Published online before print May 12, 2003, doi: 10.1161/01.HYP.0000074428.11168.EE
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(Hypertension. 2003;42:39.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Classic and Novel Risk Factor Parameters in Women With a History of Preeclampsia
From the University Departments of Pathological Biochemistry (N.S., L.C.) and Obstetrics and Gynaecology (J.R., H.C., I.A.G.), Glasgow Royal Infirmary University NHS Trust, Glasgow, Scotland.
Correspondence to Prof Ian Greer, Department of Obstetrics and Gynaecology, University of Glasgow, Glasgow Royal Infirmary, Glasgow G31 2ER UK. E-mail I.A.Greer{at}clinmed.gla.ac.uk
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Abstract |
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Epidemiological studies demonstrate a relation between preeclampsia (PE) and an increased risk of maternal coronary heart disease (CHD) in later life. However, there are few data available to explain any underlying mechanism. We recruited 40 primigravid women with a history of proteinuric PE delivering between 1975 and 1985 and 40 controls, matched as a group for time of index pregnancy, smoking, and current body mass index to assess classic (lipids, blood pressure) and novel (adhesion molecules, insulin, leptin) risk factor pathways. Women with a history of PE had higher diastolic blood pressure compared with controls (83 vs 76 mm Hg, P<0.05), but there were no significant differences in fasting lipoprotein concentrations (P>0.20). However, concentrations of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 (ICAM-1) in particular were higher in the PE group by 14% (P=0.038) and 44% (P=0.002), respectively. The cases also demonstrated a tendency toward higher fasting insulin (P=0.08) concentrations and had higher glycosylated hemoglobin levels (P=0.004). Leptin concentrations were not significantly elevated. Interestingly, significantly more of the women with history of PE were classified as menopausal (37.55% vs 17.5%, P=0.045). The differences in ICAM-1 concentration persisted (P=0.010) after adjustment for potential confounders, including hormonal use/menopausal status, antihypertensive or lipid-lowering therapy, and social class. We conclude that classic risk factors alone cannot fully explain the elevated CHD risk in women with a history of PE. Rather markedly elevated ICAM-1 concentrations and specific but subtle features of the metabolic syndrome (glucose, blood pressure) are likely to be involved.
Key Words: pregnancy • endothelium • insulin resistance • lipoproteins • coronary disease
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Introduction |
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Epidemiological studies have recently demonstrated a relation between preeclampsia (PE) and an increased risk of maternal coronary heart disease (CHD) in later life.1,2 However, there are few data available to explain any underlying mechanism. PE shares common pathologic features with atherosclerosis, both biochemical (insulin resistance, hypertriglyceridemia, thrombotic and proinflammatory changes)3–5 and biologic (endothelial dysfunction).6–8 Thus, common risk factors, either genotypic or phenotypic, might underlie both PE and CHD.
Only one small study examining insulin sensitivity9 has assessed women at a considerable interval (17 years) after a PE pregnancy, perhaps an age when risk factors for CHD might be more relevant. Furthermore, despite the predictive value of endothelial inflammatory markers for vascular disease,10,11 there are limited data available in relation to women with previous PE. The product of these metabolic disruptions is believed to be endothelial dysfunction, and this has been proposed as a mechanism preceding the development of CHD.12,13 Endothelial dysfunction has been demonstrated in vessels from PE women during pregnancy, and recently, Chambers et al14 demonstrated in vivo impaired endothelial function at least 3 months (median, 3 years) postnatally. Our aim in this study, therefore, was to examine whether classic or novel risk factors were elevated in women with a history of PE up to 15 to 25 years after pregnancy. We specifically assessed novel risk factors pathways not only reported to be perturbed in women with PE and considered relevant to its pathogenesis14–17 but also linked prospectively to cardiovascular events.10,11,18,19 Thus, in addition to blood pressure and fasting lipoprotein concentrations, we examined circulating concentrations of the cell adhesion molecules, intracellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion-1 (VCAM-1), and E-selection. In addition, we measured factors more directly linked to fat mass and insulin action, namely, leptin, fasting insulin, and glycosylated hemoglobin (HbA1c).
