Journal of the American College of Cardiology
© 2006 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 47, No. 6, 2006
ISSN 0735-1097/06/$32.00
doi:10.1016/j.jacc.2005.10.060
The Role of Inheritance
and Environment in Predisposition
to Vascular Disease in People of African Descent
Lalit Kalra, PHD, FRCP,* Curtis Rambaran, MRCP,* Elizabeth Iveson, MRCP,†
Philip J. Chowienczyk, MD, FRCP,* Ian Hambleton, PHD,† James M. Ritter, MD, FRCP,*
Ajay Shah, MD, FRCP,* Rainford Wilks, DM, FRCP,† Terrence Forrester, DM, PHD†
London, United Kingdom; and Kingston, Jamaica
This study sought to compare vascular reactivity and carotid intima media thickness (CIMT)
between Afro-Caribbean people in the United Kingdom (UK) and the West Indies and
Afro-Caribbean and Caucasian people in the UK.
BACKGROUND Attenuated vascular reactivity and increased CIMT in black patients is seen as evidence for
predisposition to vascular disease, but no comparisons exist between Afro-Caribbean people
in different settings, which can provide insight into non-inherited determinants of increased
ethnic susceptibility.
METHODS
A representative community sample of 81 healthy Afro-Caribbean people and 101 Caucasian
people in the UK was compared with 197 matched Afro-Caribbean people in Jamaica. Small
vessel reactivity was assessed by measuring the absolute change from baseline in the reflection
index (RI) of the digital volume pulse during intravenous infusion of albuterol (5 ␮g/min,
⌬RIALB) and glyceryl trinitrate (5 ␮g/min, ⌬RIGTN). The CIMT was measured ultrasonographically in the distal 1 cm of the common carotid artery.
RESULTS
Mean ⌬RIALB was 4.2 percentage points (95% confidence interval [CI], 2.3 to 6.1, p ⬍
0.001) lower in UK Afro-Caribbean people compared with Jamaican Afro-Caribbean people
and 2.6 percentage points (95% CI, 0.4 to 4.7, p ⫽ 0.02) lower compared with Caucasian
people, after adjusting for vascular risk profile. Adjusted mean CIMT of UK Afro-Caribbean
people was 0.13 mm (95% CI, 0.08 to 0.17, p ⬍ 0.001) greater compared with Jamaican
Afro-Caribbean people and 0.05 mm (95% CI, 0.01 to 0.10, p ⫽ 0.02) greater compared with
Caucasian people.
CONCLUSIONS Healthy UK Afro-Caribbean people have greater and Jamaican Afro-Caribbean people have
less impairment of vascular reactivity and intima media thickness compared with UK
Caucasian people, suggesting that potentially modifiable environmental interactions may
contribute to excess vascular disease in Afro-Caribbean people. (J Am Coll Cardiol 2006;
47:1126 –33) © 2006 by the American College of Cardiology Foundation
OBJECTIVES
Several studies have shown a higher incidence of vascular
diseases in people of African descent compared with Caucasian people in Western environments (1–3). Although
much of the excess risk is attributed to a higher prevalence
of hypertension and other risk factors in this population,
ethnicity itself has emerged as an important independent
risk factor (4 – 6). Ethnicity represents a clustering of genetic
and environmental factors. Phenotype expression can be
represented schematically by:
phenotype ⫽ genotype ⫹ environment ⫹ gene ⫻ environment
Hence, differences attributed to ethnicity may not be caused
by genetic differences alone, but may also reflect differences in
environmental influences or interactions between genetic
heterogeneity and environmental pressures (7).
From the *Cardiovascular Division, King’s College London School of Medicine,
London, United Kingdom; and the †Tropical Medicine Research Institute, University
of West Indies, Mona, Kingston, Jamaica. This research was supported by a project
grant from the Wellcome Trust (GR061574FR). Dr. Shah is supported by the British
Heart Foundation. Dr. Chowienczyk advised Micromed on the development of the
equipment used for digital volume photoplethysmography.
Manuscript received April 5, 2005; revised manuscript received October 6, 2005,
accepted October 10, 2005.
