Cell Biochem Biophys DOI 10.1007/s12013-014-9958-8
ORIGINAL PAPER
Myocardial Dysfunction in Early Diabetes Patients with Microalbuminuria: A 2-Dimensional Speckle Tracking Strain Study Ran Guo • Ke Wang • Wei Song • Tao Cong • Zhi-Juan Shang • Ying-Hui Sun • Yi-Nong Jiang
Ó Springer Science+Business Media New York 2014
Abstract The aim of this study was to assess myocardial dysfunction in primary diabetes patients with microalbuminuria by 2-dimensional speckle tracking strain. Sixtytwo patients with diabetes with or without hypertension and 37 matched hypertension controls were consecutively recruited from January 2011 to 2013. Routine physical examinations, laboratory tests, and echocardiography were performed in all patients. Subjects enrolled were divided into three groups according to history and urine albumin/ creatinine ratio (ACR): group I: patients with only hypertension and normoalbuminuria (ACR \ 30 mg/g), group II: patients with both hypertension and diabetes and normoalbuminuria (ACR \ 30 mg/g), and group III: patients with both hypertension and diabetes and microalbuminuria (ACR 30–300 mg/g). Echocardiographic images of three cardiac cycles were acquired for off-line analysis using the GE EchoPAC software. Indices of cardiac function, including longitudinal, radial and circumferential strains, torsion, and left ventricular ejection fraction (LVEF) were assessed. Statistical analysis was performed using SPSS 13.0. Finally, 56 subjects and 32 controls were included in the analyses. There was no significant difference in age, gender, heart rate, BMI, and LVEF among groups, except for the blood pressure, ACR, and HbA1c. E wave, A wave, EDT, Em, and E/Em in group III were different with those in group I. Mean longitudinal strain (mSL), average SL of six segments in 4-chamber apical view (SL4) decreased obviously. The peak circumferential strain decreased in group III, while the torsion was compensatively increased.
R. Guo K. Wang W. Song T. Cong Z.-J. Shang Y.-H. Sun Y.-N. Jiang (&) Department of Cardiological, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China e-mail: [email protected]
ACR was negatively related to mSL, SL4, E/Em, and positively related to torsion. We deduced that ACR maybe a predictor for myocardial damage in primary diabetes. Keywords Diabetes Hypertension Microalbuminuria 2-Dimensional speckle tracking strain
Introduction Diabetes is a world-wide disease affecting large populations. Its chronic complications lay huge burden on the society. Studies showed that myocardial damage occurred in at least 30 % diabetic patients when left ventricular (LV) diameter and LV ejection fraction (LVEF) were normal [1– 3]. Early detection and treatment could prevent or inhibit the progression of cardiac damage. Diabetic cardiomyopathy refers to myocardial dysfunction independent of coronary artery disease. The underlying mechanisms are proposed to be multifactorial, including microangiopathy, myocardial fibrosis, insulin resistance, and so on [4]. Proteinuria, being a predictor of renal dysfunction, has been demonstrated to be closely related to cardiac morbidity and mortality in diabetic and hypertensive subjects [5, 6]. Microalbuminuria, being its early manifestation, was demonstrated to be the result of vascular endothelial damage and podocytes with increased permeability [7]. Meta-analysis showed that even low levels of microalbuminuria had predictive values [8]. It is a reversible marker of renal damage in diabetic nephropathy and an independent predictive factor of cardiac events [9]. Moreover, the urine albumin/creatinine ratio (ACR) was reported to be the most sensitive and most important marker of early renal dysfunction [10–12].
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Cell Biochem Biophys
As to the heart, there is still no good markers that can indicate subclinical myocardial dysfunction. So far, some markers were mentioned, including R wave of aVL lead on electrocardiograms [13], brain natriuretic peptide [14], left ventricular (LV) global function index [15], and LV hypertrophy [16]. However, these markers are either not enough specific or not enough sensitive to be used in a clinical setting. Recent studies have shown that two-dimensional speckle tracking strain (2DSTS) is a feasible and reliable technique for quantification of regional myocardial fibers deformation in contraction, dilation, and twist [17]. Our study aimed to evaluate whether ACR could indicate myocardial dysfunction in early stage of untreated diabetes using 2DSTS.
