How can retinal biomarkers serve as a window into cardiovascular health? That’s what we’re exploring in this blog. The eyes offer a unique view into the body, and with advanced ophthalmic imaging and AI, we’re unlocking faster, more reliable ways to detect and monitor systemic conditions. After exploring the impact of retinal biomarkers in monitoring neurodegenerative conditions in our previous blog article, we now turn our attention to how retinal biomarkers can detect and monitor cardiovascular diseases.
What is Cardiovascular Disease?
The term "Cardiovascular Diseases" (CVDs) is broad and can refer to several conditions affecting the heart and the blood vessels. These include: coronary heart disease, cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease, and deep vein thrombosis and pulmonary embolism1,2.
The initial indication of an underlying cardiovascular condition often manifests as a heart attack or stroke, primarily resulting from a blockage impeding the blood flow to reach the heart or brain.
Why is early detection important?
Globally, CVDs stand as the primary cause of mortality, claiming approximately 19.8 million lives in 2022, with 85% attributed to heart attacks and strokes3. Most CVDs can be prevented by addressing behavioural risk factors (smoking habits, obesity, sedentarism, alcohol, and fat intake) and controlling the associated physiological components such as high blood pressure (hypertension), high blood cholesterol, and high blood sugar4,5.
Moreover, environmental risk factors such as outdoor and indoor air pollution, noise, extreme temperatures, second-hand smoke, and chemicals, among others, play a detrimental role in the burden of CVDs.
In this scenario, early detection of the disease is fundamental to enable timely pharmacological management and to change the unhealthy habits of patients at high risk. This will improve the quality of life, save resources for the healthcare system, and reduce productivity losses.
Why is the retina an ideal target for studying cardiovascular diseases?
The retina interconnects with the cardiovascular system via its extensive vascular network and shares similar physiological, embryological, and anatomical characteristics with the coronary circulation6. In fact, retinal microvascular changes, such as arteriolar abnormalities and retinopathy, parallel the systemic and coronary vasculature damage triggered by, for instance, hypertension, and have been recently incorporated as markers for some CVDs7.
Importantly, the retina shows a major advantage: it can be easily and non-invasively visualised through routine eye examination (e.g., fundus examination and optical coherence tomography -OCT). Moreover, retinal vessels are observed relatively easily due to the translucence of the ophthalmic medium. This renders it a practical and relatively economical target for disease screening and monitoring, with potential application to massive population studies.
Ophthalmic imaging: opening a window to the whole body
Ophthalmic imaging serves as a gateway to comprehensive health assessment by providing valuable insights into various systemic conditions beyond ocular health. Through techniques like OCT and fundus photography, ophthalmologists can detect subtle changes in the retina and optic nerve, offering early indications of systemic diseases such as diabetes, neurodegenerative disorders, and cardiovascular diseases.
More recently, OCT angiography (OCTA) has garnered particular attention due to its capability to provide a three-dimensional depiction of the intricate retinal vascular network.
These non-invasive techniques not only aid in early diagnosis but also allow for continuous monitoring of disease progression and treatment effectiveness. In addition, their high reproducibility allows for reliable repeated measurements in the same individual, facilitating long-term follow-ups.
Finally, ophthalmic imaging offers a cost-effective and efficient means of screening large populations, potentially reducing the burden on healthcare systems and improving patient outcomes. By peering into the eye, clinicians can gain a deeper understanding of the overall health status, making ophthalmic imaging a pivotal tool in preventive medicine and holistic patient care.
Retinal biomarkers for the screening and prognostics of cardiovascular diseases
The concept of using retinal biomarkers for the screening and prognostics of CVDs has gained significant attention in recent years. Several studies have identified various retinal biomarkers that may reflect underlying cardiovascular health or predict future cardiovascular events.
Retinal microvasculature abnormalities
It has been suggested that retinal vessels, being of similar size to coronary microvasculature (around 100-250 μm in diameter), could act as a proxy for understanding vascular or cardiac dysfunction7,8. Even if there is no apparent eye disease present, quantitative analysis of the retinal microcirculation allows for assessing systemic cardiovascular risk. Microvascular abnormalities are observed not only in the retinal circulation but also in the choroids and the optic nerve.
Population-based studies have shown that these microvascular changes are detected more frequently in people with hypertension than in normotensive patients, and pose a higher risk of deadly cardiovascular events (e.g., heart attack, stroke)9,10. Consequently, fundus examination and photography have been included in the guidelines for the management of arterial hypertension and should be performed in patients with grade 2 or 3 hypertension or hypertensive patients with diabetes, in whom significant retinopathy is more likely11. Interestingly, epidemiological studies have shown that hypertensive retinopathy signs are also observed in the general adult population and are associated with subclinical vascular disease, forecasting future cardiovascular events10.
