Download Cardiac function in diabetic and non

Cardiac function in diabetic and nondiabetic patients with and without ischemic
heart disease: the role of inflammation and
adipocytes
Auteur: Richard de Leth
Studentnummer: 1260065
Emailadres: [email protected]
Telefoonnummer: 06-xxxxxxxx
Begeleiders: Prof. Dr. W.J. Paulus, Dr. M. Diamant en Drs. M.E. Tushuizen,
Afdeling Endocrinologie/ Diabetescentrum
VU Medisch Centrum Amsterdam
Periode stage: 8 mei – 25 augustus 2006
CONTENTS
Summary……………………………………………………………………………..page 3
Introduction…………………………………………………………………………..page 4-5
Methods……………………………………………………………………………...page 5-7
Results……………………………………………………………………………….page 7-12
Discussion…………………………………………………………………………...page 12-13
Abbreviations and Acronyms...……………………………………………………..page 13
Reference List………………………………………………………………………page 14-15
2
Summary
Introduction/Background: Type 2 diabetes (DM2) is associated with a high risk of coronary
artery disease (CAD) and heart failure. Even in asymptomatic patients, left ventricular (LV)
mass enlargement and cardiac dysfunction have been described. Visceral obesity is a risk
factor for the development of the metabolic syndrome (MetS), DM2 and CAD. Adipose tissue
is an active endocrine and paracrine organ that releases a large number of (adipo)cytokines
with pro-inflammatory properties. At present, not much is known regarding cardiac structural
and functional abnormalities in people with MetS and DM2 with and without CAD and the
relationship of cardiac function, inflammation, adipose tissue characteristics in these disease
states.
Methods: Twelve DM2 patients, 26 MetS subjects and 18 controls (n=56) who underwent
coronary angiography were studied. After obtaining medical history and anthropometrical
data and prior to coronary angiography, arterial blood samples were obtained and the
electrocardiogram was evaluated. During coronary angiography hemodynamic parameters and
various left ventricular (LV) systolic and diastolic functional parameters were collected. Left
ventricular wall thickness (LVWT) was measured by echocardiography.
Results: Weight, body mass index, waist and glucose were significantly higher in DM2
patients and MetS subjects in comparison with controls (all P<0.01). There were no
significant differences in leukocytes and C-reactive protein (CRP) (P=0.422). CRP was higher
in DM2 patients compared to non-diabetic patients, although not significant (P=0.187).
LVWT was also significantly higher in DM2 patients and MetS subjects when compared to
controls, both end-systolic and end-diastolic (P=0.007, P=0.049, respectively). Both LVWT
were independent of age and smoking, associated with waist. LV myocardial stiffness
modulus is significantly associated with the presence of CAD (P=0.048) and severity of CAD
(P=0.011). LV end-diastolic pressure was significantly higher in DM2 patients and MetS
subjects in comparison with controls (P=0.041). There was no significant difference between
the groups in LV end-diastolic volume index (P=0.155). CRP is significantly associated with
LV end-systolic volume index (r=0.347, P=0.026) and LV ejection fraction (r=0.328,
P=0.016). There were no significant associations between leukocytes and cardiac function
parameters.
Conclusion: Cardiomyocyte hypertrophy in the left ventricle is already present in subjects
with MetS, also known as a prediabetic state, and further deteriorates in DM2 patients,
compared to controls. Furthermore, the end-diastolic distensibility is reduced in the left
ventricle of DM2 patients and MetS subjects in comparison with controls. These findings
suggest that there is concentric remodeling in the left ventricle of DM2 patients and MetS
subjects. Lowgrade inflammation present in these subjects may be one of the underlying
mechanisms.
3
Introduction
Obesity carries a high risk for the development of type 2 diabetes (DM2) and cardiovascular
disease (CVD). 1 CVD is the foremost killer of patients with DM2, in particular coronary
artery disease (CAD) and congestive heart failure (CHF).2-4
World Health Organization (WHO) now predicts that by 2020, CVD will become the
most important condition that is treated across global health systems.5 Even in asymptomatic
DM2 patients without hypertension or CAD, cardiac functional and structural abnormalities
can be detected.6 Thus, left ventricular (LV) enlargement, and most notably diastolic
dysfunction either in the absence or presence of systolic dysfunction have been described.
