Myopia is an important global public health issue and can lead to significant vision impairment (1–3). Anisomyopia, a condition related to myopia, is defined as an unequal refractive error between the right and left eyes. This is characterized by an interocular difference in myopic spherical equivalent refraction (SER) ≥ 1.00 D (4). This unequal state of anisomyopia is typically caused by one eye experiencing accelerated growth compared to the contralateral eye during myopia development (5–8). Anisomyopia is significantly prevalent, and its incidence rate has been confirmed to be relatively high, approximately 2 to 5 times higher than that of hyperopic anisometropia (9). Severe anisomyopia is a causative factor for a range of significant visual impairments, including visual fatigue, diplopia, declined stereovision, amblyopia, and strabismus, among others (10, 11).

To date, the pathophysiology of myopia, which is the root cause of the condition of anisomyopia, remains incompletely understood. The majority of previous studies have primarily focused on ocular length, corneal curvature, and anterior chamber depth (ACD) (12–14). However, relying on these downstream indicators alone cannot fully reflect the rapid progression of myopia. Regarding fundus structures, although studies have reached a certain degree of consensus that the retina is impaired as myopia progresses (11, 15, 16), the limited detection techniques have confined fundus research only to the retina, leaving the exploration of the choroid largely untapped. The choroid, as a highly vascularized tissue, the integrity of the structure and function of the choroid are crucial for maintaining retinal homeostasis; any malfunction or malformation in the choroid can be indicative of myopic onset and progression (17–19). Recently, it has been observed that there is already a significant decrease in choroid thickness (ChT) during the initial phase of myopia, even while the retina remains stable (20). Furthermore, another study reported that abnormal variations in choroidal tissue appeared in high myopia before the occurrence of retinopathy (21, 22). Moreover, Ho et al. (23) pointed out that decreased visual acuity in myopic patients was only related to choroid changes in the macular fovea. All these compelling findings strongly imply that the involvement of choroidal mechanisms may contribute to myopia, offering us a novel perspective and guiding myopia research in a new direction. Therefore, we confidently speculate that alterations in the choroid may serve as a potential indicator of myopia. Currently, there are few studies focused on the choroid in anisomyopia. In fact, research on anisomyopia is urgently needed because examining and comparing both eyes of the same individual can minimize the influence of confounding inter-individual variables such as genetics and environment. These natural experimental paradigms can prompt a deeper comprehension of how human myopia develops.

Moreover, previous medical practice has faced challenges in visualizing the choroid using fluorescein angiography (FA) due to obstructions caused by the pigment in the layer of the retinal pigment epithelium and choroid. Traditional imaging modality, indocyanine green angiography (ICGA), allows for the exploration of the choroid, but it is restricted to generating two-dimensional (2D) images of large vessels (17, 24). OCTA is a reliable in vivo quasi-histological imaging technology that offers detailed information and quantitative evaluations without the use of dyes or physical contact. Particularly, recent advancements in swept-source optical coherence tomography (SS-OCTA) represent a significant milestone. This technology enables 3D visualization and is equipped with higher frequency, faster scanning speed, deeper signal penetration, and better sensitivity, allowing for unprecedented, optimal visualization of the choroid (7, 24, 25). Furthermore, to the best of our knowledge, anisomyopia has not been extensively observed using OCTA to date. Thus, it is imperative to obtain precise measurements of choroidal circulation and thickness changes using SS-OCTA to investigate the interocular differences between the paired eyes of anisomyopic adults, which will aid in revealing the underlying connection between the choroid and myopia.

The relationship between the choroid and myopia remains an important topic that needs to be elucidated. Therefore, the current study explored the interocular differences in choroidal thickness and circulation in the paired eyes of anisomyopic adults, aiming to identify whether there is a potential association between the choroid and myopia. In summary, in all anisomyopic individuals, the more myopic eyes had lower MCT, CBFA, CVV, and CVI than the less myopic fellow eyes, and the interocular differences in MCT, CVV, and CVI were positively correlated with that in SER and negatively correlated with that in AL. The multiple linear regression model confirmed that the interocular difference in CVV was significantly associated with the interocular difference in SER. These results indicate that both choroidal thickness and circulation are compromised as myopia progresses, and they are more likely to decrease with worsening myopia. The choroid is regarded as an important biomarker for myopia, and our findings may shed some light on the relationship between choroid alterations and human myopia.

Recently, an inverse association between ChT and the severity of myopia has been demonstrated in some cross-sectional and longitudinal studies (20, 30, 31). Consistently, our result showed that the more myopic eyes have thinner ChT than the contralateral eyes in anisomyopic adults. Similarly, a study with a larger sample size (70 pediatric anisomyopic individuals) and another involving a smaller population (44 anisomyopic teenagers) provided evidence supporting our observations (7, 32), although the areas explored in the above two studies (3 × 3 mm) were relatively smaller than our study (6 × 6 mm). In addition, some scholars have proposed a theory named “choroidal accommodation,” pointing out that ChT has the characteristics of bidirectional variation in response to the process of imposed myopic or hyperopic defocusing (32, 33). These findings suggest that individuals with considerable ChT reduction may be more likely to experience accelerated myopic progression. However, Liu et al. (34) suggested that ChT thinning may not be solely due to passive stretching from axial myopia, and Vincent et al. (35) also suggested that variation in globe expansion from simple passive stretching cannot fully account for the binocular difference in ChT observed between the paired eyes of anisomyopic individuals. Therefore, it is reasonable to speculate that changes in ChT may be related to the modulation of myopic eye elongation to some extent, but additional factors must also be considered.

