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Retinal ischemic perivascular lesions (RIPLs) are characteristic focal thinning of the inner nuclear layer, with an upward expansion of the outer nuclear layer identified by spectral domain optical coherence tomography (SD-OCT), causing a focal irregular appearance of the middle retina. RIPLs result from retinal hypoperfusion in the deep capillary plexus, as a legacy of paracentral acute middle maculopathy, representing permanent anatomical markers of prior ischemic events. Although frequently found incidentally during routine eye examinations, RIPLs may provide insights into subclinical vascular damage that underpins various cardio- and cerebrovascular diseases. The aim of this narrative review is to summarize the relationships of RIPLs with retinal and systemic vascular diseases, including arterial hypertension, coronary artery disease, carotid artery stenosis, atrial fibrillation, stroke, sickle cell disease, and diabetes mellitus. Cardiovascular and metabolic diseases, which are the leading causes of morbidity and mortality worldwide, often remain asymptomatic for years despite early structural changes until severe adverse events occur. Noninvasive retinal biomarkers such as RIPLs, which are readily and noninvasively detected through SD-OCT scans, could help in the early detection and stratification of patients at risk for cardiovascular diseases, facilitate timely medical interventions and lifestyle changes, and ultimately improve disease prevention in a “personalized medicine” approach. While further research is needed to establish the prevalence of RIPLs in the general population and their full clinical significance, advances in ophthalmic imaging technologies combined with rapid progress in artificial intelligence applications in medical research could accelerate the development of RIPLs in retinal imaging-based oculomics.
Key Summary Points
Retinal ischemic perivascular lesions (RIPLs) are focal thinning of the inner nuclear layer with outer nuclear layer expansion identified by spectral domain optical coherence tomography (SD-OCT) resulting from hypoperfusion in the deep capillary plexus.
As early signs of macular ischemia, the incidental finding of RIPLs during eye examinations may indicate subclinical vascular damage related to systemic cardiovascular risk and disease.
RIPLs have been associated with systemic vascular diseases, including hypertension, coronary artery disease, stroke, atrial fibrillation, carotid artery stenosis, sickle cell disease, and diabetes mellitus.
Noninvasive detection of RIPLs via SD-OCT could facilitate early identification and stratification of patients at risk for cardio- and cerebrovascular diseases, enabling early intervention and improved outcomes.
Further research is needed to understand the mechanisms and general prevalence of RIPLs and establish them as clinical biomarkers in retinal imaging-based oculomics.
Introduction
Back in 1892, Marcus Gunn was the first to describe visible retinal features of hypertensive retinopathy as seen by ophthalmoscopy in patients with chronic renal impairment and hypertension [1], leading the way to a field of research now known as oculomics [2]. Nowadays, the most frequent way to image more subtle changes of the retina is optical coherence tomography (OCT) [3], providing insights into retinal sublayer thickness and alterations to the retinal vasculature.
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This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Overview of the Pathogenesis of RIPLs
The retinal microvasculature supplies oxygen and nutrients to the metabolically active inner and middle layers of the retina. In the parafoveal region, this network is structured into three distinct retinal capillary plexuses (RCPs): the superficial capillary plexus (SCP), the intermediate capillary plexus (ICP), and the deep capillary plexus (DCP) [4‐6].
The hypoxia of these plexuses can lead to ischemic injury and retinal atrophy, with the severity depending on the extent and duration of the ischemic cascade [7‐9]. Acute retinal ischemia in retinal vascular occlusions initially develops at the level of the DCP, manifesting as paracentral acute middle maculopathy (PAMM) [6, 8, 10, 11], a specific retinal finding characterized by hyperreflective bands within the inner nuclear layer (INL) in the paracentral region on OCT cross-sectional scans, accompanied by a corresponding acute-onset, painless paracentral scotoma [6]. This is likely due to the middle retina’s high risk of ischemic damage, given the higher metabolic demands and the vertical organization of the RCP [6, 8].
In the most severe cases of vascular occlusions, PAMM can evolve into a diffuse retinal whitening, affecting both the middle and inner layers.
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The initial hyperreflective PAMM lesions gradually evolve into corresponding retinal ischemic perivascular lesions (RIPLs) [12]. RIPLs refer to a characteristic focal thinning of the inner nuclear layer (INL) with a compensatory upward expansion of the outer nuclear layer (ONL), resulting in a wavy appearance of the middle layers of the retina [12] (Fig. 1).