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Methods |
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Primigravid women who delivered between 1975 and 1985 with proteinuric PE and controls, matched as a group for time of index pregnancy, smoking, and current body mass index, were identified from medical records. Our diagnosis of PE was robust, in that it was in line with International Society for the Study of Hypertension in Pregnancy (ISSHP) criteria. The relevant data to determine diagnosis were taken from comprehensive maternity records, recorded at the time of the index pregnancy, available from 1975. Thus, all women with PE were primigravid, had a diastolic blood pressure >90 mm Hg at diagnosis (but normal blood pressure at booking), and had >2+ of proteinuria on dipstick testing in the absence of renal disease or infection. Forty women with a history of PE and 40 controls were recruited. No subject had any clinical disease at the time of sampling or had a recent infection within the last 10 days. Blood pressure, body mass index, and abdominal circumference were measured. Menopause was defined as the absence of periods for one year or the use of hormonal replacement therapy. All work was performed according to the Declaration of Helsinki, approval was granted by the institutional ethics committee, and all patients gave written, informed consent.
Venous blood was taken after an overnight fast for analysis of lipids and lipoproteins, by a modification of the standard Lipid Research Clinics Protocol. The intra-assay and interassay coefficients of variation for all lipid measures were <3%. Other measures included HbA1c (high-performance liquid chromatography; HA8121 analyzer, Menarini Diagnostics) and insulin (competitive radioimmunoassay; Coat-A-Count I, DPC). Adhesion molecules VCAM-1 (Parameter Human sVCAM-1 Immunoassay, R&D Systems Inc), ICAM-1 (Parameter Human sICAM-1 Immunoassay, R&D Systems Inc), and E-selectin (Parameter Human sE-Selectin Immunoassay, R&D Systems Inc) were also measured. Plasma leptin was measured by an in-house radioimmunoassay validated thoroughly against the commercially available Linco assay, as detailed before.20 The intra-assay and interassay coefficients of variation were <7% and <10%, respectively, over the sample concentration range. The detection limit of the assay was 0.5 ng/mL.
Statistical Analyses
Data are expressed as medians, with the interquartile range as the measure of variability. Mann Whitney U tests or, where indicated, 
2 tests, were used for comparisons between groups.
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Results |
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The demographic details of these groups are demonstrated in Table 1. There were no significant differences in age, body mass index, waist circumference, smoking status, and parity between the 2 groups at the time of testing. The women with a past history of PE were found to have higher blood pressure than did the controls (124/83 vs 116/76 mm Hg), with the diastolic difference reaching significance (P=0.035). In addition, despite similar ages, a significantly greater proportion of the women with a past history of PE were menopausal (P=0.045). With regard to the index pregnancy, the women with PE had a significantly greater body mass index (P=0.02) and earlier gestation of delivery (P<0.001) and gave birth to babies with a lower birth weight centile (P=0.006).
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There was no difference in fasting lipoprotein concentrations (Table 2). VCAM-1 and ICAM-1 concentrations were significantly higher in the PE group, by 14% and 44%, respectively. Moreover, the case-control difference in ICAM-1 (t=-2.65, P=0.010) but not VCAM-1 concentrations persisted after adjustment for hormonal use/menopausal status, antihypertensive and lipid-lowering therapy, and social class (as determined by validated Deprivation Category [DEPCAT] score). The difference was also present when only premenopausal cases and controls were compared (P=0.007 crude difference; P=0.001 after adjustment for age, body mass index, and smoking). The women with a past history of PE had higher fasting insulin and significantly greater HbA1c concentrations (P=0.004), a difference that also persisted after adjustment for the aforementioned factors (t=-2.60 P=0.012). Smoking influenced ICAM concentration, but the relation with PE persisted on logistic regression (t=-2.15, P=0.035).
