Original Research

Cardiology 2008;109:99–104 Received: October 20, 2006

Accepted after revision: December 8, 2006
DOI: 10.1159/000105549
Published online: August 14, 2007

Aortic Elastic Properties Are Related to

Left Ventricular Diastolic Function in
Patients with Type 1 Diabetes Mellitus
Theodoros D. Karamitsos a, d Haralambos I. Karvounis a
Triantafyllos P. Didangelos b Christodoulos E. Papadopoulos a
Melania K. Kachrimanidou c Joseph B. Selvanayagam d Georgios E. Parharidis a
a
First Cardiology Department, AHEPA University Hospital, b Diabetes Centre, Second Propedeutic Department of
Internal Medicine, Hippocration University Hospital, and c First Laboratory of Microbiology, Aristotle University of
Thessaloniki, Thessaloniki, Greece; d Department of Cardiovascular Medicine, University of Oxford,
John Radcliffe Hospital, Oxford, UK

Key Words
Diabetes mellitus, type 1  Diastolic dysfunction  Aortic
stiffness  Doppler echocardiography
Abstract
Objective: The aim of the study was to evaluate left ventric-
ular diastolic function and its relation to aortic wall stiffness
in patients with type 1 diabetes mellitus without coronary
artery disease or hypertension. Patients: Sixty-six patients
with type 1 diabetes mellitus were examined by echocar-
diography and divided into two groups according to the di-
astolic filling pattern determined by mitral annulus tissue
Doppler velocities. Group A patients (n = 21) presented dia-
stolic dysfunction with a peak early diastolic mitral annular
velocity (Em)/peak late diastolic mitral annular velocity (Am)
ratio !1 whereas in group B patients (n = 45) the Em/Am ratio
was 11. Coronary artery disease was excluded based on nor-
mal thallium scintigraphy. Aortic stiffness index was calcu-
lated from aortic diameters measured by echocardiography,
using accepted criteria. Results: Aortic stiffness index dif-
fered significantly among the two groups. Significant corre-
lations were found between parameters of left ventricular
diastolic function (Em/Am, isovolumic relaxation time, de-
celeration time) and aortic stiffness index. Multiple stepwise
linear regression analysis revealed aortic stiffness index ( =
–0.39, p = 0.001) and isovolumic relaxation time ( = –0.46,
p ! 0.001) as the main predictors of Em/Am ratio. Conclu-
sions: Aortic stiffness is increased in type 1 diabetic patients
with left ventricular diastolic dysfunction. This impairment
in aortic elastic properties seems to be related to parameters
of diastolic function. Copyright © 2007 S. Karger AG, Basel
Introduction
Diabetes mellitus (DM) is a chronic progressive dis-
ease that results in micro- and macrovascular complica-
tions. The structural alterations that diabetes cause on
vessels result in impaired large artery function [1]. The
aorta, having an elastic structure, not only serves as a
conduit delivering blood to the tissues but also as an im-
portant modulator of the entire cardiovascular system,
buffering the intermittent pulsatile cardiac output to pro-
vide a steady flow to capillary beds. Thus, the aorta plays
an important role in the regulation of left ventricular per-
formance and coronary blood flow [2]. Aortic function

