2015 Volume 79 Issue 8 Pages 1749-1755
Background: It remains uncertain whether diabetes itself causes specific echocardiographic features of myocardial morphology and function in the absence of hypertension or ischemic heart disease. The purpose of the present study was to determine the characteristics of pure diabetic cardiomyopathy-related echocardiographic morphology and function using layer-by-layer evaluation with myocardial strain echocardiography.
Methods and Results: We enrolled 104 patients with poorly controlled type 2 diabetes mellitus (mean HbA1c level, 10%) with (n=74) or without (n=40) hypertension and 24 age- and sex-matched healthy volunteers. Patients with coronary artery stenosis or structural heart disease were excluded. Myocardial layer-specific strain was analyzed by speckle tracking echocardiography. Compared with the healthy control group, the normotensive diabetes group showed no significant difference in ejection fraction, left ventricular mass index, diastolic properties, left atrial volume index, or B-type natriuretic protein (BNP) level, but global longitudinal strain and subendocardial radial strain were significantly deteriorated. The deterioration of longitudinal strain correlated with body mass index (R=0.49, P<0.01) and blood pressure (R=0.36, P<0.01) in the normotensive diabetes group.
Conclusions: Deterioration of left ventricular longitudinal shortening accompanied by decreased subendocardial wall thickening are the characteristic functional abnormalities of diabetic cardiomyopathy in patients without hypertrophy, diastolic dysfunction, or elevated BNP. Obesity and blood pressure may also play important roles in this strain abnormality in asymptomatic patients with type 2 diabetes. (Circ J 2015; 79: 1749–1755)
The incidence and mortality of diabetic mellitus (DM) in and of itself may be increased in patients with congestive heart failure, irrespective of their hypertensive or ischemic heart disease status.1,2 The prevalence of DM continues to increase in the general population and in community-based patients with heart failure.3 In an analysis of heart failure with preserved ejection fraction (EF), type 2 DM was associated with a significantly increased risk of developing adverse outcomes of heart failure.4 To prevent the progression of heart failure in diabetic patients, a sensitive method of diagnosing the presence of diabetic cardiomyopathy is important;5 however, clinical diagnostic surrogates to monitor myocardial disease progression in diabetic patients are not well established.2
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Myocardial strain echocardiography can detect myocardial damage beyond that indicated by EF by assessing myocardial deformation in any direction. Furthermore, newly developed layer-specific speckle tracking imaging can evaluate myocardial function layer-by-layer.6 This technique allows the noninvasive evaluation of layer-specific myocardial damage. Accordingly, the present study aimed to identify the myocardial strain characteristics of diabetic cardiomyopathy in patients with and without hypertension using layer-specific strain analysis by 2D speckle tracking echocardiography.
We enrolled a consecutive sample of 74 hospitalized normotensive patients with poorly controlled type 2 diabetes (DM-normo-BP group, mean age 51±15 years), 40 diabetic hypertensive patients (DM-HT group, mean age 54±12 years), and 24 age- and sex-matched healthy controls (mean age 49±12 years) in this study. The local institutional review board approved the study protocol, and all participants were recruited for the study after giving written informed consent. HT was definition as a history and treatment with a prescribed antihypertensive drug or a blood pressure (BP) consistently >140/90 mmHg measured at rest while seated. The Homeostatic Model Assessment of Insulin Resistance (HOMA-R) value, a marker of insulin resistance, was calculated using the following formula: HOMA-R=(fasting serum insulin value [μU/ml]×fasting plasma glucose [mg/dl])/405.
Patients with coronary artery disease (CAD) were excluded by coronary computed tomography angiography or myocardial scintigraphy. Reasons for performing coronary computed tomography angiography included carotid atherosclerosis, ischemic changes on ECG, positive exercise ECG test results, or left ventricular (LV) wall motion abnormalities on echocardiography. ECG abnormalities, such as Q waves, ST-T changes, and negative T waves, or positive exercise ECG test results or LV wall motion abnormalities on echocardiography were considered suggestive of the presence of CAD.7 Patients with significant mitral or aortic valvular heart disease, a rhythm other than normal sinus rhythm, or LVEF <50% were also excluded.
