Which Is the Endothelium-Dependent “Fair Sex” in Hypertension?


Costas G. Thomopoulos, MD, 8, L. Mpellou str. Nea Filothei, Athens 11524, Greece

In a recent issue of The Journal of Clinical Hypertension, Rutledge and colleagues1 by using a cross-sectional design reported that endothelial dysfunction at conduit vessels was more impaired in middle-aged women compared with men of similar age with untreated and uncomplicated mild hypertension. Participants of both sexes were overweight, with well-preserved lipid, glycemic, and kidney function profiles. Although smoking status and alcohol intake did not differ among the sex-oriented arms of the study, men were more physically active compared with women as assessed by actigraphy. Less than one third of women were in a postmenopausal state, and among premenopausal women, 83% resided in luteal or follicular phase of the menstrual cycle. Patients with high clinical suspicion for sleep apnea syndrome or illness with potential confounding effect on the association under investigation were preliminarily excluded. Measurements of 24-hour blood pressure were implemented to better determine the overall hemodynamic load, and high-sensitivity C-reactive protein was measured in order to provide evidence of the underlying low-grade inflammation in both sexes. Endothelial dysfunction was measured by flow-mediated vasodilation technique further complemented by evaluation of shear stress ratio (ie, hyperemic/baseline shear stress), a valuable index of the hyperemic physical stimulus. For the same level of hemodynamic and systemic inflammatory load after adjustment for confounders including baseline arterial diameter, endothelial-mediated vasodilation was more impaired in women independently of the menopausal status compared with men. By contrast, nonendothelial-mediated vasodilation did not differ between men and women. Rutledge and colleagues1 suggested that mild hypertension in middle-aged women (40–60 years) has a more detrimental impact on the vasculature with respect to men, a finding that challenges the previous knowledge on the natural history of endothelial dysfunction among sexes.2 Since 17% of the studied women were in postmenopausal status, the effect of menopause could not be ruled out solely by statistical means; however, the protective role of premenopausal status might be attenuated in hypertension and anticipate much earlier the postmenopausal decline of endothelial function.

In a previous pivotal study2 performed almost 15 years ago, normoweight men and women (age range 20–76 years) with and without hypertension and well-preserved metabolic profile were studied by comparative evaluation of endothelial function determined at the microcirculatory bed in order to address whether menopause is associated with impairment in endothelium-dependent vasodilation. Investigators suggested that the hormonal mechanism protecting endothelial function is still preserved in hypertensive premonopausal women, and hypertension per se did not alter the sex-oriented natural history of endothelial dysfunction in middle-aged patients. The two studies1,2 reported divergent results, but their design was by far different. Indeed, the American study1 recruited 90 untreated participants with stage 1 hypertension, while the Italian study2 enrolled hypertensive patients who were previously treated with antihypertensive medications after a washout period of >2 weeks. Additionally, the American study1 investigated endothelial dysfunction at conduit vessels, while the Italian investigation2 observed the endothelial-dependent vasodilation at microcirculation. Based on the above, the impact of the previously administered antihypertensive therapy may confound the comparative evaluation of endothelial function at different levels of the vasculature.3

The cardiovascular risk Young Finns Study4 recruited men and women aged 24–39 years without hypertension and obesity, and men demonstrated better endothelial-mediated vasodilation as compared with women after adjustment for hemodynamic and metabolic parameters, as well as for baseline arterial diameter. Of note, systolic blood pressure did not contribute to the sex-oriented difference of flow-mediated vasodilation. Although the Scandinavian Study4 did not include African Americans, the study by Rutledge and colleagues1 did not find any differential impact on the outcome in sex by race interaction.

The Scandinavian4 and American1 studies taken together suggest that premenopausal women without hypertension present with better endothelial function at their conduit vessels as compared with men, whereas the presence of hypertension may reverse the direction of this association. Accordingly, premenopausal development of hypertension may neutralize the beneficial effect of estrogens on the vasculature or, by contrast, the vasculature in these hypertensive women is less responsive to estrogens. Indeed, estradiol, above its favorable effects on nitric oxide production, has been suggested to inhibit renin release and the angiotensin-converting enzyme,5 whereas in a hypertensive substrate, these effects might not be efficient to preserve a better endothelial-dependent vasodilation in women compared with men.