© 2007 S. Karger AG, Basel Theodoros D. Karamitsos, MD

0008–6312/08/1092–0099$24.50/0 Department of Cardiovascular Medicine, University of Oxford
Fax +41 61 306 12 34 L5, John Radcliffe Hospital, OX3 9DU Oxford (UK)
E-Mail karger@karger.ch Accessible online at: Tel. +44 1865 221 875, Fax +44 1865 221 111
www.karger.com www.karger.com/crd E-Mail theo.karamitsos@cardiov.ox.ac.uk
can be easily assessed non-invasively by measuring aortic
stiffness index from the aortic diameters measured by
echocardiography and blood pressure obtained by sphyg-
momanometry [3]. Furthermore, left ventricular diastol-
ic function can be easily determined by tissue Doppler
echocardiography [4]. However, the relation between
aortic function and left ventricular diastolic function in
diabetic heart disease and especially in type 1 diabetes
remains unclear. The aim of our study was to evaluate left
ventricular diastolic function and its relation to aortic
performance in patients with type 1 DM without known
coronary artery disease or hypertension.
Methods
Patient Population
The study included 66 long-term type 1 diabetic adult patients
who were recruited from the patient population attending the Di-
abetes Outpatient Clinic of our hospital. Coronary artery disease
was excluded based on a normal thallium-201 myocardial perfu-
sion imaging study. Other exclusion criteria were: poor quality of
echocardiographic imaging, valvular or congenital heart disease,
decreased left ventricular ejection fraction !55%, conduction or
rhythm disturbances, pulmonary diseases, pulmonary hyperten-
sion and serum creatinine 1177 mol/l. Additionally, no subject
had a history of arterial hypertension and the arterial blood pres-
sure measured in the supine posture on 3 or more occasions was
consistently !130/85 mm Hg. Insulin was the only medication
used by the patients enrolled in the study. The study was approved
by our institutional ethics committee. Each participant gave writ-
ten informed consent.
Echocardiography
A complete echocardiographic study was performed on each
patient using a standard commercial ultrasound machine (Vivid
7; GE Vingmed, Horten, Norway) with a 1.7–3.4 MHz phased ar-
ray transducer. All images were saved digitally in raw data format
to magneto optical discs for offline analysis. Resting left ventric-
ular end-diastolic, end-systolic volumes and ejection fraction
were computed using a modified Simpson biplane method. Mitral
early inflow peak velocity (E), late inflow peak velocity (A), decel-
eration time of E wave and isovolumic relaxation time (IVRT)
were calculated with the conventional Doppler technique.
After routine echocardiographic examination, the ascending
aorta was recorded in the two-dimensional guided M-mode trac-
ings. The aortic diameter was recorded by M-mode echocardiog-
raphy 3 cm above the aortic valve. Aortic systolic diameter was
measured at the time of full opening of the aortic valve and dia-
stolic diameter was measured at the peak of the QRS complex of
the simultaneously recorded electrocardiogram.
The same ultrasound machine was used to acquire pulsed tis-
sue Doppler data. The imaging angle was adjusted to ensure a
parallel alignment of the beam with the myocardial segment of
interest. Filters were set to exclude high-frequency signals, and
the Nyquist limit was adjusted to a velocity range of 15–20 cm/s.
Gains were minimized to allow for a clear tissue signal with min-
100 Cardiology 2008;109:99–104
imum background noise. All tissue Doppler recordings were ob-
tained during non-forced end-expiration apnoea. A 5-mm sample
volume was placed at the apical four-chamber view on the septal
corner of the mitral annulus. Myocardial peak systolic, early dia-
stolic filling (Em) and late diastolic atrial filling (Am) velocities
were measured at 3 consecutive beats and averaged for each sub-
ject.
The study population was divided into two groups, according
to the diastolic filling pattern determined by tissue Doppler ve-
locities in the mitral annulus. The presence of left ventricular di-
astolic dysfunction was defined as an Em/Am ratio !1. All pa-
tients had blood pressure measured in the supine position with a
mercury sphygmomanometer. Korotkoff phases I and V were
used to determine systolic and diastolic blood pressure, respec-
tively; the mean of 3 readings was used in the analysis. Pulse pres-
sure was calculated as the difference between systolic and dia-
stolic pressure. Aortic stiffness index was used as a parameter of
aortic function and calculated according to the formula [3]: aortic
stiffness index = ln(SBP/DBP)/(AoS – AoD)/AoD (pure number),
where SBP is systolic blood pressure, DBP is diastolic blood pres-
sure, AoS is aortic systolic diameter and AoD is aortic diastolic
diameter.
Glycated haemoglobin (HbA1c) was measured using the Hi-
Auto A1c HA-8140 analyser (Menarini Diagnostics, Florence, It-
aly; non-diabetic reference range 3.8–5.5%).
Statistical Analysis
Data are expressed as means 8 SD and frequencies are ex-
pressed as percentages. All continuous variables were normally
distributed. Differences between groups were assessed by Stu-
dent’s unpaired t test. Categorical variables were compared using
the 2 test. Pearson’s correlation coefficients were calculated for
pairs of continuous variables. To assess the major determinants
of Em/Am ratio (the index that determined the presence or not of
diastolic dysfunction), a stepwise multiple linear regression anal-
ysis was performed. The multivariate model consisted of Em/Am
ratio as dependent variable and of independent variables that had
a significant relation with Em/Am in the simple linear regression
analysis. Intra- and interobserver variability were estimated for
aortic diameter measurements. Intraobserver variability was es-
tablished by having one observer measure data on at least 2 occa-
sions (4 weeks apart) in 10 subjects selected at random from the
patient population under study. Interobserver variability was de-
termined by having a second operator independently measure the
same parameters in these subjects. A probability value of p ! 0.05
was considered significant and two-tailed p values were used for
all statistics. The SPSS statistical software (version 13.0; SPSS Inc.,
Chicago, Ill., USA) was used.
Results
Baseline Characteristics
Of the 66 diabetic patients studied, 21 (31.8%) were
found to have diastolic dysfunction according to an Em/
Am ratio !1 and comprised group A patients, whereas
diastolic function was unimpaired (Em/Am ratio 11) in
the remaining 45 (68.2%) patients (group B). The base-
Karamitsos et al.
Table 1. Demographic characteristics,
clinical parameters and aortic function Group A Group B p value
indices of diabetic patients stratified by Em/Am <1 Em/Am >1
Em/Am ratio (n = 21) (n = 45)

