Recently postmenopausal women have the same prevalence of subclinical carotid atherosclerosis as age and traditional risk factor matched men

Atherosclerosis 221 (2012) 508–513

Contents lists available at SciVerse ScienceDirect

Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis

Recently postmenopausal women have the same prevalence of subclinical carotid atherosclerosis as age and traditional risk factor matched men Kimon S. Stamatelopoulos a,∗ , Eleni Armeni b , Georgios Georgiopoulos a , Maria Kazani a , Katerina Kyrkou a , Konstantinos Stellos c , Athanasios Koliviras a , Andreas Alexandrou b , Maria Creatsa b , Christos Papamichael a , Irene Lambrinoudaki b a

Department of Clinical Therapeutics, 80 Vas. Sofias Ave., University of Athens, Alexandra Hospital, Athens, Greece 2nd Department of Obstetrics and Gynecology, 76 Vas. Sofias Ave., University of Athens, Aretaieio Hospital, Athens, Greece c Department of Cardiology, Centre of Internal Medicine III, Johann Wolfgang Goethe University Frankfurt am Main, Frankfurt, Germany b

a r t i c l e

i n f o

Article history: Received 4 June 2011 Received in revised form 21 October 2011 Accepted 3 December 2011 Available online 9 December 2011 Keywords: Menopause Primary prevention Subclinical atherosclerosis IMT

a b s t r a c t Objective: To compare the prevalence of subclinical atherosclerosis between postmenopausal women and men of similar age early after the onset of menopause. Methods: In the first part of this cross-sectional study 186 non-diabetic young postmenopausal women (n = 101, menopausal age ≤10 years) and men (n = 85) aged 40–60 years without overt CVD were consecutively recruited from the outpatients clinics of an academic hospital. Subclinical carotid atherosclerosis was assessed by high-resolution ultrasonography. The presence of carotid atherosclerosis was defined as either increased carotid intima-media thickness (IMT > 0.9 mm) and/or the presence of plaques. In the second part, 1:1 matching for age and traditional risk factors (hyperlipidemia, smoking, hypertension and BMI) was performed between men and women of this cohort resulting in a matched sub-sample of 76 subjects. Results: By multivariate analysis, gender was not an independent determinant of any measure of carotid atherosclerosis. In the matched sub-sample, carotid IMT and the number of segments with atherosclerosis did not significantly differ between women and men (0.734 ± 0.119 mm and 1.47 ± 1.6 versus 0.717 ± 0.138 mm and 1.47 ± 1.5, p = 0.575 and p = 0.999, respectively). Also, the prevalence of increased IMT (60.5% in both genders), carotid plaques and subclinical atherosclerosis (31.6% and 63.2% versus 28.9% and 65.8%, p = 0.803 and p = 0.811, respectively) was similar between men and women. Conclusions: The prevalence and severity of carotid atherosclerosis was similar between men and young postmenopausal women matched for traditional risk factors. Whether these women may be better risk stratified irrespective of gender should be further assessed in prospective studies. © 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Primary prevention practitioners recognize gender-specific variations in cardiovascular risk [1] and tend to consider cardiovascular disease (CVD) as a “male” problem, mainly due to the premenopausal atheroprotective role of estrogens [1]. This impression may have contributed to a disproportionate increase to female rates of cardiovascular mortality as compared to male rates since 1980 [2]. Cardiovascular risk progressively increases soon after menopause with the frequency of obstructive coronary artery disease in women reaching the incidence-rates of men approximately in their 7th decade [3–4]. This is attributed to the differential impact