Subjects and Methods Study population Among patients receiving regular physical examinations and hypertension, diabetes clinics at the first affiliated hospital of Dalian Medical University from January 2011 to 2013, those with untreated (within 3 months) type 2 diabetes and/or essential hypertension were consecutively enrolled. History and medical records were carefully reviewed. Exclusion criteria were: (1) coronary artery disease (CAD); (2) heavy smoker ([20 cigarettes/day); (3) dyslipidemia; (4) age \ 35 or [65 years; (5) evidence of obvious nephropathy, i.e., overt proteinuria or decreased glomerular filtration rate \60 ml/min/1.73 m2 calculated by the Cockcroft–Gault formula; (6) receive antihypertensive or hypoglycemic drug treatment within 3 months; (7) LV hypertrophy or decreased LV ejection fraction (LVEF) (\45 %) by routine echocardiography; (8) obvious valvular heart disease, valve replacement, or pacemaker; (9) cardiomyopathy; and (10) cancer history. This study was approved by the ethics committee of Dalian Medical University, Dalian, China. Essential hypertension was diagnosed according to the Seventh Report of the Joint National Committee on High Blood Pressure. CAD was diagnosed according to a history of myocardial infarction, to an invasive procedure for cardiovascular diseases CVD (including coronary artery bypass graft and angioplasty), or to the result of coronary computed tomography (CT) indicating one or more vascular stenosis [50 %. The diagnosis was done by two experienced doctors reaching a consensus. Diabetes was diagnosed according to the 2010 ADA guidelines, based on fasting blood glucose or oral glucose tolerance test. Dyslipidemia was diagnosed according to the criteria of the ESC guidelines: total cholesterol (TC) [ 200 mg/dl, and/or
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low-density lipoprotein cholesterol (LDL-C) [ 130 mg/dl, and/or high-density lipoprotein cholesterol (HDL-C) \ 40 mg/dl. Baseline Physical and Laboratory Exams All enrolled subjects provided a written informed consent before participation. Blood pressure was measured three times after a 5-min rest in the seated position at 1- or 2-min interval, and the average value was recorded. Body mass index (BMI) was calculated as weight/height2 (kg/m2). Fasting venous blood samples were obtained from every subject to perform routine blood biochemical tests, including serum creatinine levels, glutamic–pyruvic transaminase, aspartate amino-transferase, lipid profile, and routine blood test. In addition, first morning urine samples from every subject were collected for three consecutive days to determine ACR [18]. The mean value of these 3 days was regarded as the final ACR. Those with ACR[300 mg/g were finally excluded. Subjects enrolled were divided into three groups according to history and ACR: group I: patients with only hypertension and normoalbuminuria (ACR \ 30 mg/g), group II: patients with both hypertension and diabetes and normoalbuminuria (ACR \ 30 mg/g), and group III: patients with both hypertension and diabetes and microalbuminuria (ACR 30–300 mg/g). Echocardiography Standard transthoracic echocardiography was performed using a Vivid 7 ultrasound system (GE Healthcare, Waukesha, WI, USAGE Vingmed Ultrasound) and a M3S probe with the subjects in partial left decubitus. Standard optimized 4-chamber, 2-chamber, 3-chamber apical views, and parasternal short-axis views at basal, middle, and apical levels were obtained with LV zoomed and the a frame-rate of over 80 frames/second. Three cardiac cycles were stored in cineloop format in order to provide images of better quality for off-line analysis. Data analysis was performed using the EchoPAC software (GE Healthcare, Horten, Norway). The thickness and dimensions of cardiac walls and cavities were measured according to the American Society of Echocardiography (ASE) guidelines. LVEF was computed using the Simpson’s biplane method. The peak early mitral inflow velocity (E), peak atrial filling velocity (A), E wave deceleration time (EDT), and E/A ratio were obtained from the apical 4-chamber view in pulsed-wave Doppler mode, placing the sample volume at the tip of the mitral leaflets. Then enter the pulse-wave TDI mode to measure the peak early diastolic myocardial velocity (Em) by placing the sample at septal annulus. Longitudinal strains were derived from the average of six segments in 4-chamber apical view (SL4), 2-chamber
Cell Biochem Biophys
apical view (SL2), 3-chamber apical view (SL3), respectively, and eighteen segments of three apical views (mSL). Global radial strain (SR) and circumferential strain (CS) values were obtained from three parasternal short-axis planes (basal, papillary muscle, and apex). In practice, strains in the posterior and inferior walls of LV in basal short-axis view vibrated dramatically, partially caused by unsatisfied image acquisition. Thus, we used the average strains of the six segments in the middle level (papillary muscle level) to take the place of global SR and CS. LV torsion was defined as the net difference of the peak systolic rotation between the apical and basal plane in shortaxis view. Observers were blinded to the clinical data of the subjects.
