Traditional cardiovascular disease (CVD) risk factors (smoking, hypertension, diabetes mellitus, and hyperlipidemia) are strongly associated with the development and progression of PAD in both women and men.2
PAD prevalence increases in both women and men as the population ages, but women tend to be older than men when they present with symptoms of PAD.46
In addition, African-Americans are disproportionately affected with PAD.1
Although African-Americans have a higher prevalence of obesity, hypertension, and diabetes mellitus compared with Caucasians,52
these traditional risk factors alone do not account for the excess risk of PAD in African-Americans.37
The odds for PAD were 1.7 times higher in African-Americans than Caucasians in the Multi-Ethnic Study of Atherosclerosis (MESA)57
and 2.4 times higher in African-Americans than in Caucasians in the San Diego Population Study.58
These cross-sectional studies demonstrated that the higher odds for PAD in African-Americans than in Caucasians were only modestly attenuated after adjustment for traditional CVD risk factors as well as several inflammatory biomarkers.
It is plausible that women might have different risk factors for PAD development than men. For example, smoking is one of the strongest risk factors for the development of PAD. However, in a cohort of 15,173 African-American and Caucasian individuals aged 45–64 years old, women who had never smoked were still more likely to develop PAD than men (2.6% vs 0.4%, respectively.) This remained statistically significant even after adjustment for age, low-density lipoprotein cholesterol, hypertension, and diabetes.31
Another study of 1932 participants free of four traditional CVD risk factors (smoking, diabetes, hypertension, and dyslipidemia) in MESA demonstrated there to be a significant association between female sex and low ABI, suggesting that novel risk factors might contribute more to PAD in women than in men.26
It is unknown what these novel risk factors are, as there is a lack of published data in this field of study. However, one possible explanation could be differences in the underlying inflammatory profiles in women and men. Inflammation is a known strong risk factor for PAD. C-reactive protein (CRP) is an acute-phase protein that is elevated in individuals with PAD59
and associated with the progression of PAD.61
In addition, CRP levels may differ according to sex. In both MESA65
and the Dallas Heart Study,66
women had significantly higher CRP levels than men, despite adjustment for estrogen use, body mass index, and other variables. CRP has been shown in several studies to be an important risk factor for PAD in women. In a prospective cohort study of 27,935 US female health professionals aged over 45 years without baseline vascular disease, CRP was significantly associated with incident symptomatic PAD.67
Among 1611 US participants aged 40 years or older without CVD, diabetes, or hypertension, higher CRP levels were positively associated with PAD, despite adjustment for multiple potential confounders.68
In this study, women with CRP values in the highest quartile represented the highest risk group.
Another potential novel risk marker for PAD in women is adiponectin. Adiponectin is the most abundant circulating adipokine and has both anti-atherogenic and anti- inflammatory effects.69
Adiponectin levels are also significantly higher in women than in men,72
even after adjusting for body mass index.77
In a nested case-control study conducted within the Women’s Health Study, baseline adiponectin levels were significantly lower in women who subsequently developed PAD.78
Further studies are needed to better characterize the possible sex-specific association between adiponectin and PAD.
Chronic kidney disease (CKD) is an independent risk factor for PAD79
as well as an independent predictor of mortality in patients with PAD.81
The prevalence and incidence of PAD is higher among patients with renal insufficiency than among those with normal renal function.79
A cross-sectional analysis demonstrated that persons with renal insufficiency were 2.5-fold more likely to have an ABI of <0.9 than those with a normal creatinine clearance, even after adjustment for multiple CVD risk factors.84
A longitudinal study in the Atherosclerosis Risk in Communities study demonstrated that those with CKD (estimated glomerular filtration rate < 60) had a 1.6 times increased risk for incident PAD over a mean follow-up of 13.1 years.88
CKD has become a major public health problem worldwide and, interestingly, there appears to be a higher prevalence of CKD in women than in men. In the National Health and Nutrition Examination Survey, the prevalence of both albuminuria and decreased glomerular filtration rate increased from 1988–1994 to 1999–2004, rising from 8.2% to 11.1% in men, and 12.1% to 15.0% among women.89
In a recent systematic review of population-based studies, the prevalence of CKD was found to be greater in women than in men, regardless of age and ethnicity.90
Although CKD is a risk factor for PAD, and CKD prevalence is higher in women than in men, the impact of the association between CKD and PAD according to sex has not yet been thoroughly evaluated.
It was long believed that estrogen was associated with a protective effect against atherosclerotic disease in women. Hence, hormone replacement therapy (HRT) was frequently prescribed to postmenopausal women. The Rotterdam study suggested a protective effect on the risk of PAD in long-term HRT users.91
In addition, a recent prospective database of 847,982 postmenopausal women associated the use of HRT with a significant decrease in the prevalence of PAD, despite a high number of atherosclerotic risk factors among the women who used HRT.92
However, large randomized controlled trials – the Heart and Estrogen/Progestin Replacement Study (HERS), Women’s Health Initiative (WHI) Estrogen plus Progestin Trial, and WHI Estrogen-Alone Study – demonstrated different results. These randomized studies failed to demonstrate a protective effect of HRT on PAD,93
and the WHI studies demonstrated an increased incidence of early peripheral vascular events in the treatment group. Based on these data, we conclude that HRT does not provide protection against PAD, and may be a risk factor for peripheral arterial events.