Because of the small sample study size drawn from a larger cohort, the inclusion of women before and after menopause and the more impaired glycemic profile of men compared with women, further well-designed studies are needed to confirm the intriguing findings from the American investigational team.1 Whether the more impaired endothelial dysfunction in mildly hypertensive middle-aged women as compared with men is a cause or consequence of increased hemodynamic load remains unclear. Furthermore, whether the increased incidence of first myocardial infarction in middle-aged women than men6 could be attributed to hypertension accompanied by endothelial dysfunction, at present represents a foggy suggestion that should be investigated in future prospective studies, yet lacking in patients at risk for cardiovascular disease younger than 50 years.7

Projecting Studies in Endothelial Dysfunction: Determinants and Outcome


Cross-sectional studies aiming to investigate the extent of endothelial dysfunction in participants with different disease burden should take into account the potential impact of multiple effect modifiers on the outcome including age, sex, traditional risk factors for cardiovascular disease, emerging markers or comorbid conditions with adverse effects on endothelial function, and finally the ongoing pharmacologic/nonpharmacologic treatment. Whenever projecting future sex-oriented studies, it should be acknowledged that age should not differ among the studied groups; the date of menopause represents a triggering step in the natural history of endothelial performance2 and history of preeclampsia (especially that of early-onset) constitutes a potential confounder3; the phases of menstrual cycle should be always taken into account since the follicular and luteal phase are characterized by 80% increase in the flow-mediated vasodilation as compared with that observed in men or during the menstrual phase of the cycle8; a matching process for body adiposity might be important in group comparisons, because obesity constitutes a major determinant of endothelial dysfunction strongly associated with impaired glucose metabolism9; although, hypertension per se is associated with endothelial dysfunction, ambulatory blood pressure levels reflect in a more integrated manner the overall hemodynamic load on the vasculature as compared with office blood pressure; smoking status should be always assessed in detail and smoking posology further complemented by measures of passive smoking exposure might further unmask hidden determinants of the outcome10,11; sleep apnea syndrome12,13 and chronic periodontal disease14,15 constitute hidden partners of endothelial dysfunction and such as their preliminary either exclusion or assessment should be encountered; alternative molecular markers of endothelial dysfunction (ie, microalbuminuria, asymmetric dimethyl-arginine, high-sensitivity C-reactive protein) might refine and strengthen the study findings16; and exclusion of patients receiving drugs with potential vasoactive properties is recommended in order to provide straightforward results to the native physical history of endothelial dysfunction.


Studies of endothelial function generally evaluate the vascular responses to endothelium-dependent and endothelium-independent physical or chemical stimuli. The appropriate domain where endothelial function should be determined in hypertension is the microcirculatory bed because blood pressure regulation is mostly accomplished at the level of resistance vessels. In conduit vessels, changes in arterial diameter may contribute to the evaluation of endothelial function along with the investigation of mechanisms linking hypertension and atherosclerosis. Accordingly, the forearm perfusion technique is used for the former investigational pathway, while the ultrasound-guided flow-mediated vasodilation for the latter. In this latter case, the endothelium-dependent stimulus is the increased shear stress caused by the rise in blood flow following a short period of ischemia, whereas the endothelium-independent stimulus is provided by the systemic administration of a vasodilator based on nitrates.17 Lastly, the baseline arterial diameter should always be taken into account since women have lower diameters with respect to men of similar age, and brachial flow-mediated vasodilation correlates strongly to this measure.

In conclusion, whether untreated hypertension abrogates more impaired endothelial function at conduit vessels in women as compared with men should be evaluated in future studies in order to confirm or not the new findings by Rutledge and colleagues.1