Serial Assessment of Left Ventricular Remodeling and Function by Echo-Tissue Doppler Imaging After Myocardial Infarction in Streptozotocin-Induced Diabetic Swine

PRE-CLINICAL INVESTIGATIONS

Serial Assessment of Left Ventricular Remodeling and Function by Echo-Tissue Doppler Imaging After Myocardial Infarction in Streptozotocin-Induced Diabetic Swine Wen Ruan, MD, Lin Lu, MD,* Qi Zhang, MD,* Min Cao, MD, Zheng Bin Zhu, MSc(Med), Ling Jie Wang, MD, and Wei Feng Shen, MD, PhD, Shanghai, People’s Republic of China

Background: The aim of this study was to determine the value of Doppler tissue imaging (DTI) in detecting serial changes in left ventricular (LV) geometry and function after myocardial infarction (MI) in diabetic swine. Methods: Thirteen minipigs with streptozotocin-induced diabetes for 1 month and 13 controls were subjected to occlusion of the left anterior descending coronary artery. Echocardiography and DTI were performed before, 30 minutes, 90 minutes, and 4 weeks after left anterior descending coronary artery occlusion. Results: At baseline, LV end-diastolic volume and mass were greater in pigs with diabetes. After MI, LV ejection fractions and systolic mitral annular velocities were decreased and LV chambers dilated in both groups, which were exacerbated in animals with diabetes. At 30 minutes, 90 minutes, and 4 weeks after MI, strain rates were significantly lower in both infarct and noninfarct areas in the diabetic group than in controls. Conclusions: DTI proved to be a useful tool in the serial assessment of subclinical LV dysfunction after MI in pigs with diabetes. (J Am Soc Echocardiogr 2009;22:530-536.) Keywords: Myocardial infarction, Left ventricular remodeling, Diabetes mellitus, Echocardiography, Doppler tissue imaging

Diabetes mellitus is a major comorbidity in patients with acute myocardial infarctions (MIs). Previous studies have shown that patients with diabetes experienced worse clinical outcomes after acute MIs compared with subjects without diabetes, including a higher incidence of post-MI angina, heart failure, and death, irrespective of infarct size and the severity of left ventricular (LV) systolic dysfunction.1,2 The presence of diabetes confers the same excess risk as that associated with prior MI for patients without diabetes.3-5 Diabetes, even in the absence of hypertensive, ischemic, or significant valvular diseases, is an independent risk factor for the development of heart failure and has adverse prognostic implications.6,7 Although the deleterious effects of diabetes per se on the LV remodeling process and the incidence of heart failure after MI have been evaluated in rodents, determination of its impact in large animals may be of more clinical relevance. Previous studies have demonstrated the value of serum biomarkers in terms of reflecting LV hypertrophy, cardiac dysfunction, and myocardial fibrosis in streptozotocin From the Department of Cardiology, Rui Jin Hospital, Jiao Tong University School of Medicine, Shanghai, People’s Republic of China. *Lin Lu, MD, and Qi Zhang, MD, contributed equally to this paper. Reprint requests: Wei Feng Shen, MD, PhD, Rui Jin Hospital, Department of Cardiology, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Raod II, Shanghai 200025, People’s Republic of China (E-mail: rjshenweifeng@yahoo. com.cn). 0894-7317/$36.00 Copyright 2009 by the American Society of Echocardiography. doi:10.1016/j.echo.2009.02.023

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(STZ)–induced diabetic swine models,8 but the prediction of LV remodeling by quantification of regional contractility remains an elusive goal. Conventional echocardiography may not detect subtle myocardial changes and is more operator dependent.9 In contrast, Doppler tissue imaging (DTI) permits the quantitative assessment of both global and regional function and the timing of myocardial events through the derivation of deformation indices such as myocardial strain and strain rate,10,11 and its utility in assessing LV function in diabetic pigs has recently been reported.8,11,12 Little is known about the relationship between regional systolic dysfunction and unfavorable LV remodeling early and late after acute MI in diabetes. We hypothesized that DTI is able to detect early and subclinical changes during the acute phase of MI and over time, which may be used as objective surrogate markers of LV remodeling and dysfunction. METHODS Animals The study was approved by our institutional animal research committee and conformed to the Animal Care Guidelines of the American Physiological Society. Twenty-six male Chinese Guizhou minipigs (age, 5-6 months; body weight, 20-25 kg) were obtained from Jiao Tong University Agriculture College and raised in separated pens under controlled conditions in the Department of Animals for Scientific Research at Jiao Tong University School of Medicine.13 All animals had normal day-night cycles, and room temperature was kept between 18  C and 25  C, with continuous air changing. The animals were fed 200 to 250 g commercial plain porcine fodder (15%