Fig. 1
A, B Spectral-domain optical coherence tomography (SD-OCT) scans of an asymptomatic 67-year-old male patient, illustrating retinal ischemic perivascular lesions (RIPLs) (white arrows), which were found incidentally during routine eye examinations. Best-corrected visual acuity is 20/30 in both eyes. RIPLs refer to characteristic focal thinning of the inner nuclear layer (INL), with compensatory upward expansion of the outer nuclear layer (ONL), resulting in a focal wavy appearance of the middle retinal layers
These lesions were initially described as “chronic PAMM” [12, 13], “asymptomatic PAMM with old focal lesions” [14], or “resolved PAMM lesions” [15], as they represent the legacy of acute PAMM lesions [6, 8, 16]. The term “RIPL” was formally introduced by Long and colleagues in 2021 on the basis of the spectral domain (SD)-OCT descriptive features [12]. “Perivascular” refers to the characteristic location of RIPLs near retinal vessels, as seen in en-face OCT reconstructions, where these lesions appear as dark spots distributed perivascularly at the level of the outer plexiform layer [12].
OCT angiography (OCTA) studies have provided quantitative evidence of the ischemic nature of these lesions, showing either reduced vessel density in the foveal DCP [9, 16, 17] or lower superficial vascular complex (SVC) density [18] at the lesion sites.
Unlike PAMM lesions, which typically resolve within weeks, RIPLs are irreversible anatomical changes and may occur without overt ischemia or scotoma. As the earliest subclinical sign of macular ischemia [6, 8, 16], RIPLs could offer insights into subclinical vascular damage in systemic cardiovascular risk and disease [16, 19].
The concept of RIPLs as imaging biomarkers of retinal ischemia has recently emerged in the literature. They may be potential findings of the multimodal imaging picture in a wide variety of systemic vascular diseases, or alongside signs of retinal vascular occlusion [15].
In the past few years, RIPLs have been associated with various cardiovascular and cerebrovascular diseases, including arterial hypertension [13, 15], coronary artery disease (CAD) [12, 20, 21], stroke [17, 22], atrial fibrillation (AF) [22, 23], carotid artery stenosis (CAS) [16, 18, 24], diabetes mellitus (DM) [25], and sickle cell disease (SCD) [26].
The pathophysiology of isolated RIPLs in the context of systemic vascular disease is thought to result from retinal hypoperfusion in the DCP, potentially caused by microemboli formation or reduced blood flow due to factors such as atherosclerosis or low ventricular ejection fraction [21].
Noncommunicable diseases, such as heart disease and stroke, which are the leading causes of morbidity and mortality worldwide, often remain asymptomatic for years despite early structural changes until severe adverse events occur [27]. Noninvasive retinal biomarkers such as RIPLs could help in the early identification and stratification of patients at risk, facilitate timely medical interventions and lifestyle changes, and ultimately improve disease prevention [28].
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In this review, we discuss available data on the relationships of RIPLs with retinal vascular diseases, cardio- and cerebrovascular diseases, and diabetes mellitus. We also discuss the clinical and diagnostic significance of RIPLs in the increasingly wider spectrum of systemic vascular diseases in which they have been observed and future research directions. As a relatively novel OCT finding, the prevalence of RIPLs in the general population has yet to be established.
Methods
We conducted an extensive peer-reviewed literature search on Google Scholar, PubMed, Medline, Scopus, and Embase databases on 13 January 2025, focusing on articles published in English describing RIPLs between December 2012 and February 2025. All searches were made by one trained author (C.L.). Two authors (J.H. and H.K.) independently reviewed reference lists for additional studies. Consensus was reached through review, discussion, and agreement among all authors.
Search terms included “chronic PAMM,” “resolved PAMM,” “RIPLs,” “INL infarction,” and “INL ischemia.” We retrieved additional studies through citation mapping and hand-searching of study references. We use the term “RIPL” throughout this review for consistency and clarity.
Results
Table 1 summarizes the studies published to date regarding the association between RIPLs and systemic vascular diseases.