The concept of an inherited predisposition to vascular
disease in people of African descent is supported by studies
in the United Kingdom (UK) and the U.S., which show that
healthy Afro-Caribbean patients have attenuated vascular
responsiveness and increased artery intima thickness (8 –15),
widely regarded as functional and morphologic markers of
early atherosclerotic processes (16,17). Other studies have
shown differences in the frequency of gene polymorphisms
for several proteins that modulate vascular function (18 –20)
between Afro-Caribbean and Caucasian patients, further
supporting this concept. However, most observations of
impaired vasomotor function in African-origin people have
been based on direct comparisons between small numbers
of selected Caucasian and Afro-Caribbean or AfricanAmerican volunteers in Western settings, and are potentially vulnerable to sampling bias. Many studies lack the
power to evaluate the effect of ethnicity independent of
blood pressure, blood glucose, or serum cholesterol levels, all
known to be higher in healthy Afro-Caribbean people.
There are few studies comparing intermediate phenotypes
of vascular disease between matched healthy AfroCaribbean people living in the UK and in the West Indies,
JACC Vol. 47, No. 6, 2006
March 21, 2006:1126–33
Abbreviations and Acronyms
BMI
⫽ body mass index
CI
⫽ confidence interval
CIMT ⫽ carotid intima media thickness
DVP
⫽ digital volume pulse
GTN
⫽ glyceryl trinitrate
RI
⫽ reflection index
⌬RIALB ⫽ change in reflection index with albuterol
⌬RIGTN ⫽ change in reflection index with glyceryl
trinitrate
a design that could provide insight into the impact of
non-inherited determinants of ethnic susceptibility to vascular disease.
The objective of this study was to investigate differences
in vascular reactivity between Afro-Caribbean patients living in two different environments, as well as between
Afro-Caribbean and Caucasian patients living in the same
environment, after adjusting for differences in blood pressure, blood glucose, serum cholesterol, body mass index
(BMI), and smoking status. Similar comparisons of differences in carotid intima media thickness (CIMT) were
undertaken to assess early changes in arterial morphology.
METHODS
A major threat to the validity of the study lies in potential
differences in patient selection and measurement techniques
between the UK and Jamaica. We validated and implemented rigorous standardized protocols for epidemiologic
sampling, defining ethnicity and vascular risk factors, anthropometric measurement, and collection and storage of
biological specimens. Pilot experiments were undertaken to
standardize techniques for the measurements of vascular
reactivity and intima media thickness between observers and
to establish inter- and intra-rater reliability. The same make
and model of digital venous plethysmography equipment
was used to measure vascular reactivity in both settings and
was calibrated for concordance before undertaking the
study. The mean coefficient of variation for the change in
reflection index with albuterol (⌬RIALB) was 4.5 ⫾ 1.1
percentage points (within-patient) and 5.2 ⫾ 3.2 percentage
points (between patients). The CIMT was measured using
the same ultrasound equipment for all patients in both
settings (Accuson Sequoia in the UK and Logiq500GE in
Jamaica). Because there was a possibility that a systematic
inter-machine bias might confound comparisons between
the two settings, concordance between the two machines
was established by calibration using the same Gammex
RMI precision small part phantom (RMI 404GSLE;
Middleton, Wisconsin). The mean bias in CIMT measurements was 0.001 ⫾ 0.08 mm (within patient) and 0.006 ⫾
0.11 mm (between sonographers). The intra-correlation
coefficient for between manual and automated readings was
0.95 (95% confidence interval [CI], 0.93 to 0.97) and
between the two machines was 0.92 (95% CI, 0.88 to 0.96).
Kalra et al.
Environment Increases Vascular Risk in Black Patients
1127
Patient selection. The family practice register is the most
accurate and comprehensive register of the general population in the UK (21), and individuals in the age range of 45
to 64 years registered at one large general practice were
sampled randomly, stratified by age group, gender, and
ethnicity. The practice was located in a relatively homogeneous and predominantly middle class area (social class II
and III) (22) of South London and had a list size of 32,000
patients, of whom 28% were black people of Caribbean
descent. Ethnicity was self-defined; only patients with both
parents and all four grandparents belonging to the same
ethnic group and of Caribbean descent were included (23).
If a potential patient failed to meet inclusion criteria or
declined, the next person on the list who matched age,
gender, and ethnicity characteristics was selected.
