Distinguishing from the survey areas of previous studies in Asia (e.g., Beijing and Singapore) and western countries[1-13], the county of Shuangcheng was selected for study to represent the typical environmental region, which was characterized by a cold climate (average 4.5℃yearly, approach to subfrigid zone), lower elevation (approximately 200 m), farming communities, and plains. This study provides vital epidemiological data on the prevalence of retinal microvascular abnormalities and their associations with CCVds in this environment. Each retinal outcome was determined by the assessment of retinal digital images. First, we found that the overall prevalence of retinal microvascular abnormalities in the present population was relatively higher but the prevalence of retinopathy was lower than those reported in other regions of the world[3,14,25-27]. Our finding adds to existing data, details retinal microvascular abnormalities in a rural population in a region of northeast China with a low altitude and cold climate. Second, we showed that retinopathy was associated with a self-reported diagnosis of a stroke, while AVN was associated with a self-reported diagnosis of CHD; but FAN, GAN and AS were not consistently related to the self-reported diagnosis of CHD or previous cerebrovascular events such as stroke. Thus, an examination of retinal microvascular characteristics may offer clues regarding CCVds and could be a potentially novel biomarker of CCVds risk.
In the present study, among the total sample, the prevalence of FAN, AVN, AS, retinopathy, and GAN were 9.1%, 8.9%, 6.6%, and 6.2%, respectively. In comparison, using almost the same assessment methods, the prevalence rates of FAN, AVN, AS and GAN were 6.3%, 6.6%, 4.8%, and 4.3% respectively, in the Beijing Eye Study (Chinese population: 40-101 years of age, including those with diabetes). The prevalence of RVAs in the present study was relatively higher than that of the Beijing Eye Study. The prevalence rates of FAN, AVN, AS and retinopathy in persons without diabetes were 9.0%, 8.9%, 5.0%, and 6.8% respectively in the present study. In comparison, the ARIC study, which examined a non-diabetic study population aged 48 to 73 years, found that the prevalence rates were 7.3% for FAN, 6.0% for AVN, and 4.0% for retinopathy. And the Cardiovascular Heart Study (CHS), which also included a non-diabetes population aged 69 to 97 years found that the prevalence rates were 9.6% for FAN, 7.7% for AVN, and 8.3% for retinopathy. Obviously, the prevalence of RVAs in the present study was roughly equivalent to the data of the CHS study but was relatively higher than that of the ARIC study. First, these differences might result from sample selection and population characteristics (e.g., the average age[3,28,29] and the frequency of hypertension[29-33] among these studies). Second, the average latitude of the survey area was relatively high(Figure 1), and the average annual temperature was approximately 4.5℃, stimulation by cold air is a precipitating factor for CCVds[34,35]. Presumably, this factor may be related to the high frequency of RVA in this area. In addition, our study employed a 40° non-mydriatic camera to obtain fundus images and used the digital images to grade retinal lesions in the present study. These methods differ from those used in previous studies and thus may have also contributed to the difference between our results and previous findings.
Notably, the prevalence of retinopathy (5.1%) in persons with diabetes was lower than that in Chinese in Beijing (27.9%, ≥45 years), Koreans (15.8%,≥40 years), and Chinese in rural Handan (43.1%, ≥30 years). The specific reasons for the low prevalence were not clear, in addition to different examination techniques and the grading systems, the prevalence was presumably associated with a still lower living standard and employment involving mainly physical labour. Interestingly, for all types of retinal lesions, no significant differences were detected between the subjects with and without diabetes of the whole sample, which is consistent with the Beijing study. That is to say, although retinopathy (e.g., microaneurysms, haemorrhages, soft exudates or cotton wool spots, hard exudates, etc.) is a landmark of diabetic retinopathy, it is still common in subjects without diabetes who are over 50 years old. We should be cautious in diagnosing diabetic retinopathy, especially in elderly patients.
After stratifying the population by age and gender (Table 2), males and older subjects tended to have more frequent RVAs of all types than their counterparts. These findings were consistent with those of previous reports such as those from the ARIC study and the National Health and Nutrition Examination Survey (NHANES) but different from those of the Beijing Eye study which even showed that AS was more frequent in females than in males.