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protein, 50% carbohydrate, 5% fat; Shanghai Animal Fodder Factory, China) twice daily and allowed free access to water. The animals were allocated to the diabetic (n = 13) or control (n = 13) group. Diabetes mellitus was induced by an intravenous injection of STZ, as described previously.8,13 In brief, STZ (S0130; Sigma-Aldrich Corporation, St Louis, MO) was administered intravenously through an indwelling cannula at a dose of 125 mg/kg after dissolving in sodium citrate buffer (pH = 4.7). Elevated blood glucose levels were always observed on the third or fourth day after STZ administration using a one-touch SurePlus instrument (Johnson & Johnson, New Brunswick, NJ). Insulin therapy was initiated to maintain a fasting blood glucose level < 10 mmol/L in all animals.8,13 Serum concentrations of glucose, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, blood urea nitrogen, creatinine, alanine transaminase, and asparagine transaminase were measured by standard methods. Hemodynamic Measurement and Infarction Model Swine MI was induced 1 month after the administration of STZ. General anesthesia was initiated with intramuscular ketamine hydrochloride (20 mg/kg) and midazolam (1 mg/kg) and maintained by intravenous injection throughout the procedures. A 7Fr arterial sheath was introduced into the right femoral artery, and a 6Fr angiographic catheter was inserted over a guide wire. All pigs received heparin (200 IU/kg) as an intra-arterial bolus. Aortic and LV pressures and heart rate were recorded at baseline and monitored continuously during the procedure. Left ventriculography was performed in the right anterior oblique view, and LV end-diastolic and end-systolic volumes and ejection fractions were determined. Coronary arteriography was performed in the left lateral projection using a 6Fr Amplatzer right coronary catheter (AGA Medical Corporation, Golden Valley, MN). An over-the-wire percutaneous coronary angioplasty balloon mounted on a 0.014-inch wire was advanced into the left anterior descending coronary artery (LAD), positioned at approximately one third of the distance from the apex.14 The balloon was then inflated to totally occlude the artery for 90 minutes. Complete coronary occlusion was documented by distal coronary injection through the wire lumen of the over-the-wire balloon and electrocardiographic ST-segment elevation. After the study, the intervened femoral arteries were repaired or ligated. All animals were treated with antibiotics for 2 days. Repeat cardiac catheterization and angiography were performed 4 weeks later. Doppler Echocardiographic Assessments Echocardiography and DTI were performed during anesthesia and spontaneous respiration in all animals using Vivid 7 system (GE Vingmed Ultrasound AS, Horten, Norway) with a 1.7/3.4-MHz transducer. Images were obtained at baseline, 30 minutes and 90 minutes after coronary artery occlusion, and 4 weeks after the procedure. Echocardiographic image loops of $3 heart cycles containing both tissue Doppler and grayscale data were obtained for subsequent offline analysis, using the software incorporated in the machine (Figure 1). LVend-diastolic and end-systolic diameters and wall thickness were determined according to the American Society of Echocardiography, and LV mass was calculated from the formula LV mass = 0.8  (1.04[intraventricular septal thickness + LV diastolic diameter + posterior wall thickness]3) +0.6 g.15 LV volumes and ejection fractions were assessed using Simpson’s single-plane method. For the semiquantification of regional wall motion, the left ventricle was divided