Age, years 44810 3287 <0.001

Diabetes duration, years 2788 1687 <0.001
Female, % 15 (71) 25 (56) 0.2
Smoking, % 7 (33) 12 (27) 0.7
Body mass index 23.481.9 22.881.6 0.19
Heart rate, beats/min 77810 7689 0.4
Systolic blood pressure, mm Hg 12786 11986 <0.001
Diastolic blood pressure, mm Hg 7987 7886 0.6
Pulse pressure, mm Hg 4888 4188 0.001
Aortic stiffness index 6.182.1 481.6 <0.001
HbA1c, % 7.180.7 7.280.8 0.7

Data are presented as means 8 SD.

line characteristics of the study participants together Table 2. Echocardiographic parameters of diabetic patients strat-
with aortic function parameters are shown in table 1. Age ified by Em/Am ratio
and diabetes duration were significantly higher in group
Group A Group B p value
A diabetic individuals. Significant differences were found Em/Am <1 Em/Am >1
in systolic blood pressure and pulse pressure, whereas di- (n = 21) (n = 45)
astolic blood pressure did not differ between the two
groups. The HbA1c values were also similar in the two E, m/s 0.7880.21 0.8380.13 0.3
groups. A, m/s 0.8180.15 0.5980.11 <0.001
E/A 0.9680.19 1.4480.24 <0.001
E deceleration
Echocardiographic Parameters time, ms 200825 171817 0.001
Diabetic patients with diastolic dysfunction differed IVRT, ms 90812 7489 0.001
significantly compared to patients with normal diastolic Sm, cm/s 5.981.2 6.280.9 0.25
function in terms of aortic function parameters, such as Em, cm/s 6.381.1 8.381.2 <0.001
Am, cm/s 8.281.5 5.981.1 <0.001
aortic stiffness index. Importantly, indices of left ventric- Em/Am 0.7880.15 1.4480.33 <0.001
ular systolic function such as ejection fraction and sys- E/Em 10.382.6 10.182.2 0.75
tolic velocity of mitral annulus were similar in the two EDV, ml 89818 92823 0.7
groups of diabetic patients. Significant differences were ESV, ml 3288 33811 0.6
demonstrated (table 2), as expected, between the two EF, % 6486 6386 0.3
groups of patients regarding left ventricular diastolic Data are presented as means 8 SD. A = Peak late diastolic
function parameters such as Em/Am, IVRT, deceleration transmitral velocity; E = peak early diastolic transmitral velocity;
time and E/A mitral inflow ratio, whereas E/Em ratios EDV = left ventricular end-diastolic volume; EF = left ventricular
were in between the two groups. ejection fraction; ESV = left ventricular end-systolic volume;
Sm = peak systolic mitral annular velocity.
Relationship between Aortic Stiffness and Left
Ventricular Diastolic Function
Aortic stiffness index was significantly related to Em/
Am ratio and E/A ratio (fig. 1) as well as IVRT (r = 0.42, To assess the major determinants of Em/Am ratio (the
p = 0.001). Age and diabetes duration were also related index that determined the presence or not of diastolic
significantly to aortic stiffness index (fig. 2). The relation dysfunction), a stepwise multiple linear regression analy-
between aortic stiffness index and Em/Am remained sig- sis was performed. The multivariate model consisted of
nificant even after adjusting for age (r = –0.36, p = Em/Am ratio as dependent variable and of independent
0.003). variables that had a significant relation with Em/Am in