Standard EchocardiographyThe standard echocardiographic examinations were performed using a commercially available ultrasound machine (Artida TM, Toshiba Medical Systems Co, Tochigi, Japan) equipped with a multifrequency transducer. Echocardiographic images were recorded with the patients lying in the left lateral decubitus position. LV diameter and wall thickness were measured on the 2D M-mode images. Relative wall thickness, LV mass, and LV mass index according to Devereux’s formula were measured using the following formulae:8
relative wall thickness=2×PWT/LVDd
LV mass (g)=0.8×(1.04×((LVDd+PWTd+SWTd)3–(LVDd)3))+0.6
LV mass index (g/m2)=LV mass/body surface area
where LVDd is LV diastolic dimension, PWTd is posterior wall thickness at end-diastole, and SWTd is septal wall thickness at end-diastole.
LV hypertrophy (LVH) was defined as an LV mass index >115 g/m2 in men and >95 g/m2 in women. The transmitral peak early diastolic velocity (E), peak late diastolic velocity (A), the ratio of E to A (E/A), deceleration time of the E wave, and duration of the A wave (Ad) were measured by pulsed Doppler echocardiography from the apical long-axis view. Pulmonary venous flow was measured at the right upper pulmonary vein on the apical 4-chamber view. Peak systolic (S) and peak diastolic (D) flows, the ratio of S to D (S/D), atrial reversal velocity (PVA), and the duration of the reversal wave during atrial contraction (PVAd) were measured. Pulsed-wave tissue Doppler echocardiography was used to measure the mean peak early diastolic velocity (E’) and peak late diastolic velocity (A’) of both the lateral and medial mitral annulus. The propagation velocity was measured by color M-mode Doppler images from the apical 3-chamber view at the first slope in the aliasing area at 40–50% of transmitral early diastolic wave velocity.9
2D Speckle Tracking EchocardiographyMyocardial strain was measured in separate subendocardial and subepicardial half layers by a single analyzer (M.E.), who was blinded to the patients’ clinical characteristics.6 Radial and circumferential strains (RS and CS) were measured in the mid-ventricular short-axis view. RS was measured in the subendocardial and subepicardial layers and the total wall (inner RS, outer RS, and total RS, respectively). CS was measured in 2 separate layers: the subendocardial and subepicardial layers (inner CS and outer CS, respectively).10 In the apical 4-chamber view, longitudinal strain (LS) was measured at the endocardial border. All images were stored electronically, and LV strain was analyzed off-line with 2D speckle tracking software (2D Wall Motion Tracking, Toshiba Medical Systems Co).
ReproducibilityWe selected 15 studies at random for the assessment of intra- and interobserver reproducibility of speckle tracking analysis. To test intraobserver variability, a single observer analyzed the data twice. The second analysis was done more than 2 weeks after the first analysis. To test interobserver variability, a second observer analyzed the data without knowledge of the first observer’s measurements. Reproducibility was assessed as the mean percent error (absolute difference divided by the mean of the 2 individual observations).
Statistical AnalysisValues are reported as the mean±SD. Student’s t-test was used to compare the differences in continuous variables of 2 groups. The Pearson correlation coefficient was used for assessment of univariate relations. Comparison of variances among 3 groups was examined by 1-way analysis of variance. When significant differences between groups were present, Fisher’s post-hoc test was used to compare individual groups. P<0.05 was considered to indicate statistical significance. Statistical calculations were performed with the Dr. SPSS II for Windows statistical software program (SPSS Inc, Chicago, IL, USA).
Patient clinical characteristics are summarized in Table 1. Systolic and diastolic BP and body mass index (BMI) were similar between the control and DM-normo-BP groups, but both were significantly higher in the DM-HT group. The high-density lipoprotein cholesterol level was significantly higher in the DM-normo-BP than in the DM-HT group. Only 2 patients, 1 each in the DM-normo-BP and DM-HT groups, had abnormal serum N-terminal proBNP levels >125 pg/ml.