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into 16 segments. Wall motion score index was visually assessed by an experienced investigator (W.R.) blinded to all animal data and was defined as follows: 1 = normal or hyperkinesia, 2 = hypokinesia, 3 = akinesia, and 4 = dyskinesia. Pulsed Doppler imaging was obtained from the apical 4-chamber view, with the Doppler beam aligned perpendicularly to the plane of the mitral annulus. The sample volume was placed between the tips of the mitral leaflets to obtain the peak early (E) transmitral filling velocity. Early diastolic (Em) and systolic (Sm) mitral annular velocities were measured by placing the sample volume at the lateral aspect of the mitral annulus.16 The E/Em ratio (an index reflecting LV filling pressure) was then derived. Sm is regarded as a simple and reliable index for assessing overall longitudinal LV systolic function.17 The timing of aortic valve opening and closure was determined from pulsed Doppler interrogation at the LV outflow tract. Ejection time was measured as time interval between aortic valve opening and closure. DTI was assessed at a frame rate of >120 frames/min, with 5-mm sample volumes placed at the basal, middle, and apical LV myocardium. Peak systolic tissue velocity was determined as the maximal positive velocity within the ejection time. Strain was derived as a dimensionless quantity as a percentage of regional deformation. Strain rate was obtained by measuring strain over time. Peak systolic strain and strain rate were located within the ejection time. Irregular cardiac cycles due to rhythm abnormalities were excluded. In this study, because the apical 2-chamber view was not consistently available due to the rotation of the swine heart, the apical 4chamber view was applied for the analysis of longitudinal LV function. We predefined the middle and apical septum and lateral apex as the infarct regions supplied by the LAD, whereas the basal septum and basal and middle lateral segments were the noninfarct area. All images were interpreted by experienced cardiologists, who were blinded to the clinical status (presence or absence of diabetes and MI). An average of 3 measurements was used for each parameter. Statistical Analysis Quantified image data in experiments are expressed as mean 6 SD. Strain and strain rate measurements are presented as absolute values. Comparisons among the means (baseline and 30 minutes, 90 minutes, and 4 weeks after MI) and mean differences (average changes from baseline to 30 minutes, 90 minutes, and 4 weeks after MI) of DTI measurements within each group and outcome were performed using analysis of variance, followed by post hoc t tests. Bonferroni’s corrections were performed for multiple comparisons of the means among the groups. Comparisons of means and mean differences between the diabetic and control groups at each time point before and after MI were performed using 2-sample t test. A c2 test was performed to assess the difference in survival between the two groups. The data sets of 10 randomly selected segments from 5 animals (2 segments from each animal) were analyzed by the first operator (W.R.) 2 weeks after the first analyses for the determination of intraobserver variability and by second operator (M.C.) who was blinded to the results of the first operator and other echocardiographic or clinical data for evaluation of interobserver variability. Interobserver and intraobserver variability were obtained using Bland-Altman plots as well as by calculating the standard deviation of the differences between the two observations divided by the means of the observations, which were expressed as both absolute numbers and percentages. SPSS for Windows version 13.0 was used for statistical analysis (SPSS, Inc, Chicago, IL). A P value < .05 was considered significant.

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Figure 1 Measurement of peak myocardial systolic strain rate (SR) by DTI in controls (A,B) and swine with diabetes mellitus (DM) (C,D) at baseline and 4 weeks after MI. In the infarct zone (yellow line), the systolic SR (SRsys) in diabetic swine became more attenuated after MI compared with that in controls. AVC, Aortic valve closure; AVO, aortic valve opening.

RESULTS Procedural and Biochemical Features There were 13 animals each in the diabetic and control groups. In the diabetic group, 8 pigs developed ventricular fibrillation during LAD occlusion. Four animals died because of cardiac arrhythmias during the procedure (2 pigs), heart failure (1 pig), or respiratory infection (1 pig) 2 to 10 days after the procedure. In the control group, 4 animals had ventricular fibrillation during procedure; they were successfully resuscitated. Only 1 pig died from a respiratory infection 15 days after the procedure. Therefore, a statistically significant difference in overall mortality was not detected between the diabetic and control groups (30.8% vs 7.7%, P = .135). At the same time, the cardiac death rate tended to be higher in the diabetic group than in controls (23.1% vs 0%, P = .066). Baseline covariates (weight, heart rate, systolic blood pressure, fasting glucose, cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol) were similar between the two groups. At 4 weeks after MI, body weights were lower and fasting glucose levels were higher in the diabetic group than in controls, but lipid profiles and renal and liver function were similar (Table 1). Hemodynamic and Angiographic Findings Heart rate was comparable, but aortic systolic pressure was lower and LVend-diastolic pressure was higher after MI in diabetic group than in

