This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Paradisi, G. Articles by Caruso, A. Search for Related Content PubMed PubMed Citation Articles by Paradisi, G. Articles by Caruso, A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure High Risk Pregnancy Hazardous Substances DB NITROGLYCERIN Related Collections Cardiovascular Endocrinology Female Endocrinology

Cardiovascular Risk Factors in Healthy Women with Previous Gestational Hypertension

Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, 00168 Rome, Italy

Address all correspondence and requests for reprints to: Dr. Giancarlo Paradisi, Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Via Servilio IV 4, 00178 Rome, Italy. E-mail: giancarlo.paradisi{at}tin.it.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Epidemiological studies indicate that gestational hypertension (Gh) during pregnancy is associated with increased risk of cardiovascular disease in later life. However, it is unclear whether particular metabolic and hemodynamic characteristics are related to this risk.

Objective: The objective of this study was to investigate endothelial function and carbohydrate and lipid metabolism in healthy, normotensive women with previous pregnancy complicated by Gh.

Design, Setting, and Participants: Brachial artery flow-mediated dilatation (FMD; endothelium dependent) and nitroglycerin-induced dilatation (endothelium independent) were measured in 15 subjects with previous Gh and in 15 controls with previous normal pregnancies. Lipid panel, glucose, insulin, homocysteine, and androgens were also measured.

Results: FMD was significantly reduced in women with previous Gh compared with controls (P < 0.0001), whereas nitroglycerin-induced dilatation was comparable in both groups. Gh women showed increased fasting insulin (P = 0.011), insulin resistance measured by homeostasis model assessment (P = 0.018), free fatty acids (P = 0.0018), and testosterone (P = 0.0012) and decreased high-density lipoprotein cholesterol (P = 0.0017) compared with controls. Across all subjects, FMD showed a strong independent negative correlation with testosterone and homeostasis model assessment and a positive correlation with high-density lipoprotein cholesterol (r = –0.60, P = 0.0003; r = –0.43, P = 0.016; and r = 0.58, P = 0.0005, respectively).

Conclusions: Endothelial dysfunction and early alteration of carbohydrate and lipid metabolism are present in otherwise healthy women with previous Gh. These abnormalities along with a relative hyperandrogenism could explain, at least in part, the increased risk for cardiovascular disease in later life in these women.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
GESTATIONAL HYPERTENSION (Gh), namely, the presence of de novo blood hypertension after the 20th wk of pregnancy without proteinuria, is a relatively common complication of pregnancy, affecting 2–5% of women. The exact pathophysiology of this disease is still unclear. Recently, studies have demonstrated that Gh is associated with a cluster of metabolic abnormalities, such as hyperinsulinemia, insulin resistance, and dyslipidemia, thus suggesting analogies with the insulin-resistant syndrome (1, 2). According to epidemiological evidence, women with previous Gh seem to be at increased risk for cardiovascular diseases. Jonsdottir et al. (3) in a population of 7543 women found that those with hypertension during pregnancy had an augmented risk of death for heart ischemia in later life compared with the general population, with a significantly higher relative risk among eclamptic women and those with preeclampsia than in those with hypertension alone. More recently, Wilson et al. (4) reported an increased risk of hypertension and stroke in women with a history of Gh, similar to that observed in women with previous preeclampsia.

Reduced insulin sensitivity, altered angiogenesis and endothelial function, and relative hyperandrogenemia found in women with previous preeclampsia have been indicated to contribute to their increased risk of cardiovascular disease (5, 6, 7). We hypothesize that similar abnormalities may have a role on the increased cardiovascular risk of women with previous Gh. To test this hypothesis, we investigated whether healthy, normotensive women with previous pregnancy complicated by Gh have carbohydrate and lipid metabolic derangement typical of the insulin-resistant state. Furthermore, given that endothelial dysfunction represents an early indicator of cardiovascular risk (8, 9, 10), we performed an in vivo evaluation of endothelial function in these women.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study was conducted at Catholic University (Rome, Italy) and was approved by the institutional review board. Informed consent was obtained from each subject before the study. During the study, approximately 1000 women were seen at our outpatient care center for routine gynecological clinical examination. Of these, 36 had a previous pregnancy complicated by Gh, defined as diastolic blood pressure of 90 mm Hg or more at two consecutive measurements 6 h apart with the patient resting in the semirecumbent position, without proteinuria greater than 0.3 g/24 h or more than 1 g/liter (or 2+ with dipstick) in a random sample. According to the International Society for the Study of Hypertension in Pregnancy criteria, the elevation in blood pressure was diagnosed after 20 wk gestation in a previously normotensive woman (11).