| Control (n=24) | DM-normo-BP (n=74) | DM-HT (n=40) | |
|---|---|---|---|
| Age (years) | 49±12 | 51±15 | 54±12 |
| Sex (M/F) | 16/8 | 32/42 | 19/21 |
| DM duration (years) | 7.7±7.5 | 10.0±7.0 | |
| DM microangiopathy | |||
| Nephropathy stage I/II/III/IV (n) | 60/10/4/0 | 23/7/7/1† | |
| Retinopathy, n (%) | 17 (23) | 13 (32) | |
| BMI (kg/m2) | 23.1±2.9 | 23.8±5.2 | 26.9±5.4*,† |
| Systolic BP (mmHg) | 113±15 | 112±16 | 133±16*,† |
| Diastolic BP (mmHg) | 65±13 | 68±10 | 77±10*,† |
| Heart rate (beats/min) | 65±11 | 68±12 | 70±9 |
| Total cholesterol (mg/dl) | 197±39 | 193±41 | |
| Triglycerides (mg/dl) | 134±73 | 154±59 | |
| HDL-cholesterol (mg/dl) | 52±15† | 43±10 | |
| LDL-cholesterol (mg/dl) | 118±34 | 118±36 | |
| CRP (mg/dl) | 0.27±0.46 | 0.27±0.36 | |
| NT-proBNP (pg/ml) | 37.6±46.6 | 61.9±123.4 | |
| Hemoglobin A1c (%) | 10.3±2.6 | 9.7±1.8 | |
| Fasting blood glucose (mg/dl) | 176±52 | 160±55 | |
| Fasting insulin (μU/ml) | 5.0±4.6 | 6.4±4.6 | |
| HOMA-R | 2.0±4.6 | 2.3±1.6 | |
| Diabetic therapy | |||
| Insulin, n (%) | 41 (55) | 8 (20) | |
| Oral hypoglycemic agent, n (%) | 23 (31) | 29 (73) | |
| Insulin+oral hypoglycemic agent, n (%) | 6 (8) | 2 (5) | |
| None (diet therapy only), n (%) | 4 (5) | 1 (3) | |
| Antihypertensive medication, n (%) | |||
| Calcium antagonist | 15 (38) | ||
| ACEI | 2 (5) | ||
| ARB | 21 (53) | ||
| Diuretic | 2 (5) | ||
| β-blocker | 0 (0) | ||
*P<0.05 vs. Control group; †P<0.05 vs. DM-normo-BP group. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BMI, body mass index; BP, blood pressure; CRP, C-reactive protein; DM, diabetes mellitus; HDL, high-density lipoprotein; HOMA-R, Homeostatic Model Assessment of Insulin Resistance; HT, hypertension; LDL, low-density lipoprotein; NT-proBNP, N-terminal pro-B-type natriuretic peptide.
The LV diastolic dimension was significantly smaller in the DM-normo-BP group than in the control group; however, there were no significant differences in LV volume, LV wall thickness, LV mass index, and EF among the 3 groups (Table 2). LVH was recognized in only 2 (2.7%) DM-normo-BP patients and 3 (7.5%) DM-HT patients. E/A was significantly lower in the DM-HT group compared with the control and DM-normo-BP groups. E/E’ was significantly higher in the DM-HT group compared with the control group. There was no significant difference in E/A, E/E’, and the pulmonary venous S/D ratios between the control and the DM-normo-BP groups.
| Control (n=24) | DM-normo-BP (n=74) | DM-HT (n=40) | |
|---|---|---|---|
| LV diastolic dimension (mm) | 48±5 | 45±5* | 47±4 |
| LV systolic dimension (mm) | 30±4 | 28±4 | 28±4 |
| LV end-diastolic volume (ml) | 107±24 | 95±25 | 102±21 |
| LV end-systolic volume (ml) | 37±14 | 31±12 | 31±10 |
| LV ejection fraction (%) | 67±7 | 67±6 | 69±7 |
| LV septal wall thickness (mm) | 8.2±1.0 | 8.0±1.5 | 8.6±1.6 |
| LV posterior wall thickness (mm) | 8.1±1.1 | 8.2±1.3 | 8.6±1.3 |
| LV mass index (g/m2) | 77.6±12.1 | 71.6±18.1 | 75.7±22.4 |
| Relative wall thickness | 0.34±0.06 | 0.37±0.08 | 0.37±0.09 |
| LAVI (ml/m2) | 25.5±5.7 | 25.1±7.8 | 23.9±6.7 |
| Mitral flow and mitral annulus tissue velocity | |||
| E (cm/s) | 74±19 | 72±20 | 68±15 |
| A (cm/s) | 65±20 | 67±19 | 79±15*,† |
| E/A | 1.2±0.4 | 1.2±0.5 | 0.9±0.3*,† |
| Deceleration time (ms) | 196±41 | 196±54 | 215±59 |
| A duration (ms) | 126±15 | 135±19 | 136±23 |
| Lateral E’ (cm/s) | 13.0±2.4 | 11.6±4.1 | 9.6±2.8*,† |
| Medial E’ (cm/s) | 10.4±2.1 | 8.8±3.0* | 7.5±1.8*,† |
| E/E’ | 6.4±1.6 | 7.5±2.6 | 8.2±1.6* |
| Pulmonary venous flow | |||
| S (cm/s) | 55.9±22.2 | 55.2±11.7 | 54.1±11.8 |
| D (cm/s) | 42.1±16.3 | 41.7±13.6 | 37.1±8.6 |
| S/D | 1.3±0.4 | 1.5±0.6 | 1.5±0.4 |
| Atrial reversal velocity (cm/s) | 39.5±10.7 | 30.4±10.6 | 31.9±16.7 |
| PVA duration (ms) | 118±33 | 113±21 | 116±17 |
| Propagation velocity (cm/s) | 41.0±12.2 | 41.9±11.7 | 44.3±12.9 |
*P<0.05 vs. Control group; †P<0.05 vs. the DM-HT group. A, peak late diastolic velocity; D, peak diastolic velocity; E, peak early diastolic velocity; E’, peak early diastolic mitral annular velocity; LAVI, left atrial volume index; LV, left ventricular; S, peak systolic velocity. Other abbreviations as in Table 1.
