Introduction

People of South Asian descent, whether resident in the Indian subcontinent [1] or other countries, [2] have an increased risk of cardiovascular disease (CVD), particularly myocardial infarction and stoke. Increased levels of diabetes, insulin resistance and hyperglycaemia contribute to this increased risk of CVD, but do not fully explain it. [3].

The microcirculation is increasingly recognized as an important and early determinant of CVD [4]. Diabetes and insulin resistance adversely affect the microcirculation, while conversely microcirculatory dysfunction also contributes to insulin resistance and impaired glucose tolerance. [5] However information on the prevalence of microvascular disease in South Asians and its relationship to CVD and diabetes is limited. It has been suggested that capillary rarefaction could contribute to their risk of CVD; [6] however, there are conflicting reports regarding the prevalence of microalbuminuria in people of South Asian descent with or without diabetes[7]–[10] and comparisons of diabetic retinopathy have been similarly inconsistent.[7], [11]–[13].

Abnormalities of the retinal microvasculature are commonly observed in the general population, and are associated with target organ damage including left ventricular remodelling; [14] increased coronary artery calcification, [15] and impaired myocardial perfusion in individuals without manifest coronary artery disease [16], suggesting a close link between micro- and macro-vascular disease. Retinal microvascular abnormalities also independently predict future diabetes [17] and CVD[18]–[20] suggesting a possible etiological role for microvascular changes.

In view of the high rates of diabetes and CVD in South Asians we investigated whether abnormalities of the retinal microcirculation were more prevalent in this ethnic group, and explored whether any differences observed could be explained by conventional CVD risk factors, including abnormalities of glycaemic control.

Methods

Results

Two thirds of participants were male, and the mean age was approximately 62 years (table 1). Height and weight was lower in South Asians but waist hip ratio was higher. There were also fewer current smokers; more people with diabetes and measures of hyperglycaemia, and insulin resistance were more adverse in the South Asian group.

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Table 1. Characteristics of the two ethnic groups.

https://doi.org/10.1371/journal.pone.0076680.t001

Compared to Europeans, South Asians had significantly fewer arteriolar vessels and bifurcations, and arterioles were longer, and consequently LDR was higher, although arteriolar diameters did not differ significantly (Table 2). The difference in arteriolar number was most evident in 2^nd and 3^rd order arterioles (Table2).

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Table 2. Geometrical measures of retinal arterioles by ethnic group.

https://doi.org/10.1371/journal.pone.0076680.t002

South Asians also had fewer venular bifurcations; venules were longer and more tortuous, and venular LDR was higher (Table 3). Since changes in retinal microvascular architecture could result in biased estimates of arteriolar or venular diameter we also compared the diameters of only first order arterioles and venules, but these also did not differ significantly between ethnic groups (Table 2 & 3). There were no other significant differences in retinal vessels between ethnic groups.

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Table 3. Geometrical measures of retinal venules by ethnic group.

https://doi.org/10.1371/journal.pone.0076680.t003

In all participants there was a positive relationship between systolic blood pressure and arteriolar narrowing, assessed as arteriolar LDR (r = 0.14; p = 0.01); this relationship did not differ by ethnicity (p interaction systolic blood pressure×ethnicity = 0.3). The number of arteriolar bifurcations was also negatively correlated with blood pressure (r = −0.18; p = 0.003) and pulse wave velocity (r = −0.15; p = 0.01). Diabetes was associated with wider arterioles (arteriolar LDR in people without diabetes = 15.7 (15.2, 16.3) pixels, n = 239 vs. 17.5 (15.2, 19.7) pixels in people with diabetes, n = 48; p = 0.03); this difference also did not differ by ethnicity (p interaction diabetes×ethnicity = 0.4). Diabetes was also associated with significantly fewer arteriolar (8.0 (7.2, 8.8), n = 48 vs. 9.4 (8.9, 9.8), n = 239; p = 0.01) and venular (10.2 (8.8, 11.6) ); n = 48 vs. 11.8 (11.2, 12.5), n = 239; p = 0.03) bifurcations.

We proceeded to explore possible explanations for these ethnic differences in the retinal microcirculation through multivariate analysis, using age, sex, blood pressure, heart rate, diabetes (or HbA_1c, HOMA, or fasting glucose) as covariates for arteriolar measures, and age, sex, blood pressure, BMI, diabetes (or HbA_1c, HOMA, or fasting glucose) and smoking for venular parameters. These covariates were chosen a priori on the basis of previous studies [27], [28]. Adjustment for these covariates alone or in combination only marginally attenuated the ethnic differences and did not abolish statistical significance (Table 2). Further exploratory analyses using variables that differed significantly between ethnic groups (height, weight, waist hip ratio, cholesterol, triglycerides, smoking, use of antihypertensive drugs) also failed to substantially modify the ethnic differences in retinal microvascular measures (data not shown).

