This meta-analysis of over 44,000 individuals found that higher BMI levels were associated with narrower arteriolar and wider venular caliber, independent of conventional cardiovascular risk factors. This association was consistent across regions, ethnicity, age groups and study sample size. In studies of children significant heterogeneity in the pooled data was observed. This is likely to be explained by differences in the age range of the participants (two studies were conducted in children with mean age of 12–13 years 
and the third was conducted in children with mean age 6.7 years 
), and the different levels of adjustment for confounding covariates.]. In spite of the heterogeneity in the pooled data for children, similar differences in retinal microvasculature were observed in adults and children with retinal arteriolar and wider venular calibres with increasing BMI, suggesting biological mechanisms involved in retinal microcirculation alterations are not age-dependent.
Our study suggests a significant influence of obesity on the human microcirculation. We offer several explanations for our findings. Nitric oxide (NO) is a key endothelium-derived relaxing factor causing vasodilatation and therefore an increase in volume perfusion in response to elevated metabolic demand. In obesity, decreased levels of NO have been observed and could explain impaired dilatation of the vasculature. 
This endothelium-dependent dysfunction has been proposed to be responsible for the vasoconstriction observed in obese subjects. Moreover, increased levels of vasoconstrictor molecules (endothelin-1, angiotensin-II and other metabolites of arachidonic acid) have been associated with higher BMI. 
Enhanced myogenic activation, mediated by antagonizism of calcium-activated potassium channels, has also been hypothesized to play a key role in alterations in blood flow in animal models of obesity 
. In addition, a decrease in microvessel density, that may lead to tissue hypoxia and ischemia has been observed in obese subjects. Moreover, obesity-mediated insulin resistance may result in impaired capillary recruitment via insulin-mediated mechanisms 
Alterations in vascular stucture have previously been descibed in both animal and human models of obesity. These have included thickening of basement membranes, an increase in vascular diameter, stiffness of resistance arterioles and a decrease in lumen size. These changes lead to hypertension and increase the risk of ischemia, peripheral vascular disease and aneurysms 
Finally, excess release of inflammatory markers in obese subjects has been described and may contribute to vascular dysfunction. For example, TNFα is associated with impaired capillary recruitment and vasodilatation, and angiotensinogen is responsible for the activation of the renin-angiotensin system, resulting in higher production of angiotensin II, which is a powerful vasoconstrictor 
. Vasoconstrictor and vasodilator mechanism alterations and anatomical changes result in impaired functional hyperemia in response to metabolic demand. Animal and human models have shown a reduced blood flow response to an increase in local metabolic activity in conditions of obesity 
An association between obesity and CVD such as coronary heart diseases, 
venous thromboembolism, 
and even cardiovascular mortality 
has long been described. More recently retinal caliber has also been shown to predict stroke 
and coronary heart diseases 
. Based on the results of our meta-analysis, we hypothesize that obesity induces microvascular alterations, reflected here in retinal vessel caliber. The clinical significance of these changes however, remain unclear. In children for example, the absolute differences in arteriolar and venular calibers between overweight and normal weight children were less than 1%, and whether these differences are clinically meaningful requires further study. If found to be clinically important retinal photography could be a useful non-invasive preventive tool to assess long-term microvascular changes as a marker of cardiovascular risk in overweight and obese persons. Review of longer-term inter-relationships between changes in obesity, retinal vessels and outcomes are now needed to determine whether changes are causally related to clinical outcomes.
The strengths of this meta-analysis are its large sample size and also the participation of all authors that were identified and contacted on the basis of the systematic search. Finally, because we were able to collect retinal vascular caliber data per BMI categories from each study, this reduced any heterogeneity in the categorisation of outcomes. This meta-analysis also has a number of limitations. First, an important limitation worth highlighting is the paucity of data on the prospective association between BMI and retinal vascular caliber, and also on the relationship between changes in BMI and in retinal vascular caliber over time. Consequently, a causal link cannot be extrapolated from these findings. Second, our study was limited to studies published in English, which results in a potential source of bias limiting the search to published reports. However, authors in this field were contacted to enhance the search field to grey litterature. Third, there is potential measurement bias due to different photographic procedures and software used in measuring retinal vascular caliber, resulting in possible overestimation or underestimation of the true association between BMI and retinal vascular calibers. Fourth, we standardized BMI categories according to the WHO classification for Caucasians whereas three studies were conducted in Asians 
. Also, both unmeasured and residual confounding, e.g. due to measurement error, may have influenced our findings. However, when regression coefficients were pooled to obtain a summary estimate corresponding to the change in retinal parameters for a 1 kg/m2 increase in BMI, results were still significant and had a similar level of magnitude. Fifth, because we had no access to individual participant data we used the same BMI categories for adults and children.
In conclusion, we observed in a large pooled population a significant association between overweight/obesity and narrower retinal arteriolar and wider venular caliber, while controlling for traditional cardiovascular risk factors (age, smoking, diabetes and hypertension). These findings suggest that obesity is not only linked to macrovascular pathology but also to microvascular changes. Further prospective studies are needed to explore a possible causative association between BMI and retinal microvasculature, which mirrors changes in the systemic microvasculature, including the microcirculation of the heart. If such a relationship is confirmed, examining retinal vascular caliber may provide information about small vessel alterations among individuals with obesity and other cardiovascular risk profiles. Small vessel disease is increasingly being recognized as a contributor to cardiovascular and cerebrovascular diseases, however, there is no widely available tool by which to assess small vessel condition. Retinal imaging and retinal vascular structural assessment may help to fill in this gap.