A similar age- and gender-stratified sample was recruited
from the Kingston Metropolitan area in Jamaica. Enumeration districts were selected according to techniques described previously (24), and five persons in each age/gender
category were screened for eligibility from successive households in each enumeration district. No more than one
individual in each age/gender grid was selected at each
household or from a family group to avoid bias caused by
large households or related families.
To minimize the confounding effects of conventional risk
factors or pharmacological interventions, patients with a
history of stroke, ischemic heart disease, peripheral vascular
disease, hypertension, diabetes mellitus, or hypercholesterolemia or who were taking regular medication were excluded. Patients gave written informed consent, and the
study was approved by the research ethics committees of
King’s College Hospital and the University Hospital of the
West Indies.
Baseline assessments. Details of age, gender, ethnicity,
place of birth, duration of residence, and smoking habits
were recorded in all patients (Table 1). Blood pressure was
measured in seated patients using a mercury sphygmomanometer and appropriate-sized cuff. Three measurements
were taken at five-minute intervals of quiet rest, and the
average of second and third reading was used. The BMI and
waist-to-hip ratio were calculated using standardized validated techniques. A fasting blood sample was taken for
measuring blood glucose and lipid levels.
Assessment of vascular reactivity. Vascular reactivity was
measured non-invasively using digital volume pulse (DVP)
plethysmography (25,26). All experiments were performed
in the morning in temperature-controlled (24 ⫾ 1°C)
vascular laboratories with patients resting supine. An infrared photoplethysmograph (MicroMedical, Gillingham,
United Kingdom) was placed on the index finger of the left
hand of the patients. The DVP waveform consists of a
systolic component (first peak) transmitted directly from the
left ventricle and a diastolic component (second peak)
formed by reflection from small muscular arteries (Fig. 1).
The reflection index (RI) is the height of the diastolic peak
expressed as a percentage of the systolic peak and is a
1128
Kalra et al.
Environment Increases Vascular Risk in Black Patients
JACC Vol. 47, No. 6, 2006
March 21, 2006:1126–33
Table 1. Baseline Characteristics, Arterial Structure, and Function by Ethnic Group Among 379
Study Participants
Baseline characteristics
Age (yrs)
Gender (% female)
Body mass index
Waist-to-hip ratio
Diastolic blood pressure (mm Hg)
Systolic blood pressure (mm Hg)
Mean blood glucose (mmol/l)
Mean cholesterol (mmol/l)
Mean high-density lipoprotein (mmol/l)
Mean triglycerides (mmol/l)
Current smoker (%)
Vascular measurements
Baseline heart rate (min⫺1)
Baseline RI (percentage points)
⌬RIALB (percentage points)
⌬RIGTN (percentage points)
CIMT (mm)
Jamaica
Afro-Caribbean
(n ⴝ 197)
UK
Afro-Caribbean
(n ⴝ 81)
UK
Caucasian
(n ⴝ 101)
p Value
57.8 (13.9)
51.2
26.9 (6.0)
0.84 (0.07)
76.4 (12.6)
130.4 (21.1)
5.3 (1.5)
5.7 (1.2)
1.6 (0.5)
1.3 (0.9)
21.9
54.7 (11.9)
49.4
28.6 (5.9)
0.86 (0.06)
80.3 (7.2)
131.6 (16.0)
5.4 (1.0)
5.1 (1.0)
1.5 (0.4)
1.1 (0.6)
14.8
59.0 (14.6)
50.5
26.7 (4.4)
0.87 (0.07)
77.7 (8.4)
130.2 (15.4)
5.3 (0.9)
5.4 (1.0)
1.6 (0.4)
1.3 (0.7)
12.9
0.10
0.96
0.05
0.09
0.02
0.86
0.87
0.002
0.16
0.051
0.10
63.0 (9.2)
78.4 (8.8)
12.3 (9.5)
12.6 (8.6)
0.71 (0.19)
63.9 (9.0)
76.0 (8.0)
6.4 (7.5)
11.8 (7.9)
0.82 (0.20)
65.9 (8.8)
74.9 (9.5)
11.7 (8.6)
13.6 (8.1)
0.79 (0.18)
0.03
0.003
⬍0.001
0.36
⬍0.001
Data are mean (SD) or %.