Aortic Stiffness and Diastolic Function in Cardiology 2008;109:99–104 101

Type 1 Diabetes
 r = –0.59, p = 0.001 2.0 r = –0.50, p = 0.001

2.0

1.5

Em/Am (cm/s)
1.5

E/A (m/s)
1.0
Fig. 1. Scatterplot graphs showing the sig- 1.0
nificant correlations between aortic stiff-
ness index and diastolic function indices 0.5
in the whole type 1 diabetic population.
The relationships of aortic stiffness index 2 4 6 8 10 2 4 6 8 10
with mitral annular Em/Am ratio (a) and a Aortic stiffness index b Aortic stiffness index
mitral inflow E/A ratio (b) are shown.

r = 0.64, p = 0.001 40 r = 0.53, p = 0.001

60

50

DM duration (years)
30
Age (years)

40
20

30

10
Fig. 2. Scatterplot graphs showing the sig- 20
nificant correlation between aortic stiff-
ness index and age (a) and between aortic 2 4 6 8 10 2 4 6 8 10
stiffness index and diabetes duration (b) a Aortic stiffness index b Aortic stiffness index
in the whole type 1 diabetic population.

the simple linear regression analysis (aortic stiffness, Discussion

IVRT, age, diabetes duration and deceleration time).
Multivariate analysis in the whole type 1 diabetic cohort
revealed aortic stiffness index ( = –0.39, p = 0.001) and
IVRT ( = –0.46, p ! 0.001) as the main predictors of
Em/Am ratio (overall R 2 = 0.53).
Reproducibility
The analysis of the reproducibility of aortic dimen-
sions by means of Bland-Altman analysis showed that the
intraobserver coefficients of variation for diastolic and
systolic diameters were 4.09% (bias –0.15, 95% limits of
agreement 81.21) and 4.43% (bias –0.14, 95% limits of
agreement 81.17), respectively. Similarly, the interob-
server coefficients of variation for aortic diastolic and
systolic diameters were 5% (bias –0.94, 95% limits of
agreement 81.41) and 6% (bias –0.37, 95% limits of agree-
ment 81.45), respectively.
In the present study, we demonstrated that there are
significant differences in aortic performance in a type 1
diabetic population according to the diastolic filling pat-
tern of the left ventricle. Importantly, our study shows
that there are significant relationships between tissue
Doppler diastolic function indices and the echocardio-
graphic measure of aortic wall stiffness, independent of
age. Our findings have important implications for under-
standing the effects of diabetes per se, independent of hy-
pertension and coronary artery disease, on both myocar-
dial and central artery vascular function.
Previous studies, by measuring distensibility, have
demonstrated that type 1 diabetic patients have impaired
aortic elastic properties, compared to non-diabetic indi-
viduals [1, 5]. Moreover, using conventional Doppler
echocardiography, patients with type 1 DM were found