Over 40% of patients with diabetes may have abnormal diastolic function on
echocardiogram.7 These disturbances are ascribed to diabetes cardiomyopathy (DCM).
Obesity is also a strong risk factor for the metabolic syndrome (MetS). MetS is a
constellation of metabolic abnormalities, including hyperglycemia, hypertension,
dyslipidemia, and increased waist circumference.8-13 MetS may be regarded as a prediabetic
condition, which is characterized by insulin resistance but a (still) preserved ß-cell function.
14,15
Left ventricular abnormalities are common in type 2 diabetic patients, especially left
ventricular hypertrophy and diastolic filling abnormalities.6,16 High diastolic LV stiffness is
recognised as the earliest manifestation of diabetes-induced LV dysfunction6,17-23 and
frequently becomes the main functional deficit of the diabetic heart as many diabetics present
with heart failure and normal LV ejection fraction.24-25 Although CAD is the most important
contributor to the myocardial dysfunction observed in DM2, metabolic disturbances
associated with DM2 can also induce myocardial dysfunction as a result of direct actions on
the myocardium of hyperlipidemia, hyperglycemia and hyper- or hypoinsulinemia.
Hyperinsulinemia stimulates prohypertrophic signalling in insulin responsive tissues, such as
the myocardium.26
As mentioned above, metabolic or diabetic cardiomyopathy already exists in a high
proportion of asymptomatic DM2 patients even in the absence of hypertension and CAD. Due
to the diabetes-related metabolic abnormalities, lipotoxicity and glucose toxicity with
subsequent oxidative stress, mitochondrial dysfunction and abnormal cardiac energy
metabolism, have been proposed as important factors contributing to the development of
DCM. However, recently, a role of (systemic) inflammation has been proposed.27 However, at
present, this concept needs further elaboration with regard to the underlying mechanisms.
Adipose tissue is an active endocrine and paracrine organ that releases a large number
of (adipo)cytokines and bioactive mediators that not only influence body weight homeostasis
but also inflammation, coagulation and insulin resistance, that may lead to an pro-atherogenic
environment.28 Adverse fat distribution, most notably visceral fat, rather than the total amount
of body fat seems an important risk factor for CVD, therefore qualitative rather than
quantitative features of adipose tissue appear to be more essential. Most recently, epicardial
fat was not only found to importantly correlate with the amount of visceral fat and the insulin
resistant state, it also was shown to secrete pro-inflammatory mediators.29 It has been
proposed that excessive epicardial fat may be involved in the development of CAD and
possibly also in cardiac dysfunction.29,30 However, not much is known about the proinflammatory qualities of epicardial fat pads in patients with and without DM2 and their
associations with CVD/CAD and/or cardiac dysfunction. Recent studies show that human
epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with
CVD31 and a lower adiponectin expression in patients with CAD.32
4
Research questions
The present study is part of a larger study addressing the following research questions:
I. What are the LV myocardial structural and functional abnormalities of patients
undergoing coronary angiography when patients are subdivided into normal, MetS or
DM2?
II. What are the determinants of these LV myocardial structural and functional
properties?
III. Are there associations between general markers of inflammation, such as leukocyte
count and high-sensitive C-reactive protein (hsCRP) and these LV myocardial
structural and functional parameters?
IV. What are the levels of pro-inflammatory markers, such as interleukin-6 (IL-6), hsCRP, tumor necrosis factor (TNF ) and monocyte chemotactic protein-1 (MCP-1)
in CAD patients with DM2 as compared to those without?
V. What are the expression levels of inflammation, including adipokines (adiponectin,
leptin, resistin), and macrophage specific genes, morphology and/or
immunohistological properties in adipose tissue samples obtained from various fat
depots, including subcutaneous, visceral and epicardial fat?
VI. Are there differences in expression levels of inflammation, including adipokines
(adiponectin, leptin, resistin), and macrophage specific genes, morphology and/or
immunohistological properties in adipose tissue samples from CAD patients with
DM2 as compared to those without diabetes?
VII.Are there differences in expression levels of inflammation, including adipokines
(adiponectin, leptin, resistin), and macrophage specific genes, morphology and/or
immunohistological properties in adipose tissue samples from patients with CAD as
compared to those without CAD?
In the present study, due to the limited time period of the research elective, we investigated
the first 3 of the above-listed research questions. The other questions will be part of future
research.
