Download Decreased left ventricular longitudinal contraction

Clinical Science (2003) 105, 59–66 (Printed in Great Britain)
Decreased left ventricular longitudinal
contraction in normotensive and
normoalbuminuric patients with Type II
diabetes mellitus: a Doppler tissue tracking
and strain rate echocardiography study
N. H. ANDERSEN∗ , S. H. POULSEN†, H. EISKJÆR†, P. L. POULSEN∗
and C. E. MOGENSEN∗
*Department of Internal Medicine, Diabetes and Endocrinology, Aarhus University Hospital, Nørrebrogade 44, Aarhus C-8000,
Denmark, and †Department of Cardiology, Skejby University Hospital, Brendstrupgaardsvej, Aarhus N-8200, Denmark
A
B
S
T
R
A
C
T
Type II diabetes mellitus is associated with congestive heart failure with preserved ejection
fraction. This group of patients has been assumed to have isolated diastolic dysfunction; however,
the longitudinal systolic contraction of the left ventricle has not been studied previously. The
objective of the present study was to investigate the longitudinal contraction of the left ventricle
in normotensive Type II diabetes mellitus patients with normal ejection fraction. We examined
32 normotensive patients with Type II diabetes mellitus with ejection fraction > 0.55 and
fractional shortening > 0.25. Exclusion criteria were angina pectoris, cardiac valve disease,
albuminuria, retinopathy or neuropathy. Normal subjects (n = 32) served as controls. A 16segment model of motion amplitude assessed left ventricular longitudinal contraction and the
average of the segments was calculated as the tissue tracking score index. Peak systolic velocity
and strain rate was also obtained in each segment. Patients with Type II diabetes mellitus had
a significantly lower tissue tracking score index compared with normal subjects (5.8 +
− 1.6 mm
compared with 7.7 +
1.1
mm;
P
<
0.001).
Mean
peak
systolic
velocity
was
also
significantly
−
lower (4.3 +
− 1.0 cm/s; P < 0.001), as well as peak systolic strain
− 1.5 cm/s compared with 5.4 +
−1
−1
+
0.3
s
rate (−1.2 +
compared
with
−1.6
−
− 0.4 s ; P < 0.001). Patients with Type II diabetes
mellitus and preserved diastolic function had a significantly lower tissue tracking score index
compared with normal subjects (6.6 +
− 1.5 mm; P < 0.001), but patients with diastolic dysfunction
had an even more profound decrease in tissue tracking score index compared with patients
without diastolic dysfunction (4.9 +
− 0.9 mm; P < 0.01). In conclusion, the longitudinal systolic
contraction was significantly decreased in normotensive patients with Type II diabetes mellitus
with normal ejection fraction, which was most profound in patients with concomitant diastolic
dysfunction.
Key words: echocardiography, left ventricle, systole, tissue Doppler, Type II diabetes mellitus.
Abbreviations: A-wave, peak atrial filling velocity; BMI, body mass index; CHF, congestive heart failure; EF, ejection fraction;
E-wave, peak early mitral inflow velocity; DT, E-wave deceleration time; FS, Fractional shortening; HbA1c , glycosylated
haemoglobin; LV, left ventricular; SR, strain rate; TT, tissue tracking; V p , velocity flow propagation.
Correspondence: Dr Niels Andersen (e-mail [email protected]).
C
2003 The Biochemical Society
59
60
N. H. Andersen and others
INTRODUCTION
Clinical and epidemiological data indicate a significant
association between diabetes mellitus and congestive
heart failure (CHF) with normal ejection fraction (EF)
[1–4]. Although these patients have a lower mortality risk
than patients with decreased EF, they have a significantly
increased mortality risk compared with age-matched
controls without CHF [5].
The presence of left ventricular (LV) diastolic
dysfunction seems to be an early complication in
Type II diabetes mellitus and has been suggested to
be the first stage in the development of the ‘diabetic
cardiomyopathy’.
In recent Doppler echocardiographic studies with
analysis of combined mitral and pulmonary venous flow
and flow during the Valsalva manoeuvre [6,7], abnormal
LV diastolic filling was demonstrated to be present in
approx. 50 % of normotensive patients with Type II
diabetes mellitus with normal systolic function. However,
LV systolic function is often described in terms of LVEF
or fractional shortening (FS), reflecting global and radial
shortening of the left ventricle, whereas the longitudinal
systolic contraction of the outer and inner layer of
the myocardium contributes less in these parameters.
Tissue Doppler imaging has been introduced as a new
method of quantifying segmental and global LV function
by measuring systolic and diastolic tissue velocities. A
derivative of tissue Doppler imaging is tissue tracking
(TT), which allows assessment of the systolic baso-apical
myocardial shortening, whereas strain rate (SR) imaging
is a new method for detection of segmental myocardial
contraction or stretching [8,9].
