Abstract
Abdominal aortic aneurysm (AAA) disease is particularly lethal for women [1]. Despite a sixfold greater disease prevalence in men, women account for up to 40% of 15,000 annual AAA-related deaths in the USA [2,3,101]. Recognition of this disproportionate mortality has prompted examination of gender-specific risk factors and associations in AAA disease, beginning with a re-evaluation of indications for surgical intervention. In the UK Small Aneurysm Trial (UKSAT) participants, AAA rupture was three times more likely in women after adjusting for age, body habitus and initial aneurysm diameter, and ruptures occurred much earlier in the course of the disease (mean diameter 5 cm in women vs 6 cm in men) [4]. As a result, elective surgical repair is now recommended at 4.5–5.0 cm for women as compared with greater than or equal to 5.5 cm in men [5].
Differential rupture risk is only one of many relevant gender-specific distinctions in AAA. Women are less likely to be hospitalized or offered potentially life-saving surgery once rupture occurs [6]. Reduced iliac artery diameter in women may preclude management with newer and safer endovascular techniques [7,8]. After AAA repairs, women have decreased survival, longer hospital stays and fewer discharges to home [9]. While startlingly significant in scale and clinical impact, the reasons behind these important distinctions have remained elusive. The disproportionate prevalence of disease in men has rendered most population-based studies unable to analyze gender as an independent influence on disease progression [10,11]. Using data obtained from the NIH Women's Health Initiative (WHI), Lederle and colleagues have provided the most detailed analysis available to date on the role of gender in AAA disease.
Methods
Associations between AAA-related ‘event’ and self-reported or measured disease risk factors were analyzed in 161,808 women [1]. Participants were 50–79 years of age at study entry with a life expectancy of at least 3 years. Baseline variables collected included a self-reported historical diagnosis of abdominal or thoracic aortic aneurysm disease. Biomorphic data, including height, weight, waist circumference and blood pressure, were obtained via measurement. Health outcomes were recorded following enrolment. Mean study follow-up was 7.8 years. For the purposes of this analysis, study end point was an aneurysm-related death or other event recorded following hospitalization and performance of a diagnostic or interventional procedure for AAA disease. Scheduled standardized questionnaires were administered at regular intervals in order to update study-related health outcomes. Accuracy of AAA-related event reporting was confirmed by medical record review.
Results
A total of 301 women reported a history of aortic aneurysm disease at study enrolment and 184 AAA events were encountered during follow-up, including 14 deaths within 5 days of an event. Only 18 women who experienced events reported a prior history at enrolment, resulting in a prevalence of 0.3% (467 out of 161,808) in this population. Multivariate analysis (odds ratio [OR], 95% confidence interval [CI]) was performed to analyze AAA associations with age (OR: 1.77 per 10 years; 95% CI: 1.37–2.29), history of cigarette smoking (OR: 8.73; 95% CI: 5.04–15.12) and previous diagnosis of aortic aneurysm (OR: 9.00; 95% CI: 4.71–17.20). Positive associations were also identified for height, hypertension, coronary artery disease, peripheral artery disease and cholesterol-lowering treatment. Negative associations with AAA events were observed with diabetes (OR: 0.29; 95% CI: 0.13–0.68), and postmenopausal hormone therapy use at enrolment (OR: 0.48; 95% CI: 0.31–0.73) or for more than 5 years (OR: 0.52; 95% CI: 0.34–0.78).
Significance of results
The study provides compelling evidence that the strong AAA-related associations previously identified and validated in mainly male cohorts (positive: age and smoking; negative: diabetes) also apply to women. Although few novel associations are identified, the power provided by the size of this population validates the significance of associations suggested in earlier reports [2,12,13]. A significant limitation of this study is the reliance on self-reported historical data at baseline assessment. Multiple previous population screening studies, while examining fewer women, have consistently suggested higher disease prevalence, and the lack of objective confirmation or screening for AAA disease in this study renders it prone to detection and spectrum bias [14]. Previous population-based studies place the true prevalence of AAA disease at up to 2% of women 60 years of age and older. Unfortunately, the true prevalence of known risks such as cigarette smoking and peripheral arterial disease is also uncertain in the absence of confirmatory diagnostic testing at baseline.