Table 1
Cross-sectional studies exploring the association between RIPLs and systemic vascular diseases
Systemic disease
Study (year)
Study design
Case group (n)
Control group (n)
Sex and age distribution
Retinal imaging
RIPL prevalence
Key findings
Clinical implications
Study limitations
RIPLs as biomarkers of retinal and systemic diseases typically associated with retinopathy
Hypertension
Burnasheva et al. (2019)
Case–control observational study
27 patients with mild HTN and with low CVD risk
24 healthy subjects
HTN group: 21 M, 6 F; 50.3 ± 22 6.3 years
Control group: 15 M, 9 F; 46.3 ± 13.0 years
Cross-sectional OCT images of 6-mm volume scans
6 × 6 mm OCTA scans
RIPLs found in:
24/27 (88.9%)
hypertensive pts
4/24 (16.7%) controls
OD for the presence of at least one RIPL in one eye of patient with HTN compared with healthy individual 40.0, 95% CI 8.0–200.1, P < 0.001)
OCTA: no difference in VD of SCP and DCP or FAZ area
Suggests a link between retinal microvascular changes and HTN, possibly relevant for early detection
Study design did not include 3-mm OCTA scans centered on the lesions
Limited number of participants
Skewed male-to-female ratio (0.29)
Retinal vein occlusion
Maltsev et al. (2020)
Case–control observational study
66 patients with RVO, including 45 unilateral BRVO and 21 CRVO
57 healthy controls
BRVO cohort: 17 M, 28 F; 64.7 ± 10.8 years
CRVO cohort: 17 M, 4 F; 68.8 ± 11.2 years
Controls: 25 M, 32 F; 67.4 ± 10.5 years)
SD-OCT
8 × 8 mm OCTA scans
RIPLs found in:
32/45 (71.1%) patients with BRVO
15/21 (71.4%) patients with CRVO
11/57 (19.3%) controls
Higher prevalence of RIPLs in fellow eye of patient with RVO compared with healthy individual (OD 10.6. P < 0.001, 95% CI 4.5–24.6)
Hypertension significantly associated with
RVO (OR 2.3, P = 0.04, 95% CI 1.1–4.8)
RIPLs (OR 5.6, P = 0.045, 95% CI 1.0– 27.6)
Indicates potential association between RIPLs and RVO
No longitudinal data
No data regarding the time point of occurrence of RIPLs
Diabetes mellitus
Maltsev et al. (2022)
Cross-sectional
64 patients with diabetes, divided into subgroups based on DR severity
NA
38 M and 26 F; 58.3 ± 12.7 years
3 × 3 mm and 6 × 6 mm OCTA scans
RIPLs found in:
49 (94.9%) patients with diabetes and DR
Mild NPDR: 11 (84.6%)
Moderate-to-severe
NPDR: 18 (100%)
PDR: 20 (100%)
7 (53.8%) patients with diabetes without DR
Eyes with DR were 21.8 times more likely to have RIPLs than eyes of patients with diabetes without DR (P < 0.001, 95% CI 7.0–67.8)
Statistically significant increase in RIPL prevalence with worsening DR severity (P < 0.001)
RIPLs may be an early indicator for diabetic retinal damage and the progression of DR
Limited number of severe NPDR eyes
Quantitative characteristics of lesions unknown
Did not analyze other diabetic retinal lesions
RIPLs as potential biomarkers of systemic diseases not typically associated with retinopathy
Cardiovascular disease
Long et al. (2021)
Cross-sectional, retrospective chart review
84 with CVD, including 26 with stroke, 58 with CHD
76 controls
CVD cohort: M 41, F 43, 72.0 ± 12.5
Controls: M 21, F 55.2 ± 6.8 years)
6 × 6 mm SD-OCT macular raster scan consisting of 49 B-scans
Total number of RIPLs per patient was significantly higher in the CVD group compared with controls (2.8 versus 0.8, P < 0.001)
After adjusting for covariates, RIPL was associated with an OD of having CVD of 1.60 (95% CI 1.09–2.37), P = 0.02
age, sex, and smoking status, presence of RIPLs was associated with OD for having CVD:
1 RIPL—2.34 (CI 1.16–4.74, P = 0.02)
2 RIPLs—4.17 (CI 1.6–10.61, P = 0.003)
3 RIPLs—5.34 (CI 1.71–16.65, P = 0.004)
Higher RIPLs in patients with intermediate and high 10-year ASCVD risk scores than in those with low ASCVD risk scores (1.7 versus 0.64, P = 0.02 and 2.9 versus 0.64, P = 0.002, respectively)
RIPLs may serve as an anatomical marker of prior retinal ischemic infarcts and a biomarker and may improve cardiovascular risk stratification
No longitudinal data
Exclusion of patients with retinal diseases, likely underestimation of the number of RIPLs in the cardiovascular group
Cardiovascular disease
Madala et al. (2022)
Cross-sectional, retrospective chart review
11 subjects, with no prior history of CVD, other than essential HTN
NA
5 M and 6 F; 44–80 years age range
6 × 6 mm SD-OCT volume macular scan consisting of 49 B-scans
NA
Evaluated by primary care physicians or cardiologists for cardiovascular workup:
Potential of RIPLs to uncover underlying CVD in a real-world clinical setting
Relatively small number and nonconsecutive ascertainment of patients
Lack of standardized workup
To determine whether RIPLs vary in different age groups