The aim of the present study was to describe the
systolic longitudinal contraction of the left ventricle in
normotensive Type II diabetes mellitus patients with
normal LVEF and FS assessed by TT and SR imaging.
METHODS
Patients
The study population consisted of 32 patients with
Type II diabetes mellitus admitted to the outpatient
clinic. All patients had normal untreated arterial blood
pressure (130/85 mmHg) and did not have any clinical
signs of ischaemic heart disease. All patients were in sinus
rhythm with a normal 12-lead ECG without signs of
hypertrophy, ischaemia or right or left bundle branch
block. LVEF was 55 %, as measured by Simpson’s
method of discs [10], and FS was 25 %, as evaluated
by two-dimensional and M-mode echocardiography.
Exclusion criteria were a family history of cardiac
disease, angina pectoris, prior myocardial infarction or
a urine albumin/creatinine ratio > 2.5 mg/ml. Abnormal
biothesiometry or detection of any grade of retinopathy
C
2003 The Biochemical Society
also excluded the patient. Age- and sex-matched normal
subjects (n = 32) served as controls. The study was
conducted in accordance with the Helsinki II declaration
and approved by the Local Ethics Committee. All
participants gave a written informed consent before
entering the study.
Echocardiography
All echocardiography examinations were performed on
a GE Vivid Five ultrasound machine (GE Medical
System, Horden, Norway) with a 2.5 MHz transducer.
Echocardiograms were stored digitally and analysed by
one observer without knowledge of the clinical data. All
smokers were kept from smoking at least 30 min before
the examination.
LV mass was estimated according to the American
Society of Echocardiography recommendations based
on the average of five measurements of LV diameter
and wall thickness. The LV mass was calculated from
the formula: LV mass = 0.8 × [1.04 × (intraventricular
septal thickness + LV diastolic diameter + posterior
wall thickness)3 − (LV diastolic diameter)3 ] + 0.6 g.
Measurements of FS was derived from standard M-mode
measurements.
LV volumes and ejection fraction were estimated using
Simpson’s modified biplane method [10] based on three
measurements. LV mass and volume measurements were
corrected for body surface [10]. Endocardial border
detection was enhanced by use of second harmonic
imaging [11].
Pulsed Doppler measurements were obtained with
the transducer in the apical four-chamber view, with the
Doppler beam aligned perpendicular to the plane of
the mitral annulus. The sample volume was placed
between the tips of the mitral leaflets. Five consecutive
beats during quiet respiration were used for calculation
of the Doppler variables. Assessment of colour M-mode
flow propagation recordings were performed in the apical
four-chamber view and with the M-mode cursor aligned
parallel with the LV inflow. Adjustments were made
to obtain the longest column of flow from the mitral
annulus to the apex of the left ventricle. The M-mode
cursor was positioned through the centre of the inflow to
avoid boundary regions. The velocity flow propagation
was measured as the slope of the first aliasing velocity
(41 cm/s) from the mitral annulus in early diastole to
4 cm distally into the ventricular cavity [12].
Diastolic filling was classified on the basis of the
mitral inflow Doppler parameters and colour M-mode
flow propagation. Peak early mitral inflow velocity
(E-wave) deceleration time (DT) > 140 ms and 240 ms,
an E-wave/peak atrial filling velocity (A-wave) ratio
between 1 and 2 and velocity flow propagation (V p ) >
45 cm/s indicated normal diastolic filling, whereas
abnormal filling was defined as DT > 240 ms and Ewave/A-wave ratio < 1, suggestive of impaired relaxation.
Cardiac dysfunction in Type II diabetes mellitus
Figure 1 Schematic drawing displaying the principals of TT echocardiography
Middle panel, a normal subject with all 7 colour bands displayed. TT wall index, 8.7 mm. Right-hand panel: a patient with Type II diabetes mellitus. TT wall index,
5 mm.
A DT > 140 ms and 240 ms with V p 45 cm/s was
suggestive of a pseudonormal filling, and DT < 140 ms
was suggestive of a restrictive filling pattern. The cut-off
points were chosen based on recent recommendations
[13,14].
Tissue Doppler imaging
Tissue Doppler imaging was obtained from the four- and
two-chamber apical views and the apical long axis view
during end expiration apnoea. TT and systolic SR analysis
were performed as special modalities of tissue Doppler
imaging. TT displays the integral of tissue velocity
during systole, which equals the distance of motion along
the Doppler axis [15]. TT requires simultaneous ECG
registration to define the beginning and the end of the
systole. There are seven colour bands, which indicate
different distances of motion with a stepwise increase
in the distance of motion. The range of distance of
motion displayed by the seven colour bands can be
altered. The maximal distance of motion during systole
was adjusted depending on the LV function to stretch
the seven colour bands between the apex and the mitral
annular level. When analysing the left ventricle in apical
views, the lowest distance of motion is at the apex and the
greatest distance at the mitral annulus. Figure 1 shows
the principles of TT.
