Although gender-related differences in the diagnosis and management of cardiovascular disease have been well established, gender differences in noncoronary vascular disease have gained increasing awareness only in the recent years. Much of the known research has suggested delays in diagnosis, anatomic differences, and clinicians’ underestimation of disease magnitude to contribute to gender-driven differences in disease prevalence and outcome.¹

This chapter will review the available literature regarding gender differences in noncoronary vascular disease. Specifically, we will focus on peripheral arterial disease (PAD), cerebrovascular disease, carotid artery disease, renovascular disease, pulmonary vascular disease, mesenteric arterial disease, and the systemic vasculitides. Only with a continued effort into understanding these differences can solutions be offered to help enhance vascular disease recognition and outcomes in women.

PAD is a highly prevalent disease, affecting as much as 12 million people in the United States, and is a major cause of disability, loss of work, and lifestyle changes.^{2,3,4,5,6,7,8,9,10,11} PAD can raise one’s risk of death between two- and sixfold over a 10-year period.^11,12 The incidence of PAD dramatically increases with age and, considering the extended longevity in industrialized nations, this number is only expected to increase in the upcoming years.^13,14 More importantly, it is predicted that nearly two-thirds of those affected with PAD over the age of 65 would be females.¹⁵

Although less so recently, traditionally little attention has focused on gender differences in PAD or its epidemiology in women. Many studies cite no gender differences in PAD epidemiology, while others do.¹⁶ It has become widely recognized, however, that the number of PAD cases has been underreported by clinicians especially among women, as symptoms of intermittent claudication on presentation only represent a small fraction of all cases.^3,17,18,19

Epidemiology

Nearly 12% of men and women in the community and up to 16% to 19% of the elderly population are affected with PAD.^20,21,22 Although intermittent claudication is the most common presenting symptom for patients with PAD, it alone is an insufficient diagnostic indicator for PAD in women particularly.¹ In a study of PAD detection, only 7% of female participants reported symptoms of claudication.²³ In a large observational study of more than 3000 patients only one-quarter of those with PAD reporting symptoms of claudication were female.¹⁸

However, ankle–branchial index (ABI) has been found to detect at least four- to fivefold more PAD in women than intermittent claudication by history.²⁴ While only 7% of females reported symptoms of claudication in the above mentioned Chicago-based study of PAD detection including nearly 500 participants with significant PAD, more than 35% of female participants met diagnostic criteria using an ABI < 0.90. Among elderly women, 82% of those with PAD were asymptomatic.²⁴ Several studies have noted that the average resting ABI is lower in women than men.^5,25 When asymptomatic PAD prevalence is determined, women may comprise as many, if not more, cases as men.^4,18,26,27

Although women with asymptomatic PAD may not present with classical symptoms of claudication, they have reported more difficulty with activities of daily living, are less active, have lower physical endurance, diminished leg strength, and have a slower cadence.^22,28,29 These functional impairments all contribute to masking symptoms of intermittent claudication. It has also been suggested that, like coronary heart disease, women may more frequently present with atypical symptoms of PAD.^4,28,30

The true prevalence of PAD in women is likely much higher than has been reported and is comparable to that of men. More recent studies have demonstrated an equal prevalence of PAD in men and women when more sensitive and specific noninvasive measures of PAD such as ABI are taken into account.^5,17,31,32 Risk factor profiles are similar between men and women with PAD.³¹ Among females, African American and Hispanic women were noted to have a nonsignificant trend toward increased PAD prevalence when compared with white women.³¹

Disease Course and Clinical Outcomes

Women with PAD were found to have similar percentages for comorbidities except for lower levels of cardiovascular disease in certain studies.^4,17,33 Additionally, women with PAD are also found to be more functionally impaired than men.³³ On measures of walking performance, women were found to be significantly worse for walking distance, walking speed, and stair climbing.^31,33 One prior study has demonstrated that variation in leg strength, with women having poorer leg strength than men, may at least partially explain the gender variation in walking impairment.³³ Women with PAD are also reported to have a lower quality of life as compared to men.³⁴ As mentioned before, women are known to have more difficulty carrying out daily living activities and have lower physical endurance.