CIMT ⫽ carotid intima media thickness; RI ⫽ reflection index; ⌬RIALB ⫽ change in reflection index with albuterol;
⌬RIGTN ⫽ change in reflection index with glyceryl trinitrate.
measure of the amount of pulse wave reflection, determined
predominantly by the tone of small muscular arteries. The
beta2-adrenoceptor responses in these arteries are mediated
through activation of the endothelial L-arginine/nitric oxide
pathway (25–29), and the contour of the DVP is highly
sensitive to vasodilation by small doses of beta-agonists and
glyceryl trinitrate (GTN), which do not change heart rate or
blood pressure.
After intravenous cannulation and infusion of 0.9% saline
at 0.5 ml/min, patients rested supine for 30 min. Baseline
measurements of heart rate, blood pressure (Omron 705CP,
Kyoto, Japan) and DVP were obtained at 5-min intervals for
15 min; 5 ␮g/min of albuterol (Allen and Hanbury, Uxbridge, United Kingdom) was infused for 30 min, during
which hemodynamic measurements were recorded at 3-min
intervals. After a washout period of 60 min during which
Figure 1. Digital volume pulse (DVP) wave form.
0.9% saline was infused, all parameters returned to baseline.
Next, 5 ␮g/min of GTN (Faulding, Warwickshire, United
Kingdom) was then infused for 30 min and hemodynamic
measurements were recorded at 3-min intervals. The means
of the four readings immediately before starting the drug
infusions were used as the baseline for each agent. The DVP
response was measured as the mean absolute change in RI
from baseline to between 12 and 21 min for albuterol
(⌬RIALB) and from baseline to between 9 and 12 min for
GTN (⌬RIGTN). A preliminary study had shown that the
mean within-patient coefficient of variation of the response
curve for ⌬RIALB and ⌬RIGTN was least between these
times.
Measurement of carotid artery intima thickness. An
Accuson Sequoia 512 machine (Logiq500GE in Jamaica)
with an 8-MHz transducer was used to image the carotid
arteries. Each examination cycle included sequential longitudinal and transverse views of the common carotid
artery, the carotid bifurcation, and the internal carotid
artery bulb. Settings for depth-gain compensation, preprocessing, persistence, and post-processing were held constant. All ultrasonic examinations were stored digitally for
subsequent offline processing. Images from the UK and
Jamaica were analyzed together by an experienced ultrasonographer blinded to patient identity and ethnicity.
The CIMT was defined as the mean of differences
between the blood/intima borderline and the media/
adventitia borderline and measured on the far wall of the left
and right common carotid artery. The distal 1 cm of the
common carotid artery just proximal to the bulb was
measured. Mean CIMT was measured by using a semi-
JACC Vol. 47, No. 6, 2006
March 21, 2006:1126–33
automated computer analysis system over the 1 cm segment
and confirmed by the mean of five manual readings at
20-mm intervals along the common carotid artery.
Statistical analysis. The primary outcome measure for the
study on which sample size calculations were based was
⌬RIALB because previous studies have consistently shown
significant ethnic differences in endothelium-dependent
vasodilatation in healthy patients (8,10 –13). A preliminary
study of digital venous plethysmography in 40 patients
showed that the mean standard deviation for ⌬RI was
11 percentage points and that a sample size of 77 patients in
each group would have 80% power to detect a difference in
⌬RI of 5 percentage points using a two-grouped t test with
a 0.05 two-sided significance level. Extending this calculation to three ethnic groups increased the required sample
size to 80 per group using a one-way analysis of variance.
This sample size also had 80% power at the 5% significance
level to detect a difference of 0.07 mm in CIMT between
the UK and the Jamaican Afro-Caribbean people.
Each continuous outcome measure, confounder, and
potential risk factor was compared across the three ethnic
groups using one-way analysis of variance. Statistically
important results on this analysis were investigated further
by three pairwise tests for each analysis of variance and
adjusted for multiple testing using Bonferroni correction.