Anatomically, based on the highly vascularized choroid and its characteristics of rapidly changing blood flow, it seems plausible that variation in choroidal circulation may primarily contribute to changes in ChT. Currently, several pharmacological studies have demonstrated that changes in ChT are accompanied by concomitant variation in choroidal perfusion, with both parameters showing enhancement after administration of prazosin (a vasodilator) (36) and a decrease after intravitreal injection of bevacizumab (an anti-vascular endothelial growth factor drug) (37). Moreover, this feature of bidirectional changes in choroidal circulation has also been observed in myopic models, with decreases during experimentally induced myopia and increases during subsequent recovery (38). Therefore, considering that choroidal thinning may reflect myopia development, it is plausible to theorize that myopic-related ChT reduction might coincide with diminished choroidal circulation. Furthermore, it is conceivable that choroidal circulation may be directly or indirectly related to myopia, with or without the involvement of ChT.

Our main finding was that choroidal vascularity was lower in the more myopic eyes of the anisomyopic individuals. The concomitant decrease in CVV and CVI revealed that the large and middle choroidal vessels gradually deteriorate with increasing myopia, suggesting a potential connection between choroidal vascularity attenuation and myopia. Our results are in line with several recent studies. Gupta et al. (39) first reported a reduction in choroidal vascular area in patients with high myopia. Then, Li et al. (40) reported that the luminal area of the choroid exhibits a decreasing trend in low-to-moderate myopia. Later, Wu et al. (6) and Su et al. (41) demonstrated that reduction in choroidal vascularity was positively associated with increased myopic severity. More recently, a study on pediatric anisomyopic patients reported that the more myopic eyes exhibited reduced choroidal vascularity than the fellow eyes (7). Collectively, all these findings indicate that decreased choroidal vascularity is associated with myopia progression. A key issue that remains unresolved is whether attenuation in choroidal vascularity leads to myopia development or vice versa; their cause-and-effect relationship needs to be illustrated.

Considering that the choriocapillaris is supplied by the large and middle vascular tissues, variations in choroidal vascularity may affect its circulation, but the existing conclusions are inconsistent. Milani (42) and Liu et al. (32) found no significant differences in choriocapillaris perfusion between the control and myopic eyes. Similarly, Scherm et al. (43) observed that choriocapillaris blood flow remained stable with increasing physiological myopia. In contrast, in both anisomyopic adults and children, Wu et al. (6, 7) discovered that the eyes with a greater degree of myopia tended to have higher choriocapillaris flow deficits than the contralateral eyes. Moreover, Al-Sheikh et al. (44) studied patients with high myopia and confirmed that choriocapillaris flow deficits had an increasing tendency in eyes with severe myopia. However, Mo et al. (45) reported that choriocapillaris flow densities decreased in pathological myopia. Our result revealed a significant decrease in CBFA in the more myopic eyes. Different sizes of covered choroidal regions, variations in detection indicators that identify choriocapillaris perfusion, and, more importantly, the lack of unified and standardized machine algorithms may largely account for the inconsistent results.

Recently, hypoxia has emerged as a new perspective. Hao et al. (1) first creatively put forward a new theory of myopia: External visual stimulation may change hemodynamics and hemorheology by regulating choroidal circulation, thereby causing hypoxia in the adjacent scleral, which, in turn, modulates scleral remodeling and axial elongation, eventually leading to the development of myopia. This theory provides a new insight into the role of the choroid in the pathogenesis of myopia. Later, their another study revealed that increased choroidal perfusion can inhibit both the development of myopia and the elongation of the eyeball by attenuating scleral hypoxia (36). Consistently, our results showed that the more myopic eyes were associated with thinner ChT and reduced choroidal circulation. Therefore, it is plausible that reduced ChT and circulation may result in a relatively hypoxic environment, which could trigger multiple downstream receptor-related signaling pathway events, and, in turn, induce responses to promote the onset and progression of myopia.

There are limitations that should not be overlooked. First, our study consisted of a relatively small population and included only young subjects. Further research is needed with larger populations across different age groups, and long-term, longitudinal observations are warranted. In addition, whether a causal relationship exists between choroidal thickness and circulation and whether these two parameters have correlated or independent effects on the onset and development of myopia remain to be illustrated. Finally, we did not consider some important confounding factors, such as ocular perfusion pressure and systolic blood pressure.

In conclusion, both choroidal thickness and circulation were found to be reduced in the more myopic eyes of anisomyopic adults. We observed that the greater the interocular difference in SER, the lower the choroidal circulation and thinner thickness, indicating that the choroid is affected in individuals with myopia and is more likely to be compromised in severe myopia. Although current evidence remains insufficient to make any definitive conclusions regarding the association between the choroid and myopia, our findings may contribute to a better understanding of their relationship.