Journal of Hypertension:
Retinal vascular caliber and the development of hypertension: a meta-analysis of individual participant data
Rizzoni, Damiano; Muiesan, Maria Lorenza
Department of Clinical and Experimental Sciences, Clinica Medica, University of Brescia, Brescia, Italy
Correspondence to Damiano Rizzoni, Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia. c/o 2a Medicina Spedali Civili di Brescia, Piazza Spedali Civili 1, 25100 Brescia, Italy. Tel: +39 030 3905251; fax: +39 030 3384348; e-mail: email@example.com
Systemic arterial hypertension is associated with vascular changes in the retina that may occur in both chronic and acute stages. The retinal microcirculation represents perhaps the only microvascular district that may be directly observed and evaluated by a relatively simple funduscopic examination. For this reason, a classification of hypertensive changes in the retina in a severity scale was already proposed by Keith in 1939  and the now currently known Keith–Wegener–Barker grading system was widely applied in recent decades for the stratification of risk in hypertensive patients. More recently, several studies have proved a weak clinical usefulness of the Keith–Wegener classification, due to poor reproducibility and association with other indices of target organ damage [2–4]. For this reason, already in the 2007 guidelines for the management of arterial hypertension, the European Society of Hypertension and the European Society of Cardiology (ESH/ESC) recommended examination of eye grounds in hypertensive with severe disease only, as the mildest retinal changes appeared to be largely nonspecific alterations except in young patients . The 2013 ESH/ESC guidelines for the management of arterial hypertension maintain such an approach, suggesting to consider fundoscopy as an additional evaluation, depending on history, physical examination, and findings from routine laboratory tests .
In the last 10 years, more sensitive methods for quantitatively assessing retinal vascular changes have been developed. The calculation of the arteriolar to venular ratio (AVR) in retinal vessels was proposed as an index of vascular structural alterations . In fact, Wong et al. could observe that, in a population-based cohort study of 9648 patients (the Atherosclerosis Risk in Communities Study – ARIC Study), a arteriolar narrowing, as evaluated by retinal photographs, was associated with a higher risk of coronary artery disease in women, although not in men. In particular, for each decrease of one standard deviation of the retinal AVR, a relative risk of coronary artery disease of 1.37 and of myocardial infarction of 1.50 occurs.
A similar evaluation was performed in another general population cohort of 4926 patients in Wisconsin (Beaver Dam Study) . The presence of retinal disease (microaneurysms, blot hemorrhages, cotton-wool spots, hard exudates, venous beading, new vessels on the disk and preretinal or vitreous hemorrhages) was associated with increased cardiovascular mortality, with an odds ratio of 1.8 , and with a higher prevalence of cerebral white-matter lesions and stroke . No relation between smaller AVR and 10-year mortality was observed .
Retinal arteriolar narrowing, as suggested by a lower AVR, was found to be associated with risk of incident clinical diabetes  in the ARIC study population and of incident essential hypertension in the Beaver Dam population . In this case no difference in sex was observed. Obesity is associated with narrower retinal arteriolar and wider venular caliber .
However, retinal AVR seems to be of limited value in identifying hypertensive patients at high cardiovascular risk, as indicated by the presence of cardiac and extracardiac organ damage .
Indeed, the prognostic significance of retinal AVR remains a controversial issue.
In recent years, some systematic review and meta-analyses, performed mainly by the META-EYE Study group have addressed the problem of the possible relationships between retinal AVR, or its two separate components and clinical events. An association of this index with incident stroke was initially postulated on the basis of some data from the ARIC study . However, in a recent meta-analysis only a wider retinal venular calibre, but not the caliber of retinal arterioles was associated with the incidence of stroke . Again, a meta-analysis published in 2009 confirmed an association between retinal vessel caliber and increased risk of coronary heart disease in women but not in men , while an analysis performed a couple of years before suggested that, regardless of the sex, only extreme values of venular or arteriolar caliber were associated with cardiovascular events . The authors themselves admitted that ‘although retinal vascular caliber independently predicted CHD risk in women, the incremental predictive ability over that of the Framingham model was modest and unlikely to translate meaningfully into clinical practice’  or that ‘the association of retinal vascular caliber with clinical coronary artery disease seen in epidemiological studies may not be applicable to clinical symptomatic patients’ . In a study published in the present issue of the Journal of Hypertension, the previously mentioned authors have pooled together data from population studies in which a possible interrelation between retinal vascular caliber and subsequent development of hypertension was evaluated . The results of this study suggest that both narrower retinal arterioles and wider venules predict the development of hypertension . The authors confirm in a wider number of patients what was previously observed , extending the analysis to the separate evaluation of arterial and venular caliber. The age of the participants exerts a strong influence on such interrelations, being more evident in younger patients. Altogether, the study, although methodologically correct and interesting, may be considered mainly a confirmative one. The reasons advocated by the authors to explain the association between a wider venular caliber in the retina and the development of hypertension (venular caliber related to systemic inflammation, atherosclerosis and metabolic abnormalities, or marker of retinal ischemia and hypoperfusion secondary to microvascular rarefaction or even of endothelial dysfunction)  seem extremely speculative and feebly supported by available data. In addition, as recognized by the authors themselves, the study has the limitations of observational research, and, in particular, the possible confounding effect of medications, mainly antihypertensive drugs, on retinal vascular caliber, was not controlled in this analysis .