Although more functionally impaired than men, women with PAD are found to have lower rates of lower extremity revascularization.^33,35 The lower prevalence of typical claudication symptoms in women and differences in types of activities performed based on gender may explain the lower revascularization rates.³³ Women who do undergo revascularization procedures are reported to have more adverse outcomes than men.^36,37,38,39 These include lower long-term patency rates following vascular bypass grafting and higher rates of graft occlusion.^36,38 Delayed diagnosis, decreased referrals, more postoperative complications, and possibly the effect of their smaller arteries have all been suggested in order to account for these gender-based differences in outcomes.^19,37,40 Mortality for women with PAD, however, has been shown to be similar to that of men.¹⁶

Hormonal Factors

An abundance of evidence has suggested an association between the hormones estrogen/progestin as protective agents and the development of PAD in postmenopausal women. However, considering more recent research findings, it remains unclear what role hormones play in the development and progression of PAD.

Total and low-density lipoprotein cholesterol levels become higher in the postmenopausal years.¹⁶ Both of these cholesterol components increase the risk of developing PAD in women.³² Through this mechanism, the loss of estrogen and progesterone may amplify the risk of PAD in women.

Intermittent claudication is less frequent in premenopausal women and only in the postmenopausal years begins to approach that of men, usually by the sixth or seventh decade of life.⁴¹ Framingham data have found the incidence in women more than doubled from the ages 45–54 years to 55–64 years.⁴² However, as more objective criteria such as the ABI have become prevalent, rather than symptom based, current data have shown that prevalence does not seem to be significantly different between genders.

Hormone replacement therapy (HRT) in the prevention of vascular disease has gained considerable attention over the past decade. While HRT has been clearly shown to have no benefit but rather potential harm in the prevention of cardiovascular disease, its role in peripheral vascular disease remains in question.⁴³ Several clinical trials have evaluated the effects of combined HRT on PAD as measured in the carotid and/or femoral artery (Table 2-1).^44,45,46,47 None of these studies showed any differences in arterial thickness or slowed progression of arterial atherosclerosis between the treatment and control groups. One observational study has proposed that study length maybe playing a role in these conflicting results. More than 50% reduction in PAD was documented in postmenopausal users.⁴⁸ No benefit was seen though in the subset of patients who used HRT for less than 1 year.

Estrogen, however, has been shown to improve endothelial function in postmenopausal women and may exert an independent protective effect in the development of PAD.^49,50 Trials of estrogen-only HRT have had more promising results showing decreased progression of carotid artery atherosclerosis (Table 2-1).^51,52 However, because of the overall deleterious cardiac outcomes, HRT is generally not recommended for women with PAD.

Stroke is the third leading cause of death in the developed world and is a major cause of chronic disability.⁵³ Seventy percent of strokes are a result of cerebral ischemia, while the rest are predominantly caused by cerebral hemorrhage.⁵³ The incidence of stroke has varied according to reports from different countries.⁵⁴ Annual stroke rates have ranged from 1.35 to 4 cases per 1000.^{55,56,57,58,59,60} While attention to understanding cerebrovascular diseases is strong, relatively little of this has been focused on gender-specific aspects of the disease.

Although stroke maybe similar in both sexes with regard to presentation and management, gender differences are clearly present in the epidemiology, pathophysiology, and outcomes of stroke.

Epidemiology

Stroke incidence appears to be higher in men than women, but increases with age in both sexes, with a doubling of stroke rates for each decade after the age of 55.^61,62,63,64 Overall, however, nearly 40 000 more women than men suffer a stroke each year.⁶⁵ This is thought to be a result of greater average life expectancy in women. Stroke prevalence data are similar. Up to approximately age 80, the prevalence, like the incidence, is higher among men.^66,67,68 After the age of 80, the prevalence of stroke is significantly higher in women. Again, this finding is thought to be secondary to the greater long-term survival of women.⁶⁹ As a result, stroke occurs, on average, approximately 5 to 10 years later in women than in men.^{63,65,70,71,72} In terms of stroke recurrence, 5-year recurrence rates were almost twice as high in men than women.⁷³

