The main findings of this study were as follows: 1) the presence of carotid plaque and baPWV were higher in patients with RVO than in those without RVO; 2) smoking, LDL cholesterol level, baPWV, and the presence of carotid plaques were independently associated with the development of RVO; 3) LDL cholesterol level and the presence of carotid plaques were significantly associated with the development of BRVO, whereas smoking was significantly associated and baPWV was marginally associated with the occurrence of CRVO. To the best of our knowledge, this study is the first to show that the markers for subclinical atherosclerosis, including carotid plaque and baPWV, were associated with the development of RVO.
The pathophysiology of RVO is still unclear, but it is thought that age-related alterations of collagen tissue causing stiffening of the lamina cribrosa and/or atherosclerosis of retinal arteries inducing remodeling and thickening of the arterial wall may cause compression of the adjacent veins within the shared adventitial sheath, leading to blood flow stasis and formation of an endoluminal thrombus5,16. Some studies showed an association with conventional cardiovascular risk factors, such as hypertension, dyslipidemia, diabetes mellitus, and cigarette smoking16. In this respect, the role of atherosclerosis in the development of RVO is very important, but there is no recommended tool for evaluating atherosclerosis and no rigorous evidence is available concerning the clinical significance of subclinical atherosclerosis in patients with RVO.
Atherosclerosis is a chronic inflammatory disease of the arteries that is the most common pathophysiologic process underlying cardiovascular disease.6 Atherosclerosis exists along a continuum from subclinical atherosclerosis to clinical atherosclerotic vascular disease, can start early in life, and can remain clinically undetected throughout life until an acute event, such as myocardial infarction or stroke. Subclinical atherosclerosis is an early indicator of atherosclerotic burden, and its timely recognition can slow or prevent the progression to overt cardiovascular disease as well as an optimal approach for primary and secondary prevention of RVO.
Our findings suggest that cardiovascular risk factors and subclinical atherosclerosis are independently associated with RVO, highlighting the close relationship between retinal microvascular abnormalities and systemic atherosclerosis. Furthermore, the differences in the associated predictors between BRVO and CRVO may reflect the differences in pathophysiology between BRVO and CRVO. LDL cholesterol level and the presence of carotid plaques were associated with BRVO, whereas smoking was associated with CRVO in our results. BRVO predominantly occurs at arteriovenous crossing sites where a retinal artery may compress the retinal vein to narrow the lumen17,18. Therefore, retinal artery atherosclerosis plays an important role in the pathogenesis, and retinal artery atherosclerosis may correlate with atherosclerosis in the carotid arteries. In contrast, CRVO is associated with thrombus formation resulting from endothelial dysfunction in the retinal veins near the lamina cribrosa, where the retinal veins are normally narrowed, which could be easily promoted by smoking19,20. Further studies are needed to determine the exact role of subclinical atherosclerosis in the development of BRVO and CRVO.
In the present study, we documented that the prevalence of carotid plaque was higher in patients with RVO and independently associated with RVO, especially BRVO. Traditionally, carotid plaque and CIMT have been used as surrogate markers for atherosclerotic disease. However, there is debate about the better marker and whether carotid plaques have a stronger association with atherosclerotic disease than CIMT21–23. Previous studies attempted to show evidence of atherosclerosis in patients with RVO, but could not provide definitive evidence of the association because of the lack of a control group or the small number of patients who underwent carotid ultrasound. In 2005, Wong et al. pooled data from two large population-based cardiovascular studies, Atherosclerosis Risk in Communities Study, and the Cardiovascular Health Study, which included 33 patients with BRVO and 6 patients with CRVO24. They showed that about a quarter of participants with RVO (9 of 33) had evidence of carotid plaque on carotid ultrasonography. In addition, carotid plaque was included in the final multivariable model as a significant independent predictor for RVO. However, this study had only 9 patients with RVO and carotid plaque, and was obviously limited by the cross-sectional design. Compared to previous studies, we conducted a case-control study by recruiting patients without RVO, and propensity score matching was used to control for potential confounding variables. Thus, our study suggests a more obvious influence of carotid plaque on the development of RVO, especially BRVO. Further studies are needed to clarify the characteristics of carotid plaques in patients with RVO, and their association with pathophysiology, clinical course, complications, and treatment prognosis.
We also documented that higher baPWV, which is representative of arterial stiffness, was associated with the development of RVO, which supports the hypothesis of a vascular etiology for RVO. Measurement of arterial stiffness is clinically important since arterial stiffness is associated with a patient’s future cardiovascular events, independent of traditional cardiovascular risk factors25,26. There are various methods for measuring arterial stiffness; however, baPWV is non-invasive and relatively simple to measure, making it widely used clinically because measurement of the baPWV requires only wrapping BP cuffs on four extremities. Our results are consistent with those of a previous study by Gouliopoulos et al.27, stating that patients with RVO have increased arterial stiffness by measuring the carotid-femoral pulse wave velocity, and that elevated pulse wave velocity is significantly associated with RVO. However, our data suggest that the role of arterial stiffness is greater in patients with CRVO than in those with BRVO.
This study has several potential limitations. First, it had an observational, single-center design, and may be biased by institutional expertise. Second, although the sample size of patients with RVO was small, we tried to overcome this limitation by propensity score matching. Moreover, although the sample size of patients with CRVO was relatively small compared to that of patients with BRVO, it has the advantage of presenting the difference between the pathophysiology and risk factors of BRVO and CRVO through subgroup analysis. Third, our control subjects without RVO had more cardiovascular risk factors than the general population because they were recruited in a cardiology outpatient clinic. However, the inclusion of these covariates in the multivariable logistic regression model allowed us to adjust all the risk estimates for their potential confounding effects. Finally, we did not have information on the type of treatment and subsequent follow-up after the episode of RVO; therefore, we could not test the impact of carotid plaque and cardiovascular risk factors on clinical outcome. Future large-scale, population-based, prospective cohort studies on RVO in subjects with carotid plaque could verify whether early atherosclerosis increases the risk of RVO.
In this respect, the role of atherosclerosis in the development of RVO is very important, but there is no established tool for evaluating subclinical atherosclerosis in patients with RVO. Our study suggests that carotid ultrasound may be a good assessment tool to evaluate atherosclerosis and its complications, such as coronary artery disease and stroke, in patients with RVO. In this regard, further studies are needed to clarify the characteristics of carotid plaques in patients with RVO and their association with pathophysiology, clinical course, complications, and treatment prognosis.
In our study, we documented that RVO is significantly associated with subclinical atherosclerosis, represented as carotid plaque and baPWV. Our results support the hypothesis of a vascular etiology of RVO. Evaluating subclinical atherosclerosis may be useful in evaluating cardiovascular risk and tailoring proper management in patients with RVO. Further studies are needed to determine the exact role of subclinical atherosclerosis in the pathogenesis of RVO and to reveal its value in predicting systemic morbidity and mortality in patients with RVO.