Taken together, this project will enable us to gain insight into the relationship between the
various body fat depots, such as subcutaneous and epicardial fat and inflammation and cardiac
structure and function.
Subjects and Methods
This study is a sub study focusing on the differences between patients with DM2, MetS and
patients without DM2 and MetS (controls).
The clinical, hemodynamic, cardiac and plasma data will be used to answer research question
I-III. The expression levels of inflammation, including adipokines, in adipose tissue samples
obtained from various fat depots will be analyzed in the future to answer the other research
questions. This sub study shows the results so far.
Subjects
56 subjects, i.e. 12 patients with DM2, 26 patients with MetS and 18 controls were studied.
Males and females aged 40-85 yr, LVEF >50%,33 and with documented LV function by
echocardiography were selected.
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Exclusion criteria for all participants were severe inflammation (CRP>20 mg/dl);
cancer; renal disease (serum creatinine >150 µmol/l); known liver disease; use of drugs like
prednisone and anti-cancer therapy.
A patient was defined as having DM2, when DM2 was diagnosed according to the
WHO criteria,34 treated with diet or oral hypoglycemic medication (sulfonylurea’s or
metformin).
A patient was defined as having MetS from Adult Treatment Panel (ATP)/NCEP III
criteria.8 At least 3 or more of the following criteria had to be present: abdominal obesity
(men: waist circumference > 102 cm, women: waist circumference > 88 cm), elevated BP
(=130/=85 mmHg), high triglycerides (TG) (=1.7 mmol/l), low HDL cholesterol (men: <1.03
mmol/l, women: <1.29 mmol/l), increased fasting plasma glucose (=5.6 mmol/l).
Controls were defined as having no MetS and DM2.
Study design
The study comprised 56 patients who were in the hospital for coronary angiography. The
indications for coronary angiography were angina pectoris (41%), dyspneu (20%), atypical
chest pain (12,5%), atrium fibrillation (9%), syncope (7%) and palpitations (4%).
Data collection
Before coronary angiography weight, length, BMI, waist circumference (measured 2 cm
above the anterior superior iliac crest), medication, medical history, current operation and
operation indication were collected. The electrocardiogram (ECG) was also evaluated.
Blood collection
Prior to coronary angiography, arterial blood samples were obtained to determine: glucose,
total cholesterol (Tchol), LDL-cholesterol, HDL-cholesterol, and TG. Blood was collected
into citrate tubes and centrifuged at room temperature for 20 minutes and filled out in aliquots
of 250 µl. The aliquots were snap frozen in liquid nitrogen. Inflammatory markers and
adipo(cyto)kines will also be determined in the samples.
Hemodynamic parameters collection
During coronary angiography hemodynamic parameters and various LV systolic and diastolic
functional parameters were collected.
Left ventricular wall thickness (LVWT) was measured by echocardiography. The radial
myocardial stiffness modulus (E) was calculated to assess myocardial material properties
from the formula: E= s R/ eR= P/( h/h)= - P/ ln h and assuming the increment in radial
stress ( s R) to be equal but opposite in sign to the increment in P at the endocardium and the
increment in radial strain ( eR) to be equal to the increment in wall thickness ( h) relative to
the instantaneous wall thickness.35 In the formula, P stands for left ventricular end-diastolic
pressure (LVEDP) and h is echocardiographically determined LV wall thickness. Because
h/h= ln h, E equals the slope of a P versus ln h plot.36,37
Tissue collection
Subcutaneous fat tissue was collected from the groin, at the insertion site of the catheter sheet
prior to coronary angiography. Epicardial fat tissue was collected from near the proximal right
coronary artery during cardiothoracic surgery. After removal of visible blood vessels and
clots, the tissue was frozen immediately in liquid nitrogen and stored at –80°C for further
analysis.
6
Statistical analysis
Data on quantitative characteristics are expressed as mean ± SD. Participants were divided
into three groups. Statistical significance was set at P<0.05 and was obtained for multiple
comparisons between groups by ANOVA and for single comparisons by an unpaired Student t
test. Furthermore, bivariate comparisons with respect to the correlation between LVWT and
baseline/hemodynamic/cardiac function characteristics were performed by bivariate
correlation (Spearman). All statistical analysis were performed with SPSS software (version
13.0).
Results
Table 1: Baseline characteristics
Controls
MetS
DM 2
Sign.
