilateral oophorectomy had higher triglyceride levels, relative to the natural post-menopausal women (Table 2) (Figure 1 shows the covariate-adjusted means (95% confidence intervals) on the basis of predicted values from linear regression models within each year.) The LDL-C, triglycerides, and ApoA1 levels increased annually before and after FMP, whereas HDL-C decreased annually after FMP. The ApoB increased before FMP and nonsignificantly declined after FMP. The change in these factors was similar before and after surgery compared with before and after FMP, with 2 exceptions. The increase in ApoA1 levels was larger, with a modest decline in triglyceride levels before surgery in women with hysterectomy with ovarian conservation, compared with those who became naturally post-menopausal. Further adjustments for BMI did not alter the results.
Other cardiovascular risk factors
At the index visit, groups did not differ in HOMA-IR, SBP, tPA-ag, Factor VIIc, or CRP levels (Table 3). From study entry to FMP, women increased annually in SBP, tPA-ag, and Factor VIIc and declined annually in PAI-1 and CRP. These changes were similar to those experienced by women from baseline to surgery, except that tPA-ag decreased annually in women who had a hysterectomy with ovarian conservation, and CRP levels increased annually more in the women who subsequently had a hysterectomy with bilateral oophorectomy (Table 3). After FMP, HOMA-IR increased annually, and PAI-1 declined. After surgery the changes were similar to those experienced by the natural menopause group.
Further adjustments for BMI did alter the results somewhat for tPA-ag and CRP: after FMP, tPA-ag increased annually (estimate [SE] = 0.74 [0.35] p = 0.04), whereas it declined annually after either hysterectomy with ovarian conservation (estimate = −0.14 [0.43], p = 0.04) or after hysterectomy with bilateral oophorectomy (estimate = −0.13 [0.47], p = 0.06). The CRP levels after hysterectomy with ovarian conservation declined annually (estimate = −0.24 [0.17], p = 0.04), relative to after FMP (estimate = 0.11 [0.08]).
There were no significant effects of ethnicity and change in CV risk factors before and after FMP or surgery. In other words, the impact of hysterectomy with or without oophorectomy in relation to FMP did not differ between African Americans and Caucasians.
The objective of the present paper was to compare the annual CVD risk factor changes that occur in midlife women before and after natural menopause or hysterectomy with or without ovarian conservation. The influence of natural menopause and hysterectomy with or without ovarian conservation was similar for HDL-C, LDL-C, ApoB, HOMA-IR, SBP, PAI-1, and Factor VIIc over time. Several CVD risk factor changes did differ during the intervals before and after hysterectomy, compared with the changes before and after FMP but not in a pattern suggesting increasing cardiovascular risk after hysterectomy. Before hysterectomy with ovarian conservation, triglycerides and tPA changes declined and ApoA1 increased, compared with the changes before natural menopause, suggesting a lower risk trajectory among these women pre-surgically. Before hysterectomy with bilateral oophorectomy, CRP increases were greater than before a natural menopause, but no differences occurred after surgery, compared with after FMP. The absence of effects for the group that should presumably be at the highest risk—women who had a hysterectomy with bilateral oophorectomy—might be due to the influence of HT use, although some evidence points to elevated CRP being associated with HT (23). Thus, we conclude that hysterectomy with or without bilateral oophorectomy does not introduce a substantial increase in cardiovascular risk factors among midlife women.
On the surface, our results differ from those of the Women's Health Initiative. In that study, elderly women who had reported having a hysterectomy, regardless of oophorectomy status, had at baseline higher levels of CVD risk factors (8) and a higher proportion of hypertension, diabetes, high cholesterol, and obesity, compared with women who had natural menopause. There are likely to be a number of reasons for the differences. Our focus was on risk factor levels, adjusted for medications for hypertension, diabetes, and high cholesterol. In the Women's Health Initiative, CVD risk factor data collection had typically occurred many years after surgery, whereas in the present study the risk factor, surgical status, and menstrual cycle information were collected annually and concurrently for 11 years. Our analyses were restricted to elective surgery, and we excluded surgery due to cancer because of treatment and disease effects, whereas the Women's Health Initiative did not exclude women with specific causes for the surgery. Finally, the frequency and reasons for surgical menopause are undoubtedly different for the 2 cohorts, because of changes in recommendations with regard to hysterectomy over the decades.
Our study findings are limited by a number of factors. First, the sample was composed of pre-menopausal women who were initially 42 to 52 years of age, all of whom had a uterus and at least 1 ovary at entry. Perhaps they were not young enough, because bilateral oophorectomy might have a greater impact on CVD risk if the surgery is performed at younger ages (24), when the decline in ovarian hormones is more pronounced. Given that we could evaluate surgeries only occurring after study entry, restricting the range in age and time of surgery in the sample, we could not evaluate the influence of age at surgery on our results. Second, there were relatively few cases of hysterectomy and bilateral oophorectomy. Many women who have elective hysterectomy are entering the peri-menopause and would not have been eligible initially for the cohort. Thus, the SWAN sample is not typical of the general population of midlife women, many of whom have had a hysterectomy or oophorectomy by midlife. Given the large number of risk factors and comparisons tested, the few significant associations observed might be due to chance. Finally, the study could not address the impact of surgery on clinical events, because the follow-up ended before the high-risk period in women (i.e., above 65 years of age).
The study has a number of strengths. It is composed of a large, well-characterized sample of midlife women. Detailed data were collected annually with women having an average of over 10 assessments. The analytic approach compared annual changes in CVD risk before and after FMP or surgery and was robust to missing data. A large number of covariates, including use of medications known to influence risk factors and HT, were included. Thus, it is the only study that has carefully tracked prospective changes in CVD risk factors relative to FMP or surgical menopause.
Although women in midlife experienced significant increases in CVD risk, the women who had surgical menopause in their 40s and 50s were not at any greater risk for increases in CVD risk factors compared with women who had a natural menopause. These results should provide reassurance to women and their clinicians that hysterectomy with or without ovarian conservation in midlife is not likely to substantially accelerate the CVD risk of women.
The authors thank the study staff at each site and all the women who participated in the Study of Women's Health Across the Nation.
For a list of the participating centers and investigators, please see the online version of this article.
The SWAN has grant support from the National Institutes of Health (NIH), Department of Health and Human Services, through the National Institute on Aging, the National Institute of Nursing Research, and the NIH Office of Research on Women's Health (Grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, and U01AG012495). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging, National Institute of Nursing Research, Office of Research on Women's Health, or the NIH. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- body mass index
- C-reactive protein
- cardiovascular disease
- final menstrual period
- high-density lipoprotein cholesterol
- homeostasis model of assessment–insulin resistance
- hormone therapy
- low-density lipoprotein cholesterol
- plasminogen activator inhibitor
- systolic blood pressure
- tissue plasminogen activator antigen
- Received January 25, 2013.
- Revision received April 4, 2013.
- Accepted April 8, 2013.
- American College of Cardiology Foundation
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