The outcome measures of interest were ⌬RIALB and
CIMT. For each measure, vascular function was modeled in
three stages. In stage one, the confounding effects of age,
gender, height, baseline RI, and heart rate were assessed. In
stage two, the univariate effect of each potential predictor
(BMI, blood pressure, fasting glucose, total cholesterol,
high-density lipoprotein, triglycerides, and smoking) was
assessed after adjusting for confounders identified in stage
one. In stage three, the independent contribution of ethnicity and all potential predictors variables that were biologically plausible or significant at the 0.2 level in the first two
stages was assessed in a stepwise multiple regression model.
Ethnic differences were examined by comparing UK
Afro-Caribbean people with Jamaican Afro-Caribbean people, UK Afro-Caribbean people with Caucasian people, and
Jamaican Afro-Caribbean people with UK Caucasian people. The same regression model was used for these comparisons. The UK Afro-Caribbean people were set as the
reference category, and comparisons were performed against
UK Caucasian people and Jamaican Afro-Caribbean people.
The UK Caucasian people were then reset as the reference
category, and a third comparison was performed between
UK Caucasian people and Jamaican Afro-Caribbean people.
Each comparison was assessed for significance using a
partial F test. All comparisons were made after adjustment
for differences in heart rate, baseline RI, blood pressure,
BMI, blood glucose, serum lipids, and smoking habits and
weighted to adjust for the relative oversampling of the
Jamaican population.
Kalra et al.
Environment Increases Vascular Risk in Black Patients
1129
RESULTS
Baseline characteristics. Of 379 patients studied, 81 were
UK Afro-Caribbean people, 101 were UK Caucasian people, and 197 were Jamaican Afro-Caribbean people. Their
mean age was 57.4 years (standard deviation, 13.8 years) and
50.7% were women. Although UK Afro-Caribbean people
were younger and had higher mean BMI, waist-to-hip ratio,
and diastolic blood pressure values compared with Jamaican
Afro-Caribbean people (Table 1), only higher diastolic blood
pressure in UK Afro-Caribbean people remained significant
after adjusting for multiple testing (mean difference, 3.9 mm
Hg, p ⫽ 0.02). Higher fasting total cholesterol and triglyceride levels and smoking were more common in Jamaican
Afro-Caribbean people, but only cholesterol levels compared with UK Afro-Caribbean people remained significant
after pairwise comparisons (mean difference, 0.52 mmol/l,
p ⫽ 0.004).
Comparisons of vascular reactivity and structure. Statistically important differences in vascular reactivity were seen
between the three groups (Table 1). Mean baseline RI
was greater in Jamaican Afro-Caribbean people compared
with UK Caucasian people (mean difference, 3.5%; p ⫽
0.01). The mean ⌬RIALB was least in UK Afro-Caribbean
people and greatest in Jamaican Afro-Caribbean people
(difference, 5.9%; p ⬍ 0.001). The mean ⌬RIALB in UK
Afro-Caribbean people was also significantly less than that
of UK Caucasian people (difference, 5.3%; p ⫽ 0.001).
There were no significant differences in mean ⌬RIGTN between the three groups. There also was a significant difference in CIMT measurements between the three groups
(Table 1). The UK Afro-Caribbean people had the highest
and the Jamaican Afro-Caribbean people had the lowest
mean CIMT measurements (mean difference, 0.10 mm, p
⬍ 0.001). The mean CIMT of UK Afro-Caribbean people
was also greater than that of UK Caucasian people (difference, 0.08 mm; p ⫽ 0.01).
Ethnic comparisons adjusted for differences in risk profile. Differences in ⌬RIALB and CIMT between the three
groups persisted after adjustment for the confounding effects of age, gender, baseline RI, baseline heart rate, BMI,
blood pressure, blood glucose, cholesterol and triglyceride
levels, and smoking profile in regression models (Fig. 2).
The adjusted mean ⌬RIALB was 4.2 percentage points (95%
CI, 2.3 to 6.1; p ⬍ 0.001) lower in UK Afro-Caribbean
people compared with Jamaican Afro-Caribbean people
and 2.6 percentage points (95% CI, 0.4 to 4.7; p ⫽ 0.02)
lower compared with UK Caucasian people (Table 2).