Statistical Analysis Continuous variables are expressed as mean ± SD, and were compared by t tests. Categorical variables are shown as frequency, and were compared by Chi square tests. Comparisons between groups were examined by ANOVA. The relationships between strains and ACR were analyzed using the Pearson correlation. Statistical analysis was performed using SPSS 13.0 (SPSS Inc., Chicago, IL, USA). A P value \0.05 was considered to be significant.
Table 1 Clinical and echocardiographic characteristics
Age (year)
Group I (n = 32)
Group II (n = 29)
Group III (n = 33)
48 ± 12.1
50 ± 13.7
46 ± 12.2
Male (%)
22 (68.8)
19 (65.5)
20 (60.1)
HR (beats/ min) SBP (mmHg)
73.1 ± 10.0
72.7 ± 9.4
68.7 ± 10.9
149 ± 6.5
150 ± 6.6
152 ± 6.2#
DBP (mmHg)
93 ± 6.4
94 ± 6.8
97 ± 7.5#
BMI (kg/m )
24.8 ± 1.8
25.1 ± 1.9
25.5 ± 1.9
Dyslipidemia (%)
3 (9 %)
5 (17 %)
7 (21 %)
HbA1c (%)
5.5 ± 1.2
7.0 ± 1.6##
7.9 ± 1.9##*
Creatinine (mg/dl)
1.0 ± 0.2
1.1 ± 0.2
1.1 ± 0.3
ACR (mg/day) LVEF (%)
17.4 ± 4.5 62.5 ± 4.83
19.4 ± 5.0 60.4 ± 3.61
166.1 ± 73.5##** 60.9 ± 3.77
2
E (cm/s)
78.0 ± 15.4
80 ± 19.2
69 ± 23.1*
A (cm/s)
66 ± 18.4
80 ± 27.6#
77 ± 19.3#
EDT (ms)
193 ± 38.7
202 ± 55.2
215 ± 47.9#
Em (cm/s)
9.7 ± 2.2
8.5 ± 3.0
7.5 ± 2.4##
E/Em
8.0 ± 2.1
9.4 ± 3.0
#
9.2 ± 2.3#
HR heart rate, SBP systolic blood pressure, DBP diastolic blood pressure, LVEF left ventricular ejection fraction, E mitral early peak velocity, A mitral late peak velocity, EDT E wave deceleration time, Em myocardial early peak velocity Compared with group I: group II: * P \ 0.05
#
P \ 0.05,
##
P \ 0.01; compared with
Results A total of 62 diabetic subjects and 37 age- and gendermatched hypertension controls were consecutively enrolled. Six diabetic subjects and five hypertension controls were excluded for poor quality of echocardiographic images. Thus, 56 diabetic subjects and 32 controls were included in the analyses. Subjects’ baseline clinical and echocardiographic characteristics are shown in Table 1. There was no significant difference in age, gender, heart rate, BMI, and LVEF among groups, except for blood pressure, ACR, and HbA1c. As to diastolic indexes, E wave, A wave, EDT, Em, and E/Em in group III were different with those in group I. A wave and E/Em in group II were also higher than those in group I. Compared with group I, mSL and SL4, which represent the LV longitudinal function, decreased in group III, whereas SL2 and SL3, which partially reflect the LV longitudinal function, did not decrease significantly. Moreover, the peak CS, which reflects the LV short-axis function, decreased in group III. On the contrary, the rotation difference between the apex and basal segment of LV obviously increased in group III, whose longitudinal function was demonstrated to be damaged. There were no
Table 2 2D speckle tracking strains of the left ventricle Variables
Group I
Group II
mSL (%)
23.4 ± 4.75
21.5 ± 4.28
SL4 (%)
25.3 ± 3.09
21.7 ± 3.58
Group III 20.3 ± 4.08## ##
20.0 ± 4.01##
SL2 (%)
23.2 ± 5.88
22.2 ± 5.11
SL3 (%)
21.6 ± 5.10
20.7 ± 4.97
21.6 ± 4.77 19.3 ± 3.98
SR (%)
49.0 ± 18.59
51.2 ± 16.00
52.4 ± 16.83
CS (%)
24.5 ± 5.43
22.7 ± 3.83
21.5 ± 4.09#
Torsion (°)
19.8 ± 4.36
19.9 ± 4.29
22.3 ± 4.57#*
mSL mean value of eighteen segments of the longitudinal strain, SL4 mean value of six segments of the longitudinal strain in 4-chamber left ventricular longitudinal view, SL2 mean value of six segments of the longitudinal strain in 2-chamber left ventricular longitudinal view, SL3 mean value of six segments of the longitudinal strain in 3-chamber left ventricular longitudinal view, SR global radial strain, CS global circumferential strain Compared with group I: group II: * P \ 0.05
#
P \ 0.05,
##
P \ 0.01; compared with
significant difference in strains between group I and II, except SL4 (Table 2). Furthermore, ACR was negatively related to mSL, SL4, E/Em, and positively related to torsion (Table 3).