Cardiovascular disease
Yeo et al. (2025)
Retrospective chart review
11 patients presenting to the medical retina clinic
NA
9 M and 2 F; 66.27 years, range 48–94
SD-OCT
RIPLs found in
18 of the 21 eyes
77.8% bilaterally
9 of 11 patients were found with CVD
36.4% patients with arrhythmia
27.3% patients with CAD
36.4% patients with cerebrovascular events including stroke and/or transient ischemic attack
27.3% patients with peripheral vascular disease
Potential role of RIPLs in assessing cardiovascular risk status and supporting a multidisciplinary CVD management
Relatively small number and nonconsecutive patient selection
No standardized workup in determining cardiovascular risk factors and diseases
Atrial fibrillation
Bakhoum et al. (2023)
Cross-sectional, retrospective chart review
106 patients with AF
91 controls
AF cohort: M 56, F 50; 72.5 ± 7.8 years
Controls: M 47, F 44; 70.6 ± 7.4 years
SD-OCT
Higher percentage of patients with RIPLs was higher in the AF group compared with controls (57.5% versus 37.4%; P = 0.005)
After adjusting for age and sex, presence of RIPLs was significantly associated with AF, OR 2.19,95% CI 1.21–3.97, P = 0.009
Potential noninvasive screening tool for AF-related stroke risk
Cross-sectional nature, cannot infer causality
Potential selection bias
Lack of vascular anatomic features on OCTA
Potential residual confounding
Single-center study, mostly white patients
Stroke
Bakhoum et al. (2024)
Retrospective, cross-sectional study
169 individuals with AF (aged 50–90 years)
NA
NA
OCT
RIPLs found in 67 patients with AF (39.6%)
The presence of RIPLs was significantly associated with stroke OR of 2.59, 95% CI 1.04–6.79, P = 0.04)
Higher rates of HTN (95.2% versus 71.6%, P = 0.016) and RIPL (61.9% versus 36.5%, P = 0.03) in patients with stroke compared with those without stroke
When combining the presence of RIPLs with CHA2D-VASc in a ROC analysis, the AUC in determining stroke was 0.69, which was an increase from 0.61 when using CHA2D-VASc alone
Presence of RIPLs in patients with AF may indicate an increased risk of stroke
Retrospective, cross-sectional analysis prevents determining if RIPLs precede stroke development
Stroke outcome not adjudicated by a neurologist
Small sample size
Participants were followed at only 2 academic centers, limiting generalizability
Myocardial infarction
Bousquet et al. (2024)
Retrospective, cross-sectional study
54 patients with CAD and MI
263 with CAD and without MI
MI cohort: M 39, F 15; 65.9 ± 8.9 years
Non-MI cohort: M 188, F 75; 68.1 ± 7.1 years
SD-OCT
Greater prevalence of RIPLs in the MI cohort compared with the non-MI group (59.3% versus 35.7%; P < 0.001)
RIPL were associated with MI (OR 3 [1.91–4.74]; P < 0.001
After adjusting for CV risk factors, RIPLs remained associated with MI
RIPLs may be a marker of MI in patients with CAD, potentially useful for risk assessment
Patients with macular pathologies excluded, potential underestimation of RIPL, as MI is linked to a higher rate of retinal vascular occlusion
Cross-sectional design, no establishment of causality between MI and RIPLs
Selection bias, as all included patients required SD-OCT, which may affect generalizability
CAD and MI diagnoses based on chart reviews
Stroke (single subcortical infarction)
Kwapong et al. (2024)
Prospective, cross-sectional study
105 patients with SSI
80 controls
SSI cohort: M 65, F 40; 54.83 ± 10.49 years
Controls: M 51, F 29; 57.46 ± 6.22 years
SS-OCT
6 × 6 mm macular OCTA volume scans centered at the fovea
Higher incidence of RIPLs in patients with SSI (54 eyes, 34.62%) compared with the control group (6 eyes, 4.17%)
After adjusting for vascular risk factors, the presence of RIPLs was associated with:
SSI, OR 1.506, 95% CI 1.365–1.662, P < 0.001)
increased periventricular white matter hyperintensity burden (β = 0.414, 95% CI 0.181–0.647, P < 0.001)
perivascular spaces-basal ganglia (β = 0.296, 95% CI 0.079–0.512, P = 0.008)
Eyes with RIPLs showed lower DVC density (P = 0.035) compared with eyes without RIPLs
RIPLs may be a marker of cerebral small vessel disease, helping to identify patients at high risk for silent cerebral ischemia
Cross-sectional design, cannot infer causality
Small number of patients with coronary artery disease in either group
Some patients excluded due to retinal abnormalities and poor imaging quality
Carotid artery stenosis
Drakopoulos et al. (2023)
Prospective, cross-sectional study
22 consecutive patients with CAS
14 consecutive controls
Case: 48–84 years (median 73.5)
Control: 55–80 years (median 70.5)
6 × 6 mm macular OCTA volume scans centered at the fovea
At least 1 RIPL found in:
20/22 patients with CAS (91%) with a mean of 3.4 RIPLs total
10/14 controls (71%), with a mean of 2.0 RIPLs total
DCP VLD at RIPLs:
Decrease in patients with CAS and controls
(P < 0.05)
SCP VLD at RIPLs:
Decrease in patients with CAS (P < 0.05)
Increase in controls (P < 0.05)
RIPLs:
Localized decrease in SCP VLD in
patients with CAS
Localized increase in SCP VLD in
controls
No changes in VT
Eyes with RIPLs had similar VLD and VT as RIPL-free fellow eyes
RIPLs associated with local, but not global, ischemia
Supports the idea of shared pathophysiology with classic PAMM lesions
Suggests a continuum of ischemia severity
No discussion of VLD changes at RIPLs in patients with retinal disease
Excluding patients with a history of retinal vein occlusion removes those with potentially greater RIPL severity
Carotid artery stenosis
Zhang et al. (2023)
Prospective, cross-sectional study
22 patients with CAS, including 11 with < 60% stenosis and 11 CAS post-endarterectomy
11 age-matched controls without CAS
CAS (< 60%)
M 4, F 7,
72 (64–75) years
CAS post op
M 7, F 4
75 (66–76) years
Controls
M 4, F 7
69 (61–75) years
SS-OCT (500 B-scans per 6 × 6 mm en face image)
Patients with CAS had a higher mean number of RIPLs compared with controls (3.5 versus 1.2, respectively; P < 0.02)
Significant differences in RIPL number between < 60% stenosis, post-endarterectomy, and control
RIPLS potential biomarkers for underlying cardiovascular disease
Small sample size
Exclusion of patients with retinal disease, potential underestimation of RIPLs
Cross-sectional nature, cannot infer causality
Carotid artery stenosis
Wang et al. (2025)
Prospective, cross-sectional study
474 patients with CAS
NA
62.71 ± 10.64 years
SS-OCT
6 × 6 mm macular OCTA volume scans centered at the fovea
RIPLs found in 273 eyes (31.97%)
After adjusting for cardiovascular risk factors:
Greater incidence of RIPLs in ipsilateral eyes than in contralateral eyes (36.01% versus 26.72%, RR 1.33, 95% CI 1.09–1.63, P = 0.005),
Higher number of RIPLs and broader distribution in ipsilateral eyes (both P < 0.001)
Higher incidence of RIPLs in patients with CAS with cerebral infarction than patients without infarction (37.86% versus 27.85%, RR 1.33, 95% CI 1.09–1.62, P = 0.004)
Presence of RIPLs positively associated with stenotic degree (P < 0.001)
Lower SVC density (45.48 ± 6.31%) in eyes with RIPLs than those without RIPLs (46.90 ± 5.63%)(P = 0.020)
RIPLs can serve as a biomarker for CAS severity and risk of cerebral infarction
Cross-sectional design, limited the inference of causality
Exclusion of patients with CAS with severe ophthalmic diseases, possible underestimation of the prevalence rate of RIPLs
RIPLs as Biomarkers of Retinal and Systemic Diseases Typically Associated with Retinopathy
Retinal vascular occlusions In 2020, Maltsev et al. [15] demonstrated a higher prevalence of RIPLs in the healthy eye of patients with unilateral retinal vein occlusion (RVO), including branch RVO (n = 45) and central RVO (n = 21), compared with healthy individuals (n = 57) (odds ratio (OR) 10.6, P < 0.001).
The higher prevalence of RIPLs in the fellow eye of patients with RVO suggests that RIPLs might reflect systemic vascular dysfunction, which causes subclinical ischemia in both eyes simultaneously. Given the well-known increased risk of RVO in the fellow eye of patients with unilateral RVO, the authors concluded that RIPLs may indicate a higher risk of severe retinal vascular events. This supports the strong association between RVO and systemic vascular risk factors, highlighting the need for systemic management to reduce further complications.
Arterial hypertension The same study also found an association of RIPLs with hypertension in otherwise healthy individuals (OR 5.6, P = 0.045), although this was not the primary focus of the research [15].
In addition, analysis of 8-mm OCTA scans showed flow signal attenuation or voids in large RIPLs (defined as > 300 µm at the greatest dimension) and their proximity to vessels, indicating that RIPLs could represent minimally ischemic areas [15].
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Therefore, RIPLs could be regarded as one of the earliest signs of altered retinal microcirculation, including those associated with hypertension.
In a subsequent study, the same research group further explored the relationship with hypertension, finding a strong association between mild hypertension (systolic blood pressure (BP) of 140–159 mmHg and diastolic BP of 90–99 mmHg) and the presence of at least one RIPL in 24 of 27 otherwise healthy individuals (OR 40.0, P < 0.001), compared with the age-matched controls with normal BP [13].
