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ORIGINAL ARTICLE
Effects of coexisting hypertension and
type II diabetes mellitus on arterial
stiffness
MA Tedesco, F Natale, G Di Salvo, S Caputo, M Capasso and R Calabro
´
Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Monaldi Hospital,
Naples, Italy
Hypertension (HT) is frequently associated with diabetes
mellitus (DM) and its prevalence doubles in diabetics
compared to the general population. This high preva-
lence is associated with increased stiffness of large
arteries, which often precedes macrovascular events.
The aim of our study was to evaluate the influence of HT
and type II DM on aortic stiffness in patients with one
disease or the other compared to those with both HT
and type II DM. We studied 220 patients, 50 with type II
DM (Group A), 50 with HT (Group B), 85 with both
diseases (Group C), and 35 healthy subjects (HS).
Regional arterial stiffness was assessed by automatic
measurement of the carotid–femoral pulse wave velocity
(PWV). For each patient, we evaluated: age, sex, body
mass index, smoking habit, heart rate, SBP/DBP, pulse
pressure (PP), mean BP, fasting glucose, lipid profile,
uric acid, and fibrinogen. Group C had significantly
more women and non smokers and the highest PP
(61714 mmHg). Of biochemical parameters, only fibri-
nogen was higher in Group A and in Group C (Po0.01
and Po0.001, respectively). Group C had a significantly
higher PWV than the other four groups (Po0.0001).
Stepwise forward regression analysis showed that
fasting glucose was the first independent determinant
of PWV (Po0.0001). In conclusion, this study shows that
patients with DM and HT have higher arterial stiffness
compared to HS and those with one disease or the other.
Fasting glucose is the major independent determinant
of PWV, which may be used as a relevant tool to assess
the influence of cardiovascular risk factors on arterial
stiffness in high-risk patients.
Journal of Human Hypertension (2004) 18, 469–473.
doi:10.1038/sj.jhh.1001690
Published online 26 February 2004
Keywords:
type II diabetes mellitus; arterial stiffness; pulse wave velocity; pulse pressure
Introduction
Hypertension (HT) and diabetes mellitus (DM) are
on the rise in industrialised nations because
populations are ageing, and both increase with age.
Frequently, HT is associated with DM and its
prevalence doubles in diabetics compared to the
general population.
1,2
Many type II diabetics devel-
op HT. This high prevalence is associated with
increased stiffness of large arteries, which often
precedes macrovascular events.
3,4
The arterial sys-
tem propagates pressure and flow waves at a certain
velocity largely determined by the elastic properties
of the arterial wall.
5
Aortic stiffness can be assessed
noninvasively in large populations by measuring
carotid–femoral pulse wave velocity (PWV), a
simple and reproducible method.
6,7
Several studies
have shown significant interactions between PWV
and the major cardiovascular risk factors, such as
age, gender, HT, DM, smoking, and a close correla-
tion with atherosclerosis.
8–10
In the presence of
atherosclerotic lesions, a high carotid–femoral
PWV was found even after adjustments on con-
founding factors.
10
Little is known about the effect of
both high blood pressure (BP) and DM on aortic
stiffness.
11–13
The aim of our study was to evaluate
the influence of BP and type II DM on aortic stiffness
in patients with one disease or the other compared
to those with both HT and type II DM.
Methods
Study population
This investigation studied aortic stiffness in dia-
betic, hypertensive, and diabetic and hypertensive
patients, who attended the outpatient HT clinic at
the Second University of Naples between January
and October 2002. We selected 185 patients, 50 with
type II DM (Group A, mean age 5577 years, 34
men), 50 with HT (Group B, mean age 53710 years,
Received 06 August 2003; revised 22 December 2003; accepted 06
January 2004; published online 26 February 2004
Correspondence: Dr MA Tedesco, Salita Due Porte 14, Naples
80136, Italy. E-mail: tedesco@pandoranapoli.it
Journal of Human Hypertension (2004) 18, 469–473
&
2004 Nature Publishing Group All rights reserved 0950-9240/04
$30.00
www.nature.com/jhh
30 men) and 85 with type II DM and HT (Group C,
mean age 5578 years, 33 men), for whom arterial
stiffness measurements by PWV were available. A
control group included 35 healthy subjects (HS,
mean age 5277 years, 21 men). Participants had
been diagnosed with DM and HT for at least 1 year
(duration of both diseases: 7.671.5). The diagnosis
of HT was considered when SBP was 4140 mmHg
and/or DBP 490 mmHg and when antihypertensive
therapy was present. BP was measured by a mercury
sphygmomanometer with an appropriate size rubber
cuff. Readings were based on Korotkoff first and fifth
phase sounds. Three consecutive BP readings were
obtained with the subject in supine position after a
rest of at least 15 min. The average of the last two
readings was used for the analyses, recorded to the
nearest 2 mmHg on the scale. Measurements were
performed early in the morning and carried out by a
trained investigator.