102 Cardiology 2008;109:99–104 Karamitsos et al.

to have impaired left ventricular diastolic function, again
compared to normal subjects [6, 7]. To our knowledge,
there is only one study by Eren et al. [8] that previously
reported a relation between diastolic dysfunction and
aortic stiffness, but in a non-uniform type 1 and type 2
diabetic population. However, in this particular study
only patients with coronary artery disease were excluded,
whereas in our study both patients with coronary artery
disease and arterial hypertension were excluded. That ar-
terial hypertension is a potential confounder of arterial
wall function was shown by Mottram et al. [9] in a recent
study. By measuring arterial compliance using the pulse
pressure method, they found a significant relation be-
tween arterial stiffness and diastolic dysfunction in a hy-
pertensive population [9]. Thus we confirm the previous
results of Eren et al. [8], but in a population of patients
comprised exclusively of type 1 diabetes, without clinical
evidence of hypertension or coronary artery disease.
The underlying mechanisms by which DM compro-
mises aortic elastic function remain unclear. Accumula-
tion of advanced glycosylated end products has been im-
plicated [10] in addition to the structural changes in large
arteries that derive from increased collagen production
in the hyperglycaemic milieu [11]. Furthermore, endo-
thelial dysfunction could play a role in impaired aortic
function [12].
At least two possible explanations exist for the rela-
tionship between aortic wall function and left ventricular
diastolic function seen in this study. Firstly, aortic disten-
sibility is one of the main determinants of left ventricular
afterload [13]. It is tempting to speculate that increased
aortic stiffness results in increased afterload, which in
turn induces structural changes in left ventricular myo-
cardium leading to diastolic dysfunction. In this way a
causal relationship between impaired aortic elastic prop-
erties and diastolic dysfunction is implied. A second (not
mutually exclusive) explanation is that metabolic altera-
tions in diabetes induce structural changes both in the
large vessel wall and myocardium, which result in a stiff-
er ventricle and a less distensible aortic wall. However,
whilst fibrosis, either perivascular or interstitial, seems to
be one of the cardinal manifestations of diabetic cardio-
myopathy [14], a cause-effect relationship is difficult to
establish without a longitudinal study. Hence, a cross-
sectional study like ours does not have the power and the
design to definitely answer either of the above possibili-
ties.
Aortic distensibility and aortic stiffness have been
studied in depth so far, using techniques based on arte-
rial pulse properties [15] although the measurement of
Aortic Stiffness and Diastolic Function in
Type 1 Diabetes
pulse wave velocity is impaired by various factors related
to haematological [16] and physiological factors [17]. The
echocardiographic method of aortic stiffness determina-
tion that we used in this study is a valid and robust meth-
od – the latter also supported by our finding of low inter-
and intraobserver variability. Furthermore, there is a
very good correlation between aortic distensibility calcu-
lated non-invasively (using echocardiography) and aortic
distensibility measured invasively using contrast ventric-
ulography and aortic pressure [3].
A possible limitation of our study is that coronary an-
giography was not performed in our patient population
as a prerequisite for enrolment in the trial. However, this
limitation is unavoidable because it would be difficult to
justify coronary angiography in asymptomatic diabetic
patients with normal thallium-201 myocardial perfusion
imaging studies on ethical grounds. A thallium-201 myo-
cardial scintigraphy study negative for inducible isch-
emia could be considered as the best non-invasive reliable