∗ Corresponding author at: 14 Eginis Str, PO Box 16674 Glyfada Athens, Greece. Tel.: +30 6974 317698; fax: +30 210 3381487. E-mail address: [email protected] (K.S. Stamatelopoulos). 0021-9150/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2011.12.006

or augmentation of existing traditional risk factors such as abdominal fat accumulation, dyslipidaemia and insulin resistance [2] plus the effect of newly arising menopause-specific conditions including changes in sex hormone milieu, osteoporosis, climacteric symptoms and menopausal aging [5–8]. Considering that all of the above risk factors invading early in menopausal life have been associated with increased subclinical atherosclerosis [2,5–7] their net effect on cardiovascular risk may be mediated to the most part by accelerated atherogenesis. Indeed, very early in their menopausal life, women suffer from more advanced atherosclerosis than premenopausal women after adjustment for age [9]. Thus, although not assessed so far, the prevalence of subclinical atherosclerosis in women may reach and possibly exceed that of men of similar age early in their postmenopausal life, if their risk is expected to equalize that of men in the next one or two decades. The presence of subclinical atherosclerosis particularly in the carotid arteries is considered evidence of high cardiovascular risk and successfully reclassifies

K.S. Stamatelopoulos et al. / Atherosclerosis 221 (2012) 508–513

individuals initially considered to be in low or intermediate risk by currently used risk scores [10] to higher risk, which renders them eligible for aggressive primary prevention therapeutic strategies. Furthermore, currently used traditional risk factor-based scores of risk estimation may significantly underestimate cardiovascular danger in postmenopausal women [11]. In this setting, we hypothesized that the burden of subclinical atherosclerosis in women in early menopause would be at least as heavy as that in men of comparable age and risk factor profile. Such data would strengthen the current impression that young postmenopausal women would greatly benefit from increased alertness to recognize those at high cardiovascular risk needing similarly aggressive primary prevention strategies as those recommended in men, despite the only recently lost premenopausal “athero-protection”. Furthermore, the current investigation could offer primary conclusions for the introduction of carotid intima-media thickness in the risk stratification of apparently healthy young postmenopausal women but prospective studies would be needed to elaborate and further address this issue. 2. Material and methods 2.1. Subjects This cross-sectional study included 186 men and postmenopausal women (n = 101) in the first decade after menopause aged 40–60 years. The number of participants was decided after sample size calculations as described in the statistics section. More specifically, men and women were consecutively recruited in a predefined 6-month period (July 2010–January 2011) from the Vascular Laboratory and the Menopause Clinic of an academic hospital. Initially, 263 subjects were screened (115 men and 148 women) and 77 of them were excluded from the study for not meeting inclusion criteria. From the final sample of 186 participants, women by presentation order, were individually matched 1:1 to men for age and traditional risk factors (BMI, undiagnosed and/or untreated dyslipidemia and hypertension and smoking) resulting to a sub-sample of 76 men and women. Matching was performed according to the following criteria: age ±2 years, BMI ±1 kg/m2 , presence of hypertension, dyslipidemia and smoking status. Before recruitment, all participants were subjected in a routine evaluation program in order to exclude diabetes, thyroid, liver and renal dysfunction. In addition, women underwent gynecological evaluation, which included breast mammography and clinical examination, PAP smear and transvaginal sonography. Exclusion criteria were: clinically overt or treated CVD, thromboembolism, diabetes mellitus, untreated thyroid dysfunction and treatment with lipid-lowering, or antihypertensive medication. Subjects on hypolipidemic or antihypertensive medication were excluded in order to eliminate bias from treatment regimens well known to affect markers of subclinical atherosclerosis [12–13] and CV risk, considering that some of them might also confer gender-specific effects [14–15]. In order to be eligible for the study, recruited women should be in postmenopausal status for at least one year with an endometrial thickness of ≤5 mm, with absence of premature ovarian failure or gynecological malignancy and should not be current or past users of hormone therapy or raloxifene. Menopause was defined as levels of follicle stimulating hormone (FSH) > 25 mIU/ml and estradiol E2 < 50pg/ml in women without menses for at least 12 consecutive months. Patients with adherence and retention concerns (e.g., alcoholism) were not included in the study. 2.2. Protocol study procedures A detailed medical history was recorded for every subject, using questionnaires regarding demographic and lifestyle