Type II DM was defined as a fasting blood glucose
level 4126 mg/dl (7.0 mmol/l), confirmed on a
subsequent day, according to the report of the Expert
Committee on the diagnosis and classification of
DM,
14
or use of hypoglycaemic agents. None had
any evidence or history of atherosclerotic disease,
myocardial infarction, or stroke. Patients with
cardiovascular conditions who can produce
altered BP waveforms, including arrhythmias,
valvular heart disease, or congestive heart failure,
were excluded. Additional exclusions were being
overweight, defined as a body mass index (BMI)
435 kg/m
2
and smoking more than 20 cigarettes per
day. In the 4 h before the instrumental procedures,
subjects were prohibited from eating, smoking,
drinking coffee, or doing any heavy physical
activity. All patients followed a diet with normal
salt intake (3 g/day).
Among hypertensive patients, 61 subjects used
antihypertensive drug therapy: ACE inhibitors
(n ¼ 30), calcium antagonists (n ¼ 21), beta-blockers
(n ¼ 5), diuretics (n ¼ 5); among diabetic patients, 80
were receiving hypoglycaemic agents: sulphamides
(n ¼ 30), and/or biguanids (n ¼ 50). Pharmacological
treatment was stopped 4 days before inclusion.
Moreover, for each patient we evaluated clinical
parameters such as age, sex, BMI, smoking habit,
heart rate, pulse pressure (PP, defined as systolic BP
minus diastolic BP), and mean BP (MBP, calculated
as MBP ¼ DBP þ PP/3). We also determined lipid
profile, uric acid, and fibrinogen in the serum.
Venous blood samples were obtained after an over-
night fast. Each subject provided informed consent
for the study.
PMV measurement
Regional arterial stiffness was assessed by
carotid–femoral PWV. The acquisition frequency of
pressure waveforms was 500 Hz obtained by using
two pressure transducers with a large-frequency
bandwidth (TY-306; Fukuda Denshi Co., Tokyo,
Japan) connected to an automatic processor (Com-
plior
s
; Colson AS, Paris, France). Assessment of
arterial stiffness by PWV measurement is a standar-
dised, repeatable and widely used method.
6
It is
based on a simple technique, which consists of
recording pressure waveforms at two different
arterial sites: at the base of the neck for the common
carotid artery and over the right femoral artery. The
pulse transit time between the two recording sites is
related to the distance between the two points of
measurement. The on-line computerised measure-
ments were analysed using an algorithm based on
the time-shifted and repeated linear correlation
calculation between the initial rise in the pressure
waveforms. All measurements were performed, after
15 min of supine rest, by the same observer, who was
blind to the BP of the subject. Since the biophysical
properties of the aorta can vary on a short-term
basis, possibly as a result of sympathetic activity, a
minimum of 10 and a maximum of 22 measurements
were performed and used for the calculation of the
mean velocity. The inter-intraobserver reproducibil-
ity coefficients were 40.90, calculated in a sample
of 35 normal subjects.
Statistical analysis
Statistical analysis was carried out by Stat View
software (SAS Institute, Cary, NC, USA). Compar-
ison among groups was performed using ANOVA
plus Bonferroni’s t-test for unpaired data. Bonferro-
ni’s correction was used to assess differences (P
values p0.008 indicated significance). Comparisons
of categorical data were made using Fisher’s exact
test. Stepwise forward regression analysis was
performed to assess which factors independently
influence PWV and was used to determine which
variable was selected first. Variables selected for
inclusion in the model were those significant at
univariate analysis. Significance was defined as
Po0.05.