In all cases, more than 12 months had elapsed since the delivery (20.4 ± 1.5 months). Those who during the pregnancy had the coexistence of gestational diabetes were excluded, as were those who smoked; drank more than 60 g alcohol/d; were clinically diagnosed with liver disease, hypertension, diabetes, renal disease, or were taking birth control pill; or medications known to affect endothelial function or glycemic and lipid metabolism. Twenty-four women who met the above conditions were approached to participate in the study. Fifteen agreed to be enrolled. Twenty-two nonsmoking, healthy women with previous normal pregnancy were approached to participate in the study as controls. All were matched with the study group patients for age and body mass index [calculated as the ratio between weight (in kilograms) and height (in meters) squared]. Fifteen agreed to be enrolled.

All women, those with and without Gh, were followed for the entire length of their previous pregnancies in our department, and all data regarding family history of hypertension, diagnosis of hypertension, birth weight, birth weight percentile, and week of delivery were obtained by our chart record. Subjects in both groups had regular menses every 27–31 d and no clinical signs of hyperandrogenism.

The studies were carried out over 2 d. On d 1, glucose, insulin, homocysteine, androgens, and lipid measurements were made. On d 2, bioelectrical impedance, blood pressure, and endothelial function were measured. The investigations were performed in the morning after abstaining from alcohol, caffeine, and food for 8 h, in a supine position at a temperature of about 25 C. Given that previous studies have shown that endothelial function may vary according to the phase of menstrual cycle, with a substantial impairment during the luteal phase, all subjects were studied during the midfollicular phase (12).

Measurement of endothelial function

The ultrasound investigation for measuring endothelium-dependent and -independent arterial dilatation was performed as described previously (13). Briefly, brachial artery diameter was measured by B-mode ultrasound image using a 7.5-MHz linear array transducer and a standard ESAOTE AU 570 A system (Ansaldo, Milan, Italy). In all studies, scans were obtained with the subject at rest, during reactive hyperemia, again with the subject at rest, and after sublingual administration of nitroglycerin. The velocity of arterial flow was measured with a pulsed Doppler signal. Increased flow was induced by the inflation of a pneumatic tourniquet placed around the forearm to a pressure of 250 mm Hg for 4.5 min, followed by release. A scan was performed continuously for 30 sec before and 90 sec after deflation of the cuff, including a repeat recording of flow velocity for the first 15 sec after the cuff was released. Thereafter, 10–15 min was allowed for recovery of the vessel, after which an additional resting scan was performed. A sublingual nitroglycerin spray (400 µg) was then administered, and 3–4 min later, the last scan was performed. For the reactive hyperemia scan, measurements of diameter were taken 50–60 sec after deflation of the cuff. The vessel diameter in scans obtained after reactive hyperemia [flow-mediated dilatation (FMD)] and the administration of nitroglycerin (nitrate-induced dilatation) was expressed as a percentage of the average diameter of the artery in the two resting (or control) scans (considered 100%). Reactive hyperemia was calculated as the maximal flow recorded in the first 15 sec after cuff deflation divided by the flow during the first resting (baseline) scan.

Analytical methods

Plasma glucose levels were measured by the glucose oxidase method (Beckman, Fullerton, CA), and all hormone levels were determined using commercial RIA kits (Radim, Rome, Italy). Insulin resistance was calculated by homeostasis model assessment [HOMA; fasting plasma insulin (microunits per milliliter) x fasting plasma glucose (millimoles per liter)/22.5]. The free testosterone index was calculated as previously reported (14).