In this study three groups
(mean ± SD) (mean ± SD) (mean ± SD) (*p<0.05)
were studied; DM2
18 (10)
26 (15)
12 (8)
patients, MetS subjects and Numbers (male)
Age, years
64.1 ± 11.1
67.6 ± 11.6
68.3 ± 9.1
P=0.495
controls.
71.1 ± 8.7
77.4 ± 13.2
87.4 ± 16.2 P=0.005*
Baseline characteristics are Weight, kg
BMI, kg/m2
24.1 ± 2.7
27.5 ± 3.6
29.6 ± 4.7
P< 0.001*
listed in table 1.
Waist, cm
90.6 ± 9.6
101.3 ± 10.8 103.3 ± 10.8 P =0.002*
There were no
BPsyst, mmHg
126.8 ± 22.3 146.1 ± 26.0 134.4 ± 11.3 P= 0.087
significant differences in
BPdiast, mmHg
79.6 ± 13.3
80.4 ± 11.5
78.9 ± 9.6
P=0.948
Glucose, mmol/l
4.9 ± 0.4
5.7 ± 0.8
8.6 ± 3.0
P< 0.001*
age, BPsys, BPdiast,
Tchol, mmol/l
5.1 ± 1.2
5.1 ± 1.2
4.3 ± 1.3
P=0.146
Tchol, HDL, leukocytes
HDL, mmol/l
1.5 ± 0.3
1.4 ± 0.5
1.3 ± 0.6
P=0.387
and C-reactive protein
TG, mmol/l
1.4 ± 0.8
2.4 ±- 1.9
2.3 ± 1.3
P =0.102
(CRP) (P=0.422). CRP
Leukocytes,
6.5 ± 1.3
7.0 ± 2.1
6.6 ± 3.1
P=0.803
was higher in DM2
*106/l
patients compared to non- CRP, mg/dl
2.8 ± 3.5
2.8 ± 4.0
4.8 ± 6.6
P=0.422
diabetic patients, although
not significant (P=0.187).
There was a significant difference between the groups for weight (P=0.005). Mean
weight in controls was lower than MetS, and mean weight in MetS was lower than DM2. BMI
was significantly different in DM2 patients, MetS subjects and controls (P<0.001). The same
accounts for waist, with values of 103.8±10.8 cm (DM2), 101.3±10.8 cm (MetS) and
90.6±9.6 cm (controls) (P=0.002).
Glucose was significantly different in DM2 patients, MetS subjects and controls
(P<0.001). For these four parameters (weight, BMI, waist and glucose), DM2 patients had the
highest levels followed by the MetS subjects. The lowest levels were found in the controlgroup.
TG values were similar in the DM2 and MetS group (2.3±1.3 vs 2.4±1.9 mmol/l
respectively). The control-group had significantly lower TG levels compared with the DM2
and MetS group (1.4±0.8 mmol/l; P=0.033).
Table 2 shows the hemodynamics and left ventricular function parameters. Diastolic aorta
pressure (AoPdiast) was similar in the control and MetS group. AoPdiast was significantly
higher in this two non-diabetic groups in comparison with the DM2 patients (P=0.034).
Mean aorta pressure (AoPmean) was also significantly higher in the two non-diabetic
groups in comparison with the DM2 patients (P=0.043). There was no significant difference
in systolic aorta pressure (AoPsyst) (P=0.074).
Left ventricular peak systolic pressure (LVPSP) was significantly different in DM2
patients, MetS subjects and controls (P=0.025). The same accounts for left ventricular enddiastolic pressure (LVEDP), with values of 17.5±9.0 mmHg (DM2), 21.1±7.6 mmHg (MetS)
and 14.9±7.1 mmHg (controls) (P=0.041).
7
There was a significant difference between the MetS group and the control-group in
left ventricular end-systolic volume index (LVESVIangio) (16.2±8.0 ml/m² vs 23.6±10.7
ml/m²) (P=0.029). There was no significant difference between the groups in left ventricular
end-diastolic volume index (LVEDVIangio) (P=0.155) and left ventricular ejection fraction
(LVEF) (P=0.399).
Table 2: Hemodynamics and left ventricular (LV) function parameters
Numbers
CAD=0
CAD=1
CAD=2
CAD=3
HR, beats/min
AoPsyst, mmHg
AoPdiast, mmHg
AoPmean,mmHg
Systolic LV function:
LVPSP, mmHg
LVESVIangio, ml/m2
LVWTe.s., mm
LVEF, %
Diastolic LV function:
LVEDP, mmHg
LVEDVIangio, ml/m2
LVWTe.d., mm
StifMod, kN/m2
Controls
(mean ± SD)
MetS
(mean ± SD)
DM 2
(mean ± SD)
Sign.