Results
Table 1 shows the anthropometric characteristics
and the haemodynamic parameters of the groups.
There were no significant differences in age,
BMI, and heart rate among the four groups. The
hypertensive diabetic group had significantly
more women and nonsmokers and the highest PP
(61714 mmHg). Of the biochemical parameters,
only fibrinogen was significantly higher in Group
A and in Group C (Po0.01 and Po0.001, respec-
tively). The highest PWV were observed in patients
with hypertension and type II DM (Group C),
showing a significant difference compared to the
other groups (Po0.0001). Stepwise forward regres-
sion analysis (Table 2) showed that fasting glucose
followed by MBP were independent predictors of
Hypertension, type II diabetes and arterial stiffness
MA Tedesco et al
470
Journal of Human Hypertension
PWV (Po0.0001). We introduced MBP into the
model, rather than SBP/DBP and PP, because MBP
is not directly dependent on arterial stiffness.
Discussion
The main result of this study is that arterial stiffness,
measured through PWV, was higher in patients with
both DM and HT. The analysis showed the greater
influence of DM on increasing arterial stiffness
and that fasting glucose is the first independent
determinant of PWV. Diabetics had a slightly higher
PWV with a lower MBP than hypertensives and
diabetic/hypertensive patients had a greatest PWV
with no significant difference in MBP compared
to hypertensives. The observed differences in
PWV among groups cannot be attributed to other
variables (such as age, BMI, and heart rate)
since they were similar in all of them. However,
the highly significant correlation between PWV
and another risk factor, fasting glucose, suggests an
underlying diffuse atherosclerosis involving large
arteries.
Morbidity and mortality in diabetes are caused
mainly by vascular complications in the microcir-
culation and large vessels, and consist of accelerated
atherosclerosis.
3,15,16
Changes in arterial stiffness
have been observed even at an early stage of disease
and in young nondiabetic adults with a family
history of type II DM. The prevention of micro- and
macroangiopathy requires tight blood glucose con-
trol.
17
The results of several studies, analysing the
effect of DM on the arterial wall, are heterogeneous
despite a general tendency toward an increase of the
arterial stiffness in diabetics.
18
The mechanism of increased arterial stiffness
relates to changes in elastin and collagen within
the walls; the elastin fibres become fractured and
collagen deposition is increased. Moreover, high
glucose levels promote the formation of advanced
glycation end-products, which has been associated
with changes in the vessel walls. On the other hand,
the role of hyperglycaemia in the physiopathology
of macroangiopathy remains controversial and
the prevention of macrovascular events seems to
involve the treatment of cardiovascular risk factors
associated with DM, essentially HT.
19
There is
strong evidence that in essential HT, the main
change in vasculature resistance is a change in
structure; the stiffness of arteries is strongly influ-
enced by transmural distending pressure and hence
by MBP. The prevalence of HT is at least twice as
high in the diabetic population as in the background
population. In type II DM, arterial HT plays an
important role in the initiation and the progression
of diabetic micro–macroangiopathy, and both are
the most important risk factors for cardiovascular
Table 1 Clinical characteristics of the four groups
Group A Group B Group C HS
(n ¼ 50) (n ¼ 50) (n ¼ 85) (n ¼ 35)
Age (years) 557753710 55785277
Men (%) 68 60 39*^ 60
Body mass index (kg/m
2
)2874297429752873
Smokers (%) 42** 25 19 30
Fasting glucose (mmol/l) 7.8072.02 5.0970.50*** 7.8772.20 5.2070.59***
SBP (mmHg) 128711
w
154719 155716 125711
w
DBP (mmHg) 7778
w
977994797976
w
Pulse pressure (mmHg) 50710
y
1 57716 61714 4678
y
MBP (mmHg) 9478
w
116711 114799477
w
Heart rate (b.p.m) 74711 71711 73712 7479
Total cholesterol (mmol/l) 5.2370.83 5.5270.95 5.3070.99 5.5070.70
HDL-cholesterol (mmol/l) 1.0970.25 1.1970.27 1.1770.24 1.0970.24
Triglycerides (mmol/l) 1.5470.63 1.6070.88 1.7870.95 1.4970.44
Uric acid (mmol/l) 0.2970.06 0.3070.09 0.3070.08 0.2870.06
Fibrinogen (mg/dl) 3327701 288764 34279211 313750
Pulse wave velocity (m/s) 11.872.1
z
1171.4
z
13.873.6
ww
9.471.2
Values are means7S.D. or number (%).