509

parameters, cardiovascular risk, obstetrical and gynecological history for women. Subsequently, blood pressure, weight and height were recorded in the morning and in light clothing and body mass index (BMI) were calculated. Patients abstained from eating, smoking or drinking except water and all medications for 12 h before the study. Fasting venous blood samples were drawn at 8:30–9:30 a.m. for the biochemical evaluation. Ultrasound examinations were performed immediately thereafter by an operator blinded to the medical history of the patients. An automated Omron 705IT device (Omron) was used to record the blood pressure of each subject by oscillometry (twice, 1 min apart), after resting in the sitting position for 5 min, and the average of these measures was used in data analysis. Hypertension was defined as systolic arterial pressure (SBP) ≥140 mmHg and/or diastolic arterial pressure (DBP) ≥90 mmHg, after 2 blood pressure measurements in each of 2 consecutive office visits. Dyslipidemia was defined as total blood cholesterol level ≥200 mg/dl. TC was chosen over several ratios of lipoproteins such as TC/HDL for the definition of dylipidemia because despite their utility in risk estimation, currently they are not recommended for diagnosis of dylipidemia [16]. Institutional Review Board approval was obtained by the Ethics Committee of Aretaieio Hospital. 2.3. Biochemical assays Serum total cholesterol, triglycerides and HDL-cholesterol (HDL-C) were assessed enzymatically by an autoanalyzer (COBASMIRA, Roche Diagnostics Limited, Lewes, East Sussex, UK). The Friedewald equation (LDL-cholesterol = total cholesterol – triglycerides/5 – HDL-cholesterol) was used to estimate LDL-cholesterol (LDL-C). A high cholesterol to HDL (TC/HDL) ratio, indicative of high cardiovascular risk, was defined as TC/HDL > 5.6 for women and TC/HDL > 6.4 for men [17]. Glomerular filtration rate (GFR) was estimated by the MDRD formula using serum creatinine measured by standard techniques [18]. 2.4. Intima-media thickness IMT was measured in three paired segments, of both right and left common carotid artery, carotid bulb, and internal carotid artery, from a fixed lateral transducer angle using B-mode ultrasound imaging (14.0 MHz multifrequency linear array probe, Vivid 7 Pro, GE). In each segment, three measurements of the maximal IMT in the far wall were averaged, and the average IMT was calculated for each of the two carotid arteries. The average value of right and left carotid IMT was defined as the mean carotid IMT [19]. All scans were digitally recorded for offline analysis. A single operator blinded to the cardiovascular risk profiles of the participants performed all scans and offline analyses (coefficient of variation for mean carotid IMT: 10.6%). Plaques were defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm [19]. 2.5. Statistical analysis Data are expressed as percent values or absolute numbers (mean ± SD). Simulations were used in order to assess the effect of varying sample sizes at the statistical power of linear and logistic regression models involved in our analysis. Simulated data were generated in R software (version 2.11.1) and the number of replications was set at 1000. Although a sample size of 100 subjects was sufficient to demonstrate 99% power to detect a clinically relevant change of 0.02 mm for the mean carotid IMT when regressed across gender (male–female), a sample size of 180 subjects was necessary to achieve 85% power for identification of a 20% difference in the

510

K.S. Stamatelopoulos et al. / Atherosclerosis 221 (2012) 508–513

Table 1 Demographic, biochemical and vascular characteristics of all subjects participating in the study. Mean ± SD or Frequency (%) Age (years) Men/Women YSM (years) BMI (kg/m2 ) SBP (mmHg) DBP (mmHg) Hypertension Dyslipidemia Smoking TC (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) TG (mg/dl) High TC/HDL ratiob Smoking GFR (ml/min) Vascular characteristics Carotid IMT (mm) At least one segment with IMT > 0.9 mm At least one carotid plaque Mean number of segments with IMT > 0.9 mm (range) Mean number of segments with carotid plaque (range) Mean number of segments with IMT > 0.9 mm and/or plaque (range) Carotid atherosclerosisa

51.20 ± 5.5 85/101 4.8 ± 2.8 26.9 ± 3.9 119.7 ± 16.3 76.6 ± 9.7 10.8% 73.7% 48% 227.2 ± 37.7 55.5 ± 16.5 148.6 ± 36.8 112.0 ± 58.9 13.6% 41.3% 90.3 ± 21.6 0.721 ± 0.118 68.3% 18.3% 1.2 ± 1.1 (0–5) 0.2 ± 0.45(0–2) 1.4 ± 1.3 (0–5) 70%