The focus of the present study was the correlation between RVAs and CCVds, which was discussed respectively. In general, after adjusting for age, gender and left/right eyes, FAN, and AVN were found to be associated with a self-reported diagnosis histories of CHD (OR, 1.72; 95% CI, 1.31, 2.25; and OR, 1.89; 95% CI, 1.45, 2.46, respectively), and its risk factors (e.g., hypertension, hyperlipidaemia, and habits of past/current smoking or alcohol consumption), and when we further adjusted for these above risk factors, the FAN association with CHD disappeared, suggesting that FAN was only related to the risk factors of CHD but was not related to CHD itself. And the AVN-CHD association was attenuated but still existed (OR, from 1.89 to 1.44) (Table 3, 4), suggesting that the changes in AVN could partly reflect the changes in the cardiac macrovasculature in addition to the microvasculature. In the same way, when adjusted for age, gender and left/right eyes, retinopathy was associated with a self-reported diagnosis history of stroke(OR, 3.27; 95% CI, 1.93,5.54) and its risk factors(hypertension, hyperlipidaemia, habits of past or current smoking, habits of past or current alcohol consumption). When further adjusted for these above risk factors, the retinopathy–stroke association also weakened (OR, from 3.27 to 2.05) but still existed. Thus, these data suggest that a point-to-point association between retinal vascular changes and CCVds may exist (e.g., the AVN-CHD association or retinopathy-stroke association). A multicentre study even demonstrated that different retinopathy signs were associated with specific stroke subtypes; for example, retinal arteriolar narrowing was associated with lacunar stroke, whereas retinal haemorrhages were linked with cerebral haemorrhages[6,8,11,39,40]. However, the results of the CHS study showed that only retinopathy was associated with prevalent CHD and stroke and the results of the Beijing Eye Study showed that RVAs were not related to the self-reported diagnosis of CHD or previous cerebrovascular events such as stroke. These inconsistent results might be due to the different assessment methods and grading thresholds among these studies.
The rest, except for retinopathy, of the RVAs were not related to the self-reported diagnosis history of stroke, but were associated with its risk factors; AS, retinopathy and GAN were not related to the self-reported diagnosis history of CHD, but were associated with the risk factors of CHD (Table 3). Although RVA and CVDs share some of the same risk factors, they are different in structure. Certain types of retinal microvascular abnormalities appear to be associated with systemic processes that are different from those associated with macrovascular changes (e.g., structural, and pathological features), supporting the ARIC and CHS study findings in middle-aged people.
Some factors may have influenced our evaluation of the prevalence of RVAs and their possible correlation with CCVds. First, images were not obtained from some of the participants, and some photos could not be evaluated due to refractive interstitial opacity. A relatively high proportion of these images were obtained from elderly patients, who generally have more RVAs. Second, the evaluation of retinal abnormalities was performed manually, which may lead to the relatively low κ values, for intraobserver and interobserver variation. Third, we used questionnaires to collect the histories of diseases as the basis of the prevalence estimates of CCVds. This may underestimate the associations with systemic diseases. Fourth, for the assessment of GAN, considering the engorged and tortuous of veins may caused by other reasons, such as branch or central retinal vein occlusion, so these eyes were not defined as GAN. This would lead to an underestimation of the prevalence of GAN. Last, due to the use of a cross-sectional study design rather than a cohort study design, the current study could not elucidate the evolution of RVAs and their real-time relationship with systemic diseases.
What is the innovative points and clinical significance of the present study?revious studies mostly tended to describe the association between RVAs and CCVds in general or to explore the association between retinal vessel diameter and CCVds with image analysis technology[5-11,39,41-43]. In this study, we found that point-to-point associations might exist between specific types of RVAs and CCVds(e.g., the AVN-CHD association or retinopathy-stroke association). If such associations could be demonstrated as stable, we may need to pay more attention to the correlation between specific types of RVAs and CCVds. Thus, the prediction of CCVds may become more targeted, especially in rural primary hospitals where medical equipment was relatively scarce. In addition, a semi-quantitative classification method for RVAs was used in this study. Due to the use of digital fundus photographs and standard evaluation system (ARIC), the variability among observers is significantly lower than that of the use of direct fundoscopic examination. Moreover, because this method is low-cost and efficient and it does not need professional technicians and expensive professional software, it could be popularized and implemented in primary hospitals in undeveloped regions. However, due to the relatively limited geographical scope of this study, future clinical studies involving large samples and multiple regions are needed clarify the stability of this correlation between specific types of RVAs and CCVds.