Young children with narrow retinal artery diameters were more likely to develop higher blood pressure, and children with higher blood pressure levels were more likely to develop retinal microvascular impairment during early childhood, according to a new study published today in Hypertension, an American Heart Association journal.
This is the first study to show this connection in children.
High blood pressure, the main risk factor for the development of cardiovascular disease (CVD), can manifest as early as childhood, and the prevalence of high blood pressure among children continues to rise.
In previous studies, analysis of blood vessels in the retina has shown promise as a predictor of CVD risk among adults.
In the study titled, “Retinal Vessel Diameters and Blood Pressure Progression in Children,” researchers sought to predict the development of high blood pressure in children over four years based on retinal blood vessel measurements.
“Hypertension continues as the main risk factor for the development of cardiovascular diseases and mortality,” says Henner Hanssen, M.D., the study’s lead author and a professor in the department of sport, exercise and health at the University of Basel in Switzerland.
“Primary prevention strategies are needed to focus on screening retinal microvascular health and blood pressure in young children in order to identify those at increased risk of developing hypertension. The earlier we can provide treatment and implement lifestyle changes to reduce hypertension, the greater the benefit for these children.”
Researchers screened 262 children ages six to eight from 26 schools in Basel, Switzerland, in 2014, for baseline blood pressure and retinal arterial measurements. Both measures were taken again in 2018.
Blood pressure measurements at both baseline and follow-up were performed in a sitting position after a minimum of five minutes of rest and were categorized based on the American Academy of Pediatrics’ blood pressure guidelines.
These guidelines utilize the same measurements as the American Heart Association/American College of Cardiology 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults.
Results from the analysis indicate:
- children with narrower retinal vessel diameters at baseline developed higher systolic blood pressure at follow-up;
- retinal vessel diameters could explain 29 -31% of the changes in systolic blood pressure progression between 2014 and 2018;
- children with higher blood pressure levels at baseline developed significantly narrower arteriolar diameters at follow-up, depending on weight and cardiorespiratory fitness; and
- initial blood pressure measures explained 66-69% of the change in retinal arteriolar diameter from baseline to follow-up.
“Early childhood assessments of retinal microvascular health and blood pressure monitoring can improve cardiovascular risk classification. Timely primary prevention strategies for children at risk of developing hypertension could potentially counteract its growing burden among both children and adults,” said Hanssen.
Researchers noted limitations of their study include that they could not confirm blood pressure measurements over a single 24-hour period, so they would not account for “white coat” hypertension, a condition where patients have high blood pressure readings when measured in a medical setting.
Developmental stage including puberty status of each child was not accounted for in the study, as well as genetic factors or birth weight – variables that could impact blood pressure development and microvascular health.
In addition, reference values for appropriate retinal vessel diameters in children do not currently exist, so future studies are needed to determine age-related normal values during childhood.
To examine the baseline associations of retinal vessel morphometry with blood pressure (BP) and arterial stiffness in United Kingdom Biobank. The United Kingdom Biobank included 68 550 participants aged 40 to 69 years who underwent nonmydriatic retinal imaging, BP, and arterial stiffness index assessment.
A fully automated image analysis program (QUARTZ [Quantitative Analysis of Retinal Vessel Topology and Size]) provided measures of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiovascular disease risk factors/outcomes were examined using multilevel linear regression to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing within person clustering), adjusted for age, sex, ethnicity, clinic, body mass index, smoking, and deprivation index.
Greater arteriolar tortuosity was associated with higher systolic BP (relative increase, 1.2%; 95% CI, 0.9; 1.4% per 10 mmHg), higher mean arterial pressure, 1.3%; 0.9, 1.7% per 10 mmHg, and higher pulse pressure (PP, 1.8%; 1.4; 2.2% per 10 mmHg). Narrower arterioles were associated with higher systolic BP (−0.9 µm; −0.94, −0.87 µm per 10 mmHg), mean arterial pressure (−1.5 µm; −1.5, −1.5 µm per 10 mmHg), PP (−0.7 µm; −0.8, −0.7 µm per 10 mmHg), and arterial stiffness index (−0.12 µm; −0.14, −0.09 µm per ms/m2).
Associations were in the same direction but marginally weaker for venular tortuosity and diameter. This study assessing the retinal microvasculature at scale has shown clear associations between retinal vessel morphometry, BP, and arterial stiffness index.
These observations further our understanding of the preclinical disease processes and interplay between microvascular and macrovascular disease.
Discussion
In this study, the first to examine the retinal microvasculature at scale using fully automated software (with over 3.5 million vessel segments from over 50 000 participants), we have shown novel associations between retinal microvascular tortuosity with BP and ASI and confirmatory associations with diameters.
Each significant risk factor expressed in deciles (Figure 2) showed strong graded associations with retinal vessel morphometry measures. The associations held after adjustment for confounding factors and removal of those with self-reported diabetes mellitus and CVD morbidity. Importantly these morphometric associations may be indicative of preclinical disease processes, suggesting a role in CVD risk prediction.
Retinal Tortuosity and CVD Risk Factors
The key findings from the present study were that increased retinal tortuosity (arteriolar and venular) showed strong graded associations with higher BP, MAP, and PP, with P as small as 1×10−300. The retinal microvasculature abnormalities observed with increased BP have not been so clear until now (Figure (Figure2).2).
The European Prospective Investigation into Cancer-Norfolk Eye study of 5947 participants (which used an identical methodology) showed remarkably similar increased tortuosity with systolic BP in older adults (arteriolar tortuosity, 1.2%; 95% CI, 0.5; 1.9% per 10 mmHg and venular tortuosity, 0.5%; 95% CI, 0.02; 0.88% per 10 mmHg).8 However, evidence from other smaller scale studies have been less supportive.