controls (all P values < .05). Compared with controls, diabetic minipigs had LV dilation and dysfunction, both of which were significantly exacerbated after MI. However, the patency of the infarct-related artery on repeat angiography was similar in the two groups (Table 2). Echocardiographic Measurements At baseline, LVend-systolic volume and wall motion score index were similar, but LVend-diastolic volume, wall thickness, and mass were significantly greater and Sm was markedly impaired in the diabetic group compared with controls. After MI, LV volumes were increased and Sm and ejection fractions were reduced in both groups. There was a trend toward more obvious changes from baseline in the diabetic group, though comparisons of the changes between the two groups did not reach statistical significance. Differences in LV diastolic filling at baseline and after MI (ie, decrease in transmitral E or increase in E/Em) did not reach statistical significance between the diabetic and control groups (Table 3). Tissue Doppler Assessment The means and mean differences from baseline to different time points after MI of LV systolic velocities, strains, and strain rates in the diabetic and control groups are listed in Table 4. Comparing means of DTI measurements at each time point after MI with those at baseline in each group, at 4 weeks after MI, in

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Table 1 Biochemical assessment Control group

Variable Weight (kg) Fasting glucose (mmol/L) Cholesterol (mmol/L) Triglyceride (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) BUN (mmol/L) Creatinine (mmol/L) ALT (IU/L) AST (IU/L)

Diabetic group

Baseline

4 weeks after MI

Baseline

4 weeks after MI

(n = 13) 13.1 6 2.1 2.3 6 0.4 2.31 6 0.75 0.18 6 0.07 0.51 6 0.24 0.72 6 0.28 2.78 6 0.57 45.67 6 15.30 38.56 6 11.77 57.92 6 46.72

(n = 12) 22.4 6 3.5 2.2 6 0.8 2.50 6 1.04 0.20 6 0.11 0.56 6 0.20 0.65 6 0.37 2.92 6 0.37 48.45 6 22.34 39.36 6 11.90 68.57 6 38.78

(n = 13) 12.8 6 3.4 10.7 6 2.3 1.96 6 0.48 0.19 6 0.10 0.55 6 0.27 0.68 6 0.45 2.52 6 1.23 47.53 6 29.54 40.17 6 12.16 54.76 6 44.67

(n = 9) 14.1 6 6.2* 9.2 6 4.5* 2.11 6 0.83 0.18 6 0.12 0.53 6 0.32 0.57 6 0.34 3.23 6 2.10 40.64 6 22.76 49.32 6 32.69 64.54 6 42.56

ALT, Alanine transaminase; AST, asparagine transaminase; BUN, blood urea nitrogen; HDL, high-density lipoprotein; LDL, low-density lipoprotein. Data are expressed as mean 6 SD. *P < .01 vs control group 4 weeks after MI.

both infarct and noninfarct zones, LV systolic velocity, strain, and strain rate values were markedly decreased in the diabetic group but were unchanged or slightly decreased in the control group. Comparing means of DTI measurements between the two groups at each time point, at 30 minutes, 90 minutes, and 4 weeks after MI, in both infarct and noninfarct zones, strain rate values were significantly lower in the diabetic group than in controls. However, no significant differences were detected with respect to LV systolic velocities and strains at each time point after MI between the two groups, except at 4 weeks after MI, when systolic strain was lower in the diabetic group. After comparing the mean differences of DTI measurements from baseline to each time point after MI, we found that strain rates in the infarct area deteriorated significantly over time in the diabetic group (Table 4). Interobserver and Intraobserver Variability The interobserver variability was 0.38 cm/s (10%) for velocity, 2.22% (16%) for strain, and 0.23 s1 (13%) for strain rate. The intraobserver variability was 0.39 cm/s (8%) for velocity, 2.17% (14%) for strain, and 0.18 s1 (9%) for strain rate. Bland-Altman plots are shown in Figure 2.

