Retinal nerve fiber layer thinning as a novel fingerprint for cardiovascular events: results from the prospective cohorts in UK and China

Cardiovascular disease (CVD) is one of the greatest medical challenges worldwide. As the leading cause of morbidity and mortality, CVD affects more than 500 million people and accounts for one third of all deaths globally, posing a substantial socioeconomic burden on the public health system [1‐3]. Most CVDs can be prevented by addressing behavioral risk factors. Unfortunately, many individuals with CVD remain undiagnosed until life-threatening events occur. Thus, identifying individuals at the highest risk of developing cardiovascular event at an early stage is pivotal for the tailoring of timely interventions to preventing CVD and its related complications.

Substantial advances have been achieved concerning the pathogenesis of CVD due to various omics techniques that have identified many biomarkers [4‐6]. In contrast, the markers currently used for CVD risk stratification are non-specific (e.g., age and smoking), measures target/end organ damage (e.g., serum creatinine levels and albuminuria), or have low precision (e.g., blood pressure and LDL cholesterol levels). Furthermore, the ability of these methods to track changes in CVD risk over time and in response to treatment remains unclear. Thus, the currently established indicators of CVD risk cannot be used to accurately quantify individual risk. There is an urging need to explore novel indicators which could provide increasingly accurate and personalized risk assessments.

The retina serves as a unique window of cardiovascular system because of their sharing similar embryonic origin, anatomical structure, and blood supply [7, 8]. Retinal optical coherence tomography (OCT) enables fast, ultra-high resolution, and automatic segmentation of individual retinal layers. Using OCT, alterations of retinal nerve fiber layer (RNFL) thickness have been implicated in cardiovascular health, generating new insights into the role of retinal fingerprints in the prediction of CVD. However, emerging evidence has yielded conflicting results. Some studies reported that localized RNFL thinning was strongly correlated with the presence of ischemic stroke in a hospital-based populations [9], and reduced RNFL thickness was observed in coronary heart disease and heart failure [10‐12]. Shin et al. noted that Korean patients with thinner RNFL had a higher predicted 10-year cardiovascular risk assessed by atherosclerotic cardiovascular disease (ASCVD) risk score, compared with those without RNFL defects [13]. However, other studies reported no such correlations [14, 15]. This discrepancy might be associated with the cross-sectional nature of these studies, the fact that most merely focused on localized changes in the RNFL, the small sample size of the hospital patients, and the fact that confounding factors for CVD were not adjusted for. To date, prospective population-based cohort study focusing on the longitudinal relationship of RNFL thickness in both macular and peripapillary regions with the total cardiovascular burden is scarce.

Therefore, the objective of this study was to prospectively explore the association between macular RNFL thickness and CVD risk using data from the UK Biobank cohort in the European general population. Furthermore, given that only macular RNFL thickness was available in UK Biobank, we furtherly aimed to validate the association of peripapillary RNFL thickness with CVD onset and its reclassification value using data from the Guangzhou Diabetes Eye Study (GDES) cohort in the Chinese diabetic population.

In a large population of more than 25,000 European individuals, we found that each 5-μm reduction in macular RNFL thickness was associated with an 8% increased risk of new-onset CVD, independent of other systemic and ocular factors. Patients in the lowest baseline RNFL thickness tertile had an 18% higher incident cardiovascular risk compared with those with highest RNFL thickness tertile. The association between reduced peripapillary RNFL thickness and increased CVD risk was further validated in the Chinese diabetic cohort. Furthermore, RNFL thickness improved the risk reclassification ability on the basis of Framingham risk valuables despite the small sample. Therefore, OCT-derived RNFL thinning is a potentially preclinical fingerprint of CVD events and could act as an early non-invasive surrogate for the future risk of major vascular diseases.

Our prospective findings are in line with previous cross-sectional studies (Additional file 1: Table S5) [9, 10, 12‐15, 41‐44]. Localized RNFL thinning assessed by fundus camera has been reported to be correlated with the presence of cerebrovascular diseases, including stroke and cerebral small vessel disease [9, 42]. Utilizing quantitative OCT assessment, further studies have reported that patients with ischemic heart diseases, such as coronary heart disease, serious heart failure, and congenital heart disease had a thinner RNFL compared to age- and sex- matched healthy participants [10, 12, 41]. Moreover, reduced RNFL thickness was also delineated at an earlier stage in the condition of established cardiovascular risk factors. Localized RNFL thinning was associated with the severity of asymptomatic carotid artery stenosis and arterial hypertension, in addition to retinal microvasculature abnormalities [43, 44]. In animal studies, chronic experimentally induced atherosclerosis and hypertension led to reduced visibility of RNFL with defect in rhesus monkeys [45]. Recently, a single-center study has demonstrated higher 10-year predicted cardiovascular risk by ASCVD score in patients with RNFL thinning [13]. However, this cross-sectional study only included individuals with high cardiovascular risk and merely focused on localized RNFL defect. Using a large-scale population-based cohort and a community-based cohort, we provided the first longitudinal evidence for the association of OCT-derived average RNFL thinning with the total burden of incident CVD events.

Although the exact pathophysiology of RNFL thinning in CVD remains unknown, it has been postulated to be due to the impairment of ocular circulation. The retina is supplied by the dual end arterioles, central retinal artery, and short posterior ciliary arteries, with autoregulatory mechanisms to maintain ocular perfusion. In the case of subclinical cardiovascular and cerebrovascular abnormalities, retinal vasoconstriction reduces blood supply to the retina in favor of adequate perfusion to the systemic circulation and important organs, leaving the inner retinal layers susceptible to ischemic damage [7]. It is therefore probable that microvascular pathologies, including atherosclerosis, arterial hypertension, increased rigidity and insufficient autoregulation, could be the main driver behind the reduction of RNFL thickness [46]. Moreover, retinal ischemia/reperfusion induced oxidative stress injury, cytokines release, and nerve fiber death might contribute to secondary RNFL thinning [47]. However, further studies are warranted to uncover the relevant underlying mechanisms.