A nested case-control study by Witt et al4 among 682 adults showed an increase in arteriolar tortuosity was weakly associated with higher systolic BP, with no evidence of an association with venular tortuosity.
In contrast, a cross-sectional study by Cheung et al14 showed a decrease in arteriolar tortuosity with higher BP and MAP and an increase in venular tortuosity with higher BP and MAP, in an Asian population of adults (n=2915). Disagreements between studies may be because of smaller sample sizes together with measurement error (particularly with methods relying on manual measurement), where there is less certainty over the presence or absence of underlying associations.
While tortuosity (arteriolar and venular) was higher overall among women compared with men, in the present study, the association between CVD risk markers and tortuosity was evident in both sexes (and independent of further adjustment for height). Overall, the association of increased tortuosity (both arteriolar and venular tortuosity) with higher BP in the present study was independent of retinal diameters. This suggests that tortuosity reflects different structural vascular changes from those shown for diameters and may provide additional value to CVD risk prediction tools beyond the current testing of diameters.24
The association of retinal tortuosity with stroke has not been well studied, although 2 studies have shown a more tortuous retinal microvascular network with prevalent stroke.8,10 In UKBB, there was no evidence of an association between self-reported stroke and arteriolar tortuosity.
This difference may be related to differences in age (UKBB participants are relatively younger) and case ascertainment of stroke. In UKBB, presence of stroke was based on self-report, while in the other studies it was based on clinical information from health records.8,10
Conversely, in the present study, increased venular tortuosity was strongly associated with stroke for which some evidence has been reported previously.8,10 The discrepancies overall in findings from earlier studies with tortuosity may relate to the limited sample sizes, characteristics of the population (ie, age and risk factor profile, differences in diabetes mellitus duration, and type) or the time placement of the study.
For example, treatment has improved over time and therefore it may be harder to observe changes associated with a history of events in more recent studies compared with studies from 10 to 20 years ago.
Given the strong graded association of CVD risk factors with tortuosity (both arteriolar and venular) in the present study of over 50 000 participants and the replication of the findings observed in EPIC,8 the associations between tortuosity and CVD risk factors are now very clear warranting verification in a large longitudinal follow-up study, to confirm causality.
Retinal Diameters and CVD Risk Factors
Retinal arteriolar narrowing has consistently been associated with elevated BP in epidemiological studies6–8,25 and meta-analysis,9 supporting the finding of the present study (Figure (Figure2),2), where each 10 mmHg increase in systolic BP was associated with a 0.9 µm narrowing in arteriolar diameter.
The weaker association observed for venular diameter in the present study and no association observed in smaller previous studies6,7 suggests that the impact of BP on arterioles is more prominent than on venules. In general, the literature is in agreement that arterioles and venules are differentially associated with cardiometabolic risk factors; narrower arterioles are associated with higher BP8, and wider venules with inflammation and higher BMI/obesity.8,26 This most likely relates to the effect of different mechanistic pathways, which are yet to be fully understood.
We identified a strong association between older age and venular widening (Figure (Figure2)2) and arteriolar narrowing. The aging process has been linked to decreased retinal vessel density, reduced inner retinal layer thickness, and retinal blood flow velocity, particularly in venules.27 The sex difference, with females having narrower arteriolar and venular diameters compared with males would need to be considered in the development of CVD risk prediction tools.
Future Direction—Fully Automated CVD Risk Prediction
The work by Poplin et al15 using a convolutional neural network was able to predict CVD risk factors and outcomes from a retinal image alone as accurately as available CVD risk prediction tools. In support of growing evidence, the present study has shown that narrower arteriolar diameters are associated with increased BP, ASI, and PP very strongly and provide an indication of systemic microvascular and macrovascular changes.11
Understanding how models predict risk remains a substantial problem of the deep learning, which is very much a black box approach; therefore, assessment of vessel morphology coupled with convolutional neural network deep learning approaches may help further inform potential pathways of disease processes and prediction.
The strength of this study includes its large sample size of over 50 000 participants. The QUARTZ software is fully automated, incorporates convolutional neural network technology, and utilizes information from all vessels extracted within an image, providing precise measurement. A potential limitation is the use of the entire retinal image compared with a section of the image used by other grading systems; however, given our findings are consistent with previous literature, this is unlikely to be a major issue.
The study limitations include the cross-sectional study design, meaning the issue of causality cannot be resolved until further follow-up. Although the UKBB is not a representative sample of the United Kingdom population, which is an issue if one were attempting to determine prevalence of outcomes or genetic associations in particular.28
However, this study was focused on assessing cross-sectional phenotypic associations, and Pizzi et al29 showed that using restricted sampling for a cohort study is unlikely to appreciably bias estimates of exposure-disease associations, under a range of potential scenarios. In support of this, our findings show very similar patterns of association to those observed in an entirely independent United Kingdom-based cohort study of similar and older age (the EPIC-Norfolk study).8
The impact of hypertension treatment duration could not be assessed, so we are unsure of the impact of treatment duration on the association between retinal measures and BP, though we did note that removing those on BP treatment did not alter the associations observed. The PWV device used a nonreference method to estimate PWV, which is not as accurate as other approaches and may have led to an underestimation of the association, particularly given that pulse pressure shows stronger associations than PWV in this study. However, reassuringly, the association is in the expected direction and a P of 2.9×10−24 is highly unlikely to be a chance finding. This lends weight to the null association observed between PWV and vessel tortuosity
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More information: Hypertension (2020). DOI: 10.1161/HYPERTENSIONAHA.120.14695