BMI = body mass index; SBP = systolic blood pressure; DBP = diastolic blood pressure; TG = triglycerides; HDL-C = HDL-cholesterol; IMT = intima-media thickness, GFR = estimated glomerular filtration rate. a At least one segment with IMT > 0.9 mm and/or plaque. b Cutoff values: men > 6.4, women > 5.6.

rate of subclinical atherosclerosis between men and women. Given that for the matched subsample analysis (2nd part of the study), 10 matched pairs would be sufficient to provide 99% power to detect an absolute difference of 0.02 mm of mean carotid IMT within gender (GPower, version 3.0.10) the sample size was determined to at least 180 subjects. Type I error was predefined at 0.05 for all power calculations. Vascular IMT, the presence of plaque and combined measures of the presence and extent of subclinical atherosclerosis were the main outcome measures. The presence of subclinical atherosclerosis was defined as any segment with IMT > 0.9 mm and/or plaque while the extent of subclinical atherosclerosis was defined as the number of segments with IMT > 0.9 mm and with plaque. Initially, univariate and multivariate stepwise regression analysis was performed to determine the influence of gender on subclinical atherosclerosis as possible predictor of its variance. Subsequently, the outcomes were compared between genders in the matched subsample by paired samples t-test and McNemar’s chisquare analysis for related dichotomous variables or chi-square analysis for simple percentages comparison. Further adjustment for covariates found to be significantly different between genders (HDL) in the matched subsample was performed using either conditional logistic models or linear mixed model analysis according to the type of the dependent variable (dichotomous or continuous, respectively). Statistical significance was set at the 0.05 level. 3. Experimental results Mean values of anthropometric, biochemical and vascular characteristics of the whole population are presented in Table 1. As shown in Tables 2 and 3 gender was not a significant determinant of any marker of the presence and severity of carotid subclinical atherosclerosis including carotid IMT, the presence of carotid plaques, and the combined measure of the presence and extent of carotid atherosclerosis. Age and parameters related to

dyslipidemia were consistently found as independent determinants of these markers. As shown in Table 4, in the matched sub-sample of 76 men and women, the cardiovascular risk factor profile did not differ except for HDL cholesterol which was higher in postmenopausal women. Carotid IMT did not significantly differ between genders while the frequency of individuals with increased IMT and carotid plaque presence was almost identical between men and women (Table 4). Finally, the presence and extent of carotid atherosclerosis as this is expressed by the mean number of segments with increased IMT and/or plaques was also similar between genders. Further adjustment for HDL did not alter these results as shown in Table 4.

4. Discussion The results of the present study indicate that subclinical carotid arterial disease in a middle-aged population of men and young postmenopausal women is not determined by gender. After strictly matching for age and traditional risk factors of cardiovascular disease, the prevalence and extent of carotid atherosclerosis was strikingly similar between genders, suggesting that very early in menopausal life the associated net increase in cardiovascular risk may counterbalance the known premenopausal athero-protective effects. Although almost all existing studies find gender differences in the prevalence and distribution of atherosclerosis in the general population with or without treatment for cardiovascular risk factors as well as in populations with established cardiovascular disease, none has so far specifically addressed this issue in young postmenopausal women. Moreover, no study has compared 1:1 risk factor-matched apparently healthy men and young postmenopausal women in this setting. Risk stratification in this group of women is particularly important because atherosclerosis rapidly progresses after menopausal transition [9] and therefore discriminating women in need of aggressive primary prevention strategies as early as possible in menopausal life may confer the highest benefit in the reduction of cardiovascular events. Most of the studies comparing subclinical atherosclerosis between genders report higher prevalence in men than in women [20–23]. However, carotid IMT and particularly carotid atheromatous plaques [10,24–25] are more strongly related to cardiovascular events in women than in men. This differential association was confirmed in a sub-population of the ARIC study very similar to our sample, aged 45–64 years without CHD. However, menopausal status and age were not considered [24]. This study showed that the hazard ratio for developing CHD was 5.07 for women and 1.85 for men with increased carotid IMT [24]. The latter findings in conjunction with our observation of similar carotid atherosclerosis prevalence and extent between matched men and women early in menopausal life, may partly explain the higher rates of increasing cardiovascular danger with advancing age in postmenopausal women as compared to men [3–4,26]. Menopause significantly alters the cardiovascular risk profile due to rapid changes at multiple levels. Firstly, with the sex hormone-related cardiovascular effects withdrawn, traditional risk factors are augmented, resulting in a significantly stressful impact on the vascular wall [27]. Secondly, the net effect on accelerated atherosclerosis is partially affected by the premenopausal risk factor burden [28]. Finally, newly arising menopause-associated conditions such as climacteric symptoms, osteoporosis and menopausal aging may contribute to this progressive upgrading of cardiovascular risk in this population [6,29–30]. Thus, the young postmenopausal woman constitute a difficult case to risk stratify considering that multiple factors may affect