The left ventricle was divided into 16 segments, similar
to the wall motion score analysis [10], and the motion
distance for each segment was assessed. The average of
the 16 segments was calculated and presented as the TT
score index in mm.
Strain is originally defined as a dimensionless quantity
produced by the application of a stress and it represents
the fractional or percentage of change from the original
or unstressed dimension. SR is equal to the temporal
derivative of strain, and the total strain can therefore
be determined by combining the SR values for a given
interval [8,16,17].
The tissue Doppler technique used in the present study
allowed processing of simultaneous systolic velocity, TT
and SR from different myocardial segments in the same
cineloop. The peak myocardial systolic velocities and SR
were measured in each segment within the first 350 ms
from the R-wave in the ECG. SRs and velocities were
measured in the centre and basal one-third of each
myocardial segment. Colour noise reduction was adjusted and a colour Doppler scanning frame rate was kept
between 140 and 160 frames/s [18]. The average value of
peak systolic velocity, SR and TT of the 16 segments was
calculated. Analyses of TT score index and SR analyses
were done separately and without knowledge of twodimensional and pulsed Doppler recordings.
Statistics
Results are presented as means +
− S.D., except for diabetes
duration, which is presented as the geometric mean.
Frequencies are expressed as percentages. Differences
between groups were assessed by Student’s t test. Time of
diabetes duration was log transformed to approximate
normal distribution. Analysis of equal variance was
used to detect differences between groups. Pearson’s
correlation coefficient (ρ) was applied to estimate correlations between individual parameters. Categorical
variables were compared using Fischer’s exact test or
χ 2 whenever appropriate. A two-tailed P < 0.05 was
considered significant.
RESULTS
Table 1 shows the clinical and demographic data. Mean
systolic and diastolic blood pressure, lipid profile and
serum creatinine in the diabetes mellitus patients were
comparable with the control group. Body mass index
(BMI), surface area and heart rate were significantly
increased in patients with Type II diabetes mellitus.
C
2003 The Biochemical Society
61
62
N. H. Andersen and others
Table 1 Clinical characteristics of 32 patients with Type II
diabetes mellitus and matching controls
Table 2 Echocardiographic measurements in 32 patients
with Type II diabetes mellitus and matching controls
Values are means +
− S.D., or median (range), unless otherwise indicated. *P <
0.01 compared with controls. NEFA, non-esterified fatty acids; UACR, urine albumin/
creatinine ratio.
Values are means +
− S.D. *P < 0.01 compared with normal subjects.
Parameters
Controls (n = 32)
Type II diabetes
mellitus (n = 32)
Age
Female (%)
Smokers (%)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Heart rate (bpm)
BMI (kg/m2 )
Surface area (m2 )
Cholesterol (mmol/l)
NEFA (mmol/l)
S-Creatinine (µmol/l)
Urine albumin (mmol/l)
UACR (mg/mmol)
Duration of diabetes (years)
Diabetes therapy (%)
Dietary treatment
Oral antihyperglycaemic agents
Insulin therapy
HbA1c
Lipid-lowering therapy (%)
53 +
−7
44
20
120 +
−9
80 +
−8
67 +
−9
23.9 +
− 2.6
1.88 +
− 0.2
4.7 +
− 0.4
1.90 +
− 1.7
83 +
− 13
−
−
−
53 +
−7
44
44
121 +
−7
77 +
−7
78 +
− 13
29.4 +
− 5.3*
2.01 +
− 0.3*
4.9 +
− 0.9
2.1 +
− 1.4
78 +
− 12
12 +
−4
1.5 +
− 0.6
5 (0.5–20)
−
−
−
−
−
27
35
38
0.0083 +
− 0.002
35
Echocardiographic data are shown in Table 2.
Left atrial diameter, mitral A-wave velocity, DT and
isovolumetric relaxation time were significantly higher,
whereas E-wave/A-wave ratio and V p were significantly
decreased compared with the controls.
Table 3 shows the coherent values of regional
systolic peak velocities, TT score index and SR. Mean
peak systolic myocardial velocity for all 16 LV segments was significantly lower in patients with diabetes
mellitus than in normal subjects (4.3 cm/s compared
with 5.4 cm/s respectively; P < 0.001), as well as peak
systolic SR (−1.2 s−1 compared with −1.6 s−1 respectively; P < 0.001). Mean TT score index was also significantly decreased in diabetes mellitus patients compared
with normal subjects (5.8 mm compared with 7.7 mm
respectively; P < 0.001).