Group A: diabetic patients; Group B: hypertensive patients; Group C: diabetic and hypertensive patients; HS: healthy subjects.
*Po0.001 vs Group A, ^Po0.05 vs Group B and HS, **Po0.01 vs Group C, ***Po0.0001 vs Group A and C,
w
Po0.0001 vs Group B and C,
y
Po0.0001 Group A vs Group C, HS vs Group B and C, 1Po0.01 vs Group B, 11Po0.0001 vs B,
ww
Po0.0001 vs A, B and HS,
z
Po0.0001 vs HS.
Table 2 Independent predictors for pulse wave velocity by
stepwise forward regression analysis in the study population
b-coefficient Standard
error (b)
t P
Smokers 0.456 0.405 1.126 0.26
Fasting glucose 0.482 0.087 5.521 o0.0001
Sex 0.030 0.367 0.081 0.93
MBP 0.065 0.013 0.295 o0.0001
Fibrinogen 0.003 0.002 1.475 0.14
Multiple R ¼ 0.47; R
2
¼ 0.22.
Hypertension, type II diabetes and arterial stiffness
MA Tedesco et al
471
Journal of Human Hypertension
disease.
11
By increasing arterial stiffness, HT may
accelerate progression of complications in type II
DM. It is well established that arterial structural and
functional abnormalities are observed in hyperten-
sives even at an early stage of disease.
20–22
These
alterations modify physiological and mechanical
properties of the arterial wall, which may become
clinically evident by increasing PP, making it easier
to establish the progression of atherosclerosis.
In our study, the highest value of PP in diabetic
hypertensives may reflect already diseased arterial
walls, with several adverse cardiac implications of
potential prognostic value.
23,24
PP arises from the
interaction of cardiac ejection (stroke volume) and
viscoelastic properties of large arteries. An in-
creased stiffness of the aorta and large arteries leads
to an increase in PP through a reduction in arterial
compliance and a premature return of reflected
waves in late systole, increasing the load on the
ventricle and increasing myocardial oxygen de-
mand.
25
These abnormalities can be attributed not
only to the stretching effects of elevated BP but also
to intrinsic alterations of the arterial wall, which
could represent either adaptive structural and
functional changes secondary to the chronic in-
crease in BP, or primary abnormalities of the vessel
wall. Local hormonal factors may play a role in the
modification of the arterial wall, mainly by modify-
ing cell growth or synthesis of the extracellular
matrix.
26
Among these factors, angiotensin II may be
of particular importance, since it induces hypertro-
phy of vascular smooth muscle cells in culture and
increases collagen production by fibroblasts,
mediated by the effects of this peptide on the AT1
receptors.
27,28
These outcomes may be useful as
additional factors in risk assessment for future
therapeutic decision-making. Change in BP is a
poor indicator of changing resistance in vessel
structure. Although the effect on BP may be the
same, trials have shown that antihypertensive
treatments have different effects on the arterial
wall.
29–31
A therapeutic strategy is not only able
to reduce glycaemia, BP, and concomitant risk
factors but also to reduce aortic stiffness, and
may be an effective way to lower cardiovascular
morbidity and mortality in hypertensive diabetics.
Moreover, among risk factors, it is useful to
underscore the importance of fibrinogen, a recog-
nised marker of cardiovascular risk, which we
observed to be significantly increased in diabetic
patients with or without HT. This confirmed the
well-known association between blood glucose and
fibrinogen.
32
In conclusion, this study shows that patients
with diabetes and HT have higher arterial
stiffness compared to those with one disease or
the other. Fasting glucose is the first indepen-
dent determinant of PWV that may be used as
a relevant tool to assess the influence of cardio-
vascular risk factors on arterial stiffness in high-risk
patients.
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