LS and CS could not be obtained in 8 (10%) and 6 (8%) of the DM-normo-BP patients and in 4 (10%) and 3 (8%) of the DM-HT patients, respectively, because of poor quality echo images. Among the various strains, LS and inner RS showed a significant association (R=0.24, P=0.009). Strain results are summarized in Figure 1. In the DM-normo-BP and the DM-HT groups, longitudinal and inner RS were significantly reduced compared with the control group. If longitudinal dysfunction was defined as LS <11.2% based on –2SD in the control group, longitudinal dysfunction was present in 15% of the DM-normo-BP group and in 19% of the DM-HT group patients. There was no difference in outer and total RS or in any of the CS parameters among the 3 groups.
Myocardial strain in the control, normotensive diabetes (DM-normo), and hypertensive diabetes (DM-HT) patient groups. NS, not significant.
In the DM-normo-BP group, LS correlated with BMI (R=0.49, P<0.01) (Figure 2A), body weight (R=0.41, P<0.01) (Figure 2B), systolic BP (R=0.36, P<0.01) (Figure 3A), and diastolic BP (R=0.28, P<0.05) (Figure 3B). There was no significant correlation between HbA1c, DM duration or any of the speckle tracking parameters. In the DM-HT group, LS was significantly reduced in patients with retinopathy (−12.6±3.1%) compared with patients without retinopathy (−15.1±2.8%, P=0.03). No variable was selected by univariate analysis as being a significant determinant of LS in the control group.
Correlation between longitudinal strain and body weight (A) and body mass index (B) in normotensive diabetes patients.
Correlation between longitudinal strain and systolic blood pressure (A) and diastolic blood pressure (B) just before echocardiographic examination of normotensive diabetes patients.
The respective intra- and interobserver variabilities were as follows: 12.7±9.7% and 13.7±12.8% for inner RS, 13.1±13.2% and 16.2±12.9% for outer RS, 8.9±9.3% and 12.3±8.6% for total RS, 7.0±6.6% and 9.1±8.9% for inner CS, 10.7±12.4% and 10.2±8.2% for outer CS, and 7.9±7.9% and 7.6±8.8% for LS.
We recruited patients with poorly controlled type 2 DM with and without HT and no CAD to evaluate myocardial layer-specific strain. The main findings of the present study were as follows: (1) DM in and of itself can cause longitudinal systolic dysfunction and impairment associated with subendocardial wall thickening, (2) normotensive patients with DM showed no significant hypertrophy or diastolic dysfunction, which was present in the hypertensive DM patients, and (3) normotensive patients with DM showed a longitudinal contraction abnormality that was related to the degree of obesity and BP.
The myocardium consists of 3 layers.11 The primary orientation of subendocardial muscle fibers is longitudinal, so a deterioration in LS accompanied by a decrease in inner myocardial wall thickening may represent subendocardial myocardial dysfunction. As a strain characteristic of diabetic cardiomyopathy, longitudinal dysfunction12 with preserved circumferential and radial function has been shown in previous reports,13–15 which demonstrates that the determinants of longitudinal dysfunction were the presence of DM,14 LVH,13 and duration of DM.15 However, HT was not strictly excluded in those studies, and therefore, the pure effect of DM itself on the myocardium may not have been assessed precisely. In contrast, our study could discriminate the comorbid influence of HT on diabetic cardiomyopathy and confirm the same strain characteristics. Furthermore, we could identify the decrease in subendocardial radial dysfunction though our layer-by-layer evaluation.