Eighteen patients demonstrated a normal diastolic
filling pattern (57 %), whereas nine patients had impaired
relaxation pattern (28 %). Five patients had pseudonormal filling patterns (15 %), but we did not find
patients with restrictive filling patterns. The overall
prevalence of diastolic dysfunction was 43 %. Age, gender distribution, duration of diabetes, diabetes treatment, glycated haemoglobin (HbA1c ) and lipid profile
were similar in the groups with and without diastolic
dysfunction.
C
2003 The Biochemical Society
Parameter
Controls (n = 32)
Type II diabetes
mellitus (n = 32)
Left atrial diameter (cm)
LV diastolic diameter (cm)
LV systolic diameter (cm)
Septal wall thickness (cm)
Posterior wall thickness (cm)
Fractional shortening (%)
LV mass index (g/m2 )
E-wave (cm/s)
A-wave (cm/s)
E-wave/A-wave ratio
DT (ms)
Isovolumetric relaxation time (ms)
V p (cm/s)
E-wave/V p
End-diastolic volume (ml/m2 )
End-systolic volume (ml/m2 )
LVEF (%)
3.6 +
− 0.4
4.8 +
− 0.5
3.2 +
− 0.5
0.9 +
− 0.2
0.9 +
− 0.2
36 +
−6
107 +
− 25
70 +
− 13
59 +
− 11.5
1.2 +
− 0.3
192 +
− 19
85 +
− 15
67 +
− 16
1.1 +
− 0.3
43 +
− 12
17 +
−5
61 +
−4
4.0 +
− 0.5*
4.9 +
− 0.5
3.2 +
− 0.7
0.9 +
− 0.3
0.9 +
− 0.3
34 +
−6
99 +
− 25
74 +
− 10*
66 +
− 12*
1.1 +
− 0.2*
198 +
− 24*
94 +
− 10*
55 +
− 17*
1.3 +
− 0.4
44 +
−6
17 +
−5
64 +
−5
Patients with diabetes mellitus and preserved diastolic
function had a significantly lower TT score index
compared with normal subjects [6.6 +
− 1.5 mm (range,
3.8–9.3 mm) compared with 7.7 +
1.5
mm (range, 6–
−
11.5 mm) respectively; P < 0.001], but patients with diastolic dysfunction had an even more profound decrease
in TT score index [4.9 +
− 0.9 mm (range, 3.0–6.3 mm)]
compared with patients without diastolic dysfunction.
This was significant compared with both controls and
diabetes mellitus patients with normal diastolic filling
(Figure 2). Peak systolic myocardial velocities and SRs
were also lower in patients with impaired diastolic filling
compared with patients with normal filling, but this
−1
was not significant (SR, −1.24 +
− 0.36 s compared with
−1
+
−1.15 − 0.5 s respectively; and peak systolic velocity,
4.4 +
− 1.3 cm/s compared with 4.1 +
− 1.6 cm/s respectively;
P = 0.50).
The average SR, peak systolic myocardial velocities
and TT from the basal segments alone were calculated in a
separate analysis. We did not find any separation between
patients with impaired diastolic filling and patients with
normal diastolic filling in SR, peak systolic velocity
−1
compared
or TT measurements [SR, −1.6 +
− 1.0 s
−1
+
with −1.7 − 0.7 s respectively (P = 0.5); peak systolic
velocity, 5.3 +
− 1.7 cm/s compared with 5.0 +
− 1.0 cm/s
respectively (P = 0.50); TT, 7.9 +
− 2.0 mm compared with
9.8 +
− 1.6 mm respectively (P = 0.1)].
Table 3 displays regional values of the three systolic
tissue Doppler parameters.
Patients having insulin treatment were equally
distributed among patients with normal and impaired
Cardiac dysfunction in Type II diabetes mellitus
Table 3 Matching measurements of systolic peak velocities, SR and regional TT score
Values are means +
− S.D. *P < 0.01 compared with normal subjects.
