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Microcirculatory Rarefaction in South Asians — A
Potential Mechanism for Increased Cardiovascular Risk
and Diabetes
Alun D. Hughes*, Raj Bathula, Chloe Park, Therese Tillin, Nicholas Wit, Simon McG Thom,
Nish Chaturvedi
International Centre for Circulatory Health, NHLI Division, Faculty of Medicine, Imperial College London and Imperial College Healthcare NHS Trust, London, United
Kingdom
Abstract
People of South Asian descent have an increased risk of cardiovascular disease (CVD) and diabetes, but little is known about
the microcirculation in South Asian people despite evidence that this plays an important role in the aetiology of CVD. We
compared the retinal microcirculation in a population-based sample of 287 middle-aged adults (144 European 143 South
Asian) matched for age and sex. Retinal photographs were taken and analysed using a validated semi-automated program
and microvascular measures were compared. Blood pressure, anthropometry and fasting bloods were also measured. South
Asians had significantly fewer arteriolar and venular vessels and bifurcations. Arterioles and venules were longer and
venules were also more tortuous in South Asians. These differences were not explained by adjustment for traditional risk
factors including blood pressure, body mass index, diabetes or measures of insulin resistance. People of South Asian
descent have rarefaction of the retinal microcirculation compared to age-sex matched individuals of European descent.
Reduced microvascular density could contribute to the elevated risk of CVD and impaired glucose tolerance in South Asian
people.
Citation: Hughes AD, Bathula R, Park C, Tillin T, Wit N, et al. (2013) Microcirculatory Rarefaction in South Asians — A Potential Mechanism for Increased
Cardiovascular Risk and Diabetes. PLoS ONE 8(10): e76680. doi:10.1371/journal.pone.0076680
Editor: Partha Mukhopadhyay, National Institutes of Health, United States of America
Received July 13, 2013; Accepted August 30, 2013; Published October 7, 2013
Copyright: ß2013 Hughes et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Funding came from the British Heart Foundation NIHR Biomedical Research Centre Scheme. The funders had no role in study design, data collection
and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: a.hughes@imperial.ac.uk
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 microcir-
culatory 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 microcircu-
lation were more prevalent in this ethnic group, and explored
whether any differences observed could be explained by conven-
tional CVD risk factors, including abnormalities of glycaemic
control.
Methods
Ethics Statement
The study was conducted according to the principles expressed
in the Declaration of Helsinki; approved by the Imperial College
Healthcare NHS Trust local ethics committee and all participants
gave written informed consent.
Participants
Participants were recruited from the London Life Science
Prospective Population Study (LOLIPOP), a multi-ethnic popu-
lation-based study of chronic disease and its determinants that
includes over 25000 individuals identified from 58 primary care
lists in West London. [21] Primary care registration in the UK is
PLOS ONE | www.plosone.org 1 October 2013 | Volume 8 | Issue 10 | e76680
free and comprehensive, providing a highly representative
sampling frame. We identified 300 people at random, aiming for
equal numbers of South Asians (all Punjabi Sikh) and Europeans
and equivalent numbers of men and women, stratified by 5-year
age bands within the range 35–75 years for men and 55–75 years
for women. Participants were excluded if they had conditions that
precluded retinal photography (e.g. cataract, acute angle closure
glaucoma); or prevented full participation in the study. Response
rates did not differ significantly by ethnicity (p = 0.2 by Chi
2
test).
Of Europeans and South Asians invited to participate 47% and
48% respectively agreed to participate, 17% and 22% respectively
refused to participate and 35% and 30% respectively failed to
respond.
Study Investigations
All participants attended Imperial College Healthcare NHS
Trust after an overnight fast having completed a questionnaire
detailing demographic data, health behaviours and medical
history. Ethnicity was confirmed with the participant, based on
self -assessment and place of birth of all 4 grandparents. Height,
weight, waist and hip circumference were measured according to a
standard protocol. [22] Sitting blood pressure (BP) was measured 3
times according to British Hypertension Society guidelines using a
validated automated device (OMRON 705CP) after 5 minutes rest
[23] and the average of the final 2 readings was used in analyses.
Carotid-femoral pulse wave velocity was measured from the right
carotid artery at mid-neck and the common femoral artery at the
inguinal ligament using a PulseTrace-PWV device equipped with
a 4 MhZ CW directional Doppler probe (Carefusion, Basingstoke,
UK) according to recent consensus guidelines. [24] Fasting blood
tests were performed for serum glucose (Hexokinase method,
Roche, Basel, Switzerland), HbA1c (non-enzymatic method,
Toshoh, Tokyo, Japan), lipids (Enzymatic colorimetric method,
Roche, Basel, Switzerland) and insulin (ultra-sensitive specific
simultaneous ELISA assay using two high affinity monoclonal
antibodies, Roche, Indianapolis, USA). Insulin assay cross
reactivity with proinsulin was ,0.05% and there was no
detectable cross reactivity with C-peptide. Fasting serum glucose
and insulin were used to calculate HOMA-IR values as a measure
of insulin resistance. [25].