Retinal arteriolar changes
It refers to those abnormalities involving only the retinal arterioles, such as generalised and focal arteriolar narrowing, and arteriovenous nicking. These changes have been frequently observed in hypertensive eye disease, which is commonly associated with increased systemic blood pressure10,12. In particular, the predictive value of retinal arteriolar narrowing in the onset of hypertension is now well-recognised following several cohort studies conducted worldwide 13,14.
Similarly, population-based studies have shown an association between quantitative measures of retinal microvascular abnormalities at baseline with an increased incidence of ischemic heart disease and stroke15,16. These changes included impaired bifurcation optimality, reduced arteriolar tortuosity, and increased arteriolar narrowing, observed and analysed by fundus photography.
In line, retinal arteriolar narrowing and retinal venule widening have been linked to myocardial infarction and more diffuse and severe coronary heart disease, particularly in women17,18. More recently, these retinal biomarkers have become valuable predictors of atherosclerotic cardiovascular disease and adverse cardiac structure/function events in low-risk patients 19,20.
In summary, retinal vessel calibre and structure assessed by retinal photography represent an attractive, non-invasive, diagnostic and predictive tool for cardiovascular events, even in low-risk patients.
Retinopathy
The term retinopathy has been employed to include all microvascular changes not primarily related to arterioles6, that can be easily observed under ophthalmic examination.
It includes, among others:
- Macular Oedema. It is a condition characterized by the accumulation of fluid in the macula, leading to swelling and visual impairment. Macular oedema can occur as a result of various underlying conditions, originating locally in the eye (e.g., age-related macular degeneration -AMD, retinal vein occlusion) or arising from systemic diseases (e.g., diabetes, hypertension). It has been shown that patients with diabetic macular oedema showed an increased risk of developing incident coronary heart disease, fatal CVD, heart failure, and stroke25.
- Cotton-wood spots. They are caused by retinal nerve fibre layer infarcts secondary to arteriolar occlusion, resulting in small, yellow-white lesions observed during fundus examination. They are frequently detected alongside other signs of hypertensive retinopathy and diabetes and indicate a higher likelihood of experiencing adverse cardiovascular events (e.g., stroke and heart failure)21.
- Optic disk swelling/oedema. This term describes the ophthalmoscopic swelling of the optic disc accompanied by a simultaneous increase in fluid within or around the axons. It is usually observed in advanced stages of hypertensive retinopathy, as a result of the constantly elevated blood pressure. If hypertension persists, it may result in permanent visual impairment.
- Retinal haemorrhages. The bleeding of the retina is a key sign observed in patients with underlying systemic vascular disorders such as hypertension and diabetes. It has been associated with an increased risk of heart failure and stroke22,23.
- Microaneurysm. It is a localized swelling of small retinal blood vessels, resulting from damage to the blood vessel walls. Microaneurysms are a characteristic feature of diabetic retinopathy and early signs of the disease. However, they can also be found in hypertensive retinopathy24.
- Hard exudates. They result from the leakage of plasma lipids and proteins caused by the disruption of the blood-retinal barrier. They are mostly observed in diabetic and hypertensive retinopathies, and their presence has been associated with CVDs and plaque formation25,26. Hard exudates can be detected as bright lesions by fundus examination as well as hyperreflective foci (HRF) by OCT.
In summary, signs of retinopathy have been pointed to as independent predictors of heart failure and stroke. This was proven true even in people without a history of coronary heart disease, diabetes, or hypertension27, which makes the ophthalmic examination very appealing for early detection and large population screening.
Retinal structure morphological changes
Retinal and choroidal thickness
Retinal and choroidal thicknesses have been evaluated as potential biomarkers of various CVDs. The analysis of OCT images not only evidences the presence of macular oedema (for instance, by quantifying central subfield thickness -CST) but also provides detailed insight into specific retinal layers. In this regard, studies have linked thinning of the ganglion cell and inner plexiform layers (GCL-IPL) of the retina with increasing adiposity, as measured by body mass index, suggesting a potential association between obesity, cardiovascular risk factors, and retinal health28.
Additionally, a recent large study has proposed the retinal nerve fibre layer (RNFL) thinning as a novel fingerprint for cardiovascular events29. The authors showed that a decrease in RNFL thickness is associated with an increased risk of cardiovascular events, independent of age-related changes and ethnicity. The role of choroidal thickness in CVDs needs further elucidation. Results are controversial: while some studies found no direct link between choroidal thickness and CVDs30,31, others associated decreasing choroidal thickness with increasing coronary artery calcification and myocardial infarction32,33.