There were no significant differences in vessel density of the SCP and DCP, or FAZ area on OCTA between the hypertensive and healthy groups [13].
The study corroborated the hypothesis that RIPLs may represent one of the earliest signs of retinal microcirculation changes associated with mild hypertension, potentially aiding in its early diagnosis before detectable changes in OCTA parameters [13].
Diabetes mellitus Another study conducted by Maltsev et al. [25] investigated the association between RIPLs and DM, showing a high prevalence of these lesions among patients with DM, both with and without diabetic retinopathy (DR) (53.8% and 94.9%, respectively).
The prevalence of RIPLs increased significantly from mild nonproliferative DR (NPDR) to moderate-to-severe NPDR and proliferative DR.
The study suggested that RIPLs may be the earliest and mildest sign of ischemic retinal changes in DR, serving as an early marker of diabetic retinal damage and progression.
Also, they emphasized the role of DR as an independent risk factor for the occurrence of these lesions.
Sickle cell disease Sickle cell maculopathy (SCM) is a retinal vascular disorder recently associated with the presence of RIPLs. Delhiwala et al. [26] reported a case of a 31-year-old female with sickle cell disease, in which OCT scans revealed RIPLs, foveal splaying, and parafoveal thinning. This case suggests that the atrophic changes seen in SCM, such as macular splaying and thinning, may be attributed to acute ischemic events or PAMM and DCP hypoperfusion, likely resulting from sludging or arterial occlusion. As markers of chronic ischemic damage, RIPLs further strengthen the association between sickle cell disease and retinal ischemia.
RIPLs as Potential Biomarkers of Systemic Diseases Not Typically Associated with Retinopathy
Cardiovascular disease Long et al. [12] conducted a retrospective study that showed patients with coronary heart disease (CHD) or stroke (n = 84) had significantly more RIPLs on routine SD-OCT scans compared with healthy controls (n = 76) (2.8 versus 0.8, P < 0.001), even after adjusting for risk factors such as age, sex, smoking, blood pressure, lipids, and hemoglobin A1C (OD 1.60, 95% CI 1.09–2.37, P = 0.02).
Individuals with stroke had a higher average number of RIPLs than those with CHD (3.7 versus 2.4), suggesting that RIPLs may be more indicative of cerebral vascular atherosclerosis than coronary pathology [12]. The presence of one, two, or three RIPLs was associated with increasingly high odds of cardiovascular disease (ORs of 2.34, 4.17, and 5.34, respectively) after controlling for confounding risk factors.
In addition, RIPL count correlated with increased 10-year atherosclerotic cardiovascular disease risk, with individuals at intermediate or high risk showing significantly more RIPLs than those at low risk.
In summary, RIPLs, detectable through routine retinal scans, may serve as an additional biomarker to help identify individuals at risk for adverse cardiovascular events. However, about 44% of individuals with cardiovascular disease showed no RIPLs [12], highlighting the low sensitivity but high specificity of the biomarker. This emphasizes that RIPLs may be more useful in confirming the presence of cardiovascular disease rather than detecting it in all individuals.
In a consequent study, Madala et al. [20] found that RIPLs, detected incidentally on SD-OCT in a real-world clinical setting, could help to identify subclinical cardiovascular disease and prompt further evaluation. Following RIPL detection, 11 subjects with no prior cardiovascular history except hypertension were evaluated by their primary care providers. Of these, eight patients (72.7%) were newly diagnosed with conditions such as CAD and cerebral infarction, with two undergoing invasive procedures and three starting new treatments.
Similarly, a retrospective chart review [29] of 11 patients presenting to a medical retina clinic identified incidental findings of RIPLs in 18 of 21 eyes on SD-OCT (85.7%). Of the 11 patients, 9 (81.8%) were found with CVD. Diagnoses included arrhythmia in 36.4% patients, CAD in 27.3%, cerebrovascular events including stroke and/or transient ischemic attack (TIA) in 36.4%, CAS in 8.33%, and peripheral vascular disease in 27.3% patients.
Despite the absence of standardized workups and the lack of distinction between age groups, these studies suggest that RIPLs detected during routine eye examinations can reveal underlying subclinical cardiovascular disease, even in the absence of overt symptoms.
Therefore, it is important to consider cardiovascular assessment in individuals with RIPLs, allowing for better targeting of individuals who may benefit from further cardiovascular evaluation, potentially leading to earlier intervention and improved outcomes.
