This case highlights several risk factors that are unique to women, and others that may be more common in women than men. The epidemiology of stroke prevalence has shown that women in our patient’s age group (under age 50) are generally con- sidered to have a lower incidence and prevalence of stroke than men [1]. Recent data from the National Health and Nutrition Examination Survey, however, has shown that women are having a more substantial increase in the prevalence of stroke in midlife versus men. In this analysis, women aged 45–54 had a higher odds of stroke compared with men of the same age (OR 2.39; 95% CI: 1.32–4.32) [22].
Consistent with the surge in stroke events, there was also a surge in cardiovascular risk in women greater than in men. For instance, systolic blood pressure increased at a steeper rate in women with each decade from 35 to 44 years (average SBP 113.9 mm Hg),
45–54 years (average SBP 123.5 mm Hg), and 55–64 years (average SBP 132.0 mm Hg) [22]. Men, however, initially had a higher SBP between the ages of 35 and 44 (average SBP 120.0 mm Hg), but there was a more gradual increase to the ages of 55–64 (average SBP 128.6 mm Hg). In addition, women had a substantial increase in total cholesterol, triglyc- erides, waist circumference, homocysteine, and gly- cosylated hemoglobin, and a lowering of the ankle brachial pulsatility index, between the cohort aged 45–54 and those aged 55–64 [22]. These data suggest that there is an acceleration of multiple risk param- eters in women a decade or more before cardiovas- cular and stroke events traditionally occur. Assuming these data are valid, there is a signifi cant opportunity to increase the efforts to recognize the risk factors in women during midlife and improve prevention strategies.
Menopause
The midlife prevalence of stroke in women may be related to the menopausal transition that occurs naturally in women with at least one intact and functioning ovary. During perimenopause, estradiol levels decline by about 60% [23]. After menopause, estradiol levels continue to decline but then plateau after 1–3 years. Overall, there is a 7- to 10-fold decrease in estradiol levels between pre- and post- menopause [24]. In contrast to the rapid decline in estradiol, circulating testosterone levels are decreas- ing more gradually during this period [25], leading to a relative androgen excess [25]. Postmenopause, circulating androgens aromatized to estrogens may be the only source of estradiol, and thus, variations in estrogens parallel that of androgens [25,26].
The menopausal shifts in hormonal levels and ratios of estrogens to androgens are important because these sex steroids appear to have opposite effects on vascular risk. Estrogens have multiple benefi cial effects on the cardiovascular system, including improving vasodilation and arterial com- pliance [27] by decreasing cerebral vascular tone and increasing cerebral blood fl ow [28]. The physi- ological basis for this is that estrogen facilitates pro- duction and sensitivity to vasodilatory factors, most importantly, endothelial nitric oxide synthase (eNOS). Interestingly, progestins and testosterone have no effect on levels of cerebrovascular eNOS protein [29]. In addition, estrogen has protective
effects on cerebral endothelial cells by increasing the effi ciency of mitochondrial energy production while decreasing free radical production, and enhancing endothelial cell survival [29,30].
In addition to anti-infl ammatory and antioxidant effects, estrogen may also reduce atherosclerotic risk through its impact on lipids. Exogenous estrogen replacement improves lipid profi les by lowering total and low-density lipoprotein (LDL) cholesterol, lipoprotein (a), and raising high-density lipoprotein (HDL) cholesterol [31,32].
Conversely, androgens have a detrimental effect on cerebral blood vessels by increasing arterial tone.
They also lead to a pro-atherogenic profi le by decreasing HDL and by increasing triglycerides, LDL, and total cholesterol [25].
Concurrent with the decline in sex steroids, women develop changes in cardiovascular risk factors during menopause. Lipid measurements in women across the menopausal transition in the Healthy Women Study showed that LDL cholesterol and triglycerides increased and HDL cholesterol decreased during perimenopause, whereas fasting glucose and blood pressure levels increased during postmenopause [33]. Along with a change in body fat distribution toward abdominal obesity, the lipid, blood pressure, and glucose changes are consistent with metabolic syndrome. Some menopausal experts have argued that the changes that occur from estro- gen defi ciency during menopause justifi es the use of the term “menopausal metabolic syndrome” [34].
In addition to the metabolic changes, estrogen defi - ciency during menopause also leads to a shift from anti-infl ammatory to pro-infl ammatory cytokines such as IL-1β, IL-6, and TNF-α [35]. These cyto- kines are important because they have been associ- ated with an increased risk of heart disease and stroke [36].