Despite the inherent limitation of this study and despite, in general, the presence of conflicting evidences in this scientific area, there is hardly any doubt that the interest of the researches for a noninvasive approach that could allow an evaluation of microvascular morphology is extremely high, as retinal vessels may be considered a window to the heart , and represent the only microvascular district suitable for a direct noninvasive investigation.
The wide use of a noninvasive approach for the stratification of risk in the majority of hypertensive patients could represent a key objective of clinical research, as microvascular structure may represent a possible intermediate endpoint in the evaluation of the effects of antihypertensive treatment [6,23,24].
Recently, Harazny et al. proposed a new method of assessment of structural abnormalities in the retinal vascular district. A quantification of the wall to lumen ratio of retinal arterioles was obtained using scanning laser Doppler flowmetry (SLDF) . Using this approach, it was demonstrated that the wall to lumen ratio of retinal arterioles is increased in untreated hypertensive patients , as well as in treated patients with cerebrovascular events . In addition, wall to lumen ratio of retinal arterioles seems to correlate with indices of microvascular damage in other vascular districts, such as albumin excretion by the kidney . Therefore, the wall to lumen ratio of retinal arterioles seems to represent a robust indicator of the severity of hypertension , of the occurrence of cerebrovascular events  and of the presence of early renal damage . At difference with AVR, it is related to the extent of atherosclerotic damage in the carotid artery, as indicated by evaluation of the intima–media thickness . More recently, measurement of retinal morphology by scanning laser Doppler flowmetry was validated against the present gold standard for measurement of microvascular structure, that is wire or pressure micromyography applied to subcutaneous small arteries obtained through gluteal biopsies .
In addition to the calculation of the AVR or of the wall to lumen ratio in retinal vessels, a computer-assisted quantification of topological changes in retinal vascular architecture was proposed . Essential hypertension was associated with an increase in the arteriolar length-to-diameter ratio, and to a marked reduction in the number of terminal branches, an alteration in arteriolar topology indicative of rarefaction. These changes in the arteriolar network were exaggerated in patients with malignant hypertension . However, no data about any possible prognostic significance of these indicators of retinal vascular morphology is presently available. Furthermore, it is not presently known whether such retinal vascular abnormalities may reflect similar abnormalities in other vascular districts, such as the coronary, muscular and subcutaneous circulation, in hypertensive patients .
The relationships between some indices of retinal alterations, such as the AVR ratio, the length to diameter ratio or the number of arteriolar branching and target-organ damage or cardiovascular events are still far from being clearly and completely established. Several issues related to funduscopic examination of the retinal vascular network are still worthy of investigation . Standardization of the funduscopic approach, possibly by making use of a computerized or semi-computerized analysis system, mandatory for obtaining reliable data, could be of help in screening large population samples .
In conclusion, as commonly acknowledged, hypertension is associated with marked morphological alterations in the retinal vasculature , and quantification of these changes may be a useful novel approach to the assessment of target organ damage in hypertension [31,33]. In the future noninvasive evaluation of retinal arterioles morphology might meet the criteria requested by the European guidelines on hypertension management . In addition, it would also be clinically important to determine whether the regression of cardiac, renal and vascular target organ damage observed during treatment in hypertensive patients has the same temporal pattern of regression as retinal vascular damage. New technologies, presently under clinical evaluation, may help us in the future to noninvasively assess microvascular structural alterations and to better stratify cardiovascular risk of our patients with consequent optimization of treatment. Whether the measurement of AVR will meet the requested requirements for such a scope is still a matter of debate; in any case, its extensive investigation and application in patients with cardiovascular risk factors will further clarify and establish its real clinical potential.
Conflicts of interest
There are no conflicts of interest.
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