Pathophysiology

The risk factor profile for stroke are well established and similar in both genders.^74,75 However, evidence suggests that smoking and diabetes may have stronger relative impacts in women compared to men.^76,77 The relative risk associated with smoking maybe approximately 20% higher in women.⁷⁶ Oral contraceptives have been found to be risk factor for stroke that is unique to women. Studies have consistently indicated an increased risk ratio of between 1.5 and 3 with the use of oral contraceptives.^78,79,80,81 Recent evidence has suggested, however, that the increased risk associated with oral contraceptives is attributed to risk factors such as smoking, hypertension, and perhaps even migraines.^78,80,82,83 Along similar lines, clinical trials have shown that postmenopausal hormone therapy actually increases the risk of stroke.^84,85 Additionally, atrial fibrillation has been noted to be more frequent in female patients with stroke.^71,86

Information on stroke subtypes are relatively limited but some differences have been noted. A higher proportion of hemorrhagic strokes have been found to occur in men; however, subarachnoid hemorrhages are distinctly more commonly observed in women.^87,88 Cardioembolic strokes have been reported to be twice as frequent among women compared with men.^89,90

Gender variability has also been noted with respect to cerebrovascular occlusive disease distribution in patients with stroke. Extracranial larger artery disease, particularly the internal carotid artery, predominated in men, whereas intracranial medium artery disease was more common in women.^91,92 Finally, posterior circulation stroke is less likely to occur in female cohorts compared to male ones.⁹³

Disease Course and Clinical Outcomes

Gender appears to play a role on outcomes after stroke.^72,90,94 Women suffer from greater functional disability in terms of motor function, cognitive function, and activities of daily living function.^{72,86,95,96,97,98,99,100} Women are also more likely to be institutionalized or placed in nursing homes following strokes.⁷¹ They also have higher rates of poststroke depression and risk for suicide compared to men.^101,102,103 It must be noted, however, that on average, women are older than men at the time of the stroke and most studies did not take into account various social and cultural aspects that may have explained these differences.⁶³

Mortality data following stroke have been more conflicting and is still under exploration. According to the American Heart Association more than 60% of deaths caused by stroke in 2000 occurred in women.⁶⁵ However, when adjusted for age, reports have found an overall mortality risk that is higher in men.^104,105 Equivocal data have also been reported when specifically looking at short-term mortality as well. Case-fatality rate up to 6 months after the stroke event has been found to be higher in women in some reports but not significantly different in others.^71,72

Stratified by age, death from ischemic stroke was lower for women younger than 65 years of age, but higher for those at least 65 years old when compared to men.^65,106 Similar to patterns of prevalence, mortality risk was lower in women for intracerebral hemorrhagic stroke at all ages studied, but higher for subarachnoid hemorrhage, with gender differences widening with age.^65,106

One risk factor for stroke, carotid artery stenosis (CAS), merits its own discussion. CAS > 50% is viewed as significant carotid artery disease.¹⁰⁷ The prevalence of CAS >50% and >80% is between 2%–8% and 1%–2%, respectively.¹⁰⁸ Prevalence is higher in males, and male gender has been found to be an independent predictor for the development of CAS.¹⁰⁹

The outcome of patients with known CAS has been found to be affected by gender depending on the treatment strategy. With respect to conservative treatment of asymptomatic CAS, gender seems to be no risk factor for stroke.¹⁰⁷ Several reports have observed in women a significantly less benefit from carotid endarterectomy (CEA) and higher risk of perioperative stroke in asymptomatic as well as symptomatic disease compared to men.^{110,111,112,113,114,115,116,117} Although some studies have reported no differences in perioperative neurologic events between men and women,^118,119 no reports have shown an increased risk in men. While the risk of perioperative stroke in women is low, there seems to be a tendency of a similar to twofold higher risk in women.¹⁰⁷

