Endothelial dysfunction in hypertension

Thirty-six years have passed since the seminal article by Furchgott and Zawadzki [1], suggesting the existence of an endothelium-derived relaxing factor in arteries, was published. From that time on, an enormous body of evidence identified endothelial dysfunction as the first step of the atherosclerotic process and as a fundamental mechanism in the pathophysiology of cardiovascular disease. A solid, standardized methodology was set up for invasive and noninvasive techniques, and mechanisms of endothelial dysfunction development in different conditions have been elucidated; furthermore, endothelial function has been extensively used for the stratification of cardiovascular risk, for the testing of new cardiovascular drugs, and for the assessment of clinical consequences of emerging cardiovascular risk factors, such as environmental factors and nonprimarily cardiovascular diseases [2,3]. The history and the clinical significance of endothelial dysfunction in hypertension has been comprehensively summarized by Mordi et al.[4] in a review published in this issue of Journal of Hypertension. The article provides a brief introduction about physiology of the endothelium and methodological aspects of endothelial function assessment, then goes on exploring current evidence relating specifically to hypertension and accumulating from 1990 to nowadays. When exploring the possible cause–effect relationship between hypertension and endothelial dysfunction, Mordi and coauthors hypothesized a bidirectional one, in a ‘vicious cycle’ effect. In our opinion, there is sufficient evidence to demonstrate that endothelial dysfunction is not a cause of raised blood pressure (BP) values: an association between the degree of endothelial dysfunction and BP values has not been univocally demonstrated [5,6]; endothelial dysfunction in hypertensive patients seems to be genetically determined and present even in normotensive offspring of hypertensive patients [7]; endothelial dysfunction is not a hallmark of hypertension, but it is present in several conditions, such as diabetes mellitus, hypercholesterolemia, obesity and many others, characterized by reduced NO availability and normal BP values [3]; antihypertensive drugs do not necessarily improve endothelial function [8], and compounds, improving vascular function such as antioxidants [9], do not necessarily lower BP or may do it through different mechanisms [10]; the weak relationship between endothelial function and hypertensive target organ damage [11], though both are related to increased incidence of cardiovascular events in hypertensive patients, goes against the ‘vicious circle’ hypothesis; a relative small number of studies suggested a cause–effect relationship, in either direction, by a prospective design [12,13], whereas in big population studies, this hypothesis has not been specifically tested: a publication bias caused by negative results seem probable. On the other hand, a possible exception to this rule may be represented by preeclampsia, a hypertensive condition complicating up to 15% of human pregnancies, whose incidence is on the rise due to increased maternal age and obesity: in this disease, endothelial dysfunction might play a patogenetic role and represent a reasonable therapeutic target [14]. As Mordi and coauthors correctly pointed out, the most important open question is the prognostic role of endothelial dysfunction in hypertension. Other biomarkers of subclinical atherosclerosis have outperformed endothelial function testing in prediction of cardiovascular events in the general population, though to date some methodological issues avoid to draw firm conclusions [15,16]; furthermore, few studies specifically addressed this question in the hypertensive population. Indeed, in 172 prospectively identified uncomplicated hypertensive patients, followed up for 95 months, a reduced flow-mediated vasodilation was associated with an increased risk of cardiovascular events after adjustment for traditional cardiovascular risk factors [17]. However, there is the intriguing possibility that serial assessments by noninvasive techniques might increase the predictive value and the clinical significance of endothelial dysfunction. Lack of restoration of endothelial function despite optimal treatment might identify a subset of ‘nonresponders’, who might be suitable for new therapeutic approaches, specifically targeting the endothelium. This hypothesis was tested in patients with systemic lupus erythematosus [18], in patients with coronary artery disease [19], but also in a sample of 400 postmenopausal hypertensive women without evidence of coronary artery disease at baseline and 6 months after effectively treating BP. In those women whose flow-mediated dilation did not improve, there was a seven-fold increase in cardiovascular events during the follow-up [20]. In this scenario, the possibility of improving endothelial function pharmacologically in hypertensive patients is appealing. Mordi et al.[4] reviewed in detail the effect of antihypertensive drugs on endothelial function, though differential effects on the microcirculation and the macrocirculation might have been better characterized. Furthermore, nutraceuticals as well as other cardiovascular drugs might have a beneficial effect on vascular function and might help reduce the residual cardiovascular risk in hypertensive patients [21]. The answer to this open question will be hopefully given in the next years. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.