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Discussion |
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These data show for the first time that women with a past history of PE have increased plasma concentrations of the endothelial inflammatory marker ICAM-1, 15 to 25 years after the index pregnancy, compared with women with a history of healthy pregnancy. Chambers and colleagues14 also examined endothelial and metabolic factors in a group of women at least 3 months (median, 3 years) post partum. In concordance with our results, they did not identify any significant difference in lipids between the post-PE women and controls. However, in contrast to our data, they did not identify any elevation in the concentration of adhesion molecules in women with a single episode of PE, despite demonstrating impaired endothelial function. This might represent the much shorter interval at which these factors were evaluated after the index pregnancy in their study.14 It is possible that these phenotypic factors interact with age, resulting in significant differences from controls only being manifested many years after the index pregnancy. In this respect, it is noteworthy that the body mass index of cases and controls in our study was, on average, 4 to 5 units (
20%) higher 20 years from their index pregnancy. In other words, while not pregnant, women with a history of PE might only again demonstrate clear elevations in specific risk factors, such as ICAM-1, as a measure of endothelial cell dysfunction when they become heavier and, as a result, more metabolically stressed. Moreover, given that women with a history of PE had a weight similar to controls at recruitment, one might speculate that the tendency to insulin resistance and elevated ICAM-1 levels in such women might reflect an increased sensitivity to adiposity. Our study included both menopausal and premenopausal women. With respect to ICAM-1, there is uncertainty in the literature about effects of menopause or endogenous estrogen status on ICAM-1 concentrations. For example, whereas Oger et al21 suggested a 24% higher ICAM-1 level in menopausal women compared with premenopausal women of similar age and body mass index, Jasonni and colleagues22 could not detect any change. We have repeated our analyses by additional adjustment for menopausal status and noted that the level of significance in respect of case-control difference in ICAM-1 concentration remained nearly identical (P=0.010). The case-control difference in ICAM-1 was also significant when only premenopausal cases and controls were compared. Thus, although menopause could have been an explanation for the observed case-control ICAM-1differences, it appeared not to be so in our study.
Adhesion molecules are expressed on the surface of vascular endothelial cells in response to inflammatory cytokines and are believed to encourage adhesion of circulating leukocytes and their subsequent transendothelial migration. This process is believed to be critical in the progress of early atherogenesis, and cross-sectional data suggest that soluble forms of these proteins are elevated in patients with atherosclerosis.23–25 ICAM-1 in particular has recently been established to be independently predictive for CHD.11 Indeed, from the Atherosclerosis Risk in Communities study,10 those with baseline concentrations of sICAM-1 in the highest quartile, when followed up for 5 years, were found to have a 5-fold increased risk of incident CHD (relative risk, 5.5; 95% confidence interval, 2.5 to 12.2). These data are proposed to support the hypothesis that endothelial activation and damage, or "inflammation," occur early in the atherosclerotic process. The elevation in VCAM-1 is also of interest, as this adhesion molecule is involved in monocyte attachment and transformation to macrophages in the vascular wall.23
Our ICAM-1 case-control difference broadly concurs with the observation by He et al,26 who found an elevation in von Willebrand factor, another marker of endothelial activation, in women who had previous PE. Interestingly, He et al also noted elevated cholesterol and triglyceride levels in such women, but only during the luteal phase. We did not measure risk parameters in relation to different phases of the menstrual cycle, principally because a proportion of our cases and controls were postmenopausal.
Women with a past history of PE also had a tendency to higher insulin concentrations, and interestingly, HbA1c concentrations were significantly elevated. These combined findings are suggestive of impaired insulin sensitivity, which has been linked to elevated circulating levels of adhesion molecules.27,28
We also noted in our population that concentrations of soluble VCAM-1, HbA1c, and insulin were correlated with body mass index (data not shown). One might hypothesize, therefore, that a reduction in body mass index, with a consequent reduction in inflammation and improvement in insulin sensitivity, might provide some hope of altering this predisposed risk of cardiovascular disease. Ziccardi and colleagues29 have demonstrated in a group of obese, premenopausal women that weight loss over one year was associated with a reduction in inflammatory cytokine concentrations, a reduction in adhesion molecule concentrations, including ICAM-1, and an improvement in endothelium-dependent vascular function. These latter observations are important, because on the basis of conventional risk factor charts for CHD based on Framingham data,30 only a very small minority of women with a history of PE in our study would be considered for primary prevention with, eg, lipid lowering. Indeed, the average total cholesterol to HDL cholesterol ratio was <4, and only 2 of the 40 women with history of PE were on lipid-lowering therapy. These data therefore suggest that assessment of risk and risk factor status in women with a history of PE should be examined in greater detail.
Perspectives
Our data suggest that the phenotype associated with PE is linked to novel mechanisms that underlie CHD, namely, endothelial inflammation and other subtle features of the metabolic syndrome. Such findings might explain in part the epidemiologic association between PE and CHD. This association might be genetically or phenotypically determined, but it is reasonable to suggest that because women with a history of PE might have an increased sensitivity to adiposity, lifestyle modifications leading to weight loss might ameliorate this underlying cardiovascular disease risk.
Received February 3, 2003; first decision March 3, 2003; accepted April 18, 2003.
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