Total cholesterol and triglyceride concentrations were determined by an enzymatic assay (Bristol, Paris, France). High-density lipoprotein (HDL) cholesterol was determined after precipitation with polyethylene glycol 6000 (Delchimica Scientific, Naples, Italy). Low-density lipoprotein (LDL) cholesterol was isolated by sequential flotation in a Beckman model L7–65 ultracentrifuge using a type 70 rotor (Beckman). Free fatty acids (FFAs) were determined using an acyl-coenzyme A oxidase-based colorimetric method. Total plasma concentrations of homocysteine were estimated by HPLC.

Body composition

Bioelectrical impedance to estimate the subject’s body composition was performed with a tetrapolar impedance plethysmograph (Soft Tis-sue Analyzer, Akern Bioresearch, Florence, Italy) according to Lukaski et al. (15). Briefly, at 0700 h, each woman lay supine on a bed made of nonconductive materials. Detecting electrodes (Red Dot, 3M Health Care, St. Paul, MN) were placed in the middle of the dorsum of hands and feet proximal to the metacarpal-phalangeal metatarso-phalangeal joints, respectively, and also medially between the distal prominances of the radius and the ulna and between the medial and lateral malleoli at the ankle. The current-introducing electrodes were placed at a minimum distance of the diameter of the wrist or ankle beyond the paired detector electrode. An excitation current of 800 mA alternating current at 50 kHz was introduced at the distal electrodes, and the voltage drop across the patient was detected by the proximal electrodes. The percentage of body fat, fat-free mass, and total body water were calculated using the appropriate software (Bodygram, Akern Bioresearch, Florence, Italy).

Statistical analysis

Comparison between groups was performed using Student’s unpaired t test. Comparisons between frequencies were assessed by ² analysis. Linear regression analysis was used for relationships between FMD and the metabolic characteristics studied. Subsequently, variables whose correlation with FMD achieved near-statistical significance (P 0.1) were entered into a stepwise regression model to assess the magnitude of their individual effects on FMD. The sample size for FMD was calculated for a power of 0.80, assuming a difference in means of approximately 5 and an SD of approximately 3 from our previous findings (16). Data are given as the mean ± SD. Statistical significance was accepted at a level of P < 0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Demographic and pregnancy characteristics of the control and the previous Gh group are shown in Table 1. There were no significant differences with regard to age, body mass index, percentage of fat mass, and waist/hip ratio. By design, systolic and diastolic blood pressures during the previous pregnancy were higher in women with previous Gh. The glucose area during the oral glucose tolerance test was slightly, but not significantly, higher in women with Gh.

Fasting insulin levels and HOMA were 60% and 80% higher in women with previous Gh than in control subjects (P = 0.006 and P = 0.005, respectively; Table 2). Both groups had similar fasting glucose levels. All subjects had normal lipid profiles; however, women with previous Gh exhibited more than 20% lower HDL and roughly 60% higher FFA than controls (P = 0.0017, and P = 0.0018, respectively; Table 2). Triglycerides, total cholesterol, and LDL cholesterol were comparable in the two groups.

Hemodynamic data

Although all subjects were normotensive, both systolic and diastolic blood pressures were significantly higher in women with previous Gh (Table 2). Baseline brachial artery diameter (vessel size) was similar in the two groups (Table 2). Baseline velocity and the percent increase in blood velocity after ischemic stimulus (reactive hyperemia) were comparable in the groups. FMD (i.e. endothelium-dependent dilatation) of previous Gh women was nearly 55% that of controls (P < 0.0001). Nitroglycerin-dependent dilatation (endothelium-independent dilatation) was comparable in the two groups.

Correlational analyses

To better investigate the relation between endothelial function, carbohydrate and lipid metabolism, and hormone status, we performed linear regression analysis between FMD and the various parameters examined. Linear regression analysis showed that total testosterone levels had a strong negative association with FMD (r = –0.600; P = 0.0003). A similar, if less robust, correlation was found between FMD and free testosterone (r = –0.57; P = 0.0007; Fig. 1A). Negative significant correlations were also found between FMD and HOMA as well as between FMD and fasting insulin (r = –0.43; P = 0.0163 and r = –0.41; P = 0.024; Fig. 1, B and C, respectively). Conversely, FMD exhibited positive relations with HDL cholesterol (r = 0.58; P = 0.005; Fig. 1D). A significant correlation was also found between FMD and body mass index (r = –0.36; P = 0.046).