Differences in baseline RI did not remain significant after
adjusting for confounding variables. The adjusted mean
CIMT was 0.13 mm (95% CI, 0.08 to 0.17; p ⬍ 0.001)
greater in UK Afro-Caribbean people compared with Jamaican Afro-Caribbean people and 0.06 mm (95% CI, 0.01
to 0.10; p ⬍ 0.02) greater compared with UK Caucasian
people (Table 3). Interestingly, the adjusted ⌬RIALB of
Jamaican Afro-Caribbean people was greater than that of
1130
Kalra et al.
Environment Increases Vascular Risk in Black Patients
JACC Vol. 47, No. 6, 2006
March 21, 2006:1126–33
1-mmol/l increase in fasting blood glucose (p ⫽ 0.001), and
was 4.8 percentage points lower in smokers (p ⬍ 0.001)
(Table 2). The CIMT increased by a mean of 0.04 mm for
every 5-year increase in age (p ⬍ 0.001) and 0.01 mm for
every 5-mm increase in diastolic blood pressure (p ⫽ 0.03)
(Table 3). Although the mean CIMT of women was less
than that of men (0.74 ⫾ 0.17 mm vs. 0.76 ⫾ 0.21 mm), it
did not achieve statistical significance in this sample. There
also was a correlation between ⌬RIALB and CIMT within
the whole group on univariate analysis (coefficient, 8.3; 95%
CI, 3.2 to 13.4; p ⫽ 0.0001), but this association became
non-significant when other variables such as blood pressure,
blood glucose, lipid profile, and BMI were entered into the
multivariate model.
DISCUSSION
Figure 2. Comparison of differences in adjusted change in reflection index
with albuterol (⌬RIALB) (solid diamonds) and carotid intima media
thickness (CIMT) (solid squares) between three groups of participants.
UK Caucasian people (mean difference, 1.7 percentage
points; 95% CI, ⫺0.08 to 3.43) but just failed to achieve
statistical significance. Consistent with changes in ⌬RIALB,
the adjusted CIMT of Jamaican Afro-Caribbean people was
significantly less than that of UK Caucasian people (mean
difference, 0.07 mm; 95% CI, 0.04 to 0.10; p ⬍ 0.001).
Regression models showed that increasing BMI, blood
pressure, blood glucose levels, and smoking also had a significant effect on ⌬RIALB independent of ethnicity or environment. The ⌬RIALB decreased by a mean of 0.2 percentage
points for every unit increase in BMI (p ⫽ 0.04), 0.5
percentage points for every 5-mm increase in systolic blood
pressure (p ⬍ 0.001), and 0.9 percentage points for every
This study, in age- and gender-matched samples of AfroCaribbean people in two different environments and AfroCaribbean and Caucasian patients in the same environment,
showed that vascular reactivity to albuterol, but not to
GTN, was impaired and carotid intima media thickness was
increased in healthy Afro-Caribbean people in the UK
compared with Jamaica, despite belonging to the same
ethnic group. Consistent with previous studies (8 –15),
albuterol-dependent vasodilatation was attenuated in UK
Afro-Caribbean people compared with Caucasian people,
but in contrast to expectations, healthy Jamaican AfroCaribbean people showed greater endothelium-mediated
vasodilatation and lesser CIMT changes than Caucasian
people, even after adjusting for differences in vascular risk
factors. These observations are consistent with a recent
epidemiologic study that showed that the incidence rate for
stroke in Afro-Caribbean people in the West Indies was
half that of UK Afro-Caribbean people and comparable to
that of the Caucasian population (30). Therefore, a significant proportion of the excess of vascular disease observed in
people of African descent in Western settings may be attributable to non-inherited influences or gene-environment
Table 2. Predictors of ⌬RIALB Among 379 Study Participants
Multivariate* Adjusted R2 ⴝ 0.68
(95% CI: 0.59 to 0.73)
Univariate*
Characteristic
Coef
95% CI
p Value
Coef
95% CI
p Value
Gender (women vs. men)
UK-AC vs. J-AC
UK-AC vs. UK-C
J-AC vs. UK-C†
Body mass index
Systolic blood pressure‡
Fasting glucose
Current smoker
5.81
⫺4.26
⫺3.71
0.55
⫺0.25
⫺0.55
⫺0.98
⫺3.76
3.89 to 7.72
⫺6.22 to ⫺2.30
⫺5.94 to ⫺1.49
⫺1.33 to 2.42
⫺0.42 to ⫺0.08
⫺0.78 to ⫺0.32
⫺1.72 to ⫺0.24
⫺5.71 to ⫺1.82
⬍0.001
⬍0.001
0.001
0.57
0.003
⬍0.001
0.01
⬍0.001
4.42
⫺4.23
⫺2.56
1.67
⫺0.18
⫺0.50
⫺0.93
⫺4.77
1.94 to 6.90
⫺6.12 to ⫺2.34
⫺4.69 to ⫺0.42
⫺0.08 to 3.43
⫺0.34 to ⫺0.01
⫺0.71 to ⫺0.28
⫺1.45 to ⫺0.40
⫺6.55 to ⫺3.00
0.001
⬍0.001
0.02
0.06
0.04
⬍0.001
0.001
⬍0.001
*All univariate and multivariate risk factor models adjusted for baseline RI, heart rate, age, and gender. †Third ethnic group
comparison calculated by refitting model with UK-C as the reference category. ‡Regression coefficient describes RI change for
every 5-mm Hg increase in systolic blood pressure.