Subretinal drusenoid deposits (SDD)
SDDs, also called reticular pseudodrusen, are lipid deposits localised in the subretinal space, usually visualised in OCT as a reticular arrangement. Even though they are commonly associated with AMD, it has been recently shown that the presence of SDDs in these patients correlated with the occurrence of CVD, stroke, and lower levels of high-density lipoprotein (HDL)34,35. These results suggest that AMD patients presenting SDDs may have an increased risk of CVDs. However, evidence is controversial and studies with larger sample sizes and homogenous populations are needed.
Retinal Ischemic Perivascular Lesions (RIPLs)
RIPLs refer to areas of the retina that have experienced reduced blood flow and subsequent ischemia, resulting in tissue damage. They can be caused by retinal artery and vein occlusions, as well as by systemic hypertension. A recent study has shown that an increase in the number of RIPLs was associated with higher odds for CVDs and, in particular, a higher 10-year risk of atherosclerotic CVD36. This was further supported by an analysis of real-world data, which assessed the significance of identifying RIPLs for detecting concurrent CVD, to prevent future cardiovascular events37.
Overall, integrating retinal biomarkers into cardiovascular risk assessment holds potential for early detection, risk stratification, and personalized management of CVDs. Of note, the imaging biomarkers discussed above are not specific to CVDs but are also present in other diseases, such as ophthalmic and neurodegenerative diseases. Therefore, further research is needed to validate these biomarkers in large-scale prospective studies and effectively integrate them into clinical practice.
How Artificial Intelligence can pave the way for retinal imaging analysis in cardiovascular diseases?
Artificial Intelligence (AI) applied to image analysis has come to stay. This cutting-edge technology provides innovative solutions to overcome the challenges associated with traditional retinal imaging analysis, including the complexity of interpretation and the time-intensive nature of analysis. Moreover, AI models trained on retinal imaging data have shown promise in predicting cardiovascular outcomes38,39.
AI algorithms are exceptionally proficient in processing and interpreting complex retinal images. They can identify subtle shifts in retinal layer or choroidal thicknesses as well as small structures such as HRF, which might be missed after a rapid manual assessment. This heightened precision not only amplifies the accuracy of diagnoses but also offers time efficiency40.
Given that certain structural retinal biomarkers in CVDs are common to those found in other retinal conditions, AI can also efficiently support the analysis of retinal images in the context of cardiovascular disorders.
Additionally, AI’s inherent capability to swiftly process and automate vast amounts of data streamlines what was once a labour-intensive endeavour. Such efficiency is pivotal for the prompt detection and monitoring of CVDs on a large scale. For instance, given that hypertension affects 1 out of 3 adults worldwide and that 4 out of 5 people with hypertension are not adequately treated1, the need for fast and effective population screening programs and monitoring tools arises.
RetinAI Discovery®, a multi-disease platform
RetinAI Discovery® is not just a tool, but a comprehensive platform tailored for clinicians across different medical fields. A single data platform to manage & access your data anytime from anywhere. View all your OCTs, fundus images, DICOM datasets, PDFs, JPEG, PNG & TIFF files in one single place - no need for multiple viewers.
By capitalising on advanced AI-based algorithms, the platform streamlines the tedious process of patient ophthalmic data analysis, deploying powerful management tools that ensure precision, reproducibility and reliability without human fatigue. With an intuitive user interface and sophisticated analytical capabilities, Discovery can help you efficiently navigate the complexities of ophthalmic data (OCT, fundus, OCTA), providing a robust solution that complements human expertise when assessing retinal involvement across a spectrum of ophthalmic and non-ophthalmic diseases.
During patient consultations, Discovery empowers clinicians by providing accurate and detailed segmentation and quantification of retinal layers and fluids, the choroids, and other relevant biomarkers (e.g., HRF) in OCT scans and fundus. This real-time analysis not only fosters a comprehensive understanding of diseases affecting the retina but also paves the way for timely diagnosis and treatment planning.
Furthermore, the platform’s capabilities in monitoring retinal morphological changes over time are pivotal in the dynamic landscape of patient care. By offering insights into disease activity and the impact of therapeutic interventions on retinal morphology, Discovery becomes an ally to a physician’s decision workflow. This not only helps with personalization of treatment regimens, but also reshapes the entire clinical workflow, elevating the overall patient experience through confidence, clarity, and care.
In an era where precision and speed are paramount, RetinAI Discovery® stands as a beacon, guiding clinicians towards a future of enhanced retinal care.
Thinking of harnessing the combined force of imaging and AI to enhance cardiovascular disease detection and monitoring? Connect with our experts now.