View larger version (25K): [in this window] [in a new window]   FIG. 1. Linear regression analysis between percent increase in FMD and testosterone (A), HOMA (B), fasting insulin (C), and HDL cholesterol (D).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

FMD was examined, under resting conditions, by measuring the percent increase in vessel diameter in response to increased blood flow during postocclusion hyperemia. It is recognized that FMD depends on the ability of the endothelium to release nitric oxide in response to shear stress and is used as a reliable method to assess endothelial function in various clinical conditions (17). Although, to our knowledge, no previous studies have assessed endothelial function in women with previous Gh, our results are consistent with reports that women with a history of preeclampsia have endothelial dysfunction (6, 18). Chambers et al. (6) in a case-control study analyzed brachial artery FMD in 113 women with previous preeclampsia and in 48 women with previous uncomplicated pregnancies. They found that women with previous preeclampsia had a significant lower FMD than controls (P < 0.001), concluding that these women had impaired endothelial function (6). More recently, similar findings were reported by Agatisa et al. (18), leading the researchers to deduce that women with history of preeclampsia are at increased risk for cardiovascular disease. Some researchers believe that gestational, nonproteinuric hypertension is a mild variety of preeclampsia (19). If this assertion is true with regard to the pregnancy’s prognosis, it cannot be extended to postpregnancy life, when, as shown by our results, women with previous Gh have alteration of endothelial function as do women with previous preeclampsia.

As stated in Subjects and Methods, all subjects studied were normotensive. Despite that, women with a history of Gh presented 10% higher systolic and diastolic blood pressures compared with controls. It is known that hypertension is associated with endothelial dysfunction (20). Thus, one could hypothesize that this difference in blood pressure may account for the blunted endothelial function observed in previous Gh patients. However, as previously demonstrated in healthy and obese subjects (21), we did not find a significant correlation across all subjects among FMD, systolic blood pressure, and diastolic blood pressure (r = –0.25; P = 0.18 and r = –0.26; P = 0.17, respectively). Therefore, although we cannot exclude a contribution of blood pressure to the endothelial function of previous Gh patients, it is likely that this contribution could be minimal.

Several metabolic and hormonal variables are known to affect vascular reactivity (22, 23). Therefore, we analyzed carbohydrate metabolism, androgens, lipid panel, blood pressure, and homocysteine to assess which of these play a major role in the endothelial dysfunction displayed by women with previous Gh.

Increased resistance to insulin action is a well-established cardiovascular risk factor (24). The molecular pathways by which insulin resistance impairs endothelial function are not completely clear; however, oxidative stress and inflammation may act synergistically, leading to a reduced expression of endothelial nitric oxide synthase (25, 26). As previously observed (1), we found increased insulin resistance in Gh women, slightly during pregnancy (based on glucose area during oral glucose tolerance test in 21 women) and marked after pregnancy, with an 80% higher HOMA and a 60% higher fasting insulin in previous Gh subjects compared with controls. Interestingly, the two measurements of insulin resistance during and after pregnancy had a positive correlation, although it was not significant (r = 0.41; P = 0.06). Similar metabolic alterations have been shown in previously preeclamptic women (7), supporting the idea that hypertension during pregnancy per se is a risk factor for insulin resistance in later life. Both HOMA and fasting insulin showed significant negative correlations with FMD. Interestingly, the relation between FMD and HOMA was independently maintained even after adjusting for the other parameters studied; it was able to explain 22% of the variance in FMD. Thus, although we did not provide data about the mechanistic link between endothelial function and insulin resistance, our finding confirms the association between endothelial dysfunction and insulin resistance in premenopausal healthy women with a history of Gh.

