aClinica Medica, Ospedale San Gerardo, Monza (Milan), Department of Prevention and Clinical Medicine, University of Milano-Bicocca, Milan, Italy
bDepartment of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany
Correspondence to Professor Guido Grassi, Clinica Medica, Ospedale S. Gerardo dei Tintori, Via Pergolesi 33, 20052 Monza, Milan, Italy Tel: +39 039 233 357; fax: +39 039 322 274; e-mail: firstname.lastname@example.org
Assessment of the retinal microvascular alterations occurring in different diseases and particularly in hypertension, following several years during which it was almost completely forgotten, has recently received a renewed attention both in clinical practice and clinical research setting [1,2]. Important technical developments in the field have certainly contributed to the renaissance of the interest for retinal investigations. Indeed, one of the earlier technical improvements was the introduction of a mydiatric retinography evaluation, based on retinal photographs with semiautomatic quantification of the geometrical and topographical features of the arterial and venous microvessels [3,4]. This approach has been consistently improved and simplified later on with the development of nonmydriatic retinography, providing detailed qualitative information on retinal microcirculation [5,6]. This included data on arteriovenous narrowings, arteriolar narrowings and arteriovenous crossings. Further technical refinements of the method have allowed not only a qualitative but also a quantitative assessment of the retinal network, by providing information on the retinal arteriolar–venular ratio and diameters [7,8], thereby overcoming the subjective assessment of early hypertensive retinopathy by fundoscopy.
A further major technical advance was represented by the introduction of the scanning laser Doppler flowmeter method, which allows assessment of retinal diameters in a dynamic fashion, that is along the whole cardiac cycle through an automatic full-field perfusion imaging analysis [9,10]. This approach also allows a precise quantification of the outer and lumen diameter of the retinal vessels and calculation of wall thickness, wall-to-lumen ratio and growth index . Further dynamic information on the relationship between nitric oxide bioactivity and retinal microcirculation can be obtained with this approach by measuring the retinal capillary blood flow changes (laser Doppler flowmetry) in response to flicker-light retinal stimulation (a maneuver triggering vascular responses at least in part mediated by nitric oxide) and inhibition of nitric oxide synthase by N-monomethyl-L-arginine bolus infusion [9,12]. At present, the laser Doppler flowmetry method can be regarded as the gold standard approach to assess structural and functional aspects of the retinal network in humans, because it provides qualitative and quantitative information on the retinal network together with data related to the dynamic behavior of the retinal microcirculation.
The present issue of the Journal of Hypertension includes a study by Cheung et al.  providing interesting data on the quantitative and qualitative assessment of retinal microvascular abnormalities in a general population and their relationships with blood pressure values. The study, which has been designed and performed by investigators living in Singapore, Australia and USA, is based on data collected in the frame of the Singapore Malay Eye Study . Assessment of the retinal network was based on a semiautomated computer-assisted program, elaborated by the authors in Singapore, capable of performing a quantitative and qualitative analysis of a number of retinal vascular parameters. Among quantitative parameters, the new developed ones are the retinal vascular branching angle, the retinal vascular branching asymmetry ratio and the retinal vascular fractal dimension, that is, variables which describe the retinal branching pattern and may be sensitive markers of the effects of a given cardiovascular risk factor or disease on retinal microcirculation. The qualitative parameters, which include focal arteriolar narrowing, arteriovenous nicking, opacification of the arteriolar wall and retinopathy signs, are not computerized and thus strictly depend on the investigators' skill and experience.
As mentioned above, the assessment of the retinal vascular network includes innovative parameters, which certainly allow the investigators to improve the sensitivity and specificity of the approach in detecting retinal microcirculatory alterations. The study results also provide intriguing information on the determinants of the various retinal microvascular alterations induced by the different cardiovascular risk factors. For example, blood pressure values represent the strongest determinants of retinal arteriolar narrowing, retinal arteriolar caliber and focal arteriolar narrowing, whereas age affects more directly and exclusively arteriolar/venular branching, venular branching asymmetry ratio and opacification of the arteriolar wall. It can be thus concluded that, as in the microcirculation of other vascular districts, different risk factors exert different effects on retinal microvessels as well, leading to alterations which are quantitative, qualitative or both [15,16]. The study also provides a specific score of the retinal alterations, an approach which comprehensively includes various retinal signs and abnormalities in the overall evaluation of the retinal abnormalities associated with a given condition, risk factor or disease. Finally, the last set of information provided by the study refers to the analysis of the retinal vascular alterations in relation to untreated and treated hypertension and, in the latter case, when high blood pressure is controlled or uncontrolled. The results suggest that the finding of smaller retinal vascular fractal dimensions combined with the evidence of straighter retinal arterioles may represent a possible marker of a poor blood pressure control in treated hypertensive patients. Retinal abnormalities can thus be regarded as pathophysiological markers of the severity of the hypertensive state but also, at the same time, as therapeutic targets capable of reflecting the effectiveness of antihypertensive drug treatment in controlling elevated blood pressure values.
Problems and question marks
Although collected by making use of a solid methodology and based on a large population sample, the study results cannot address several questions related to the relationship between blood pressure and retinal network abnormalities and, more in general, to the investigation of the retinal microcirculation. Indeed, in the study by Cheung et al.  the investigators focused on the relationship between clinic blood pressure and retinal microvascular patterns. No information is available for ambulatory blood pressure values, which reflect much closer than clinic blood pressure the hemodynamic load over the 24-h period and display a greater correlation with end-organ damage at the level of carotid arteries and the heart . The issue has been addressed recently by our group in Milan in a study in which only one retinal parameter of a quantitative nature, namely the arteriolar/venular retinal ratio, has been related to 24-h ambulatory systolic and diastolic blood pressure in a large group of almost 200 treated hypertensive patients . The results show that the arteriolar/venular ratio was significantly and inversely related to 24-h blood pressure, daytime blood pressure and night-time systolic and pulse blood pressure, whereas no relation was found with diastolic blood pressure values. On a multivariate analysis the major independent predictor of the arteriolar/venular ratio was daytime pulse pressure, a finding which emphasizes once more the importance of the difference between systolic and diastolic blood pressures in determining retinal microcirculatory alterations. Whether the same results can be applied to the other quantitative and qualitative markers of retinal alterations described by the present study remains unknown. It also remains unknown whether and to what extent blood pressure variability over the daytime and night-time periods (e.g. dipping status, early morning surge) is related to the retinal network abnormalities, a question with relevant clinical implications given the evidence that blood pressure variability and its components are major determinants of cardiovascular prognosis .
Two other questions related to the study results remain largely unaddressed. First, which among the various parameters examined in the present study is the most representative for documenting an early retinal involvement in the clinical course of the hypertensive state? As also correctly acknowledged by the authors , the cross-sectional nature of the study by Cheung et al. prevents any information on this crucial point to be collected. Furthermore, are there sex-specific differences? In a systemic review and meta-analysis changes in retinal vessel caliber (narrower arterioles, wider retinal venules) were associated with an increased risk of coronary heart disease in women but not in men . Finally, the value of the retinal abnormalities as a marker of blood pressure control is not clear. Although the data analyses performed by the authors point toward a combined role of smaller retinal vascular fractal dimensions and straighter retinal arterioles, the potential impact of antihypertensive drug treatment on the patterns of the retinal microcirculation remains unknown. The absence of specific information reduces the strengths of the study results on this specific point, calling upon the need for dedicated studies in the area.
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