Four-chamber view
Septum
Basal
Mid
Apical
Anterolateral
Basal
Mid
Apical
Two-chamber view
Inferoseptal
Basal
Mid
Apical
Anterior
Basal
Mid
Apical
Peak systolic velocity (cm/s)
SR (s−1 )
Controls
Patients
Controls
Patients
Controls
6.6 +
− 1.2
4.5 +
− 1.5
2.9 +
− 1.5
5.3 +
− 1.2*
3.9 +
− 0.7*
2.0 +
− 1.0*
−1.3 +
− 0.5
−1.7 +
− 0.6
−1.7 +
− 0.7
−1.3 +
− 0.8
−1.2 +
− 0.5*
−1.0 +
− 0.9*
11.7 +
− 1.7
8.0 +
− 1.8
3.5 +
− 1.7
9.8 +
− 1.9*
6.0 +
− 1.8*
2.2 +
− 1.1*
6.4 +
− 1.5
5.3 +
− 2.2
3.9 +
− 1.6
5.8 +
− 2.5
4.3 +
− 3.0*
2.6 +
− 2.0*
−2.6 +
− 1.3
−1.6 +
− 0.9
−1.0 +
− 0.6
−1.9 +
− 1.2*
−1.0 +
− 0.9*
−0.9 +
− 0.6
11.1 +
− 2.2
7.0 +
− 2.1
3.1 +
− 1.2
9.6 +
− 2.3*
5.4 +
− 2.6*
2.3 +
− 2.0*
6.7 +
− 0.9
4.7 +
− 1.0
2.9 +
− 1.2
5.9 +
− 1.2*
3.6 +
− 1.0*
2.3 +
− 1.1
−1.5 +
− 0.6
−1.4 +
− 0.5
−1.7 +
− 0.7
−1.3 +
− 1.0*
−1.2 +
− 0.6
−0.9 +
− 0.7*
12.0 +
− 1.4
8.4 +
− 2.5
3.7 +
− 1.7
10.4 +
− 1.9*
6.9 +
− 2.1*
2.5 +
− 1.5*
6.4 +
− 1.6
3.8 +
− 1.4
2.8 +
− 1.6
5.0 +
− 2.0*
3.4 +
− 1.6
2.5 +
− 1.3
−2.5 +
− 1.0
−1.4 +
− 0.5
−1.1 +
− 0.9
−1.9 +
− 0.9*
−1.0 +
− 0.7*
−0.5 +
− 0.3*
10.8 +
− 1.4
6.6 +
− 2.0
2.6 +
− 0.9
7.6 +
− 1.7*
6.0 +
− 2.9*
1.9 +
− 0.9*
Regional TT score (mm)
Patients
Long axis view
Inferolateral
Basal
Mid
Septum
Basal
Mid
5.6 +
− 2.1
4.1 +
− 1.7
5.7 +
− 2.8
3.6 +
− 2.1
−2.3 +
− 0.6
−1.2 +
− 0.3
−1.5 +
− 0.9*
−1.0 +
− 0.4*
10.2 +
− 3.5
6.7 +
− 1.1
8.3 +
− 2.5*
4.2 +
− 2.0*
5.6 +
− 2.8
4.2 +
− 1.8
3.9 +
− 1.4*
3.3 +
− 1.9
−2.2 +
− 1.2
−1.5 +
− 0.6
−1.5 +
− 0.8*
−1.2 +
− 0.5*
10.8 +
− 1.5
6.6 +
− 2.0
7.6 +
− 2.6*
4.2 +
− 2.1*
Mean
5.4 +
− 1.0
4.3 +
− 1.5*
−1.6 +
− 0.4
−1.2 +
− 0.3*
7.7 +
− 1.1
5.8 +
− 1.6*
diastolic filling, and insulin-treated patients as a group
did not have significantly lower longitudinal shortening
than the rest of the patients (6.4 +
− 1.1 mm compared
with 5.8 +
1.7
mm;
P
=
0.25).
Likewise
SRs and peak
−
systolic myocardial velocities were also similar in insulintreated patients compared with patients without insulin
−1
treatment [SR, −1.3 +
− 0.4 compared with −1.2 +
− 0.4 s
respectively (P = 0.50); peak systolic velocity, 4.6 +
−
1.5 cm/s compared with 4.1 +
− 1.4 cm/s (P = 0.40)].
Correlation of peak systolic velocities, SR
and TT score index
Figure 2 TT score index in controls and patients with
Type II diabetes mellitus with normal diastolic filling
(normal filling) or diastolic dysfunction (impaired filling)
The vertical bars indicate the mean.
No significant correlations were found with mean
peak systolic myocardial velocities in either patients
or controls. SR was significantly correlated to systolic
blood pressure in diabetes mellitus patients (ρ = −0.56,
P < 0.01). No other correlations were found among
demographic data or echocardiographic measurements.
In control subjects, a significant negative correlation was
C
2003 The Biochemical Society
63
64
N. H. Andersen and others
found between the TT score index and age (ρ = −0.48,
P < 0.01) and systolic blood pressure (ρ = −0.43, P <
0.02). In patients with Type II diabetes mellitus, no
significant correlation was found between the TT score
index and age, gender, heart rate, blood pressure, body
surface, BMI, E-wave/A-wave ratio, DT, isovolumetic
relaxation time, V p , LV volume, FS or EF, anti-diabetic
therapy, HbA1c or duration of the diabetes mellitus
disease.
DISCUSSION
The prevalence of diabetes mellitus in the latest clinical
trials of CHF is as high as 30 % and this number will
increase, as the number of Type II diabetes mellitus
patients is escalating. The importance of assessing
detailed information of LV myocardial performance is
essential in understanding the development of CHF and
gives physicians the opportunity to initiate therapeutic
intervention at an early stage.