(*p<0.05)
18
0.4±0.5
0.2±0.4
0.2±0.4
0.2±0.4
67.6±13.7
137.2±30.6
70.7±14.9
98.4±20.9
26
0.5±0.5
0.2±0.4
0.1±0.3
0.2±0.4
71.9±24.9
153.8±26.7
72.1±13.9
104.0±16.8
12
0.1±0.3
0.4±0.5
0.3±0.5
0.2±0.4
69.8±16.1
135.3±24.0
61.6±13.3
89.1±18.1
P=0.043*
P=0.163
P=0.358
P=0.992
P=0.817
P=0.074
P=0.104
P=0.081
140.4±30.5
23.6±10.7
12.8±3.4
71.2±12.4
166.4±36.8
16.2±8.0
16.5±4.3
75.9±10.3
144.2±24.9
23.6±15.4
16.8±3.8
72.6±12.3
P=0.025*
P=0.100
P=0.007*
P=0.399
14.9±7.1
77.7±21.0
8.4±2.4
6.4 ± 7.6
21.1±7.6
66.3±17.5
9.8±2.0
6.1 ± 3.1
17.5±9.0
66.9±23.0
10.2±2.0
5.8 ± 4.9
P=0.041*
P=0.155
P=0.049*
P=0.964
Left ventricular end-systolic wall thickness (LVWTe.s.) was significantly higher in the
DM2 group and MetS group in comparison with the controls (P=0.007). The same is true for
left ventricular end-diastolic wall thickness (LVWTe.d.), with values of 10.2±2.0 mm (DM2),
9.8±2.0 mm (MetS) and 8.4±2.4 mm (controls) (P=0.049). Both LVWT were independent of
age and smoking, associated with waist. Left ventricular wall thickness is used as a measure
of left ventricular hypertrophy.
CAD=0 differed significantly in DM2 patients, MetS subjects and controls (P=0.043).
There was no significant difference in CAD=1 (P=0.163) and CAD=2 (P=0.358). CAD=3
levels were similar with values of 0.2±0.4 in all three groups (P=0.992). Heart rate (HR)
levels were comparable with values of 69.8±16.1 beats/min (DM2), 71.9±24.9 beats/min
(MetS) and 67.6±13.7 beats/min (controls) (P=0.817).
There was no significant difference between the groups in left ventricular stiffness
modulus (StifMod) (P=0.964). Table 3 shows the interaction of severity of CAD and
metabolic state on LV myocardial stiffness. LV stiffness modulus is significantly associated
with the presence of CAD (see table 4 and figure 3, P=0.048) and severity of CAD (P=0.011),
independent of age, sex, group (metabolic state), BMI, waist, systolic blood pressure and
creatinine.
8
Table 3: Interaction of severity of CAD and metabolic state on cardiac stiffness
Vessel disease
Number
N=54
StifMod, kN/m2
6.1±0.5
Mean ± SD
One-way ANOVA: P=0.011
0
N=26
5.1±0.5
1
N=12
5.0±0.9
2
N=8
9.4±2.0
3
N=8
8.0±1.4
Table 4: Influence of CAD on cardiac stiffness
CAD
Number
StifMod, kN/m2
Mean ± SD
*P=0.048
Yes
N=28
7.0±0.8
No
N=26
5.1±0.5*
Figure 3
Myocardial stiffness modulus [kN/m2]
10
9
8
7
6
control
MetS
DM2
5
4
3
2
1
0
CAD
non-CAD
Figure 3 shows the LV myocardial stiffness modulus (kN/m2) in the three groups with and
without CAD.
Table 5 shows drugs therapy in the three groups. ATII-antagonist administration differed
significantly in the DM2 patients (42%), MetS subjects (12%) and the control-group (0%)
(P=0.005). There was no significance between the other medications. Also, smoking behavior
was not significant between the groups.
