In this large-scale study of otherwise healthy middle-aged and older American women, we found a strong association between participant-reported systolic hypertension and incident symptomatic PAD. IDH was not associated with future PAD whereas both ISH and SDH conferred a 2–3 fold increase in risk. We also found a linear increase in PAD risk with increasing SBP throughout the range of baseline values. A prominent association was evident even among women with reported SBP levels below current JNC thresholds for diagnosis of hypertension. While reported DBP was individually predictive of future PAD, this relationship was no longer significant after accounting for association with elevated SBP. Furthermore, baseline SBP was the more informative blood pressure variable in all risk prediction models evaluated. Importantly, a 10 mmHg difference in reported SBP was associated with incident PAD among both younger (HR 1.54; 95% CI 1.11–2.14) and older women (HR 1.42; 95% CI 1.25–1.62).
These prospective data among a large cohort of women add to prior information regarding hypertension and development of PAD. The first prospective evaluation of this issue derives from the Framingham Heart Study.6
Gender-adjusted multivariable results demonstrated a gradient in risk for intermittent claudication with a roughly 2-fold increase in the highest blood pressure category (SBP ≥160 mmHg or DBP ≥100 mmHg),12
while gender-specific risk estimates suggested a stronger association in women (standardized regression coefficients 0.356 for women and 0.178 for men; risks in BP categories were not provided).6–7
Similar to our results, the age-adjusted incidence rate was shown to increase over the continuum of SBP while a threshold effect for DBP occurred at >85 mmHg for women (>95 mmHg in men).7
Among studies confined to men, hypertension is either not associated with subsequent PAD or findings are limited by methodological concerns. In French-Canadian men,9
while an increase in risk in the highest quintile of both SBP (RR 2.7; 95% CI 1.8–4.2) and DBP (1.5; 95% CI 1.0–2.1) were observed, results were not adjusted for baseline diabetes. In the Honolulu Heart Study11
of Japanese American men, hypertension was associated with a roughly 2-fold increased risk, however the analysis was restricted to men who survived 25 years from baseline to PAD assessment [ankle-brachial index (ABI) < 0.9]. Three other prospective cohort studies8, 10, 16
in men did not share these methodological issues and no effect of hypertension on incident PAD was seen. In other longitudinal population-based studies inclusive of women, a history of hypertension was associated with a significant 1.6–1.8 fold increase in risk.13–15
In general, it should be noted that in all but one of these reports, hypertension was considered amongst a broad range of traditional cardiovascular risk factors.9
Consequently, assessment for linearity of associations, blood pressure categories, and comparison of systolic versus diastolic hypertension was rarely performed.
The influence of aging is an important confounder in the pathophysiologic link between hypertension and PAD as the age-associated degenerative changes in vascular structure and function distinct from those attributable to elevated blood pressure alone are not easily discerned. While our data do not allow characterization of the underlying mechanisms, our findings do demonstrate that in otherwise healthy women at low risk for cardiovascular disease, a relationship between reported systolic hypertension and future peripheral artery events persisting even among younger women in the cohort. Our findings in this population of relatively healthy women are discordant with null findings from prior longitudinal studies exclusively comprised of men8, 10, 16
and thereby suggest heightened susceptibility to the effects of hypertension among women. Our results may also indicate an important role of central arterial stiffness in the development of peripheral atherosclerosis in women. Arterial stiffening results in higher transmission velocities of both forward and reflected pulse waves causing premature return of reflected waves in the central aorta during late systole rather than diastole as normally occurs. The resulting systolic augmentation of blood pressure is further amplified with progressive loss of aortic elasticity. For instance, Khaleghi et al. demonstrated that the degree of systolic augmentation significantly correlates with lower ankle-brachial index independent of other cardiovascular risk factors.27
Whether abnormalities in ABI precede arterial stiffening is not clear from this community-based, cross-sectional study27
and whether this association is stronger in women has not been evaluated.
Our findings should be interpreted in the context of both strengths and potential limitations. The major strengths of this study are the large sample size, the prospective design, long-term follow-up and annual assessment with validation of symptomatic PAD events. However, the study included predominantly non-Hispanic white women with higher levels of education and income, and our findings should not be generalized to other racial/ethnic groups, to populations of lower socioeconomic status, or to men. In addition, these findings are observational, and we cannot rule out the possibility that these associations are related to unmeasured, healthier behaviors among participants who report lower blood pressures. Perhaps more importantly, WHS participants do not undergo health examination. Therefore, the use of symptomatic PAD as our primary a priori
endpoint by definition excludes subclinical disease, which may have otherwise been detected by physical examination through abnormal pulse exam or ABI. It should be noted that women in particular may be less symptomatic relative to men.1
Although potential misclassification resulting from atypical or occult disease may have occurred, this, if anything, would have biased our results toward the null by inclusion of women with PAD among the control population. Our event rate (0.03 annualized percent) is similar to other large prospective cohorts such as the Women's Health Initiative (WHI) which defined incident PAD using hospitalizations and revascularizations. In the WHI, the annualized percentage ranged from 0.03 to 0.08.28–29
The use of self-reported blood pressure may also have led to exposure misclassification; however, in this population of female health professionals a high proportion of subjects underwent surveillance for hypertension (92.3% reported blood pressure evaluation within the first year of follow-up) and good correlation between self-reported and measured values in cohorts of medical professionals has been previously demonstrated.20
Furthermore, self-reported blood pressure in the WHS has been shown to have similar prognostic value for cardiovascular events as compared to measured blood pressure in other population-based cohort studies.23, 30
Thus, in assessing the association between participant-reported blood pressure control with incident PAD, our data demonstrate a strong prognostic role of uncontrolled blood pressure, in particular, uncontrolled systolic blood pressure in the clinical development of PAD in women. Our findings highlight the need for additional longitudinal investigations evaluating the proatherogenic effects of hypertension from other large cohorts inclusive of women.