The impact of diabetes mellitus on LV systolic and
diastolic function has been investigated previously in
the Strong Heart study [19–21]. In that study, apparent
implications of a specific diabetes mellitus effect on
the myocardium were found in both hypertensive
and normotensive patients. In normotensive diabetes
mellitus patients, in particular, these changes were closely
associated with the presence of microalbuminuria, which
is a strong predictor of cardiovascular morbidity and
mortality in diabetes mellitus patients.
In the present study, we found a high prevalence
of diastolic dysfunction (43 %) in normotensive and
normoalbuminuric patients with Type II diabetes mellitus
and normal FS and LVEF. This prevalence is equal
to what other observational studies have found on
similar populations [6,7]. We demonstrated significantly
impaired longitudinal systolic contraction, since both SR
and TT measurements, reflecting segmental myocardial
longitudinal contraction, were significantly decreased,
and we also found lower segmental myocardial systolic
velocities; however, these results were less consistent
when compared with SR and TT results. A possible
explanation for this is that peak systolic myocardial
velocity measurements describe the rate of movement
of the myocardial segment, which is severely influenced
by both frame rate and angle and also by tethering
[8]. By combining TT with SR, a global image of the
LV longitudinal contraction is obtained that discloses
whether this is actual contraction or tethering, which
pulsed tissue Doppler assessment does not.
A further important finding in the present study was
that patients with assumed isolated diastolic dysfunction
revealed a significant decrease in systolic longitudinal
contraction compared with patients without diastolic
involvement, confirming a significant interplay of both
C
2003 The Biochemical Society
systolic and diastolic dysfunction in this particular
patient group [22]. These findings were surprising, since
this myocardial involvement seemed to precede any
other complications known to be associated with CHF,
such as hypertension and albuminuria, but support
the original proposal of a diabetes-specific myocardial
disease resulting in an increased susceptibility of diabetes
mellitus patients to develop CHF [23]. This segregation
between patients with and without diastolic impairment
was not detectable with SR or peak systolic velocity
assessment alone or even in the separate analysis of the
basal segments.
Potential mechanisms behind decreased
longitudinal contraction
It is well known that the presence of the metabolic
syndrome, including obesity, insulin resistance and
poor glycaemic control, predisposes individuals to the
development of microangiopathy and also increases
the risk of cardiovascular complications, including CHF
[24–26]. Several trials have shown correlations between
cardiovascular disease and elevated HbA1c levels or
high-dose insulin treatment in this patient category
[4,24,27], and it seems that long-term hyperglycaemia
could be part of the cause, since hyperglycaemia is
associated with impaired endothelium-dependent relaxation caused by abnormal glycosylation end-products
and overproduction of free radicals [19,28]. Lack of
this vasodilatative capacity will compromise myocardial
performance [29]. In the present study, we did not
find any evidence of the metabolic syndrome being of
significant importance, since we did not find any difference in BMI, HbA1c , diabetes duration or diabetes
treatment between patients with and without diastolic
dysfunction or any correlation with the decreased SR and
TT score index. Neurohumeral activation is known to
influence myocardial function. Pronounced myocardial
conversion of angiotensin I into angiotensin II, which
is shown in diabetes mellitus patients [30,31], has
the potential to induce increased myocardial fibrosis
in the interstitial tissue, and augmented necrosis and
apoptosis of the myocytes will end in loss of contractile
function. This can be aggravated by microangiopathy
in the myocardial microcirculation, causing myocardial
malperfusion that will increase diastolic filling pressures
and enhance the extravascular component of coronary
resistance. Such mechanisms can be demonstrated in the
diabetic heart even in the absence of hypertension or
coronary artery disease [32].
The longitudinal subendocardial layers of the left
ventricle are also susceptible to macroangiopathy in
the epicardial arteries. Previous tissue Doppler studies
[33,34] have shown decreased segmental systolic and
diastolic peak velocities, due to very severe ischaemia
in patients with coronary heart disease. If these patients
Cardiac dysfunction in Type II diabetes mellitus
were affected by large vessel disease, we would have
expected regional changes in SR and systolic velocities
in areas supplied by the coronary arteries, but this was
not found. The compromised longitudinal shortening
was found to be global, affecting the entire myocardium.
It is more likely that the sum of interactions of
structural alterations of myocardium, interstitium and
coronary vasculature are likely to initiate and maintain
a process of compromised myocardial perfusion, which
can provoke functional depression of the myocardial
performance.
Limitations
No coronary angiographies, myocardial scintigraphy or
exercise test was performed in the present study, which
is a limitation to our observational study. In addition,
an analysis of TT and SR of 16 segments of the left
ventricle can be performed within 5–10 min, which
is relatively time consuming. However, these methods
give important information that cannot be detected
by conventional echocardiography. Some variation was
found in the SR measurements in the apical segments.
This was probably due to some difficulties in obtaining
optimal echocardiographic windows in the small fraction
of obese patients included in the study.