DISCUSSION This study is the first to evaluate serial changes in LV geometry and function early and late after MI in closed-chest STZ-induced diabetic swine using DTI. The novel findings from this study include that postMI diabetic swine had a poor survival rate, decreased overall and regional LV function, and exacerbated LV remodeling compared with their nondiabetic counterparts. Strain rate was a more sensitive parameter in detecting subtle LV segmental dysfunction than strain and velocity.

Cardiovascular and Overall Mortality in Diabetes Previous studies have shown that patients with diabetes had higher mortality from coronary heart disease than those without diabetes.5,6 In this study, a statistically significant difference in overall mortality was not detected between the diabetic and control groups (30.8% vs 7.7%, P = .135), but cardiovascular mortality tended to be higher in the diabetic group (23.1% vs 0%, P = .066). This may be explained at least in part by the small number of animals studied and the relatively distal and limited infarct area.

Table 2 Hemodynamic and angiographic findings Control group

Variable Heart rate (beats/min) Mean aortic pressure (mm Hg) LV end-diastolic pressure (mm Hg) LV end-diastolic volume (mL) End-systolic volume (mL) Ejection fraction (%) Patent infarct-related artery

Diabetic group

Baseline

4 weeks after MI

Baseline

4 weeks after MI

(n = 13) 149 6 21 141 6 15 11 6 5 24 6 7 10 6 5 58 6 11

(n = 12) 142 6 19 131 6 17 14 6 8 32 6 8* 15 6 7* 53 6 9† 11

(n = 13) 145 6 25 151 6 18 12 6 7 28 6 8‡ 11 6 4 61 6 10§

(n = 9) 133 6 24 124 6 25 17 6 11 39 6 11*,jj 20 6 5*,{ 49 6 11*,jj 7

Data are expressed as mean 6 SD. *P < .05 and †P < .01 vs baseline in each group. ‡P < .05 and §P < .01 vs baseline in controls. jjP < .05 and {P < .01 vs controls at 4 weeks after MI.

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Table 3 Two-dimensional and pulsed Doppler echocardiographic findings Control group

Variable LV end-diastolic volume (mL) End-systolic volume (mL) Ejection fraction (%) LV septal thickness (mm) Posterior wall thickness (mm) Mass (g) Wall motion score index E (mm/s) Em (LV free wall) E/Em Sm (mm/s) (LV free wall)

Diabetic group

Baseline

4 weeks after MI

Baseline

4 weeks after MI

(n = 13) 20.02 6 4.67 8.57 6 3.55 57.44 6 11.29 5.27 6 0.85 5.36 6 0.91 36.82 6 10.12 1.05 6 0.16 99.83 6 17.60 21.27 6 6.92 5.29 6 2.61 10.89 6 2.47

(n = 12) 31.83 6 6.03† 14.90 6 3.16† 53.01 6 6.29 5.49 6 0.69 5.30 6 0.74 48.49 6 9.05 1.69 6 0.21† 88.91 6 17.20 16.44 6 7.76 6.96 6 4.15 9.29 6 2.41

(n = 13) 24.07 6 4.48‡ 8.45 6 2.44 65.19 6 6.17‡ 8.62 6 1.86§ 7.67 6 1.43§ 68.85 6 31.40§ 1.10 6 0.23 92.17 6 16.50 15.73 6 5.16‡ 6.36 6 1.91 8.96 6 1.48‡

(n = 9) 29.32 6 5.56* 14.46 6 5.32† 51.87 6 11.41† 7.96 6 1.08jj 7.08 6 1.12jj 92.83 6 41.31jj 1.72 6 0.30† 84.22 6 32.23 15.13 6 6.13 5.85 6 1.40 7.41 6 1.53*

Data are expressed as mean 6 SD. *P < .05 and †P < .01 vs baseline in each group. ‡P < .05 and §P < .01 vs baseline in controls. jjP < .01 vs controls at 4 weeks after MI.

