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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. 5 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. 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