Conclusions
A decreased longitudinal contraction of the left ventricle
was found in normotensive in patients with Type II
diabetes mellitus despite normal EF and FS. The
impairment of longitudinal LV systolic function was
most pronounced in patients with co-existing diastolic
dysfunction, which might lead to a reconsideration of the
concept of isolated diastolic dysfunction in normotensive
Type II diabetes mellitus. The analysis of LV systolic
function assessed by TT and SR analysis gives new
important insights into LV myocardial performance.
ACKNOWLEDGMENTS
We thank The Novo Nordic Foundation and the Laurits
Peter Christensen and wife Kirsten Sigrid Christensen’s
Foundation for supporting the study.
REFERENCES
1 A Joint Editorial Statement by the American Diabetes
Association; The National Heart, Lung, and Blood
Institute; The Juvenile Diabetes Foundation International;
The National Institute of Diabetes and Digestive and
Kidney Diseases; and The American Heart Association
(1999) Diabetes mellitus: a major risk factor for
cardiovascular disease. Circulation 100, 1132–1133
2 O’Connor, C. M., Gattis, W. A., Shaw, L., Cuffe, M. S. and
Califf, R. M. (2000) Clinical characteristics and long-term
outcomes of patients with heart failure and preserved
systolic function. Am. J. Cardiol. 86, 863–867
3 Devereux, R. B., Roman, M. J., Liu, J. E. et al. (2000)
Congestive heart failure despite normal left ventricular
systolic function in a population-based sample: the strong
heart study. Am. J. Cardiol. 86, 1090–1096
4 Nichols, G. A., Hillier, T. A., Erbey, J. R. and Brown, J. B.
(2001) Congestive heart failure in type 2 diabetes:
prevalence, incidence, and risk factors. Diabetes Care 24,
1614–1619
5 Vasan, R. S., Larson, M. G., Benjamin, E. J., Evans, J. C.,
Reiss, C. K. and Levy, D. (1999) Congestive heart failure in
subjects with normal versus reduced left ventricular
ejection fraction: prevalence and mortality in a
population-based cohort. J. Am. Coll. Cardiol. 33,
1948–1955
6 Zabalgoitia, M., Ismaeil, M. F., Anderson, L. and
Maklady, F. A. (2001) Prevalence of diastolic dysfunction in
normotensive, asymptomatic patients with well-controlled
type 2 diabetes mellitus. Am. J. Cardiol. 87, 320–323
7 Poirier, P., Bogaty, P., Garneau, C., Marois, L. and
Dumesnil, J. G. (2001) Diastolic dysfunction in
normotensive men with well-controlled type 2 diabetes:
importance of maneuvers in echocardiographic screening
for preclinical diabetic cardiomyopathy. Diabetes Care 24,
5–10
8 Urheim, S., Edvardsen, T., Torp, H., Angelsen, B. and
Smiseth, O. A. (2000) Myocardial strain by doppler
echocardiography. Validation of a new method to quantify
regional myocardial function. Circulation 102, 1158–1164
9 Edvardsen, T., Urheim, S., Skulstad, H., Steine, K.,
Ihlen, H. and Smiseth, O. A. (2002) Quantification of
left ventricular systolic function by tissue Doppler
echocardiography: added value of measuring pre- and
postejection velocities in ischemic myocardium.
Circulation 105, 2071–2077
10 Schiller, N. B., Shah, P. M., Crawford, M. et al. (1989)
Recommendations for quantitation of the left ventricle by
two-dimensional echocardiography. American Society
of Echocardiography Committee on Standards,
Subcommittee On Quantitation Of Two-Dimensional
Echocardiograms. J. Am. Soc. Echocardiogr. 2, 358–367
11 Kim, W. Y., Sogaard, P., Egeblad, H., Andersen, N. T. and
Kristensen, B. (2001) Three-dimensional echocardiography
with tissue harmonic imaging shows excellent
reproducibility in assessment of left ventricular volumes.
J. Am. Soc. Echocardiogr. 14, 612–617
12 Takatsuji, H., Mikami, T., Urasawa, K. et al. (1996) A new
approach for evaluation of left ventricular diastolic
function: spatial and temporal analysis of left ventricular
filling flow propagation by color M-mode Doppler
echocardiography. J. Am. Coll. Cardiol. 27, 365–371
13 Garcia, M. J., Palac, R. T., Malenka, D. J., Terrell, P. and
Plehn, J. F. (1999) Color M-mode Doppler flow
propagation velocity is a relatively preload-independent
index of left ventricular filling. J. Am. Soc. Echocardiogr.
12, 129–137
14 Nishimura, R. A. and Tajik, A. J. (1997) Evaluation of
diastolic filling of left ventricle in health and disease:
Doppler echocardiography is the clinician’s rosetta stone.