A study report conducted by Drakopoulos et al. [30] aimed to determine whether RIPLs could serve as a biomarker for cardiovascular risk in patients with age-related macular degeneration (AMD), independent from subretinal drusenoid deposits (SDDs), which have recently been associated with increased risk of cardiovascular disease. They found that RIPLs were independent predictors of cardiovascular risk, even in the absence of SDDs. As such, the reported independence of RIPLs and SDDs supports their utility as orthogonal predictors of cardiovascular risk [30].
Atrial fibrillation CAD often coexists with conditions such as AF, the most common cardiac arrhythmia in adults, which affects 17–46% of patients with CAD and increases stroke risk fivefold due to emboli formation [31]. Early detection of AF is critical to prevent complications, as it can be managed with anticoagulation [31].
Bakhoum et al. [23] investigated the association between RIPLs and AF, independent of ischemic heart disease, and found a significantly higher prevalence of RIPLs in patients with AF (n = 106) compared with those without (n = 91) (57.5% versus 37.4%; P = 0.005), even after adjustment for important confounders. Thus, incidental detection of RIPLs during routine eye examinations may potentially guide ophthalmologists in identifying patients who may need further cardiovascular evaluation.
Given the evidence of subclinical retinal ischemia in individuals with AF, the same research group investigated whether the presence of RIPLs is associated with ischemic stroke in individuals with AF and found a significant association (OR of 2.59, 95% CI 1.04–6.79, P = 0.04), even after adjusting for the CHA2D-VASc score (modified to exclude history of stroke, transient ischemic attack, or thromboembolism), a commonly used tool to assess stroke risk in patients with AF [22]. Combining RIPLs with the CHA2D-VASc score improved the stroke prediction area under the curve (AUC) from 0.61 to 0.69 [22].
The authors concluded that RIPLs could serve as a valuable biomarker for stroke risk assessment, potentially improving the predictive capacity of existing risk stratification tools.
Myocardial infarction Building on growing evidence that RIPLs are linked to cardiovascular conditions, Bousquet et al. [21] explored the association between RIPLs, detected using SD-OCT, and a history of myocardial infarction (MI) in patients diagnosed with CAD. They found a higher prevalence of RIPLs in the MI group compared with the non-MI group (59.3% versus 35.7%; P < 0.001). After adjusting for cardiovascular risk factors, the presence of RIPLs was significantly associated with MI, showing an OD of 3 (1.91–4.74; P < 0.001) [21]. The strong association between RIPLs and ischemic heart disease, particularly MI, underscores their potential value in cardiovascular risk assessment.
Single subcortical infarction (SSI) Given the anatomical and embryological similarities between retinal and cerebral microcirculation, retinal microvascular changes may reflect cerebral microcirculation alterations. Retinal hypoperfusion in SSI, which accounts for a quarter of all acute strokes [32], is thought to indicate ischemic or hypoxic conditions in the brain, with the retina potentially showing the earliest signs of ischemia [33].
Kwapong et al. [17] found an association between RIPLs and SSI, independent of age, sex, and vascular risk factors (OR´1.506, 95% CI 1.365–1.662, P < 0.001).
The study also showed that in patients with SSI, RIPLs were associated with increased markers of cerebral small vessel disease (SVD), such as white matter hyperintensity and perivascular spaces in the basal ganglia on brain imaging [17]. The use of noninvasive OCT/OCTA to detect RIPLs could be a valuable tool for identifying SVD and suggests that retinal ischemic changes may reflect ischemic changes in the brain.
Carotid artery stenosis Drakopoulos et al. [16] observed a high prevalence of RIPLs (91%) in patients with carotid artery stenosis (CAS), which is one of the most common causes of cerebral infarction worldwide [34]. However, it is worth noting that 10 out of 14 controls (71%) also had at least one RIPL, suggesting that RIPLs may not be exclusive to patients with CAS and could be present in other conditions or even healthy individuals.
Corroborating these findings, a study conducted by Zhang et al.[24] demonstrated that RIPLs were prevalent and increased in patients with CAS compared with controls without carotid disease (3.5 versus 1.2, respectively; P = 0.02). When comparing < 60% stenosis, post-endarterectomy, and control groups, RIPL numbers were significantly higher in the post-endarterectomy group than in controls. Although the difference between the post-endarterectomy and < 60% stenosis groups was not statistically significant, a trend toward significance was observed (mean RIPL number: 4.5 vs. 2.6), as patients undergoing endarterectomy often have more advanced disease. This suggests a potential link between RIPL counts, CAS severity, and clinical status, with higher RIPL counts indicating greater cardiovascular risk.
In an observational cross-sectional study conducted by Wang et al. [18], ipsilateral eyes in patients with CAS had a higher number of RIPLs with border distribution after adjusting for important covariates (both P = 0.001) compared to the contralateral eyes.
