Sreeram Pasupuleti

Background: Cardiovascular disease causes approximately 32% of global mortality, primarily manifesting as coronary heart disease.¹ Retinal and coronary microvessels share significant structural and physiological homology, measuring under 200 micrometers in diameter and responding to identical systemic risk factors like hypertension, diabetes, and dyslipidemia.² Usual clinical tests typically detect late-stage structural damage, leaving a gap in identifying early, dynamic blood flow dysregulation before major adverse cardiovascular events.³ Because the retina provides the only non-invasive, in vivo location to directly visualize microvasculature, it offers an optimal window into systemic microvascular health.³ Establishing functional retinal biomarkers is essential to detect clinical vascular dysfunction before irreversible cardiac injury occurs.

Objectives: In this review, we examined how functional and electrophysiological alterations in retinal microcirculation can be used to assess systemic cardiovascular decline and to evaluate artificial intelligence-driven retinal imaging as a noninvasive screening tool for coronary artery disease.

Search Methods: A comprehensive literature review was conducted utilizing PubMed, spanning the period from 2017 to 2023. The search strategies employed were designed to identify relevant publications centered around the following key concepts: retinal microvasculature, flicker-induced arterial dilation, endoplasmic reticulum stress, and optical coherence tomography angiography.

Results: Literature review reveals multiple functional, cellular, electrophysiological, and structural links between retinal and cardiac pathology. Functionally, the vasomotor activity of the blood vessels measured via flicker-induced arterial dilation (FIDa) was significantly impaired in coronary artery disease (1.93%) versus controls (3.69%), and nearly absent in ischemic heart failure (0.41%), which mirrors left ventricular decline.⁴ Cellular models of diabetic atherosclerosis demonstrated that chronic endoplasmic reticulum (ER) stress and unfolded protein response activation likely drive retinal capillary degeneration, resulting in reduced microvessel density and pericyte ghosts.⁵ Systemic administration of the chemical chaperone 4PBA alleviated ER stress, down-regulated the pro-apoptotic marker CHOP, and successfully restored retinal capillary density.⁵ Electrophysiologically, non-L-type Cav2.3 calcium channels regulate both intrinsic cardiac conduction⁶ and retinal neurovascular coupling.⁷ Cav2.3-deficient mice exhibited diminished heart rate reserves and severely attenuated retinal vasodilation. Notably, 36% of Cav2.3-deficient mice demonstrated a vasodilatory response to visual flicker stimulation, in contrast to the 82% response observed in wild-type mice.⁷ Clinically, AI-driven segmentation of dye-free optical coherence tomography angiography (OCTA) images from 747 participants revealed that coronary artery disease patients exhibited significantly lower vascular area density, lower vascular length density, reduced vascular fractal dimension, and increased vessel tortuosity in the retina. These findings demonstrate the ability of AI segmentation to reliably reflect the severity of ischemic disease.⁸

Conclusion: Systemic cardiovascular disease physically manifests in the retinal microvasculature through shared pathways of endothelial dysfunction, endoplasmic reticulum stress, and altered electrophysiology. These quantifiable structural and functional metrics provide a non-invasive, accessible screening alternative to invasive, costly coronary angiography. Integrating dynamic FIDa testing with AI-powered OCTA analytics makes a novel paradigm for early risk assessment, preventative healthcare, and personalized medicine. Future examinations should target outstanding questions regarding clinical translation to build upon these preclinical and trial findings.

Works Cited:

1. Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics-2021 pdate: A report from the American Heart Association. Circulation. 2021; doi: 10.1161
2. Wang X, Zhang H, Lu H, Zhang B, Li B, Gao L. Retinal microangiopathy as a marker of coronary atherosclerotic heart disease. Int J Gen Med. 2025;18:4181-4193; doi: 10.2147/IJGM.S532841
3. Liew G, Xie J, Nguyen H, et al. Hypertensive retinopathy and cardiovascular disease risk: 6 population-based cohorts meta-analysis. Int J Cardiol Cardiovasc Risk Prev. 2023;17:200180; doi: 10.1016/j.ijcrp.2023.200180
4. Barthelmes J, Nägele MP, Cantatore S, et al. Retinal microvascular dysfunction in patients with coronary artery disease with and without heart failure: a continuum? Eur J Heart Fail. 2019;21(8):1032-1041; doi: 10.1002/ejhf.1537
5. Mazzoli V, Zhong LH, Dang VT, Shi Y, Werstuck GH. Characterization of retinal microvascular complications and the effects of endoplasmic reticulum stress in mouse models of diabetic atherosclerosis. Invest Ophthalmol Vis Sci. 2020;61(10):49; doi: 10.1167/iovs.61.10.49
6. Galetin T, Tevoufouet EE, Sandmeyer J, et al. Pharmacoresistant Cav 2.3 (E-type/R-type) voltage-gated calcium channels influence heart rate dynamics and may contribute to cardiac impulse conduction. Cell Biochem Funct. 2013;31(5):434-449; doi: 10.1002/cbf.2918
7. Neumaier F, Kotliar K, Haeren RHL, et al. Retinal vessel responses to flicker stimulation are impaired in Cav 2.3-deficient mice—An in-vivo evaluation using retinal vessel analysis (RVA). Front Neurol. 2021;12:659890.a; doi: 10.3389/fneur.2021.659890
8. Zhou S, Yan Q, Guo J, He W, Zhao Y. Early diagnosis of coronary heart disease based on retinal microvascular parameters of OCTA. Front Cell Dev Biol. 2025;13:1654159; doi: 10.3389/fcell.2025.1654159