K.S. Stamatelopoulos et al. / Atherosclerosis 221 (2012) 508–513

511

Table 2 Univariate and multivariate linear regression analysis showing the determinants of mean carotid IMT and the extent of carotid atherosclerosis. Interrelated parameters (Hypertension, SBP, DBP and Dyslipidemia, Cholesterol, LDL and high TC/HDL ratio) were inserted in different models. Mean carotid IMT

Beta Age Gender BMI Hypertension Dyslipidemia Smoking SBP DBP Cholesterol LDL HDL Triglycerides High TC/HDL ratio*** GFR

Extent of carotid atherosclerosis (number of segments with IMT > 0.9 mm and with plaque, range 0–6) P value

0.188* 0.011 0.125 0.061 0.142 0.012 0.126 0.126 0.150 0.175* −0.077 −0.015 0.093 −0.074

0.010 0.882 0.088 0.408 0.053 0.870 0.087 0.087 0.042 0.017 0.299 0.839 0.220 0.371

beta

P value

0.224** −0.038 0.090 −0.003 0.160* 0.032 0.093 0.102 0.129 0.136 −0.003 −0.075 0.087 −0.093

0.002 0.604 0.223 0.963 0.029 0.668 0.206 0.168 0.079 0.063 0.969 0.309 0.250 0.260

BMI = body mass index; SBP = systolic blood pressure; DBP = diastolic blood pressure; TG = triglycerides; HDL-C = HDL-cholesterol; IMT = intima-media thickness; GFR = glomerular filtration rate. Gender: female sex is represented as “0” and male sex as “1”. * Indicates P < 0.05 in the multivariate analysis. ** Indicates P < 0.01 in the multivariate analysis. *** Cutoff values: men > 6.4, women > 5.6.

her profile on top of traditional risk factors of cardiovascular disease, leaving a residual risk which may not be readily predictable. Accordingly, currently used risk scores, based solely on traditional risk factors, significantly underestimate cardiovascular risk in women. Less than 1% of non-diabetic women younger than 80 years are stratified by Framingham risk score as being high risk [31] which is contrasted to a 33% remaining lifetime cardiovascular risk of a woman above 40 years [32]. Possibly, as a result of these discrepancies, cardiovascular mortality has been significantly decreased over the years in men but not in women [33]. In this setting, our results indicate that the prevalence of carotid atherosclerosis is similar in young postmenopausal women and men with a similar traditional risk factor profile. This suggests that the non-traditional residual risk after menopause may rapidly accelerate atherogenesis compensating for the atheroprotrotective effects of pre-menopausal status. If this is correct, these findings further support the concept of increased alertness to

identify the vulnerable young postmenopausal woman very early at the onset of menopause in a similar manner as that in men of similar age. In addition to risk scores based on traditional risk factors an approach to risk stratify these women by carotid ultrasound might be of particular utility. Indeed, such an approach has been shown to be useful by net reclassification statistics both in men and women [10], while the use of carotid ultrasound in asymptomatic adults initially stratified as intermediate risk has been recently recommended by the American Heart Association [34]. Our study bears certain limitations. The sample size is relatively small and the ability to detect significant associations might be limited. However, according to our a priori sample size calculations the possibility to miss significant associations between the vascular end-points and gender (type 2 error) in this population was sufficiently small. Moreover, the prevalence of hypertension in our unmatched sample was relatively low, obviously due to exclusion of treated hypertensives in order to avoid bias from treatment