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Cell Biochem Biophys Table 3 Pearson correlation analysis of ACR
Correlation coefficient P values
mSL
SL4
Torsion
CS
E/Em
-0.360
-0.331
0.256
-0.040
0.587
0.041
0.029
0.037
0.758
0.007
ACR urine albumin/creatinine ratio, mSL the mean value of eighteen segments of the longitudinal strain, SL4 the mean value of six segments of the longitudinal strain in 4-chamber left ventricular longitudinal view, E/Em mitral early diastolic velocity/myocardial early diastolic velocity, CS global circumferential strain
Discussion Accumulating evidence from preclinical studies, clinical studies, and epidemiological studies have suggested that diabetes could change cardiac structure and function independent of hypertension and coronary artery diseases [19, 20]. Multifaceted mechanisms have been proposed to account for the diabetes-induced change in cardiac structure and function, which include (1) activation of renin–angiotensin–aldosteroNe system with angiotensin II as core factor [21]; (2) myocardial metabolic disturbances, including disturbances in glucose transport system [22, 23], carnitine deficiency [24], abnormal regulation of contractile proteins [25]; (3) insulin resistance; (4) myocardial fatty degeneration [26]; (5) autonomic neuropathy [27]; (6) myocardial fibrosis, which has been demonstrated by cellular calcium transport defect [28], myocardial contractile protein deficiency [29], excessive collagen [30], progressively loss of myocardial cellular transverse tubule, and sarcoplasmic reticulum, intercalated disks separation [31, 32] in diabetic animal models; (7) microangiopathy, presenting as microangioma, interstitial fibrosis and myocardial perfusion defect and radionuclide imaging of myocardial perfusion defect [33–36]. Moreover, Huynh and Khong et al. found that inhibition of oxidative stress could improve myocardial function, alleviate myocardial hypertrophy, and collagen sedimentation in rats [37, 38], which further demonstrated the effect of oxidative stress in diabetic cardiomyopathy [39]. Experience with hypoglycemic drug treatment has also suggested the correlation between hyperglycemia and myocardial structure and function [40, 41]. Diabetic myocardial diastolic dysfunction seldom existed alone and was usually associated with subclinical systolic dysfunction, although most studies showed that the diastolic dysfunction was most fragile. This might be explained by the insensitivity of techniques for detecting LV systolic function. LVEF might not be a sensitive marker for detection of subclinical LV systolic dysfunction [42]. Subclinical LV longitudinal dysfunction occurred in early stage of diabetes by TDI [43, 44]. However, TDI derived of velocity and was angle-dependent. Only
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velocities parallel to echo beam could be accurately measured. Therefore, only longitudinal strain or strain rate could be measured in apical view and only radial strain or strain rate could be measured in parasternal view. In contrast, 2DSTS overcame the above limitations of TDI. Our study found that the segmental and integral longitudinal strains significantly lowered in primary diabetes when compared with controls by 2DSTS, suggesting that LV longitudinal dysfunction occurred in early stage of diabetes. On the contrary, LV torsion increased compensatively (compared with controls, P \ 0.05), which was not consistent with Fang’s results by TDI and MRI, which might be relevant to the course of diabetes. A few studies reported that the course of diabetes was an independent factor for decrease of longitudinal strain [45, 46]. In our study, we enrolled the primarily untreated diabetic patients to remove the effect of course and to further demonstrate the close correlation of microalbuminuria and myocardial dysfunction. Based on our findings, we suggested that ACR maybe a predictor for myocardial damage in primary diabetes.
Limitation It seems that 2DSTS may be more sensitive than ACR in predicting myocardial damages of primary diabetes, although the normal range and cut-off points have not been defined yet. More work is needed on this subject. Moreover, earlier drug intervention, including angiotensin transforming enzyme inhibitors and the angiotensin receptor blockers, which can interfere myocardial remodeling, may improve cardiac strains. However, more studies are needed to confirm the clinical benefits.