Advanced age is a consistent covariate with AAA-related events [3,13,15]. Age plays a special role in gender-related risk in that women presenting with ruptured aneurysms are on average 5 years older than men, but age alone cannot explain all aspects of the outcome disparities between the sexes [9,16]. Smoking remains the other dominant risk factor regardless of gender. Overall, AAA has the closest association of any disease to cigarette smoking aside from lung cancer, and the relative risk of AAA in individuals who have ever smoked is 2.5-times greater than the relative risk of coronary artery disease [17]. In this study, current female smokers were subject to a fourfold greater risk of AAA events compared with nonsmokers. Smoking may directly augment aortic mural proteolysis among many other potential mechanisms considered in aneurysm pathogenesis [17]. Smoking is a key modifiable risk factor for prevention of AAA as well as potentially reducing the rate of disease progression [18], and emphasis on smoking cessation in women should be a public health priority.
The negative association between AAA and diabetes, while seemingly paradoxical, was originally recognized in Lederle's US Department of Veterans Affairs Aneurysm Detection and Management trial and has since been confirmed in several different large population studies on multiple continents [10,19–23]. Diabetes may augment matrix volume owing to a combination of increased synthesis and reduced degradation [24,25], processes that may prove singularly effective in limiting aneurysm progression while simultaneously exacerbating arterial occlusive disease. There is still no definitive explanation of the mechanism for this negative association and, therefore, this may be less useful for improving the management of AAA than other novel parameters.
This study is the first to consider potential associations between postmenopausal hormone therapy and AAA events. Estrogen has long been considered a cardiovascular (CV) protective agent, although this designation is not without controversy [26]. In this study, postmenopausal hormone supplementation therapy at enrolment provided relative protection against subsequent AAA-related events. While reassuring for women already on therapy, the results for postmenopausal women overall were significantly more nuanced. In the estrogen alone arm of the WHI, women randomized to hormone therapy at study entry suffered significantly more AAA events than controls. Event rates declined slightly with the addition of progesterone but did not differ between therapy and control groups [27,28].
Data derived from biologically valid AAA rodent models support the hypothesis that sex hormones may influence AAA pathophysiology. Chronic angiotensin II (Ang-II) administration in apolipoprotein E-deficient mice causes disproportionately more AAAs in male as compared with female mice. Pretreatment of males with estradiol prior to Ang-II administration attenuates AAA formation and downregulates proinflammatory gene expression [29]. While oophorectomy does not influence AAA formation in female mice, orchiectomy in males reduces AAA incidence to that observed in ovary-intact females, suggesting that the balance of androgen/estrogen production may also mediate disease progression [30]. In a complementary experimental AAA model (porcine pancreatic elastase infusion into the isolated infrarenal aortic segment), females are relatively resistant to aneurysmal degradation following elastase infusion, with reduced inflammation and proteolytic matrix metalloproteinase activity. This resistance is lost when female aortae are transplanted into male recipients prior to infusion [31]. Interestingly, the estrogenic effects of estrogen-receptor activation may not fully explain this benefit; treatment with tamoxifen, a selective estrogen receptor modulator, is also effective in reducing aneurysmal dilatation, reactive oxygen species (ROS) production and neutrophil infiltration following elastase infusion in male rats [32].