Table 3 Univariate and multivariate logistic regression analysis showing the determinants of the presence of carotid plaques and carotid atherosclerosis. Interrelated parameters (Hypertension, SBP, DBP and Dyslipidemia, Cholesterol, LDL and high TC/HDL ratio) were inserted in different models. Presence of carotid plaque

Odds ratio (CI 95%) Age Gender BMI Hypertension Dyslipidemia Smoking SBP DBP Cholesterol LDL HDL Triglycerides High TC/HDL ratio*** GFR

Presence of carotid atherosclerosis (any segment with IMT > 0.9 mm and/or plaque) P value

*

1.096 (1.015 – 1.184) 0.590 (0.273–1.277) 1.026 (0.935–1.125) 0.757 (0.209–2.745) 1.327 (0.505–3.492) 2.215 (0.566–8.678) 1.007 (0.985–1.030) 1.000 (0.962–1.039) 1.007 (0.996–1.017) 1.004 (0.994–1.014) 1.015 (0.993–1.038) 1.000 (0.994–1.007) 4.273 (1.483–12.315) 0.990 (0.970–1.011)

0.020 0.181 0.587 0.672 0.566 0.254 0.536 0.996 0.196 0.446 0.177 0.948 0.007 0.543

Odds ratio (CI 95%)

P value **

1.106 (1.043–1.173) 0.603 (0.320–1.137) 0.987 (0.910–1.070) 0.768 (0.289–2.044) 2.479 (1.190–5.162) 1.429 (0.363–5.627) 1.003 (0.983–1.023) 1.008 (0.976–1.042) 1.015 (1.006–1.025)** 1.014 (1.004–1.024) 1.006 (0.986–1.026) 0.996 (0.991–1.002) 3.403 (1.051–11.024) 0.986 (0.978–1.002)

0.001 0.118 0.746 0.598 0.015 0.610 0.777 0.630 0.002 0.005 0.552 0.194 0.041 0.089

BMI = body mass index; SBP = systolic blood pressure; DBP = diastolic blood pressure; TG = triglycerides; HDL-C = HDL-cholesterol; IMT = intima-media thickness; GFR = glomerular filtration rate. Gender: female sex is represented as “0” and male sex as “1”. * Indicates P < 0.05 in the multivariate analysis ** Indicates P < 0.01 in the multivariate analysis. *** Cutoff values: men > 6.4, women > 5.6.

512

K.S. Stamatelopoulos et al. / Atherosclerosis 221 (2012) 508–513

Table 4 Distribution of risk factors in the matched subsample of men and women and comparison of study’s main outcomes between the two genders. Men

Women

Mean ± SD or Frequency Risk factors Age (yrs) BMI (kgr/m2 ) Hypertension (%) Dyslipidemia (%) Smoking (%) SBP (mmHg) DBP (mmHg) TC (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) TG (mg/dl) High TC/HDL ratio (%) Study endpoints Carotid IMT (mm) At least one segment with IMT > 0.9 mm (%) At least one carotid plaque (%) Mean number of segments with IMT > 0.9 mm (range) Mean number of segments with carotid plaque (range) Mean number of segments with high IMT and/or carotid plaque (range) Carotid atherosclerosisb (%)

53.9 ± 4.7 27.4 ± 3.9 26.3 65.8 34.2 122.1 ± 17.0 77.4 ± 10.7 215.8 ± 33.9 51.3 ± 13.5 148.4 ± 32.5 115.5 ± 68.6 10.5 0.717 ± 0.138 60.5 28.9 1.13 ± 1.19 (0–4) 0.34 ± 0.58 (0–2) 1.47 ± 1.48 (0–6) 65.8