In women, hyperandrogenemia acts as a cardiovascular risk factor. Epidemiological evidence shows that subjects with polycystic ovary syndrome who displayed elevated androgen levels are at greater risk of developing cardiovascular disease (27, 28, 29). The reason of this augmented risk has not been well elucidated. However, the direct association among testosterone, insulin resistance, and impaired endothelial function in polycystic ovary syndrome that we and others have described seems to suggest that metabolic and hormonal impairment can play a role in it (30, 31, 32, 33). Although in the normal range, the levels of both total and free testosterone of women with previous Gh were significantly higher than those of controls (P = 0.0012 and P = 0.0025, respectively). This result is consistent with the evidence of augmented androgen levels during and after pregnancy in women with preeclampsia (34, 35, 36). Interestingly, the testosterone value was coupled with HOMA (r = 0.37; P = 0.04), and both were the major independent determinant of endothelial function, as shown by the multivariate analysis in which testosterone was able to explain 34% of the variance in FMD. To the best of our knowledge, this is the first report about the association between mild hyperandrogenemia and endothelial dysfunction, and although our data do not give any precise threshold values for definitively vasotoxic levels of androgens in women, this result suggests that testosterone may act as a cardiovascular risk factor in apparently healthy women with no clinical signs of hyperandrogenemia.

In accord with our preceding results obtained during Gh, women with a history of Gh had higher FFA values than controls. Increased FFA levels are known to negatively affect endothelial function (37). Therefore, it is possible that the moderate increase observed in the previous Gh group could influence vascular reactivity. However, given that we did not observe a significant correlation between FMD and FFA, it is likely that the influence of FFA on endothelial function could be minimal. HDL cholesterol is the antiatherogenic lipoprotein and appears to modulate endothelial function in an beneficial fashion (38). It is well recognized that low HDL cholesterol is associated with increased cardiovascular risk (38). In our study, we found 21% lower HDL levels in previous Gh women compared with controls (P = 0.0017). In addition, HDL values correlated with FMD. This relation was independently maintained after adjusting for the other parameters studied, and it was able to explain 3% of the variance in FMD. Thus, low HDL cholesterol levels appear to negatively affect endothelial function not only in the high degree of reduction seen during experimental studies (39), but also in its relatively moderate decrease exhibited by healthy subjects with previous Gh.

There were some potential limitations to our study. The groups studied were not matched for gestational age at delivery. Given that controls did not deliver at a similar gestational age as Gh women, we do not know whether some control subjects destined to have preeclampsia or Gh during the last phase of gestation avoided it by being delivered earlier. A case-control study with groups matched for all demographic and pregnancy characteristics would be a stronger design. Furthermore, our study had a low power to detect differences between groups in some of the variables analyzed, in particular, fasting glucose and SHBG. We have to underline, however, that the sample size was calculated to have at least 80% power to detect a difference in FMD between groups.

In conclusion, this study provides evidences that women with previous Gh are characterized by endothelial dysfunction and early derangement of carbohydrate, lipid, and hormonal metabolism. Given the known role that these factors have in cardiovascular disease, these findings could explain, at least in part, the clinical and epidemiological findings of augmented cardiovascular disease in subjects with previous pregnancy complicated by Gh.

	Footnotes

 
G.P., A.B., R.S., F.I., C.T., L.C., and A.C. have nothing to declare.

First Published Online January 24, 2006

Abbreviations: FFA, Free fatty acid; FMD, flow-mediated dilatation; Gh, gestational hypertension; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; LDL, low-density lipoprotein.

Received June 16, 2005.