Moreover, the prevalence of RIPLs was higher in patients with CAS and cerebral infarction than those without infarction (37.86% vs 27.85%, RR 1.33, 95% CI 1.09–1.62, P = 0.004) [18].
The distribution of RIPLs was associated with cerebral infarction (P = 0.015), while no significant association was found between the number of RIPLs and cerebral infarction. Both the number and distribution of RIPLs showed a strong association with the degree of stenosis (P < 0.001). This association was observed in both ipsilateral and contralateral eyes (all P < 0.01) [18].
These studies suggest that the presence of RIPLs in otherwise healthy patients may reflect retinal microvascular changes seen in CAS. This builds upon previous discussions, supporting the potential of RIPLs as a retinal microvascular biomarker for systemic vascular diseases.
Limitations of Current Studies and Future Directions
While the evidence linking RIPLs to cardio- and cerebrovascular diseases continues to grow, there are limitations that the current studies have not addressed.
A significant concern is that much of the research on RIPLs relies on cross-sectional studies. Longitudinal studies are needed to establish a causal relationship between RIPLs and cardio- and cerebrovascular diseases and confirm their predictive value.
The potential for confounding factors presents another major limitation, as most studies have been conducted on elderly populations with a high prevalence of comorbidities. While most studies indicate that the association between RIPLs and cardio- and cerebrovascular diseases remains significant after adjusting for systemic risk factors, suggesting an independent relationship, it is important to consider that other cardiovascular risk factors may also influence these observed associations.
Furthermore, many studies on RIPLs are limited by small sample sizes and lack of population diversity, which affects the generalizability of their findings. Larger studies with more diverse cohorts are needed to validate these associations and ensure they apply to broader populations.
Moreover, the exclusion of patients with macular pathologies and retinal vascular occlusion to prevent confounding of RIPL identification may have led to an underestimation of RIPL prevalence, as cardio- and cerebrovascular diseases are associated with a higher incidence of retinal vascular occlusion.
Finally, the lack of standardized protocols for detecting and quantifying RIPLs leads to inconsistencies across studies. Implementing standardized protocols would enhance consistency and comparability between research findings.
Artificial intelligence (AI)-based algorithms With the growth of complex imaging techniques and the size of datasets, the full benefits of RIPLs as retinal biomarkers could be realized through advanced AI methods. AI-based algorithms hold great promise beyond automating the detection of RIPLs in retinal imaging. These tools could potentially enable risk prediction and the characterization of cardio- and cerebrovascular diseases during their silent or asymptomatic stages, facilitating early intervention. AI can give deeper insights into the complex relationships between RIPLs and systemic diseases, advancing personalized healthcare strategies driven by retinal imaging.
To our knowledge, no studies have yet explored the application of AI in analyzing RIPLs, but this is likely to change soon with ongoing research efforts. An important area for future research is to investigate how the detection and measurement of RIPLs may correlate with current cardiovascular risk scores and contribute to predicting major adverse cardiovascular events.
Conclusion
RIPLs are permanent anatomical markers of retinal ischemia readily and noninvasively detected through SD-OCT scans, often found incidentally during routine eye examinations. Positioned at the less severe end of the ischemic spectrum alongside classic PAMM lesions, RIPLs are associated with systemic vascular dysfunction that underpins various cardio- and cerebrovascular diseases [12, 13, 21, 25].
Cardiovascular and metabolic diseases and related conditions are the leading causes of morbidity and mortality globally, and their incidence is projected to rise because of the increasing proportion of elderly people [35]. Detecting RIPLs during routine eye examinations in otherwise healthy individuals could prompt further investigation into potential cardiovascular diseases, 50% of whom are unaware of their subclinical condition [36], providing an opportunity for early intervention, ultimately improving morbidity and mortality outcomes in a personalized medicine approach. Advances in ophthalmic imaging technologies combined with rapid progress in AI applications in medical research could accelerate the development of RIPLs as retinal imaging biomarkers in cardio- and cerebrovascular diseases.
Further research is needed to establish the prevalence of RIPLs in the general population, address several research gaps and challenges identified in this review, and better understand the underlying pathophysiological mechanisms of these retinal findings before RIPLs can be fully translated as useful biomarkers in retinal imaging-based oculomics.
Author Contributions
All authors contributed to the study conception and design. Material preparation and data collection was performed by Celeste Limoli and Josef Huemer; analysis was performed by Celeste Limoli, Josef Huemer, Siegfried Wagner, and Hagar Khalid. The first draft of the manuscript was written by Celeste Limoli, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
No funding or sponsorship was received for this study or publication of this article.
Data Availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Declarations
Conflict of Interest
Celeste Limoli, Hagar Khalid, Siegried Wagner, and Josef Huemer declare that they have no competing interests.
Ethical Approval
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
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