The new finding of the present study is that strain abnormality was an unexpected characteristic of patients in the normotensive-DM group, who showed neither LVH nor diastolic dysfunction. Therefore, abnormal strain might be an earlier marker of diabetic cardiomyopathy than either diastolic dysfunction or LVH. A previous investigation assessing diastolic dysfunction in normotensive patients with DM by Boyer et al16 found that 75% of the patients showed diastolic dysfunction. We recognized diastolic dysfunction in 71% of the normal control group subjects and in 84% of the DM-normo-BP and 88% of the DM-HT group patients according to the same criteria used by Boyer et al. However, diastolic function parameters in the DM-normo-BP group were not significantly different from those in the healthy controls, which suggests that diastolic dysfunction, also prevalent in healthy subjects as a part of the normal aging process, may not be a specific parameter of subclinical myocardial damage caused by DM.
HT causes the development of subendocardial myocardial damage and results in LS abnormality.17 In their clinical investigation, Mizuguchi et al18 reported that HT without ventricular hypertrophy caused LS impairment. However, there was no significant difference in the strain parameters of the DM-normo-BP and DM-HT groups in the present study. A possible explanation for the lack of a significant effect of HT comorbidity on strain abnormality is that it may be related to the high prevalence of patients taking antihypertensive medications in our study. Good BP control with a renin–angiotensin system blocker may prevent or contribute to the reversal of strain abnormality. The importance of BP on LS impairment may be also supported by the fact that a dose-dependent relation between LS and BP was present in the normotensive-DM patients in whom no renin-angiotensin system inhibitors were prescribed. This may explain why meticulous BP control appears to be particularly effective in people with DM.
Body weight and BMI were revealed to be significant determinants of longitudinal systolic dysfunction in DM patients. Obesity is a major risk factor for insulin resistance and is also a risk factor for heart failure. Kishi et al reported progressive longitudinal systolic dysfunction associated with obesity in a community-based cohort study.19 In our study population, 2 patients with a BMI >35 kg/m2 showed apparently severe longitudinal dysfunction, and in patients with a BMI <35 kg/m2, a linear relationship exists between LS and BMI without the obesity paradox. However, neither serum glucose nor HbA1c showed a similar relation. Therefore, obesity, in relation to hyperinsulinemia, but not hyperglycemia, may be important in the development of subclinical myocardial damage. In the present study, HOMA-R, the parameter for insulin resistance, showed a modest but significant relation with LS among all DM patients (R=0.21, P=0.048). However, the significance disappeared in the normo-BP and hypertensive subgroups. Accordingly, the causative role of insulin resistance in LV dysfunction requires further investigation.
Although the background pathophysiology of impaired subendocardial systolic contractile function is beyond the scope of this clinical study, the pattern of strain abnormality observed in the study patients is very similar to that in myocardial ischemia.10 In the present study, the presence of retinopathy was a significant determinant of LV longitudinal dysfunction in the hypertensive DM subgroup. Microvasculopathy in DM, in which reduced coronary microcirculation leads to chronic myocardial ischemia without the ability of compensatory angiogenesis,20 may be a potential mechanism of longitudinal systolic dysfunction.
The majority of the DM patients had a BNP level within the normal range, even with abnormal strain or diastolic function as shown by echocardiography. The results support the concept that BNP may not be a sensitive biomarker of subclinical diabetic cardiomyopathy in the presence of obesity because plasma BNP levels are lower in patients with obesity and insulin resistance.21
Study limitationsFirst, this was an observational study enrolling a small number of DM patients hospitalized in a university hospital. Although type 2 DM is often accompanied by high BP as a comorbidity, the selection of normotensive DM patients requires a high-volume center such as a university hospital with a patient database containing detailed clinical information. Therefore, caution is required when applying the results of this study to community subjects because of selection bias. Also, type 2 DM, especially the subset of poorly controlled DM, is usually combined with HT as a comorbidity. Therefore, the information from this study may not be applicable to usual patients with DM. Second, no longitudinal information after therapeutic intervention for potential therapeutic intervention22 is shown. To identify the significance of LS as a surrogate echo parameter reflecting the disease severity of diabetic cardiomyopathy, serial echocardiographic assessments are warranted in this population. Third, LS could not be obtained in 10% of the patients with DM in the present study because of the poor quality of the echo image of the subendocardial contour.
Myocardial longitudinal dysfunction in normotensive patients with type 2 DM can be observed as an early subclinical manifestation of diabetic cardiomyopathy before LVH or diastolic dysfunction has developed. Obesity and BP are related to this strain abnormality, and thus the control of weight and BP is a potential therapeutic target to prevent overt heart failure.
None.