Changes in LV Geometry and Function in Diabetes The detection of early and subclinical changes in LV geometry and function in patients with diabetes after MI is becoming increasingly important, because LV remodeling is a precursor of the development of overt heart failure, even after the restoration of blood flow in the infarct-related artery.18,19 Diabetes alone increased myocyte size, extracellular matrix accumulation, and interstitial fibrosis,8 which will exacerbate this remodeling process.20 We found increased blood pressure, enlarged LV chambers, and greater LV mass in the diabetic swine, consistent with previous reports that hypertension and LV hypertrophy frequently coexist with diabetes.8,12 After MI, subendocardial and interstitial fibrosis increases, accompanied by reduced collagen tethers between myofiber bundles and a diminished ratio of collagen I to collagen III.21 This is associated with the exacerbation of LV remodeling and the impairment of systolic function (LVejection fraction and Sm).22 In addition, the degree of LV ejection fraction reduction 4 weeks after MI was even greater in diabetic swine compared with controls (20.4% vs 7.7%). This is in agreement with a previous study in STZ-induced mice, indicating that hyperglycemia may exacerbate post-MI cardiac failure even in the absence of coronary artery disease and hypertension.20 Kawata et al23 recently demonstrated that E/Em may be a reliable predictor of LV filling pressure. In this study, transmitral E/Em tended to be higher in the diabetic group than in controls, although the difference did not reach statistical significance. Changes in DTI It has been shown that subclinical LV longitudinal dysfunction was present in asymptomatic patients with diabetes and normal ejection fractions.24 Conventional echocardiography may not be able to detect subtle changes in LV function, because of its subjective and semiquantitative nature, whereas the development of DTI has made it possible to determine the subclinical changes in regional myocardial dysfunction.11,17 Strain rate imaging is a newly developed echocardiographic modality based on DTI that allows the quantitative assessment of regional myocardial wall motion. Strain rate is defined as the difference of tissue velocities between two distinct points.9 Several studies have

shown that both strain and strain rate are good indicators for the evaluation of regional LV function.9,25-27 In our study, the means of these two indices in the infarct zone of both groups were significantly reduced early (30 and 90 minutes) and late (4 weeks) after MI, consistent with the findings of Palmieri et al28 that subendocardial changes were implicated in LV dysfunction at the acute and subacute phases after MI. The present study demonstrated that strain rate was more sensitive for detecting subtle changes in LV function after distal LAD occlusion compared with strain or velocity. In the infarct zone, means of strain rates were significantly lower in the diabetic group than in controls at 30 minutes, 90 minutes, and 4 weeks after MI. Meanwhile, neither strain nor velocity was different between the two groups. It was not until late (4 weeks) after MI that strain could detect differences between the diabetic and control groups. Further comparisons of the average changes from baseline to different time points after MI also revealed a significant deterioration of strain rate in the diabetic group. Likewise, in the noninfarct zone, at baseline and early (30 and 90 minutes) or late (4 weeks) after MI, means of strain rates were significantly lower in the diabetic group than in controls, whereas strain and velocity were only slightly decreased. This may be due at least in part to severe subendocardial accumulation of fibrosis in diabetic compared with control hearts.29 Our observations further substantiate the concept that strain rate is a sensitive indicator of increased subendocardial stiffness and interstitial fibrosis in the presence of MI.30,31 The reasons for the inability of regional tissue velocities to show significant differences between infarct and noninfarct areas include tethering effects from contraction of the adjacent segments and cardiac motion. Our findings imply that velocity assessments of small and distal dysfunctional myocardial segments after acute MI may not be useful in the differentiation between active contraction and passive displacement.9,32 Limitations We evaluated only the acute and short-term changes in myocardial dysfunction in STZ-induced diabetic swine, and therefore, our findings may not be applied to long-term survival rates and heart failure in the clinical setting. In addition, the infarct size was relatively small,

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0.79 6 0.21†,{ 0.23‡,§ 1.39 6 0.32†,{ 0.42 D, Change from baseline to 30 minutes, 90 minutes, and 4 weeks, presented as mean. Data are expressed as mean 6 SD. *P < .05 and †P < .01, comparisons among mean values at baseline, 30 minutes, 90 minutes, and 4 weeks (Bonferroni corrected). ‡P < .05 vs D at 30 minutes. §P < .05 vs D at 90 minutes (Bonferroni corrected). jjP < .05 and {P < .01 vs controls after MI (t test between two groups). #P < .05 vs controls at baseline (t test between two groups).