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ORIGINAL PAPER
Myocardial Dysfunction in Early Diabetes Patients with Microalbuminuria: A 2-Dimensional Speckle Tracking Strain Study Ran Guo • Ke Wang • Wei Song • Tao Cong • Zhi-Juan Shang • Ying-Hui Sun • Yi-Nong Jiang
Ó Springer Science+Business Media New York 2014
Abstract The aim of this study was to assess myocardial dysfunction in primary diabetes patients with microalbuminuria by 2-dimensional speckle tracking strain. Sixtytwo patients with diabetes with or without hypertension and 37 matched hypertension controls were consecutively recruited from January 2011 to 2013. Routine physical examinations, laboratory tests, and echocardiography were performed in all patients. Subjects enrolled were divided into three groups according to history and urine albumin/ creatinine ratio (ACR): group I: patients with only hypertension and normoalbuminuria (ACR \ 30 mg/g), group II: patients with both hypertension and diabetes and normoalbuminuria (ACR \ 30 mg/g), and group III: patients with both hypertension and diabetes and microalbuminuria (ACR 30–300 mg/g). Echocardiographic images of three cardiac cycles were acquired for off-line analysis using the GE EchoPAC software. Indices of cardiac function, including longitudinal, radial and circumferential strains, torsion, and left ventricular ejection fraction (LVEF) were assessed. Statistical analysis was performed using SPSS 13.0. Finally, 56 subjects and 32 controls were included in the analyses. There was no significant difference in age, gender, heart rate, BMI, and LVEF among groups, except for the blood pressure, ACR, and HbA1c. E wave, A wave, EDT, Em, and E/Em in group III were different with those in group I. Mean longitudinal strain (mSL), average SL of six segments in 4-chamber apical view (SL4) decreased obviously. The peak circumferential strain decreased in group III, while the torsion was compensatively increased.
R. Guo K. Wang W. Song T. Cong Z.-J. Shang Y.-H. Sun Y.-N. Jiang (&) Department of Cardiological, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China e-mail: [email protected]
ACR was negatively related to mSL, SL4, E/Em, and positively related to torsion. We deduced that ACR maybe a predictor for myocardial damage in primary diabetes. Keywords Diabetes Hypertension Microalbuminuria 2-Dimensional speckle tracking strain
Introduction Diabetes is a world-wide disease affecting large populations. Its chronic complications lay huge burden on the society. Studies showed that myocardial damage occurred in at least 30 % diabetic patients when left ventricular (LV) diameter and LV ejection fraction (LVEF) were normal [1– 3]. Early detection and treatment could prevent or inhibit the progression of cardiac damage. Diabetic cardiomyopathy refers to myocardial dysfunction independent of coronary artery disease. The underlying mechanisms are proposed to be multifactorial, including microangiopathy, myocardial fibrosis, insulin resistance, and so on [4]. Proteinuria, being a predictor of renal dysfunction, has been demonstrated to be closely related to cardiac morbidity and mortality in diabetic and hypertensive subjects [5, 6]. Microalbuminuria, being its early manifestation, was demonstrated to be the result of vascular endothelial damage and podocytes with increased permeability [7]. Meta-analysis showed that even low levels of microalbuminuria had predictive values [8]. It is a reversible marker of renal damage in diabetic nephropathy and an independent predictive factor of cardiac events [9]. Moreover, the urine albumin/creatinine ratio (ACR) was reported to be the most sensitive and most important marker of early renal dysfunction [10–12].
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As to the heart, there is still no good markers that can indicate subclinical myocardial dysfunction. So far, some markers were mentioned, including R wave of aVL lead on electrocardiograms [13], brain natriuretic peptide [14], left ventricular (LV) global function index [15], and LV hypertrophy [16]. However, these markers are either not enough specific or not enough sensitive to be used in a clinical setting. Recent studies have shown that two-dimensional speckle tracking strain (2DSTS) is a feasible and reliable technique for quantification of regional myocardial fibers deformation in contraction, dilation, and twist [17]. Our study aimed to evaluate whether ACR could indicate myocardial dysfunction in early stage of untreated diabetes using 2DSTS.