P value (a adjusted P value) 53.7 ± 4.1 27.2 ± 3.8 26.3 65.8 34.2 123.9 ± 22.1 75.3 ± 9.4 228.4 ± 37.7 59.4 ± 17.5 145.83 ± 38.7 108.5 ± 54.2 7.9 0.734 ± 0.119 60.5 31.6 1.05 ± 1.08 (0–4) 0.42 ± 0.68 (0–2) 1.47 ± 1.58 (0–5) 63.2

0.697 0.764 1 1 1 0.984 0.313 0.234 0.032 0.532 0.912 0.692 0.733(0.453) 0.812(0.968) 0.809(0.921) 0.723(0.992) 1(0.901) 0.999(0.838) 0.808(0.972)

BMI = body mass index; SBP = systolic blood pressure; DBP = diastolic blood pressure; TC = total cholesterol; TG = triglycerides; HDL-C = HDL-cholesterol; IMT = intima-media thickness. a Adjusted for HDL cholesterol. b At least one segment with IMT > 0.9 mm and/or Plaque.

effects on markers of subclinical atherosclerosis. This prevalence however was comparable to published figures for untreated hypertension in the Greek population, showing an overall prevalence of 12.9% for untreated hypertension [35]. Finally, it should be acknowledged that the hormonal status of men was not determined, although this study aimed to address a hypothesis in the clinical setting of primary prevention for cardiovascular disease, where sex hormone profile is rarely available. In conclusion, our results indicate that contrary to popular belief, subclinical atherosclerosis is prevalent in young menopausal women, to the same extent as in men matched for traditional cardiovascular risk factors. These findings suggest that the “non-traditional” residual risk in menopause may offset the premenopausal gender-related atheroprotective effects very early in menopausal life. This was observed both for early (IMT) and advanced (plaques and number of diseased carotid segments) stages of subclinical carotid atherosclerosis. Since at the moment the clinical utility of each of the menopause-associated cardiovascular risk factors is not clearly defined, an approach to risk stratify and treat young postmenopausal women irrespective of gender might be useful if these findings are confirmed by prospective studies. Disclosure None. Conflicts of interest None. References [1] Perez-Lopez FR, Larrad-Mur L, Kallen A, Chedraui P, Taylor HS. Gender differences in cardiovascular disease: hormonal and biochemical influences. Reprod Sci 2010;17:511–31. [2] Evangelista O, McLaughlin MA. Review of cardiovascular risk factors in women. Genet Med 2009;6:17–36.

[3] Shaw LJ, Bairey Merz CN, Pepine CJ, et al. WISE investigators Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol 2006;47: 4–20. [4] Persky RW, Turtzo LC, McCullough LD. Stroke in women: disparities and outcomes. Curr Cardiol Rep 2010;12:6–13. [5] Karim R, Hodis HN, Stanczyk FZ, Lobo RA, Mack WJ. Relationship between serum levels of sex hormones and progression of subclinical atherosclerosis in postmenopausal women. J Clin Endocrinol Metab 2008;93:131–8. [6] Thurston RC, Sutton-Tyrrell K, Everson-Rose SA, Hess R, Matthews KA. Hot flushes and subclinical cardiovascular disease: findings from the Study of Women’s Health Across the Nation Heart Study. Circulation 2008;118:1234–40. [7] Ouyang P, Vaidya D, Dobs A, et al. Sex hormone levels and subclinical atherosclerosis in postmenopausal women: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 2009;204:255–61. [8] Tremollieres F, Ribot C. Bone mineral density and prediction of nonosteoporotic disease. Maturitas 2010;65:348–51. [9] Sutton-Tyrrell K, Lassila HC, Meilahn E, et al. Carotid atherosclerosis in premenopausal and postmenopausal women and its association with risk factors measured after menopause. Stroke 1998;29:1116–21. [10] Nambi V, Chambless L, Folsom AR, et al. Carotid intima-media thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk in Communities) Study. J Am Coll Cardiol 2010;55:1600–7. [11] Lambrinoudaki I, Armeni E, Georgiopoulos G, et al. Subclinical atherosclerosis in menopausal women with low to medium calculated cardiovascular risk. Int J Cardiol 2011. July (5). [Epub ahead of print]. [12] Wang JG, Staessen JA, Li Y, et al. Carotid intima-media thickness and antihypertensive treatment: a meta-analysis of randomized controlled trials. Stroke 2006;37:1933–40. Epub 2006 Jun 8. [13] Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the Prevention of Atherosclerosis TrialResearch Group, Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939–53. [14] Torrens C, Kelsall CJ, Hopkins LA, et al. Atorvastatin restores endothelial function in offspring of protein-restrictedrats in a cholesterol-independent manner. Hypertension 2009;53:661–7. [15] Zanchetti A, Julius S, Kjeldsen S, et al. Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan and amlodipine: an analysis of findings from the VALUE trial. J Hypertens 2006;4:2163–8. [16] Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS), Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011;217(Suppl. 1):1–44. [17] Kinosian B, Glick H, Garland G. Cholesterol and coronary heart disease: predicting risks by levels and ratios. Ann Intern Med 1994;121:641–7.