Accepted January 12, 2006.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Caruso A, Ferrazzani S, De Carolis S, Lucchese A, Lanzone A, De Santis L, Paradisi G 1999 Gestational hypertension but not pre-eclampsia is associated with insulin resistance syndrome characteristics. Hum Reprod 14:219–223[Abstract/Free Full Text]
2. Bartha JL, Comino-Delgado R 1997 Carbohydrate metabolism. Evaluation in women with de novo hypertension in late pregnancy. J Reprod Med 42:489–496[Medline]
3. Jonsdottir LS, Arngrimsson R, Geirsson RT, Sigvaldason H, Sigfusson N 1995 Death rates from ischemic heart disease in women with a history of hypertension in pregnancy. Acta Obstet Gynecol Scand 74:772–776[Medline]
4. Wilson BJ, Watson MS, Prescott GJ, Sunderland S, Campbell DM, Hannaford P, Smith WC 2003 Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. Br Med J 326:845–851[Abstract/Free Full Text]
5. Wolf M, Hubel CA, Lam C, Sampson M, Ecker JL, Ness RB, Rajakumar A, Daftary A, Shakir AS, Seely EW, Roberts JM, Sukhatme VP, Karumanchi SA, Thadhani R 2004 Preeclampsia and future cardiovascular disease: potential role of altered angiogenesis and insulin resistance. J Clin Endocrinol Metab 89:6239–6243[Abstract/Free Full Text]
6. Chambers JC, Fusi L, Malik IS, Haskard DO, De Swiet M, Kooner JS 2001 Association of maternal endothelial dysfunction with preeclampsia. JAMA 285:1607–1612[Abstract/Free Full Text]
7. Laivuori H, Tikkanen MJ, Ylikorkala O 1996 Hyperinsulinemia 17 years after preeclamptic first pregnancy. J Clin Endocrinol Metab 81:2908–2911[Abstract/Free Full Text]
8. Zeiher AM, Drexler H, Wollschäger H, Just H 1991 Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 83:391–401[Abstract/Free Full Text]
9. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ 1990 Impaired vasodilation of forearm vessels in hypercholesterolemic humans. J Clin Invest 86:228–234[Medline]
10. Fuster V, Badimon L, Badimon JJ, Chesebro JH 1992 The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 326:310–318[Medline]
11. Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM 2001 The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 20:IX–XIV
12. Giannattasio C, Failla M, Grappiolo A, Stella ML, Del Bo A, Colombo M, Mancia G 1999 Fluctuations of radial artery distensibility throughout the menstrual cycle. Arterioscler Thromb Vasc Biol 19:1925–1929[Abstract/Free Full Text]
13. Celermajer DS, Sorensen KE, Gooch VM 1992 Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340:1111–1115[CrossRef][Medline]
14. Vermeulen A, Verdonck L, Kaufman JM 1999 A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 84:3666–3672[Abstract/Free Full Text]
15. Lukaski HC, Bolonchuk WW, Hall CB, Siders WA 1986 Validation of tetrapolar bioelectrical impedance method to assess human body composition. J Appl Physiol 60:1327–1332[Abstract/Free Full Text]
16. Paradisi G, Biaggi A, Ferrazzani S, De Carolis S, Caruso A 2002 Abnormal carbohydrate metabolism during pregnancy: association with endothelial dysfunction. Diabetes Care 25:560–564[Abstract/Free Full Text]
17. Joannides R, Haefeli WE, Linder L, Richard V, Bakkali EH, Thuillez C, Luscher TF 1995 Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation 91:1314–1319[Abstract/Free Full Text]
18. Agatisa PK, Ness RB, Roberts JM, Costantino JP, Kuller LH, McLaughlin MK 2004 Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk. Am J Physiol 286:H1389–H1393
19. Sibai BM 2003 Diagnosis and management of gestational hypertension and preeclampsia. Obstet Gynecol 102:181–192[CrossRef][Medline]
20. Landmesser U, Hornig B, Drexler H 2004 Endothelial function: a critical determinant in atherosclerosis? Circulation 109:27–33[CrossRef]
21. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD 1996 Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 97:2601–2610[Medline]
22. Baron AD, Steinberg HO 1997 Endothelial function, insulin sensitivity, and hypertension. Circulation 96:725–726
23. Barrett-Connor E, Giardina EG, Gitt AK, Gudat U, Steinberg HO, Tschoepe D 2004 Women and heart disease: the role of diabetes and hyperglycemia. Arch Intern Med 164:934–942[Abstract/Free Full Text]