Discussion

South Asians have a reduced number of arterioles and venules and elongated arteriolar and venular segments compared to age-sex matched individuals of European descent. This rarefaction of the retinal microcirculation in South Asians is more prominent in the smaller (higher order) arterioles and is unexplained by blood pressure, diabetes, insulin resistance, or other cardiovascular risk factors known to influence the retinal microvascular architecture.

As far as we are aware no other studies have compared the retinal microcirculation between Europeans and South Asian adults. Owen et al. [29] found no difference in tortuosity between European, South Asians and African Caribbean children but did not examine vessel diameter. Jaganathan et al. [30] have reported comparisons of central retinal arteriolar and venular equivalents between Malay-, Chinese- and Indian-origin people in Singapore and, as in our study, they found that elevated blood pressure was associated with arteriolar narrowing in all ethnic groups. The authors also reported that retinal arteriolar calibre was wider in people of Malay ethnicity, while Chinese and Indian people did not differ. In contrast, the same group reported that retinal arterioles were narrower in Chinese compared to Malay and Indian children [31] and that diabetes was associated with increased arteriolar diameter irrespective of ethnicity, [32] as we also observed in adults. The number of bifurcations, lengths of vascular segments, or any other measure of rarefaction was not measured in these previous studies.

Others have studied different ethnic groups and found inter-ethnic differences in the retinal microcirculation of adults. In the Multi-ethnic Study of Atherosclerosis (MESA) retinal arteriolar calibre was larger in African Americans and Hispanics than in Whites and Chinese, while venular calibre was largest in African Americans, intermediate in Hispanics and Chinese and smallest in whites. [33] In contrast Tillin et al., [34] reported that people of Black African descent in the UK (African Caribbeans) had narrower arterioles than Europeans. This was explained by their higher blood pressure, but it was also noted that diabetes influenced the relationship between blood pressure and arteriolar diameter. This is consistent with the findings of Mahal et al. [35] who reported wider arteriolar calibre in African Caribbean people with diabetes than Europeans with diabetes. Similar observations showing an interaction between arteriolar calibre, diabetes and ethnicity have also been reported in MESA. [33] The current study extends these observations of ethnic differences in the retinal microcirculation by indicating that there appears to be little or no ethnic difference in vascular diameter between South Asians and Europeans, with or without adjustment for blood pressure or diabetes. Furthermore, unlike a previous study comparing African Caribbean people with Europeans we found no difference in optimality deviation, an indicator of microvascular endothelial function. [34] Nevertheless there are significant differences in terms of the architecture of the retinal vasculature, such that South Asians have a sparser vascular tree with longer vascular segments. There was also a significant increase in venular tortuosity; this could be simply attributable to the longer venular segments, although we cannot exclude other mechanisms. While there is evidence of abnormal large artery endothelial function [36] and arterial stiffness [37] in South Asians, current knowledge regarding the microcirculation is limited and what exists is equivocal. Microalbuminuria, an indicator of abnormal renal microvascular function has been reported to be higher [9] or lower [10] in population-based studies of South Asians compared with Europeans, and comparisons of South Asian and European people with diabetes have been equally contradictory. [7], [8] Variable precision of measurement of microalbuminuria; the necessary restriction of retinopathy studies to people with diabetes and, in limitations in sampling frame and/or sample size in some studies may account for these inconsistencies. Previously we have reported that South Asians have impaired cutaneous microvascular post-ischemic hyperaemia compared with Europeans. [38] Nama et al. [6] have reported that healthy South Asians have a significantly lower functional and structural cutaneous capillary density compared with healthy Europeans and He et al. [39] showed that a modest reduction in salt intake improved capillary rarefaction in White, Black and Asian people with hypertension. Patel et al. [40] have also reported abnormalities of retinal arteriolar flicker response in South Asians. It is tempting to speculate that widespread rarefaction and functional impairment of the microcirculation in South Asian could compromise perfusion and flow reserve and contribute to their elevated CVD risk, impaired glucose disposal and susceptibility to diabetes. [41], [42].

Our study has a number of limitations, it is cross sectional and therefore questions of causality cannot be resolved. However it is worth noting that abnormalities in the retinal microcirculation are already apparent in youth and related to low birth weight and post natal growth. [43], [44] The participants in this study were of middle age and above and so we cannot know if the differences observed would be evident in younger individuals. This may be particularly relevant since a proportion of participants are likely to have undiagnosed or subclinical CVD and use of cardiovascular medication was common. The two ethnic groups, as anticipated, differed in several respects, including prevalence of diabetes, glycaemia and smoking habit; while statistical adjustment for these factors did not alter our findings, it is possible that there is residual confounding unaccounted for in our analysis. The strengths of this study are that participants were drawn from a representative population sample and that it employed a well validated technique to examine the retinal microcirculation.

In summary, we have shown rarefaction and elongation of the vascular segments of the retinal microvasculature in people of South Asian descent compared with those of European descent in the UK. Abnormalities of the microvasculature could contribute to the elevated risk of CVD in South Asians.

Acknowledgments

We would like to thank Laura Villis and Helen Walkey for assistance with data entry and handling.