Subjects and Methods Study population Among patients receiving regular physical examinations and hypertension, diabetes clinics at the first affiliated hospital of Dalian Medical University from January 2011 to 2013, those with untreated (within 3 months) type 2 diabetes and/or essential hypertension were consecutively enrolled. History and medical records were carefully reviewed. Exclusion criteria were: (1) coronary artery disease (CAD); (2) heavy smoker ([20 cigarettes/day); (3) dyslipidemia; (4) age \ 35 or [65 years; (5) evidence of obvious nephropathy, i.e., overt proteinuria or decreased glomerular filtration rate \60 ml/min/1.73 m2 calculated by the Cockcroft–Gault formula; (6) receive antihypertensive or hypoglycemic drug treatment within 3 months; (7) LV hypertrophy or decreased LV ejection fraction (LVEF) (\45 %) by routine echocardiography; (8) obvious valvular heart disease, valve replacement, or pacemaker; (9) cardiomyopathy; and (10) cancer history. This study was approved by the ethics committee of Dalian Medical University, Dalian, China. Essential hypertension was diagnosed according to the Seventh Report of the Joint National Committee on High Blood Pressure. CAD was diagnosed according to a history of myocardial infarction, to an invasive procedure for cardiovascular diseases CVD (including coronary artery bypass graft and angioplasty), or to the result of coronary computed tomography (CT) indicating one or more vascular stenosis [50 %. The diagnosis was done by two experienced doctors reaching a consensus. Diabetes was diagnosed according to the 2010 ADA guidelines, based on fasting blood glucose or oral glucose tolerance test. Dyslipidemia was diagnosed according to the criteria of the ESC guidelines: total cholesterol (TC) [ 200 mg/dl, and/or
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low-density lipoprotein cholesterol (LDL-C) [ 130 mg/dl, and/or high-density lipoprotein cholesterol (HDL-C) \ 40 mg/dl. Baseline Physical and Laboratory Exams All enrolled subjects provided a written informed consent before participation. Blood pressure was measured three times after a 5-min rest in the seated position at 1- or 2-min interval, and the average value was recorded. Body mass index (BMI) was calculated as weight/height2 (kg/m2). Fasting venous blood samples were obtained from every subject to perform routine blood biochemical tests, including serum creatinine levels, glutamic–pyruvic transaminase, aspartate amino-transferase, lipid profile, and routine blood test. In addition, first morning urine samples from every subject were collected for three consecutive days to determine ACR [18]. The mean value of these 3 days was regarded as the final ACR. Those with ACR[300 mg/g were finally excluded. Subjects enrolled were divided into three groups according to history and ACR: group I: patients with only hypertension and normoalbuminuria (ACR \ 30 mg/g), group II: patients with both hypertension and diabetes and normoalbuminuria (ACR \ 30 mg/g), and group III: patients with both hypertension and diabetes and microalbuminuria (ACR 30–300 mg/g). Echocardiography Standard transthoracic echocardiography was performed using a Vivid 7 ultrasound system (GE Healthcare, Waukesha, WI, USAGE Vingmed Ultrasound) and a M3S probe with the subjects in partial left decubitus. Standard optimized 4-chamber, 2-chamber, 3-chamber apical views, and parasternal short-axis views at basal, middle, and apical levels were obtained with LV zoomed and the a frame-rate of over 80 frames/second. Three cardiac cycles were stored in cineloop format in order to provide images of better quality for off-line analysis. Data analysis was performed using the EchoPAC software (GE Healthcare, Horten, Norway). The thickness and dimensions of cardiac walls and cavities were measured according to the American Society of Echocardiography (ASE) guidelines. LVEF was computed using the Simpson’s biplane method. The peak early mitral inflow velocity (E), peak atrial filling velocity (A), E wave deceleration time (EDT), and E/A ratio were obtained from the apical 4-chamber view in pulsed-wave Doppler mode, placing the sample volume at the tip of the mitral leaflets. Then enter the pulse-wave TDI mode to measure the peak early diastolic myocardial velocity (Em) by placing the sample at septal annulus. Longitudinal strains were derived from the average of six segments in 4-chamber apical view (SL4), 2-chamber
Cell Biochem Biophys
apical view (SL2), 3-chamber apical view (SL3), respectively, and eighteen segments of three apical views (mSL). Global radial strain (SR) and circumferential strain (CS) values were obtained from three parasternal short-axis planes (basal, papillary muscle, and apex). In practice, strains in the posterior and inferior walls of LV in basal short-axis view vibrated dramatically, partially caused by unsatisfied image acquisition. Thus, we used the average strains of the six segments in the middle level (papillary muscle level) to take the place of global SR and CS. LV torsion was defined as the net difference of the peak systolic rotation between the apical and basal plane in shortaxis view. Observers were blinded to the clinical data of the subjects.