CI ⫽ confidence interval; Coef ⫽ coefficient; J-AC ⫽ Jamaica Afro-Caribbean; UK-AC ⫽ United Kingdom AfroCaribbean; UK-C ⫽ United Kingdom Caucasian; other abbreviations as in Table 1.
Kalra et al.
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JACC Vol. 47, No. 6, 2006
March 21, 2006:1126–33
1131
Table 3. Predictors of CIMT Among 379 study participants
Multivariate‡ Adjusted R2 ⴝ 0.46
(95% CI: 0.39 to 0.51)
Univariate*
Characteristic
Coef†
95% CI
p Value
Coef†
95% CI
p Value
Age§
UK-AC vs. J-AC
UK-AC vs. UK-C
J-AC vs. UK-C储
Systolic blood pressure¶
Diastolic blood pressure¶
3.96
13.49
6.81
⫺6.68
0.72
1.42
3.36 to 4.56
9.22 to 17.76
2.30 to 11.32
⫺9.87 to ⫺3.49
0.20 to 1.24
0.50 to 2.34
⬍0.001
⬍0.001
0.003
⬍0.001
0.01
0.003
3.98
12.56
5.49
⫺7.07
–
1.04
3.44 to 4.52
8.43 to 16.69
1.06 to 9.93
⫺10.28 to ⫺3.85
–
0.13 to 1.96
⬍0.001
⬍0.001
0.02
⬍0.001
–
0.03
*All univariate risk factor models adjusted for age. †Divide coefficients by 100 to interpret as mm change in CIMT. ‡Multivariate
model also adjusted for baseline reflective index and heart rate. §Regression coefficient describes CIMT change for every 5-year
increase in age. 储Third ethnic group comparison calculated by refitting model with UK-C as the reference category. ¶Regression
coefficient describes CIMT change for every 5-mm Hg increase in blood pressure.
Abbreviations as in Table 2.
interactions, which, in contrast to inherited factors, are
potentially amenable to interventions.
Explanations for population differences in disease susceptibility must be sought in representative samples of the
general population to ensure unbiased and generalizable
comparisons (31). A limitation of previous studies, which
seemed to support inherited differences in pharmacologically mediated vascular responsiveness, is that they were
undertaken in relatively small and selected samples from the
same environment (8 –13). In contrast, this study used
epidemiologic methods to obtain samples representative of
local populations. Bias attributable to differences in measurement techniques between the UK and Jamaica was
minimized using identical protocols, definitions, measurement techniques, equipment, and reagents. The comparability of ultrasound equipment was established using the
same phantom, transported across sites. Proficiency and
comparability of procedures and intra-observer and interobserver agreement were established in preliminary studies
before the main study. The dose of GTN and albuterol and
the times of evaluation of ⌬RIALB and ⌬RIGTN were selected
to achieve maximum change in RI with only modest
changes in heart rate and minimum within-patient variability. The CIMT measurements on recorded images were
undertaken by a senior vascular physicist masked to the
identity and location of patients.
