Retinal microvasculature assessment: useful to refine cardiovascular risk

This editorial refers to ‘Randomized 20-year infancy-onset dietary intervention, life-long cardiovascular risk factors and retinal microvasculature’, by O. Respo et al., https://doi.org/10.1093/eurheartj/ehae423. Cardiovascular disease (CVD) continues to be the leading cause of morbidity and mortality worldwide.1 This disease usually undergoes a long subclinical phase, with risk factors already present in the early stages of life. Early detection and effective risk assessment, even during pregnancy and childhood, are critical for implementing adequate preventive programmes as soon as possible and preventing future CVD events more effectively.2 Along with traditional risk factors, looking at subclinical target organ damage (TOD), mostly in the heart, brain, kidneys, and eyes, helps in more accurately dividing the CVD risk and, as a result, in using more effective treatments. The question remains: when should we start effective lifestyle programmes to achieve the highest protection against CVD? The intervention trial by Oskari Respo and colleagues, published in this issue of the European Heart Journal,3 which had 486 seven-month-old participants, found that personalized nutrition counselling based on Nordic nutrition guidelines had positive effects on CVD risk factors, mostly on changes in retinal microvascularity in youth. The main target of the intervention was to reduce saturated fat to <10%. Unfortunately, the authors did not evaluate the effects of the overall dietary pattern, which should have greater impacat due to the synergic effects between foods and nutrients. Other dietary randomized trials that have been performed in pregnant women4 have shown than an intervention based on a healthy dietary pattern such as the Mediterranean diet is able to significantly reduce the incidence of pre-eclampsia in mothers, a known CVD risk factor, as well as to reduce the incidence of newborns with foetal growth restriction, a condition that has been related to high CVD incidence and mortality in adulthood.5 Therefore, we should promote measures to develop a healthy lifestyle early in life, potentially even before conception. On the other hand, the trial by Respo and colleagues3 enabled us to track the progression of various CVD risk factors in a vast group of children with a 26-year follow-up, and to establish a correlation between the alterations in primary CVD factors and the existence of TOD in the retinal microvasculature in youth. There is evidence that TOD raises the risk of CVD by up to 25%2 and can get worse over time if not treated properly. Early detection of TOD, such as changes in retinal microvascularity, could help find people who need to take specific precautions. In this context, we can detect early signs of cumulative damage from cardiovascular risk factors in small arteries. A simple and repeatable fundoscopic examination can observe the retinal vessels non-invasively, providing an opportunity to evaluate the microvasculature in vivo. Retinal vascular parameters include calibre, tortuosity, and fractal dimension, as well as arteriovenous ratio (AVR), central retinal arteriole equivalent (CRAE), and central retinal venule equivalent (CRVE) measurements. Unfortunately, the Finnish authors3 were unable to find a cut-off point in the microvasculature measurements that would help identify the subjects who require special medical attention to reduce the incidence of future CVD events. Currently, cardiovascular risk assessment uses different scales adapted to each region or country, according to their own data. The most used scale worldwide is the Framingham score,6 but in Europe we prefer the European Systematic Coronary Risk Evaluation (SCORE) because it is based on the analysis of large representative cohorts.7 However, these scales may sometimes overestimate (especially in older people from countries with low CVD mortality) or underestimate (especially in young people from countries with high CVD mortality) vascular risk.7 Thus, we should recalibrate risk assessment to suit different populations in order to minimize mismatches. Up to now, among different laboratory parameters and imaging techniques, vascular ultrasonography has been the most used tool to adjust CVD risk because of its feasibility and relatively low cost. However, the results of the STRIP study3 suggest a reconsideration of retinal microvasculature assessment in children, adolescents, and adults. Evidence of simultaneous vascular damage across the body is stronger with advanced grades of diabetic and hypertensive retinopathies. Nonetheless, early lesions of both retinopathies have also been associated with CVD. People whose eyes have retinal microaneurysms [odds ratio (OR) 2.50, 95% confidence interval (CI) 1.05–5.98) and an AVR of <0.666 (OR 4.22, 95% CI 2.56–6.96) are more likely to have silent brain ischaemia.8 Also, narrower retinal arterioles have been associated with lower myocardial perfusion.9 Traditional retinopathy classifications are based on eye fundus images. However, the inherent interobserver variability impedes the reliability of vessel calibre measurements. Fortunately, the advent of computer-assisted analysis of digital retinal photographs reduces this variability and increases reproducibility. Another way to study the retina’s blood vessels is to measure the wall-to-lumen ratio (WLR) by