Other gender and age-related distinctions potentially relevant to AAA pathogenesis include the role of total body iron stores on systemic inflammation and the progression of vascular disease. Iron accumulation has been implicated as an independent CV disease factor (although not for AAA disease specifically) through increased iron-catalyzed oxidative stress [33]. Total body iron stores as reflected by serum ferritin levels are significantly reduced in premenopausal women compared with age-matched men on western diets but rise rapidly following menopause since no other biologic mechanism exists to reduce iron stores in excess of physiologic requirements [34,35]. Serum ferritin increases steadily in men from childhood onwards, so that by the age of 45 years levels may be fourfold higher than in women. This increase coincides neatly with observed CV disease risk differentials between men and women by the fifth decade of life. Although not specifically linked to aneurysms as opposed to other CV disease end points, the iron hypothesis has plausible relevance in that increased ROS generating enzyme activity, increased superoxide radical production and morphologic evidence of oxidative tissue injury are prominent features of human AAA disease [36]. Although differential iron-derived ROS production and oxidative stress may explain the excess prevalence of AAA disease in men, its role in mediating the differential morbidity and inferior treatment outcomes in women is less immediately apparent.
Gender-specific pathophysiologic mechanisms may also be mediated by obesity and male/female differences in truncal adipose distribution. Measures of obesity (waist circumference and waist-to-hip ratio) are independently and positively associated with AAA risk. Obesity may augment AAA inflammation and progression via adipose cell production of proinflammatory adipokines [37]. Male pattern obesity is characterized by truncal and visceral fat accumulation. This type of central adipose deposition has been independently related to insulin resistance and CV risk [38,39]. Obesity also impairs testosterone production and presumably testosterone-driven influences on immunocompetence, maintenance of muscle mass and metabolic equilibrium. Recent population-based studies have suggested that testosterone levels may be negatively associated with AAA risk [40], a finding somewhat at odds with prior experimental data. Female-pattern adiposity shifts towards male-pattern abdominal and visceral deposition in response to increased androgen:estrogen ratios associated with menopause [38], providing another potential explanation for the older age of AAA onset in women as compared with men.
Physical fitness and regular exercise may also influence AAA risk. Exercise has long been recognized to reduce all-cause mortality and vascular-related complications in patients with CV disease [41]. Long-term physiologic effects of exercise training serve to decrease heart rate and systolic blood pressure at matched workloads, and increase work capacity and oxygen uptake with a faster return to resting hemodynamic conditions. Resistive aortic hemodynamics, such as those found in the infrarenal aorta under sedentary conditions, may promote aortic inflammation, ROS production and AAA risk [42]. The antioxidative influences of increased antegrade flow, as demonstrated in the aorta following lower extremity exercise, may reduce aortic inflammation, maintain vascular cell populations and attenuate AAA progression [43]. Exercise reduces systemic markers of inflammation potentially relevant to AAA disease (including serum adipokine levels) and may attenuate progression of early disease [44–46]. A large-scale clinical trial is underway in the USA to test the effectiveness of supervised exercise training on AAA progression.
Future perspective
A greater understanding of gender-specific issues in AAA disease is needed in order to improve the effectiveness of public health awareness, screening programs and treatment outcomes in women. Recognized high-risk subgroups include smokers, those with relevant family histories or concomitant coronary or cerebral vascular disease or combinations of all three [13,15]. The addition of three such risk factors and a positive family history in the appropriate age group increases the yield in screening programs from 0.7 to 6.8% [15]. Similarly, redoubled efforts to understand the mechanism(s) responsible for differential outcomes following treatment will be necessary in order to reduce current discrepancies in treatment outcomes and survival for women with advanced disease.
Executive summary
Abdominal aortic aneurysm (AAA) is a common, asymptomatic and frequently lethal disease of older women as well as men. No validated treatment guidelines exist for women as a distinct patient subset.
Clear gender differences exist in the epidemiology of AAA disease; although prevalence is higher in men, treatment outcomes are worse in women and the risk of rupture and sudden death is remarkably disproportionate in women.
Previous association studies have been insufficiently powered to consider gender as a distinct variable. This study suggests that similar risk factor associations exist between sexes and therefore may not be sufficient to explain observed differences in mortality and treatment outcome.
Better understanding of gender-specific issues in AAA pathophysiology and treatment protocols will be necessary to improve outcome overall for women with this life threatening illness.
Footnotes
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.