0.58 6 0.19†,{ 0.51 1.28 6 0.20†,{ 0.56 0.61 6 0.12†,jj 0.47 1.29 6 0.13†,{ 0.54 1.09 6 0.14# 1.84 6 0.24# 2.06 0.90 1.58 6 0.66 2.32 6 0.53 1.24 6 0.40* 2.31 2.11 6 0.68 1.21 2.34 1.12

8.43 6 1.93† 15.95 6 2.30† 5.23 3.72 9.56 6 1.43† 16.51 6 1.29† 7.68 9.90 6 3.41* 7.11 15.32 6 4.53 2.11 14.79 6 1.77 2.05 17.78 6 6.41 3.76 22.56 6 5.60 1.40 20.23 6 1.42

6.35 9.10 6 2.20†,{ 4.82 4.28 16.83 6 2.41†,jj 2.87

1.18 1.22 2.16 6 0.88† 4.36 6 1.17* 1.96jj 2.22 1.53 6 0.65† 3.49 6 0.80† 3.49 6 1.04 5.71 6 1.09 0.86 1.00 1.77 6 1.51 3.45 6 0.99 1.83 6 1.91 0.85 2.59 6 1.36† 2.08 0.63 1.50

Systolic velocity (cm/s) Infarct area 2.69 6 1.31 2.06 6 1.35 Noninfarct area 4.67 6 1.65 3.17 6 1.18 Systolic strain (%) Infarct area 17.01 6 8.38 9.33 6 4.27† Noninfarct area 21.54 6 12.93 19.50 6 6.04 Systolic strain rate (s1) Infarct area 3.55 6 3.14 1.21 6 0.86* Noninfarct area 3.32 6 1.79 2.21 6 0.70

Variable

1.21 6 0.49† 3.21 6 0.94†

Mean D Mean D Mean Mean D Mean

D

4 weeks (n = 12) 90 minutes (n = 13) 30 minutes (n = 13)

Baseline (n = 13) Mean

Control group

Table 4 DTI measurements

2.28 2.50

Mean

90 minutes (n = 11) 30 minutes (n = 11)

Baseline (n = 13) Mean

Diabetic group

D

4 weeks (n = 9)

D

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Figure 2 Bland-Altman plots of interobserver and intraobserver variability of systolic velocity, strain, and strain rate. Dashed lines represent 61.96 SDs from the mean.

because LV ejection fraction was preserved after MI. Nevertheless, minipigs are more fragile and may die from larger infarctions, especially diabetic swine. Likewise, the infarction model was created with coronary occlusion using the technique previous described.14 We did not assess LV radial function using novel 2-dimensional strain imaging, which may be better, without the limitations of wide interrogation angles from apical windows, and has been shown to be more reproducible than DTI.11 We realize that STZ-induced diabetic pigs became malnourished because of the glucose loss in the urine and increased their food intake to attempt to obtain the needed energy, but they still lost weight. The reported results could be influenced by the loss of nutrients in the diabetic swine. Finally, there were some differences between the diabetic and control groups in systolic strain rates at baseline in both infarct and noninfarct zones (Table 4), but the major purpose of our study was to assess serial changes of DTI measurements in each group, and we also performed comparisons of average changes from baseline to overcome this limitation.

CONCLUSIONS STZ-induced diabetes exacerbates LV remodeling and regional dysfunction after MI, possibly as a result of diminished myocardial contractility and increased fibrosis. Subclinical myocardial dysfunction can be better detected by strain rate imaging, which appeared to be more sensitive than velocity or strain analyses. Clinically, because patients with diabetes who survived MI with LV dysfunction had an increased risk for death during long-term follow-up, delay or even prevention of heart failure could be achieved by instituting earlier treatment. A sensitive tool such as DTI will be useful for intensive risk stratification as well as identifying patients for and evaluating novel therapies such as revascularization and stem cell replacement.

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