This adverse effect of female gender on outcome in CEA is more pronounced in asymptomatic disease.^110,113,114 Research to understand these gender differences in outcome have helped to offer some answers as to why CEA is not as beneficial for women with asymptomatic CAS. The impact of hormones on atherosclerosis is becoming better known; however, no direct link has been found between hormones and carotid surgery outcomes.¹²⁰ Analyses of the carotid artery before surgery have demonstrated that women, compared to men, have more stable, less atheromatous, plaques (Figure 2-1). Plaque volume, a predictor of clinical outcome, is smaller in women at a comparable stenosis grade and the plaques have been found to contain less fat and macrophages and more smooth muscle cells and collagen fibers (Figure 2-1).^121,122

Within the realm of PAD, as with other vascular beds, there has been limited investigation regarding gender differences in renal atherosclerotic disease. Nevertheless, there are some differences that emerge in the existing literature. The effect of conventional risk factors for atherosclerosis on atherosclerotic renal disease maybe attenuated in women. Further, while the overall epidemiology appears to be similar, the predisposition of fibromuscular dysplasia in the renal artery to affect women creates a small, but significant distinction. Data on therapy for renovascular disease as a whole are limited, and this holds true for differences in gender as well.

Epidemiology

The epidemiology of renal atherosclerotic disease in the general population is difficult to assess because of the lack of a standardized screening study. The existing data regarding the general population come from autopsy evaluation. Other evaluations of epidemiology have focused on select populations, primarily those with existing atherosclerotic disease elsewhere or underlying risk factors.

Whether or not differences in the prevalence of renal atherosclerotic disease according to gender are present appears to depend on the population selected and, perhaps, the diagnostic method used. In a Brazilian study where individuals undergoing coronary angiography were also evaluated for renal artery stenosis as diagnosed by digital subtraction angiography, Tumulero et al. found that women were more likely than men to have renal artery stenosis ≥50%. However, when evaluating the difference in prevalence among patients with renal artery stenosis ≥70%, no significant difference was found between men and women.¹²³ In a Japanese population evaluated with magnetic resonance angiography, where atherosclerotic renal artery disease was defined as ≥50% decrease in renal artery diameter (corresponding to a ≥75% decrease in cross-sectional area), no difference in prevalence was found according to gender.¹²⁴ The patient population differed from the Brazilian study. Individuals with known preexisting aortitis or renal artery disease were excluded and the inclusion criteria were individuals older than 40 years of age with one or more risk factor atherosclerotic renal disease (hypertension, DM or dyslipidemia). In a Canadian study by Buller et al., patients with risk factors for atherosclerotic disease undergoing renal angiography found female gender to be associated with the presence of severe renal artery stenosis (70%–99%) with an odds ratio of 1.9.¹²⁵

The variable results of the above studies highlight the intrinsic difficulty in defining the epidemiology of renal artery stenosis. The overall prevalence and, thus, the epidemiological differences according to gender depend on the study population evaluated and the diagnostic criteria used. Therefore, while there are some suggestions that atherosclerotic disease maybe more prevalent and/or more severe in women, no definitive statement can be made.

Pathogenesis and Clinical Presentation

While the prevalence of renal atherosclerotic disease according to gender is variable, the general clinical experience is that progression of renal dysfunction is slower in women as compared to men.^126,127 The pathogenesis of renal atherosclerotic disease has been outlined extensively elsewhere, but the pathogenic mechanisms and their outcomes may have slight variation in women versus men and suggest a putative mechanism why female gender is protective. As previously described, endothelial dysfunction plays a role in both etiology and consequence of atherosclerotic progression.

Endothelial function and damage are linked with activity of nitric oxide and angiotensin II. Two separate animal models support the theory that the renal response to hypertension, that is, endothelial damage, differs according to gender.¹²⁸ Ji et al. found that in the renal wrap model of hypertension, blood pressure increase was the same between genders. Nevertheless, the degree of renal damage in each gender was significantly different: more necrosis, tubular dilatation, and cellular proliferation were present in the male kidneys.¹²⁶ Therefore, for the same increase in blood pressure, more damage occurs in male kidneys. The underlying reason for this difference is not clear. Ji et al. also found that the male kidneys upregulated eNOS more than do female kidneys.¹²⁶ Whether the upregulation represents a consequence of increased renal damage or highlights an increased sensitivity to nitric oxide with increased blood pressure is unclear.