Statistical Analysis Continuous variables are expressed as mean ± SD, and were compared by t tests. Categorical variables are shown as frequency, and were compared by Chi square tests. Comparisons between groups were examined by ANOVA. The relationships between strains and ACR were analyzed using the Pearson correlation. Statistical analysis was performed using SPSS 13.0 (SPSS Inc., Chicago, IL, USA). A P value \0.05 was considered to be significant.
Table 1 Clinical and echocardiographic characteristics
Age (year)
Group I (n = 32)
Group II (n = 29)
Group III (n = 33)
48 ± 12.1
50 ± 13.7
46 ± 12.2
Male (%)
22 (68.8)
19 (65.5)
20 (60.1)
HR (beats/ min) SBP (mmHg)
73.1 ± 10.0
72.7 ± 9.4
68.7 ± 10.9
149 ± 6.5
150 ± 6.6
152 ± 6.2#
DBP (mmHg)
93 ± 6.4
94 ± 6.8
97 ± 7.5#
BMI (kg/m )
24.8 ± 1.8
25.1 ± 1.9
25.5 ± 1.9
Dyslipidemia (%)
3 (9 %)
5 (17 %)
7 (21 %)
HbA1c (%)
5.5 ± 1.2
7.0 ± 1.6##
7.9 ± 1.9##*
Creatinine (mg/dl)
1.0 ± 0.2
1.1 ± 0.2
1.1 ± 0.3
ACR (mg/day) LVEF (%)
17.4 ± 4.5 62.5 ± 4.83
19.4 ± 5.0 60.4 ± 3.61
166.1 ± 73.5##** 60.9 ± 3.77
2
E (cm/s)
78.0 ± 15.4
80 ± 19.2
69 ± 23.1*
A (cm/s)
66 ± 18.4
80 ± 27.6#
77 ± 19.3#
EDT (ms)
193 ± 38.7
202 ± 55.2
215 ± 47.9#
Em (cm/s)
9.7 ± 2.2
8.5 ± 3.0
7.5 ± 2.4##
E/Em
8.0 ± 2.1
9.4 ± 3.0
#
9.2 ± 2.3#
HR heart rate, SBP systolic blood pressure, DBP diastolic blood pressure, LVEF left ventricular ejection fraction, E mitral early peak velocity, A mitral late peak velocity, EDT E wave deceleration time, Em myocardial early peak velocity Compared with group I: group II: * P \ 0.05
#
P \ 0.05,
##
P \ 0.01; compared with
Results A total of 62 diabetic subjects and 37 age- and gendermatched hypertension controls were consecutively enrolled. Six diabetic subjects and five hypertension controls were excluded for poor quality of echocardiographic images. Thus, 56 diabetic subjects and 32 controls were included in the analyses. Subjects’ baseline clinical and echocardiographic characteristics are shown in Table 1. There was no significant difference in age, gender, heart rate, BMI, and LVEF among groups, except for blood pressure, ACR, and HbA1c. As to diastolic indexes, E wave, A wave, EDT, Em, and E/Em in group III were different with those in group I. A wave and E/Em in group II were also higher than those in group I. Compared with group I, mSL and SL4, which represent the LV longitudinal function, decreased in group III, whereas SL2 and SL3, which partially reflect the LV longitudinal function, did not decrease significantly. Moreover, the peak CS, which reflects the LV short-axis function, decreased in group III. On the contrary, the rotation difference between the apex and basal segment of LV obviously increased in group III, whose longitudinal function was demonstrated to be damaged. There were no
Table 2 2D speckle tracking strains of the left ventricle Variables
Group I
Group II
mSL (%)
23.4 ± 4.75
21.5 ± 4.28
SL4 (%)
25.3 ± 3.09
21.7 ± 3.58
Group III 20.3 ± 4.08## ##
20.0 ± 4.01##
SL2 (%)
23.2 ± 5.88
22.2 ± 5.11
SL3 (%)
21.6 ± 5.10
20.7 ± 4.97
21.6 ± 4.77 19.3 ± 3.98
SR (%)
49.0 ± 18.59
51.2 ± 16.00
52.4 ± 16.83
CS (%)
24.5 ± 5.43
22.7 ± 3.83
21.5 ± 4.09#
Torsion (°)
19.8 ± 4.36
19.9 ± 4.29
22.3 ± 4.57#*
mSL mean value of eighteen segments of the longitudinal strain, SL4 mean value of six segments of the longitudinal strain in 4-chamber left ventricular longitudinal view, SL2 mean value of six segments of the longitudinal strain in 2-chamber left ventricular longitudinal view, SL3 mean value of six segments of the longitudinal strain in 3-chamber left ventricular longitudinal view, SR global radial strain, CS global circumferential strain Compared with group I: group II: * P \ 0.05
#
P \ 0.05,
##
P \ 0.01; compared with
significant difference in strains between group I and II, except SL4 (Table 2). Furthermore, ACR was negatively related to mSL, SL4, E/Em, and positively related to torsion (Table 3).