The most notable advancement in ophthalmology was the advent of high-resolution OCT technology, a rapid, non-invasive and widely available imaging modality capable of producing a high-resolution cross-sectional image reflecting the near-histological tissue microstructure in vivo [48, 49]. As the only human tissue that allows direct non-invasive visualization of microvascular circulation and the central nervous system, the retina provides a unique window for documenting systemic diseases [48, 50, 51]. OCT examination is increasingly being routinely performed in hospital and community settings. The number of OCT scans increased 14-fold from 23,500 scans in 2008 to over 330,000 scans in 2016 at Moorfields Eye Hospital NHS Foundation Trust [52]. Furthermore, it has been reported that healthcare-seeking behavior for eye health has surpassed that for cardiovascular disease [49, 53], which provides OCT with an unprecedented opportunity to detect systemic disease, predict its onset, and quantify its severity and response to treatment. With the emergence of automated segmentation and precise quantification of individual retinal layers by deep learning algorithms [54], our discovery provides a novel insight into the role of OCT derived morphological RNFL abnormalities in the pathologies of cardiovascular events.

About 25% individuals in UK Biobank were excluded due to the poor image quality in the present analysis. This may be attributed to the poor patients’ cooperation and the inefficiency of the traditional SD-OCT system for dense volume scanning, the scanning speed of which was only 27 kHz per second without eye tracking function. However, novel SS-OCT system could reach a much faster scanning speed of up to 100 kHz per second, which brought faster, deeper, and clearer OCT images [55]. Moreover, the applied eye-tracking system could reduce eye motion artifacts and improve the signal-to-noise ratio [55]. In our GDES Chinese cohort, DRI Triton SS-OCT OCT was used, and the excluded rate due to the poor quality was less than 5%, which was comparable with another RNFL study [56]. More importantly, a recently devised algorithm could help adjust the effect of poor signal strength on OCT parameters evaluation [57]. Therefore, with the state-of-the-art modalities and standardized operations, the OCT images of poor quality will be reduced and more studies with more advanced OCT systems and algorithms are required to validate our findings in clinical practice.

Notably, both macular and peripapillary average RNFL thinning were independently associated with cardiovascular risk in European and Chinese populations. Moreover, the inclusion of RNFL thickness improved the reclassification abilities for CVD events over the classic FRS prediction model. Given the non-invasive nature of OCT and the high adherence rate of regular eye examination, RNFL thickness assessment from a single “eye-check” is an attractive alternative for assessing cardiovascular risk in the primary healthcare screening. In the community optometric practice, cases of RNFL thinning, unexplained by glaucoma, diabetic retinopathy, or other ocular conditions [19] should have concomitant cardiovascular risk factors considered and be considered for referral and further cardiovascular or neurological investigations. This measure is instructive in the early identification of patients with compromised cardiovascular health, translating to timely interventions targeting modifiable CVD risk factors, such as controlling hypertension, quitting tobacco and alcohol, regulating blood sugar and lipids, and moderately increasing physical activities [58, 59]. However, we should point out that the additive NRI of 21.8% was mainly based on the small sample with incident cardiovascular events. Twenty-one out of 29 patients with cardiovascular events could not be reclassified with the novel prediction model yet and the absolute NRI was 2.0%. Despite the improved prediction by the addition of pRNFL thickness, the small sample size may limit the power effect and more evidence from large-scale longitudinal studies is of necessity. Besides, further studies are needed to determine the cutoff value of reduced RNFL thickness in different age, sex groups for cardiovascular risk. This also includes more work to estimate the cost-effectiveness and acceptability of OCT application in community screenings.

To the best of our knowledge, this is the first prospective study to investigate the association between RNFL thickness and incident CVD events. The major strengths of this study were its large sample size, the relatively long follow-up period of nearly 8 years, the prospective design of two cohorts for comprehensive analysis of RNFL thickness within the macula and peripapillary regions and the rigorous findings after adjustments for numerous covariates. Furthermore, we have verified the generalization of our findings in European and Chinese ethnicities, in general and diabetic populations, and with different RNFL assessment devices (SD-OCT or SS-OCT). Nevertheless, we also acknowledged the limitations in this study. First, given that the incidence rates of each single cardiovascular event were low, the endpoint in our analysis was the total CVD burden combining incident coronary heart disease, heart failure, and stroke. Further studies are warranted to investigate the association between RNFL thickness and the specific CVD outcomes and further validate our findings. Second, although a wide range of demographic, lifestyle, and medication factors were adjusted, many covariates were self-reported, and thus, residual confounding possibly remains. Third, the association of RNFL thickness with the progression, treatment response, and prognosis of CVD could not be interpreted in the present study, which requires further clarification. Fourthly, despite the improved reclassification ability by the inclusion of pRNFL thickness over FRS, the sample size with incident CVD events was relatively small (only 29 patients) which may limit the statistical power. Future prospective studies with larger cardiovascular events sample are required to verify the prognostic value of RNFL thickness.

In conclusion, RNFL thinning quantified by OCT were independent risk factors for CVD occurrence and improved reclassification capability, indicating RNFL thickness as a potential retinal fingerprint for cardiovascular events screening. Further prospective studies are needed to explore the predictive value of RNFL thickness for cardiovascular events progression, prognosis, and treatment response and to elucidate the possible biological mechanisms.