K.S. Stamatelopoulos et al. / Atherosclerosis 221 (2012) 508–513 [18] Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;16(130):461–70. [19] Touboul PJ, Hennerici MG, Meairs S, et al. Manheim carotid intima-media thickness consensus (2004–2006). Cerebrovasc Dis 2007;23:75–80. [20] Polak JF, Person SD, Wei GS, et al. Segment-specific associations of carotid intima-media thickness with cardiovascular risk factors: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Stroke 2010;41: 9–15. [21] Ebrahim S, Papacosta O, Whincup O, et al. Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 1999;30:841–50. [22] Howard G, Sharrett AR, Heiss G, et al. Carotid artery intimal-medial thickness distribution in general populations as evaluated by B-mode ultrasound, ARIC Investigators. Stroke 1993;24:1297–304. [23] Bonithon-Kopp C, Touboul PJ, Berr C, et al. Relation of intima-media thickness to atherosclerotic plaques in carotid arteries. The Vascular Aging (EVA) Study. Arterioscler Thromb Vasc Biol 1996;16:310–6. [24] Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987–1993. Am J Epidemiol 1997;146:483–94. [25] Johnsen SH, Mathiesen EB, Joakimsen O, et al. Carotid atherosclerosis is a stronger predictor of myocardial infarction in women than in men: a 6-year follow-up study of 6226 persons: the Tromso Study. Stroke 2007;38:2873–80.

513

[26] Sinning C, Wild PS, Echevarria FM, et al. Gutenberg-Heart Study. Sex Differences in Early Carotid Atherosclerosis (from the Community-Based Gutenberg-Heart Study). Am J Cardiol 2011. April. [Epub ahead of print]. [27] Cignarella A, Kratz M, Bolego C. Emerging role of estrogen in the control of cardiometabolic disease. Trends Pharmacol Sci 2010;31:183–9. [28] Clarkson TB. Treatment of the Postmenopausal Woman. Ed Lobo RA: Elsevier; 2007. [29] Mack WJ, Slater CC, Xiang M, et al. Elevated subclinical atherosclerosis associated with oophorectomy is related to time since menopause rather than thype of menopause. Fertil Steril 2004;82:391–7. [30] Sutton-Tyrrell K, Kuller LH, Matthews KA, et al. Subclinical atherosclerosis in multiple vascular beds: an index of atherosclerotic burden evaluated in postmenopausal women. Atherosclerosis 2002;160:407–16. [31] Ajani UA, Ford ES. Has the risk for coronary heart disease changed among U.S. adults? J Am Coll Cardiol 2006;48:1177–82. [32] Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet 1999;353:89–92. [33] Jarvie JL, Foody JM. Recognizing and improving health care disparities in the prevention of cardiovascular disease in women. Curr Cardiol Rep 2010;12:488–96. [34] Greenland P, Alpert JS, Beller GA, et al. American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2010;122:e584–636. [35] Stergiou G, Thomopoulou GC, Skeva II, Mountokalakis TDI. Prevalence, awareness treatment, and control of hypertension in Greece. The Didima Study. AJH 1999;12:959–65.