J. Am. Coll. Cardiol. 30, 8–18
15 Pan, C., Hoffmann, R., Kuhl, H., Severin, E., Franke, A.,
and Hanrath, P. (2001) Tissue tracking allows rapid and
accurate visual evaluation of left ventricular function.
Eur. J. Echocardiogr. 2, 197–202
16 Armstrong, G., Pasquet, A., Fukamachi, K., Cardon, L.,
Olstad, B. and Marwick, T. (2000) Use of peak systolic
strain as an index of regional left ventricular function:
comparison with tissue Doppler velocity during
dobutamine stress and myocardial ischemia.
J. Am. Soc. Echocardiogr. 13, 731–737
17 Heimdal, A., Stoylen, A., Torp, H. and Skjaerpe, T. (1998)
Real-time strain rate imaging of the left ventricle by
ultrasound. J. Am. Soc. Echocardiogr. 11, 1013–1019
18 Abraham, T. P. and Nishimura, R. A. (2001) Myocardial
strain: can we finally measure contractility? J. Am. Coll.
Cardiol. 37, 731–734
C
2003 The Biochemical Society
65
66
N. H. Andersen and others
19 Liu, J. E., Palmieri, V., Roman, M. J. et al. (2001) The
impact of diabetes on left ventricular filling pattern in
normotensive and hypertensive adults: the Strong Heart
Study. J. Am. Coll. Cardiol. 37, 1943–1949
20 Bella, J. N., Devereux, R. B., Roman, M. J. et al. (2001)
Separate and joint effects of systemic hypertension and
diabetes mellitus on left ventricular structure and function
in American Indians (the Strong Heart Study). Am. J.
Cardiol. 87, 1260–1265
21 Devereux, R. B., Roman, M. J., Paranicas, M. et al. (2000)
Impact of diabetes on cardiac structure and function: the
Strong Heart Study. Circulation 101, 2271–2276
22 Yu, C. M., Lin, H., Yang, H., Kong, S. L., Zhang, Q. and
Lee, S. W. (2002) Progression of systolic abnormalities in
patients with ‘isolated’ diastolic heart failure and diastolic
dysfunction. Circulation 105, 1195–1201
23 Lundbæk, K. (1954) Diabetic angiopathy: a specific
vascular disease. Lancet i, 377–379
24 Stratton, I. M., Adler, A. I., Neil, H. A. et al. (2000)
Association of glycaemia with macrovascular and
microvascular complications of type 2 diabetes (UKPDS
35): prospective observational study. Br. Med. J. 321,
405–412
25 Warram, J. H., Scott, L. J., Hanna, L. S. et al. (2000)
Progression of microalbuminuria to proteinuria in type 1
diabetes: nonlinear relationship with hyperglycemia.
Diabetes 49, 94–100
26 Sundstrom, J., Lind, L., Valind, S. et al. (2001) Myocardial
insulin-mediated glucose uptake and left ventricular
geometry. Blood Pressure 10, 27–32
27 Iribarren, C., Karter, A. J., Go, A. S. et al. (2001) Glycemic
control and heart failure among adult patients with
diabetes. Circulation 103, 2668–2673
28 van Hoeven, K. H. and Factor, S. M. (1990) A comparison
of the pathological spectrum of hypertensive, diabetic, and
hypertensive-diabetic heart disease. Circulation 82,
848–855
29 Yokoyama, I., Momomura, S., Ohtake, T. et al. (1997)
Reduced myocardial flow reserve in non-insulin-dependent
diabetes mellitus. J. Am. Coll. Cardiol. 30, 1472–1477
30 Ihara, M., Urata, H., Kinoshita, A. et al. (1999) Increased
chymase-dependent angiotensin ii formation in human
atherosclerotic aorta. Hypertension 33, 1399–1405
31 Califf, R. M. and Cohn, J. N. (2000) Cardiac protection:
evolving role of angiotensin receptor blockers.
Am. Heart J. 139, S15–S22
32 Frustaci, A., Kajstura, J., Chimenti, C. et al. (2000)
Myocardial cell death in human diabetes. Circ. Res. 87,
1123–1132
33 Derumeaux, G., Loufoua, J., Pontier, G., Cribier, A. and
Ovize, M. (2001) Tissue Doppler imaging differentiates
transmural from nontransmural acute myocardial
infarction after reperfusion therapy. Circulation 103,
589–596
34 Derumeaux, G., Ovize, M., Loufoua, J., Pontier, G.,
Andre-Fouet, X. and Cribier, A. (2000) Assessment of
nonuniformity of transmural myocardial velocities by
color-coded tissue Doppler imaging: characterization of
normal, ischemic, and stunned myocardium. Circulation
101, 1390–1395
Received 30 October 2002/11 February 2003; accepted 14 March 2003
Published as Immediate Publication 14 March 2003, DOI 10.1042/CS20020303
C
2003 The Biochemical Society