Previous studies in migrant populations have shown that
their risk of vascular diseases increases from low levels to
match that of the local population because of acquisition of
risk factors prevalent in native cultures (32–36). Although a
similar phenomenon may be predicted for Afro-Caribbean
people living in the UK, it does not fully explain why their
vascular risk should exceed that of the local Caucasian
population (1). It also does not explain our findings of
decreased vascular reactivity and increased CIMT in healthy
Afro-Caribbean people with no risk factors compared with
Caucasian people in the UK or greater changes of arterial
morphology and function in UK Afro-Caribbean people
compared with Jamaicans, despite lipid and smoking levels
being the higher in Jamaica (Fig. 2). This suggests that
there may be environmental (e.g., salt, fish oils, micronu-
trient or anti-oxidant intake) or behavioral (e.g., physical
activity, psychosocial stress) influences within the Jamaican
setting that protect against early onset of vascular impairment (37). It is also possible that differences in the frequency of certain genetic polymorphisms between AfroCaribbean people and Caucasian people, which previously
conferred advantages in the Caribbean environment, contribute to a deleterious phenotype in the UK environment.
This is exemplified by the well-known associations between
salt sensitivity, urbanization, and hypertension in people of
African descent (38).
Study limitations. Assumptions have been made that
Afro-Caribbean people in the UK and Jamaica share ethnicity and Afro-Caribbean people and Caucasian people in
the UK share environment. Eligibility for participation was
limited to African-origin people of Caribbean descent, and
the study excluded patients who had emigrated from African or other countries. UK Afro-Caribbean patients were of
Jamaican origin, and both parents and all four grandparents
belonged to the same ethnic group. Although this minimized genetic or racial differences between the two AfroCaribbean groups in the study, the possibility of a bias
caused by self-selection of people who emigrate cannot be
excluded. Afro-Caribbean and Caucasian patients in the
UK were selected from a population with homogeneous
socioeconomic status. Although differences in vascular function could not be attributed to measurable socioeconomic
differences, a detailed analysis of lifestyles and diet was not
undertaken and could have influenced observed ethnic
differences in the UK. This becomes particularly important
in the context of findings in the Jamaican cohort and
supports the need for more research into the relationship
between migration, diet, lifestyles, and vascular health.
Another limitation of the study is its cross-sectional
design; a longitudinal study would be the optimal design to
investigate the relationships between environment, intermediate phenotypes, and vascular events in people of African
descent living in different settings. A longitudinal study
would also provide better understanding of the relationships
between functional (e.g., vascular reactivity) and morphologic (e.g., CIMT) impairments in vascular diseases. De-
1132
Kalra et al.
Environment Increases Vascular Risk in Black Patients
spite these limitations, the study clearly shows that changes
in vascular reactivity (⌬RIALB) were associated with parallel
changes in arterial morphology (CIMT) and that the direction of these changes was biologically consistent across the
three groups.
It is possible that the diminished responsiveness to
albuterol seen in UK Afro-Caribbean people may be attributable to differences in the frequency of beta2-adrenoceptor
polymorphisms between Afro-Caribbean people and Caucasian people (20,39). This is unlikely because the ⌬RIALB
in Jamaican Afro-Caribbean people was significantly greater
than in UK Afro-Caribbean people and comparable to that
of Caucasian people. Bias from this source should cause
equal attenuation of ⌬RIALB in UK and Jamaican AfroCaribbean people compared with Caucasian people because
all Afro-Caribbean patients in the UK had Jamaican origins
and would be expected to have the same frequency of
beta2-adrenoceptor polymorphisms.
CONCLUSIONS
The relationship between inherited traits, environmental
pressure, and cardiovascular disease is complex, and this
study suggests that non-inherited influences within the
environment may play a significant, but potentially modifiable, role in ethnic predisposition to vascular disease. The
results of this study support a focus on the investigation of
multiple environmental factors and gene environment interactions, specific to ethnic groups in different environments, as an approach to eliminating the excess of vascular
disease in such people.
Reprint requests and correspondence: Dr. Lalit Kalra, Department of Medicine, King’s College London School of Medicine,
Denmark Hill Campus, Bessemer Road, London SE5 9PJ,
United Kingdom. E-mail: [email protected].
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