9
Table 5: Medication and smoking
B-blocker
ACE-inhibitor
ATII-antagonist
Statins
Diuretics
Aspirin
Current smoking
Smoked in the past
Total smoking
Controls
10 (56%)
4 (22%)
0 (0%)
7 (39%)
5 (28%)
12 (67%)
4 (22%)
1 (6%)
5 (28%)
MetS
19 (73%)
9 (35%)
3 (12%)
11 (42%)
5 (19%)
12 (46%)
3 (12%)
5 (19%)
8 (31%)
DM 2
8 (67%)
6 (50%)
5 (42%)
8 (67%)
4 (33%)
9 (75%)
2 (17%)
5 (42%)
7 (59%)
Sign. (*p<0.05)
P=0.497
P=0.300
P=0.005*
P=0.289
P=0.914
P=0.728
P=0.650
P=0.051
P=0.186
Table 6: Correlation between LVWT and baseline characteristics
LVWTe.s.
Sign.
LVWTe.d.
(*p<0.05)
Weight, kg
BMI, kg/m2
Waist, cm
BPsyst, mmHg
BPdiast, mmHg
Glucose, mmol/l
Tchol, mmol/l
HDL, mmol/l
TG, mmol/l
Leukocytes,
*106/l
CRP, mg/dl
Sign.
(*p<0.05)
0.405
0.443
0.520
0.159
0.149
0.361
0.041
0.206
0.371
0.084
0.003*
0.001*
<0.001*
0.370
0.401
0.009*
0.770
0.142
0.007*
0.556
0.492
0.476
0.581
0.307
0.139
0.234
0.056
0.367
0.303
0.212
<0.001*
<0.001*
<0.001*
0.072
0.425
0.092
0.688
0.006*
0.026*
0.128
0.047
0.744
0.221
0.116
Correlations (Spearman’s rank test) between LVWT and baseline characteristics are listed in
table 6. LVWTe.s. is significantly associated with weight (r=0.405, P=0.003), BMI (r=0.443,
P=0.001), waist (r=0.520, P<0.001) (figure 1), glucose (r=0.361, P=0.009) and TG (r=0.371,
P=0.007). The associations between LVWTe.s. and BPsyst (r=0.159), BPdiast (r=0.149),
Tchol (r=0.041), HDL (r=0.206), leukocytes (r=0.084) and CRP (r=0.047) were not
significant.
LVWTe.d. is significantly associated with HDL (r=0.367, P=0.006) and TG (r=0.303,
P=0.026); however the strongest associations were found between LVWTe.d. and weight
(r=0.492, P<0.001), BMI (r=0.476, P<0.001) and waist (r=0.581, P<0.001) (figure 2).
The associations between LVWTe.d. and BPsyst (r=0.307), BPdiast (r=0.139), glucose
(r=0.234), Tchol (r=0.056), leukocytes (r=0.212) and CRP (r=0.221) were not significant.
10
Figure 1
30
20
LVWT(e.s), mm
10
0
Rsq = 0.1738
70
80
90
100
110
120
130
Waist, cm
Figure 1 shows the association between left ventricular end-systolic wall thickness and waist.
Figure 2
16
14
12
10
LVWT(e.d), mm
8
6
Rsq = 0.3275
4
70
80
90
100
110
120
130
Waist, cm
Figure 2 shows the association between left ventricular end-diastolic wall thickness and waist.
11
Table 7: Correlation between LVWT and LV function parameters
Table 7 shows the
LVWTe.s.
Sign.
LVWTe.d.
Sign.
correlations (Spearman’s
(*p<0.05)
rank test) between
HR, beats/min
0.046
0.767
0.012
0.938
LVWT and
AoPsyst, mmHg
0.161
0.258
0.270
0.051
hemodynamics/LV
AoPdiast, mmHg
0.097
0.500
0.031
0.827
function parameters.
AoPmean,mmHg
0.159
0.264
0.147
0.294
LVWTe.s. is
LVPSP, mmHg
0.194
0.167
0.375
0.005*
significantly associated
LVEDP, mmHg
0.355
0.010*
0.423
0.001*
with LVEDP (r=0.355,
LVEDVIangio,
0.169
0.232
0.177
0.200
P=0.010) and LVWTe.d. ml/m2
LVESVIangio,
(r=0.690, P<0.001).