24. Reaven G. M., Lithell H., Landsberg L 1996 Hypertension and associated metabolic abnormalities–the role of insulin resistance and the sympathoadrenal system. N Engl J Med 334:374–382[Free Full Text]
25. Verma S, Kuliszewski MA, Li SH, Szmitko PE, Zucco L, Wang CH, Badiwala MV, Mickle DA, Weisel RD, Fedak PW, Stewart DJ, Kutryk MJ 2004 C-Reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. Circulation 109:2058–2067[Abstract/Free Full Text]
26. Sonnenberg GE, Krakower GR, Kissebah AH 2004 A novel pathway to the manifestations of metabolic syndrome. Obes Res 12:180–186[Medline]
27. Wild S, Pierpoint T, McKeigue P, Jacobs H 2000 Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clin Endocrinol (Oxf) 52:595–600[CrossRef][Medline]
28. Christian RC, Dumesic DA, Behrenbeck T, Oberg AL, Sheedy Jr PF, Fitzpatrick LA 2003 Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. J Clin Endocrinol Metab 88:2562–2568[Abstract/Free Full Text]
29. Solomon CG, Hu FB, Dunaif A, Rich-Edwards JE, Stampfer MJ, Willett WC, Speizer FE, Manson JE 2002 Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab 87:2013–2017[Abstract/Free Full Text]
30. Legro RS, Kunselman AR, Dodson WC, Dunaif A 1999 Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 84:165–169[Abstract/Free Full Text]
31. Paradisi G, Steinberg HO, Hempfling A, Cronin J, Hook G, Shepard MK, Baron AD 2001 Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation 103:1410–1415[Abstract/Free Full Text]
32. Orio Jr F, Palomba S, Cascella T, De Simone B, Di Biase S, Russo T, Labella D, Zullo F, Lombardi G, Colao A 2004 Early impairment of endothelial structure and function in young normal-weight women with polycystic ovary syndrome. J Clin Endocrinol Metab 89:4588–4593[Abstract/Free Full Text]
33. Vryonidou A, Papatheodorou A, Tavridou A, Terzi T, Loi V, Vatalas IA, Batakis N, Phenekos C, Dionyssiou-Asteriou A 2005 Association of hyperandrogenemic and metabolic phenotype with carotid intima-media thickness in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:2740–2746[Abstract/Free Full Text]
34. Laivuori H, Kaaja R, Rutanen EM, Viinikka L, Ylikorkala O 1998 Evidence of high circulating testosterone in women with prior preeclampsia. J Clin Endocrinol Metab 83:344–347[Abstract/Free Full Text]
35. Serin IS, Kula M, Basbug M, Unluhizarci K, Gucer S, Tayyar M 2001 Androgen levels of preeclamptic patients in the third trimester of pregnancy and six weeks after delivery. Acta Obstet Gynecol Scand 80:1009–1013[CrossRef][Medline]
36. Troisi R, Potischman N, Roberts JM, Ness R, Crombleholme W, Lykins D, Siiteri P, Hoover RN 2003 Maternal serum oestrogen and androgen concentrations in preeclamptic and uncomplicated pregnancies. Int J Epidemiol 32:455–460[Abstract/Free Full Text]
37. Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A, Bayazeed B, Baron AD 1997 Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest 100:1230–1239[Medline]
38. Gotto Jr AM 2001 Low high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report. Circulation 103:2213–2218[Free Full Text]
39. Spieker LE, Sudano I, Hurlimann D, Lerch PG, Lang MG, Binggeli C, Corti R, Ruschitzka F, Luscher TF, Noll G 2002 High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation 105:1399–1402[Abstract/Free Full Text]

This article has been cited by other articles:

				Authors/Task Force Members:, G. Mancia, G. De Backer, A. Dominiczak, R. Cifkova, R. Fagard, G. Germano, G. Grassi, A. M. Heagerty, S. E. Kjeldsen, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) Eur. Heart J., June 11, 2007; (2007) ehm236v1. [Full Text] [PDF]

				J. Girouard, Y. Giguere, J.-M. Moutquin, and J.-C. Forest Previous Hypertensive Disease of Pregnancy Is Associated With Alterations of Markers of Insulin Resistance Hypertension, May 1, 2007; 49(5): 1056 - 1062. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Paradisi, G. Articles by Caruso, A. Search for Related Content PubMed PubMed Citation Articles by Paradisi, G. Articles by Caruso, A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure High Risk Pregnancy Hazardous Substances DB NITROGLYCERIN Related Collections Cardiovascular Endocrinology Female Endocrinology