means of scanning laser Doppler flowmetry (SLDF) or adaptive optics (AO). The media-to-lumen ratio of subcutaneous small arteries, the gold standard method for microvascular evaluation, closely correlates with WLR, despite its invasive nature. Lifestyle modifications10 and medication use,11 particularly when initiated at an early stage, can reverse TOD. Anyway, despite efforts to manage cardiovascular risk factors, many forms of TOD may become irreversible over time. While treatment may slow down its progression, it cannot completely reverse the trend of a continuous increase in cardiovascular risk. Therefore, we recommend conducting a deep screening for TOD in all patients with cardiovascular risk and performing a more comprehensive evaluation when the presence of TOD impacts treatment decisions. The most recent ESC Guidelines on CVD prevention in clinical practice advised using coronary artery calcium scoring to reassess the risk of developing CVD, both higher and lower risk, in conjunction with traditional risk factors. Computed tomography angiography (CTA) enables the diagnosis of coronary stenoses and measures coronary calcium deposits, which provides predictive information about cardiac events before the patient has symptoms. We can also use ultrasonography to measure plaque in the carotid artery, potentially reclassifying the risk of CVD. This method should be considered to modify the risk for individuals who are at an intermediate level of risk.2 Non-mydriatic retinal cameras are beneficial due to their non-invasive nature, ability to detect early signs of cardiovascular damage, and utilization of new software for analysis, thereby simplifying evaluations and enhancing consistency in results. In addition, they present a fast learning curve for retinal photography performance. Nonetheless, retinal microvasculature measurements present certain limitations. There is no uniform calculation method or standardized protocol for retinal vascular parameters. In the same dataset, we lack a consistent comparison between different methods and software for retinal vascular parameter measurements. We still need to establish pathological cut-off points for CRAE, CRVE, and AVR. Moreover, the cost of non-mydriatic retinal cameras and the complexity of the software may limit the routine application of retinal examination. A strong relationship between micro- and macrovascular territories makes it difficult to determine which is the first causative factor that sets in motion and drives the vicious circle of small and large artery damage in hypertension. However, researchers hypothesize that the microvascular impairment precedes large-scale vascular damage.12 Thus, examination of the retina might be able to detect vascular changes before other methods such as measuring pulse pressure, pulse wave velocity, or atherosclerotic plaques by carotid or femoral ultrasonography. For a global assessment, we recommend also testing microvasculature biomarkers such as albuminuria. However, in hypertension-induced kidney disease, albuminuria may not appear until after the reduction in globular filtration rate (GFR) (Graphical Abstract). New technologies to further explore TOD in the retinal microvasculature have been developed. Optical coherence tomography (OCT) is a non-invasive diagnostic technique that has been used to evaluate hypertensive patients. In these patients, studies have shown a significant relationship between mean arterial blood pressure levels and the arterial venous ratio (A/Vr). Thus, OCT has been used to analyse central macular thickness and retinal nerve fibre layer thickness.13 OCT angiography (OCTA) is another non-invasive method for assessing the retinal capillary network and blood flow in patients with systemic hypertension. It has been shown that people with high blood pressure have changes in the number of vessels in the superficial plexus, the area of the foveal avascular zone, the density of the capillaries, and the thickness of the inner retina. OCTA can provide information about pre-clinical microvascular changes due to systemic hypertension and may help to initiate measures to prevent long-term retinal damage in hypertensive patients. In these patients, OCTA can also improve disease staging and clarify the pathophysiology of hypertension.14 The AO camera is a new and accurate optoelectronic device that can measure and describe the shape of small blood vessels in the retina on a scale similar to that of a tissue section. AO may contribute to a better understanding of the pathophysiology of this disease. Finally, automated systems and artificial intelligence can automate retinal vessel detection and characterize subtle changes in the retinal vasculature. Advanced image processing techniques and machine learning tools should help to quantify new and old retinal vascular network parameters.15 In conclusion, nowadays, the onset of atherosclerosis in children and adolescents appears to be earlier, necessitating the development of new tools to identify young individuals who require special attention and inclusion in intensive community preventive cardiovascular programmes. These programmes should promote a healthier lifestyle by improving adherence to healthy dietary patterns such as Mediterranean or Nordic diets, increasing physical activity, and using behavioural therapies when needed. All authors declare no disclosure of interest for this contribution.