Retinal Photography
Retinal photographs were taken using a Zeiss FF 450 plus
fundus camera (Carl Zeiss Ltd.) with a 30ufield of view following
mydriasis with tropicamide (1%) eye drops and additional
phenylephrine (2.5%) eye drops, if necessary. Images were
captured on a Basler digital camera and field 1 M of the right
eye was subsequently analysed offline as described previously, [19]
(field 1 M of the left was used for analysis if the image of the right
eye was of inadequate quality). Overall 3% (5/149) of images from
either eye from Europeans and 5% (8/151) of images from South
Asians were of too poor quality to assess and subsequent analyses
refer to the remaining 287 individuals with adequate images; those
with un-analysable photographs did not differ significantly from
those with adequate images. Retinal measurements were made
using a custom written program in Matlab (The Mathworks,
Natick, Mass; release 13) with sub-pixel resolution. [26] All vessels
up to 3
rd
order, with diameters $10 pixels (approximately 56 mm)
were measured. Arteriolar and venular diameters were measured
at a series of intensity cross-sections at 2-pixel intervals along its
length. At each cross-section, the vessel diameter was measured
using a sliding linear regression filter technique and an average
calculated for each vessel. [26] Vessel path length was measured
along the vessel centre line between bifurcations. To derive a
measure of vessel narrowing applicable to both arterioles and
venules and unaffected by the refractive properties of the eye, the
length:diameter ratio (LDR) was calculated as the ratio of the
length of a vessel segment between 2 branching points to its
average diameter. Tortuosity was estimated as the difference
between the actual path length of the vessel segment (measured by
tracking) and the straight line length of the segment divided by the
straight line length. Additional measurements included: arteriolar
bifurcation optimality ratios (the relationship between arteriolar
diameters at branching points) and the arteriolar:venular ratio
(AVR). [27] Details of reproducibility of measures have been
published elsewhere. [26].
Statistical Analysis
Population characteristics are presented as means 6SD, or
median (25th, 75th percentile) for skewed data. Retinal measures
are given as means (95% confidence intervals). Statistical
comparisons of unadjusted data were made using a Student’s t-
test after log or square root transformation as appropriate. Other
comparisons were made following covariate adjustment by
multivariate regression analysis with transformation of data as
appropriate. P,0.05 was considered statistically significant. All
statistical analyses were performed using Stata/IC 11.0 (Stata-
Corp, College Station, Texas, USA).
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.
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).
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.
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 pressure6ethnicity = 0.3).
The number of arteriolar bifurcations was also negatively
correlated with blood pressure (r = 20.18; p = 0.003) and pulse
wave velocity (r = 20.15; 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 diabetes6ethnicity = 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
Microcirculatory Rarefaction in South Asians
PLOS ONE | www.plosone.org 2 October 2013 | Volume 8 | Issue 10 | e76680
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 explor-
atory 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 microvas-
cular 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.
Table 1. Characteristics of the two ethnic groups.
Europeans South Asians
p
N 144 143
Male gender, n (%) 95 (66) 96 (67) 0.8
Age, y 62.666.4 62.166.2 0.6
Weight, kg 80.4617.3 73.8613.1 ,0.001
Height, cm 170610 166610 ,0.001
BMI, kg/m
2
27.865.2 26.964.4 0.2
Waist hip ratio 0.9360.10 0.9760.10 0.001
Systolic BP, mmHg 142618 145617 0.2
Diastolic BP, mmHg 82610 8268 0.5
Heart rate, mmHg 62610 65611 0.01
Pulse wave velocity, m/s 9.2 (8.0, 10.3) 9.3 (8.3, 10.6) 0.2
Fasting glucose, mmol/l 5.0 (4.6, 5.4) 5.0 (4.7, 5.9) 0.2
HbA1c, % 5.7 (5.4, 5.9) 6.0 (5.7, 7.0) ,0.001
Fasting insulin, pmol/l 5.4 (3.7, 9.2) 7.6 (4.9, 12.6) 0.004
HOMA-IR 1.2 (0.8, 2.2) 1.8 (1.0, 3.0) 0.004
Diabetes, n (%) 11 (8) 37 (26) ,0.001
Total cholesterol, mmol/l 5.561.1 5.261.1 0.01
HDL cholesterol, mmol/l 1.4 (1.1, 1.6) 1.3 (1.1, 1.5) 0.04
Fasting triglycerides, mmol/l 1.3 (1.0, 2.5) 1.5 (1.0, 2.0) 0.2
Current smoker, n (%) 75 (52) 4 (3) ,0.001
Hypertensive, n (%) 93 (65) 98 (69) 0.5
Lipid lowering therapy, n (%) 37 (26) 39 (27) 0.8
Values are % (n), mean 6SD, or median (25th, 75th percentile) for skewed data;
p values were calculated using the Student’s t-test or the Mann-Whitney U-test
for continuous variables and the Chi-squared test for categorical variables.