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Cell Biochem Biophys Table 3 Pearson correlation analysis of ACR
Correlation coefficient P values
mSL
SL4
Torsion
CS
E/Em
-0.360
-0.331
0.256
-0.040
0.587
0.041
0.029
0.037
0.758
0.007
ACR urine albumin/creatinine ratio, mSL the mean value of eighteen segments of the longitudinal strain, SL4 the mean value of six segments of the longitudinal strain in 4-chamber left ventricular longitudinal view, E/Em mitral early diastolic velocity/myocardial early diastolic velocity, CS global circumferential strain
Discussion Accumulating evidence from preclinical studies, clinical studies, and epidemiological studies have suggested that diabetes could change cardiac structure and function independent of hypertension and coronary artery diseases [19, 20]. Multifaceted mechanisms have been proposed to account for the diabetes-induced change in cardiac structure and function, which include (1) activation of renin–angiotensin–aldosteroNe system with angiotensin II as core factor [21]; (2) myocardial metabolic disturbances, including disturbances in glucose transport system [22, 23], carnitine deficiency [24], abnormal regulation of contractile proteins [25]; (3) insulin resistance; (4) myocardial fatty degeneration [26]; (5) autonomic neuropathy [27]; (6) myocardial fibrosis, which has been demonstrated by cellular calcium transport defect [28], myocardial contractile protein deficiency [29], excessive collagen [30], progressively loss of myocardial cellular transverse tubule, and sarcoplasmic reticulum, intercalated disks separation [31, 32] in diabetic animal models; (7) microangiopathy, presenting as microangioma, interstitial fibrosis and myocardial perfusion defect and radionuclide imaging of myocardial perfusion defect [33–36]. Moreover, Huynh and Khong et al. found that inhibition of oxidative stress could improve myocardial function, alleviate myocardial hypertrophy, and collagen sedimentation in rats [37, 38], which further demonstrated the effect of oxidative stress in diabetic cardiomyopathy [39]. Experience with hypoglycemic drug treatment has also suggested the correlation between hyperglycemia and myocardial structure and function [40, 41]. Diabetic myocardial diastolic dysfunction seldom existed alone and was usually associated with subclinical systolic dysfunction, although most studies showed that the diastolic dysfunction was most fragile. This might be explained by the insensitivity of techniques for detecting LV systolic function. LVEF might not be a sensitive marker for detection of subclinical LV systolic dysfunction [42]. Subclinical LV longitudinal dysfunction occurred in early stage of diabetes by TDI [43, 44]. However, TDI derived of velocity and was angle-dependent. Only
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velocities parallel to echo beam could be accurately measured. Therefore, only longitudinal strain or strain rate could be measured in apical view and only radial strain or strain rate could be measured in parasternal view. In contrast, 2DSTS overcame the above limitations of TDI. Our study found that the segmental and integral longitudinal strains significantly lowered in primary diabetes when compared with controls by 2DSTS, suggesting that LV longitudinal dysfunction occurred in early stage of diabetes. On the contrary, LV torsion increased compensatively (compared with controls, P \ 0.05), which was not consistent with Fang’s results by TDI and MRI, which might be relevant to the course of diabetes. A few studies reported that the course of diabetes was an independent factor for decrease of longitudinal strain [45, 46]. In our study, we enrolled the primarily untreated diabetic patients to remove the effect of course and to further demonstrate the close correlation of microalbuminuria and myocardial dysfunction. Based on our findings, we suggested that ACR maybe a predictor for myocardial damage in primary diabetes.
Limitation It seems that 2DSTS may be more sensitive than ACR in predicting myocardial damages of primary diabetes, although the normal range and cut-off points have not been defined yet. More work is needed on this subject. Moreover, earlier drug intervention, including angiotensin transforming enzyme inhibitors and the angiotensin receptor blockers, which can interfere myocardial remodeling, may improve cardiac strains. However, more studies are needed to confirm the clinical benefits.
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