To determine the signifi cance of the increased cardiovascular risk profi le associated with the meno- pausal transition, subclinical vascular disease has been measured and compared between pre- and postmenopausal women. For example, carotid intimal medial thickness was increased and plaque prevalence was higher in postmenopausal women compared with premenopausal women [37]. There are also changes in cerebrovascular blood fl ow. One study of cerebral vasomotor reserve assessed the use of transcranial Doppler measurement of blood fl ow
velocity in the setting of breath holding to induce hypercapnia [38]. Compared with premenopausal women and men at all ages, postmenopausal women had a large reduction in vasomotor reactivity, suggesting a poorer response to cerebrovascular stress [38]. Whether this observed difference between men and women is due to estradiol levels is unknown.
Although decreased vasomotor reserve has been associated with an increased risk of stroke in patients with carotid stenosis, it is unknown whether this is associated with stroke risk in the absence of extra- cranial or intracranial vessel stenosis. The evidence for cardiovascular risk increasing during and after menopause, however, suggests that it is during this transition that women should be followed most closely in order to recognize and optimally treat these risk factors to prevent stroke.
Hormone therapy
Replacing the depletion of endogenous estradiol with replacement hormone therapy was widely believed to be an effective method to reduce cardio- vascular disease in women. Randomized trials of hormone therapy (specifi cally, conjugated equine estrogens [CEEs], CEE with medroxyprogesterone acetate, and 17-beta estradiol), however, showed no benefi t for the secondary prevention of heart disease [39] and stroke [40], as well as an increased risk of both types of events in healthy women (Women’s Health Initiative [WHI]) [41]. In an attempt to investigate why hormone therapy increased the risk for cardiovascular disease in the WHI, events were analyzed based on the time of initiation following menopause. This post hoc analysis showed that there was a trend toward a reduction in the risk for heart disease among women who initiated HT within 5 years of menopause [42]. In contrast, the risk of stroke with HT was increased regardless of the timing of initiation [42]. The importance of the timing of initiation of HT has been demonstrated in animal studies of atherosclerosis. In monkeys, the administration of CEE at the time of oophorectomy was associated with a 50–70% reduction in coronary plaque, but if CEEs were started years later, there was no benefi t [43]. Once atherosclerosis has reached the stage of fi brous plaque, exogenous estrogens may actually exacerbate thrombosis and hematoma formation (Figure 9.3) [44].
Based on the strong evidence from these trials, and the supporting physiological data suggesting harm at the later stages of atherosclerosis, the only recommended use for hormone therapy is for the treatment of vasomotor symptoms (i.e., hot fl ashes) and osteoporosis [45]. The cardiovascular disease prevention guidelines for women state that both hormone therapy and selective estrogen receptor modulators should not be used for primary or sec- ondary prevention (Class III, Level A) [46].
Preeclampsia and maternal placental syndrome This patient’s second pregnancy was complicated by moderate to severe preeclampsia. Preeclampsia, one of the hypertensive disorders of pregnancy, occurs in approximately 5% of pregnancies. The diagnostic criteria includes the de novo appearance of hyper- tension (systolic blood pressures ≥140 or diastolic pressures ≥90 mm Hg) and new onset proteinuria (≥300 mg per 24 hours) [47]. This pregnancy com- plication is being increasingly recognized as the initial occurrence of hypertension in women who then develop chronic hypertension following the childbearing years, particularly women who have more than one preeclamptic pregnancy [48].
Chronic hypertension is one of the leading risk factors for ischemic and hemorrhagic stroke. There- fore, it is not surprising that preeclampsia is also associated with stroke following childbearing. In a study from Scotland, women with preeclampsia/
eclampsia were four times more likely to have hyper-
tension (OR 3.98; 95% CI 2.8–5.6) and three times more likely to have had a self-reported stroke (OR 3.4; 95% CI 0.95–12.2) [49]. The Stroke Prevention in Young Women Study, a case-control study of women with ischemic stroke between ages 15 and 44, showed a 50% higher prevalence of self-reported preeclampsia versus controls, although the associa- tion was diminished when adjusted for hypertension [50]. In addition, women with maternal placental syndrome, which includes gestational hypertension, preelcampsia/eclampsia, placental abruption, and placental infarction, have an increased risk of heart disease later in life [51].
One of the major pathophysiological conse- quences of preeclampsia is endothelial dysfunction.