documentation of the absence of coronary artery pathol-
ogy, especially one of significant prognostic extent [18].
Another limitation of our study is the small number of
patients with Em/Am !1, hence further confirmation of
our findings is needed in a larger number of diabetic pa-
tients.
Conclusion
We conclude that aortic wall stiffness is increased in
type 1 diabetic patients with left ventricular diastolic dys-
function independent of the presence of coronary artery
disease or systemic hypertension. Moreover, aortic stiff-
ness represents one of the predictors of diastolic function
in these patients.
Cardiology 2008;109:99–104 103
 References
1 Giannattasio C, Failla M, Piperno A, et al:
Early impairment of large artery structure
and function in type I diabetes mellitus. Di-
abetologia 1999;42:987–994.
2 Belz GG: Elastic properties and Windkessel
function of the human aorta. Cardiovasc
Drugs Ther 1995;9:73–83.
3 Stefanadis C, Stratos C, Boudoulas H,
Kourouklis C, Toutouzas P: Distensibility of
the ascending aorta: comparison of invasive
and non-invasive techniques in healthy men
and in men with coronary artery disease. Eur
Heart J 1990;11:990–996.
4 Dokainish H: Tissue Doppler imaging in the
evaluation of left ventricular diastolic func-
tion. Curr Opin Cardiol 2004;19:437–441.
5 Oxlund H, Rasmussen LM, Andreassen TT,
et al: Increased aortic stiffness in patients
with type 1 (insulin-dependent) diabetes
mellitus. Diabetologia 1989;32:748–752.
6 Fraser GE, Luke R, Thompson S, Smith H,
Carter S, Sharpe N: Comparison of echocar-
diographic variables between type I diabet-
ics and normal controls. Am J Cardiol 1995;
75:141–145.
104 Cardiology 2008;109:99–104
7 Schannwell CM, Schneppenheim M, Perings
S, Plehn G, Strauer BE: Left ventricular dia-
stolic dysfunction as an early manifestation
of diabetic cardiomyopathy. Cardiology
2002;98:33–39.
8 Eren M, Gorgulu S, Uslu N, Celik S, Dagde-
viren B, Tezel T: Relation between aortic
stiffness and left ventricular diastolic func-
tion in patients with hypertension, diabetes,
or both. Heart 2004;90:37–43.
9 Mottram PM, Haluska BA, Leano R, Carlier
S, Case C, Marwick TW: Relation of arterial
stiffness to diastolic dysfunction in hyper-
tensive disease. Heart 2005;91:1551–1556.
10 Basta G, Schmidt AM, De Caterina R: Ad-
vanced glycation end products and vascular
inflammation: implications for accelerated
atherosclerosis in diabetes. Cardiovasc Res
2004;63:582–592.
11 Rasmussen LM, Ledet T: Aortic collagen al-
terations in human diabetes mellitus. Chang-
es in basement membrane collagen content
and in the susceptibility of total collagen to
cyanogen bromide solubilisation. Diabetolo-
gia 1993;36:445–453.
12 Johnstone MT, Creager SJ, Scales KM, Cusco
JA, Lee BK, Creager MA: Impaired endothe-
lium-dependent vasodilation in patients
with insulin-dependent diabetes mellitus.
Circulation 1993;88:2510–2516.
13 London GM, Marchais SJ, Guerin AP, Pan-
nier B: Arterial stiffness: pathophysiology
and clinical impact. Clin Exp Hypertens
2004;26:689–699.
14 Fang ZY, Prins JB, Marwick TH: Diabetic
cardiomyopathy: evidence, mechanisms and
therapeutic implications. Endocr Rev 2004;
25:543–567.
15 Asmar R, Benetos A, Topouchian J, et al: As-
sessment of arterial distensibility by auto-
matic pulse wave velocity measurement: val-
idation and clinical application studies.
Hypertension 1995;26:485–490.
16 Bia D, Aguirre I, Zocalo Y, Devera L, Cabre-
ra Fischer E, Armentano R: Regional differ-
ences in viscosity, elasticity and wall buffer-
ing function in systemic arteries: pulse wave
analysis of the arterial pressure-diameter re-
lationship. Rev Esp Cardiol 2005; 58: 167–
174.
17 Lehmann ED: Noninvasive measurements
of aortic stiffness: methodological consider-
ations. Pathol Biol 1999; 47:716–730.
18 Shotwell M, Singh BM, Fortman C, Bauman
BD, Lukes J, Gerson MC: Improved coronary
disease detection with quantitative attenua-
tion-corrected Tl-201 images. J Nucl Cardiol
2002;9:52–62.
Karamitsos et al.