0.185
0.247
0.044
0.785
ml/m2
LVWTe.s. was not
LVEF, %
0.123
0.385
0.052
0.709
significantly associated
LVWTe.s., mm
0.690
<0.001*
with the other
0.690
<0.001*
parameters. LVWTe.d. is LVWTe.d., mm
CAD=0
0.000
1.000
0.256
0.061
significantly associated
CAD=1
0.058
0.683
0.026
0.853
with LVPSP (r=0.375,
CAD=2
0.037
0.793
0.207
0.132
P=0.005), LVEDP
CAD=3
(r=0.423, P=0.001) and
0.168
0.232
0.341
0.012*
CAD=3 (r=0.341,
CRP
Sign.
P=0.012). LVWTe.d. was not significantly
(*p<0.05)
LVESVIangio,
associated with the other parameters.
0.347
0.026*
CRP is significantly associated with LVESVIangio ml/m2
0.328
0.016*
(r=0.347, P=0.026) and LVEF (r=0.328, P=0.016). LVEF, %
There were no significant associations between leukocytes and cardiac function parameters.
Discussion
The present study demonstrates significant differences in LVWT in patients with DM2, MetS
subjects and controls. Cardiomyocyte hypertrophy in the left ventricle is already present in
subjects with MetS, also known as a prediabetic state, and further deteriorates in DM2
patients, compared to controls. Unfortunately, because this study is still in progress, the
relationship between epicardial fat, inflammation parameters and LVWT could not be
performed. This will be done in the future after all analysis are finished.
Furthermore, the end-diastolic distensibility is reduced in the left ventricle of DM2
patients and MetS subjects, because LVEDP is increased and LVEDVIangio is equal in
comparison with the controls. These findings suggest that because LVWT is increased and
LV volume did not change, there might be concentric remodeling in the left ventricle of DM2
patients and MetS subjects. This is in line with several studies that has been shown that
increasing visceral adiposity contributes to LV remodeling.38
There is an increasing level of intra-abdominal fat between the groups. Risk associated
with obesity is best identified by increased waist circumference.39 Studies have demonstrated
that even in mildly obese subjects, visceral fat accumulation is correlated with development of
CAD.40
However, CAD can be seen as a confounding factor in this study, because in the DM2
group there are only 3 patients without CAD, compared to MetS (n=13) and controls (n=10).
The high incidence of multivessel disease in the DM2 group could influence the qualities of
the myocardium, including LVWT. As expected, patients with CAD had a higher LV stiffness
12
modulus in comparison with patients without CAD. The decline in the CAD group for LV
stiffness modulus was probably related to a confounding factor, namely a higher prevalence
of previous myocardial infarction in patients suffering of MetS or DM2. The patients without
CAD show the expected trend for a progressive increase in LV myocardial stiffness modulus
from control to MetS to DM2. Other limitations of this study are that we used patients who
underwent coronary angiography as control subjects and not healthy controls.
There is an association between CRP and LV function parameters LVESVIangio and
LVEF. These associations are not strong, but in the near future we will be able to correlate the
cardiac function parameters with adipocytokines. The expectation is that these associations
will be stronger, since CRP is produced by the liver as a result of high levels of at least one of
the adipocytokines, IL-6.
We conclude that the LVWT is elevated in patients with DM2 and that this already exists
in the MetS subjects, also known as a pre-diabetic state. In the near future we will be able to
correlate these findings with the amount of epicardial fat and inflammatory parameters. These
findings may contribute to the high CVD risk present in these subjects.
Future directions
Research questions IV-VII will be addressed in future studies.
Abbreviations and acronyms
CAD
CHF
DCM
DM2
MetS
BMI
Tchol
TG
CRP
HR
BPsys
BPdiast
AoPsys
AoPdiast
= coronary artery disease
= congestive heart failure
= diabetes cardiomyopathy
= diabetes mellitus type 2
= metabolic syndrome
= body mass index
= total cholesterol
= triglycerides
= C-reactive protein
= heart rate
= systolic blood pressure
= diastolic blood pressure
= systolic aorta pressure
= diastolic aorta pressure
AoPmean
LVPSP
LVEDP
LVEDVIangio
LVESVIangio
LVEF
LVWTe.d.
LVWTe.s.
StifMod
= mean aorta pressure
= left ventricular peak systolic pressure
= left ventricular end-diastolic pressure
= left ventricular end-diastolic
volume index angiography
= left ventricular end-systolic
volume index angiography
= left ventricular ejection fraction
= left ventricular end-diastolic
wall thickness
= left ventricular end-systolic
wall thickness
= stiffness modulus
13
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