Abbreviations: BMI, body mass index; BP, blood pressure; HbA1c, glycosylated
haemoglobin; HDL, high density lipoprotein, HOMA-IR, homeostasis model of
the assessment of insulin resistance; WHR, waist hip ratio.
doi:10.1371/journal.pone.0076680.t001
Table 2. Geometrical measures of retinal arterioles by ethnic group.
Measure Europeans South Asians
P
Arteriolar vessels, n 12.9 [12.2, 13.7] 10.8 [10.2, 11.5] ,0.001
Arteriolar vessels (adjusted)
1
, n 12.8 [12.1, 13.5] 11.0 [10.2, 11.7] 0.001
Arteriolar bifurcations, n 9.9 [9.3, 10.5] 8.4 [7.9, 9.0] ,0.001
Arteriolar bifurcations (adjusted)
1
, n 9.7 [9.2, 10.3] 8.6 [8.0, 9.1] 0.004
1
st
order arterioles, n 4.4 [4.1,4.7] 3.9 [3.6, 4.2] 0.04
2
nd
order arterioles, n 5.1 [4.7, 5.4] 4.1 [3.8, 4.4] ,0.001
3
rd
order arterioles, n 2.1 [1.8, 2.3] 1.4 [1.2, 1.7] ,0.001
Arteriolar diameter, pixels 22.5 [21.9, 23.0] 22.7 [22.2, 23.3] 0.5
1
st
order arteriolar diameter, pixels 23.0 [22.5, 23.5] 23.3 [22.8, 23.8] 0.5
Arteriolar length, pixels 337 [323, 350] 494 [465, 523] ,0.001
Arteriolar length (adjusted)
1
, pixels 341 [326, 356] 369 [354, 383] 0.01
Arteriolar LDR 15.3 [14.5, 15.9] 16.8 [15.8, 17.7] 0.01
Optimality deviation 0.067 [0.054, 0.080] 0.080 [0.056, 0.104] 0.3
Arteriolar tortuosity (610
2
) 1.23 [1.01,1.48] 1.46 [1.24, 1.69] 0.2
Values are mean [95% confidence interval] either unadjusted or
1
following adjustment for age, sex, systolic blood pressure, heart rate and diabetes. Abbreviations: LDR,
length diameter ratio.
doi:10.1371/journal.pone.0076680.t002
Microcirculatory Rarefaction in South Asians
PLOS ONE | www.plosone.org 3 October 2013 | Volume 8 | Issue 10 | e76680
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 Europe-
ans, 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.
Table 3. Geometrical measures of retinal venules by ethnic group.
Vessel measure Europeans (n = 144) South Asians (n = 143)
P
Venular vessels, n 15.1 [14.0, 16.2] 12.0 [11.2, 12.8] ,0.001
Venular vessels (adjusted)
1
, n 14.6 [13.6, 15.6] 12.4 [11.4, 13.4] 0.006
Venular bifurcations, n 12.8 [11.9, 13.7] 10.3 [9.6, 11.0] ,0.001
Venular bifurcations (adjusted)
1
, n 12.9 [12.0, 13.5] 10.5 [9.7, 11.2] ,0.001
Venular diameter, pixels 25.6 [24.9, 26.2] 26.3 [25.5, 27.1] 0.1
1
st
order venular diameter, pixels 27.0 [26.3, 27.7] 27.8 [27.0, 28.5] 0.1
Venular length*, pixels 257 [244, 269] 282 [267, 299] 0.01
Venular length*(adjusted)
1
, pixels 258 [245, 271] 280 [266, 295] 0.02
Venular LDR 10.6 [10.0, 11.1] 11.7 [10.9, 12.5] 0.02
Venular tortuosity (610
2
) 0.53 [0.41, 0.67] 0.83 [0.66, 1.02] 0.007
Venular tortuosity (610
2
) (adjusted)
1
0.55 [0.42, 0.70] 0.78 [0.62, 0.96] 0.02
AVR 0.87 [0.85, 0.89] 0.85 [0.83, 0.87] 0.1
Values are mean [95% confidence interval] either unadjusted or
1
following adjustment for age, sex, body mass index, systolic blood pressure, heart rate, smoking and
diabetes. Abbreviations: AVR, arterio-venular ratio; LDR, length diameter ratio.
doi:10.1371/journal.pone.0076680.t003
Microcirculatory Rarefaction in South Asians
PLOS ONE | www.plosone.org 4 October 2013 | Volume 8 | Issue 10 | e76680
Author Contributions
Conceived and designed the experiments: AH NC ST. Performed the
experiments: RB CP. Analyzed the data: ADH RB CP TT. Contributed
reagents/materials/analysis tools: NW. Wrote the paper: AH RB CP TT
NW ST NC.
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PLOS ONE | www.plosone.org 5 October 2013 | Volume 8 | Issue 10 | e76680