This prevents the normal dilatation of the uterine spiral artery, leading to reduced placental blood fl ow [47]. In addition to endothelial dysfunction, there are other manifestations that overlap with athero- sclerosis, including hemostatic abnormalities, dys- lipidemia, elevated insulin levels, and evidence of acute atherosclerosis with lipid-laden foam cells in the placental vascular bed of women with pre- eclampsia [52]. Based on these metabolic abnor- malities, some experts have argued that preeclampsia may represent an early manifestation of identifi able risk factors for vascular disease, and that women with preeclampsia maintain a higher risk of vascular disease throughout life than women who have nor- motensive pregnancies (Figure 9.4) [53]. Therefore, at a minimum, women with a history of preeclamp- Endothelial dysfunction
Foam cells
Fatty streak
Intermediate
lesion Atheroma Fibrous
plaque
Complicated lesion/rupture
Growth mainly by lipid accumulation Smooth muscle and collagen
Thrombosis, hematoma Estrogen reduces Estrogen worsens
Fig. 9.3 The impact of the timing of initiation of estrogen replacement on the timeline of atherosclerosis and endothelial dysfunction [44].
From The ESHRE Capri Workshop Group. Hum Reprod Update. 2006;12:483–497.
sia should be carefully screened for the early onset of hypertension and other vascular risk factors early after childbearing. One of the major research gaps includes how we can identify women with pre- eclampsia who are at high risk of a developing hypertension or having stroke at a relatively young age.
Hypertension
Hypertension, one of the most common risk factors for stroke, is especially common in women. In fact, compared with men with stroke, women are consis- tently more likely to have hypertension. Unfortu- nately, hypertension in women with a history of stroke may go unrecognized and therefore untreated.
A secondary analysis of the Women Estrogen Stroke Trial, a trial of 17-beta estradiol versus placebo in women with stroke or TIA [40], showed that, about 1 month after stroke, only 44% of women had blood pressure values within national guidelines (Joint National Committee on Prevention VI at the time this analysis was published) [54]. Of those outside of the guideline measurements, 55% were still beyond the guideline at follow-up [54]. This analysis demonstrated that even women participating in a stroke secondary prevention trial had poorly con- trolled blood pressure, in part because hypertension was undiagnosed.
A study of blood pressure management in ambu- latory care clinics reported that women were less likely than men to have adequate blood pressure
control (54% for women versus 58.7% for men; P <
0.02). In addition, women aged 65–80 years had inadequate blood pressure control compared with men of the same age [55]. With regard to specifi c blood pressure treatments, men were more likely to be prescribed angiotensin-converting enzyme inhib- itors (28.7% vs. 20.9% in women; P < 0.0001), whereas women were more likely to be prescribed diuretics (20.9% vs. 16.9% in men [P = 0.05]) [55].
In those patients with cardiovascular disease, women were less likely to be taking beta-blockers and aspirin than men. The reasons for this disparity are unknown but may be related to the mispercep- tion of cardiovascular risk in women, or less adher- ence by providers to the guidelines for female patients.
Women are less likely than men to develop hyper- tension until after menopause, when the incidence of hypertension in women equals that of men [56].
The mechanism may involve the positive infl uence of estrogens on the renin-angiotensin system, thereby protecting females from vascular injury more than males [57]. Further research is needed to determine whether specifi c blood pressure-lowering therapies should be prescribed differently for men and women. For now, guidelines for blood pressure treatment and targets [58] and the recommenda- tions contained in the AHA/ASA primary and sec- ondary prevention guidelines provide evidence-based approaches to managing blood pressures in both men and women [21,59].
Threshold for vascular of metabolic disease Healthy population
Population with complicated pregnancy, e.g., preeclampsia
Vascular risk factors
Age
Neonatal life Pregnancies Middle age
Fig. 9.4 Preeclampsia represents the metabolic disease of pregnancy and a time when vascular risk factors become evident [52]. From Sattar N, Greer, I. BMJ. 2002;325:157–160.
Family history
Our patient had a signifi cant family history for two reasons. First, her mother had a stroke at the age of 46. The importance of maternal family history of stroke was shown recently with a systematic review of the literature and a meta-analysis that included unpublished data [60]. This analysis of 18 studies involving 7941 patients showed that women with stroke (probands) were about 50% more likely to have a maternal than a paternal history of stroke (OR 1.47; 95% CI: 1.27–1.70) [60]. Inter- estingly, the excess of maternal versus paternal history of stroke did not exist for male probands. In addition to stroke, there may be a higher maternal transmission for other conditions that increase vascular risk, including diabetes, hypertension, and low HDL cholesterol [60]. The other important aspect of family history was that her sister had had a DVT. Uncovering this information prompted more aggressive screening for an inherited throm- bophilia and led to the diagnosis of prothrombin gene mutation.