Cardiovascular diseases remain the leading causes of morbidity and mortality worldwide. It is increasingly recognized that the evolution of atherosclerosis has a long preclinical phase, where vascular damage accumulates in vital organs such as the heart, kidney and the brain. This progressive accumulation of vascular damage ultimately leads to the clinical manifestations of the disease. Whenever cardiovascular disease becomes clinically evident, the amount of damage to vital organs is likely to be significant and difficult to reverse with currently available treatments. In the attempt to interfere with the evolution of the atherosclerotic process, several subclinical markers of disease progression have been identified and validated. These not only enable identification of individuals at greater risk of cardiovascular complications but also are used to identify factors involved in disease evolution, potentially identifying novel therapeutic targets.
Microalbuminuria, literally the concentration of albumin in the urine collected over 24 h, was initially considered a mere marker of impaired glomerular permeability for plasma proteins. Over the last 20 years, however, several studies have shown that this marker of glomerular damage can predict not only the development of overt nephropathy , but also cardiovascular events in patients affected by hypertension, with or without diabetes [2,3].
A reduced endothelial function has been associated with microalbuminuria in type 1 and 2 diabetic patients , as well as in nondiabetic populations . This has suggested that microalbuminuria could reflect a generalized state of endothelial dysfunction because of cardiovascular risk factor exposure and, as such, be predictive of cardiovascular events. However, several reports failed to document associations between endothelial function and level of microalbuminuria, suggesting that, over and above endothelial function, other vascular factors related to the evolution of cardiovascular diseases could be involved in the development and evolution of the glomerular damage. As renal nephropathy remains an important complication and cause of death in patients affected by hypertension and diabetes mellitus, a better understanding of the relationship between endothelial function and microalbuminuria is crucial in the attempt to reduce the morbidity and mortality of these large populations of patients.
In this issue of the Journal of Hypertension, Martens et al.  used cross-sectional data from the Maastricht Study to investigate the association between microalbuminuria and microcirculatory endothelial function. The latter was assessed using two vascular reactivity tests: the flicker light-induced retinal arteriolar dilation and the heat-induced skin hyperaemia. The Maastricht Study is an observational, prospective, population-based cohort focused on determinants, complications and comorbidities of type 2 diabetes mellitus. Thus, individuals recruited in the present analysis were characterized by a wide range of glucose metabolism status, including those with normal glucose tolerance, glucose intolerance and type 2 diabetes mellitus. The availability of data on a wide range of established cardiovascular risk factors provided the opportunity to assess the independent impact of many variables on the relationship between endothelial function and microalbuminuria. Particularly, almost 50% of participants had a diagnosis of arterial hypertension. The novel finding of this elegant study is the demonstration that, after adjustment for all potential confounders, lower flicker light-induced retinal arteriolar dilation and heat-induced skin hyperaemia were independently associated with albuminuria in the whole population, and that this association was stronger in individuals with type 2 diabetes.
The article by Martens et al.  is an interesting and well conducted study, which for the first time, investigates a possible cross-talk between albuminuria and microvascular endothelial function explored in different vascular districts and not limited to patients with a specific clinical disease but extended to a general population. This study contributes to improving our knowledge of the complex relationship of an important marker of renal damage and recognized cardiovascular risk factor with what is considered an early step of the vascular atherosclerotic process. Some aspects of this interesting report deserve further comments.
A consideration concerns the assessment of endothelial function employed in this study. The Dynamic Vessel Analyzer allows real-time in-vivo assessment of retinal microvascular response to flicker light, which is thought to be an endothelium-dependent phenomenon, not affected by sympathetic influences. Indeed, previous reports have documented a blunted flicker light-induced vasodilatation in populations at risk for endothelial dysfunction, including patients with diabetes, hypertension, obesity and dyslipidemia . Of note, the blockade of nitric oxide (NO) synthesis in healthy young humans attenuates retinal arteriolar relaxation in response to flicker light, whereas infusion of NO substrate L-arginine potentiates the vascular response [7,8]. Although such pharmacological stimulations can increase the blood flow, there was no dose–response relationship, suggesting that other NO-independent mechanisms may account for flicker light-induced retinal vasodilation. These additional and not necessarily endothelium-derived vasoactive mediators do not allow, at present, to conclude that this interesting technique explores in-toto endothelial function. In addition, its prognostic significance, although already assessed and documented, needs further confirmations.
Although these limitations could raise concerns of the robustness of the results, the authors were able to confirm the association between microvascular endothelial function and microalbuminuria using a second technique, the heat-induced skin hyperemia assessed by a laser Doppler system. The advanced and rigorous methodologies employed by the authors to standardize their acquisitions make the skin microcirculation an extraordinary model for assessing mechanisms of vascular disease. However, similar to the flicker light-induced retinal arteriolar dilation, the response obtained with this second method were shown to be not completely dependent on endothelial function. Previous studies have demonstrated that NO accounts for approximately two-thirds of the heat-induced skin hyperemia, whereas endothelium-derived hyperpolarizing factors account for the remaining hyperemic response . Moreover, skin microvascular endothelial function as a surrogate endpoint in clinical trials is not established, and its role as a prognostic biomarker in cardiovascular diseases is still to be determined.
Therefore, the two different methodologies utilized by the authors to explore endothelial function, although undoubtedly promising techniques in clinical research, need further confirmations, either in specificity as a measure of NO availability, or in terms of prognostic impact. On the other hand, the limitations of the microvascular techniques used in the present study could be considered a potential strength. Indeed, the autocrine/paracrine characteristic of endothelium makes this organ functionally heterogeneous, whose response may vary according to which stimulus is utilized and which vascular district is investigated. This concept is well supported by the finding that first-line cardiovascular compounds such as angiotensin-converting enzyme (ACE) inhibitors, while effective in reversing endothelial dysfunction in a vascular district, are devoid of any effect in others . Accordingly, it is not surprising that studies evaluating the degree of correlation among measures of endothelial function in different microvascular beds have demonstrated a fairly good correlation, without any clinical relevance [11,12]. As such, the results reported by Martens et al.  are remarkable, as the authors were able to show concordant results from different methodologies, exploring endothelial function with different stimuli and in vascular districts with different mechanisms of autoregulation. This finding supports and strengthens their working hypothesis that microvascular endothelial dysfunction, marked by microalbuminuria, is likely to reflect a more generalized condition of endotheliopathy within the cardiovascular system.
The unequivocal message given by Martens et al.  is that, particularly in diabetic patients, a strict relationship between albuminuria and microvascular endothelial function in different vascular districts occurs, a finding which suggests that the two phenomena do not run in parallel but are strictly interrelated. Along with this merit, the cross-sectional design of this report encompasses unresolved questions, essentially limited to whether individuals with albuminuria, not only those with but hopefully also those without type 2 diabetes, may benefit from improving systemic endothelial function, as assessed by reduction of albuminuria.
Conflicts of interest
There are no conflicts of interest.
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