Background
Preclinical left ventricular (LV) systolic dysfunction has been documented in patients with diabetes mellitus (DM) with preserved LV ejection fractions (LVEFs). The aims of this study were to investigate whether there is any difference in myocardial deformation between patients with DM with controlled (defined as glycosylated hemoglobin [HbA 1c ] < 7%) and uncontrolled (HbA 1c ≥ 7%) blood glucose using three-dimensional speckle-tracking echocardiography and to explore whether the level of HbA 1c is associated with preclinical LV systolic dysfunction.
Methods
Thirty-one patients with DM with controlled blood glucose, 37 patients with DM with uncontrolled blood glucose, and 63 matched controls were studied. All subjects had normal LVEFs (≥55%). Global longitudinal strain (GLS), global circumferential strain, global area strain, and global radial strain were assessed using three-dimensional speckle-tracking echocardiography.
Results
Despite similar LVEFs, patients with uncontrolled DM had decreased peak systolic strain in all directions compared with the other two groups, as evidenced by GLS, global circumferential strain, global area strain, and global radial strain (all P values <.001). However, the difference between patients with controlled DM and controls was observed only for GLS ( P = .038). By multivariate liner regression analysis, the level of HbA 1c was independently associated with the values of GLS (β = −0.274, P = .024), global circumferential strain (β = −0.245, P = .042), and global area strain (β = −0.272, P = .024).
Conclusions
GLS may be a sensitive indicator of early LV systolic dysfunction in patients with DM despite normal LVEF. Poor blood glucose control, as defined by HbA 1c ≥ 7%, leads to reductions of LV systolic strain in all directions that are independently associated with preclinical LV dysfunction.
Diabetes mellitus (DM) is associated with increased risk for heart failure, even in the absence of other known cardiac diseases, and DM may increase the risk for cardiovascular diseases, including coronary artery disease and myocardial infarction. Recent studies have suggested that DM can contribute to the development of cardiac dysfunction, known as diabetic cardiomyopathy. Although diastolic dysfunction was found to be the most common initial impairment of cardiac function in patients with DM, subtle systolic dysfunction was also observed by Doppler tissue imaging (DTI) and two-dimensional (2D) speckle-tracking echocardiography (STE) in patients with early-stage DM with normal left ventricular (LV) ejection fraction (LVEF). However, it is not clear whether there is any difference in LV systolic dysfunction between DM patients with controlled and uncontrolled blood glucose, and whether the level of blood glucose contributes to preclinical impairment of LV systolic function.
Three-dimensional (3D) STE is an emerging new technique to measure different components of myocardial deformation in one cardiac cycle, which should overcome the limitations of DTI and 2D STE. Therefore, the aim of this study was to investigate LV systolic dysfunction using 3D STE between patients with DM with glycosylated hemoglobin (HbA 1c ) < 7% and HbA 1c ≥ 7%, as well as the role of HbA 1c as a determinant of preclinical impairment of LV systolic function.
Methods
Subjects
Eighty-one patients with type 2 DM with LVEFs ≥ 55% were prospectively enrolled from our DM clinic between February 2012 and April 2012. The diagnosis of DM was made according to the 2010 guidelines of the American Diabetes Association. Among these patients, three with arrhythmias, one with ischemic heart disease (documented myocardial infarction, history of revascularization procedures, and positive findings on coronary angiography or computed tomography), two with other structural heart diseases, two with albumin/creatinine ratios > 30 μg/mg, two with uncontrolled hypertension (systolic blood pressure > 140 mm Hg and/or diastolic blood pressure > 90 mm Hg at rest), and one with other serious complications of DM (diabetic ketoacidosis or nonketotic hyperosmolar coma) were excluded. Another three patients with inadequate echocardiographic image quality for 3D speckle-tracking echocardiographic quantification were also excluded. Finally, 68 patients with DM were analyzed in this study.
Sixty-three age-matched and gender-matched controls were recruited consecutively from individuals who presented for routine checkups at our hospital if they met the following criteria: no evidence of preexisting cardiac disease on transthoracic echocardiography and other examinations, no clinical history of chronic diseases or chronic medications, and normal results on 12-lead electrocardiography. However, subjects with hypertension but well-controlled blood pressure (i.e., systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg on three separate measurements during the past month) were not excluded.
Clinical and echocardiographic assessments were performed in the study subjects. This study protocol conformed to the principles outlined in the Declaration of Helsinki and was approved by the institutional ethics committee.
Echocardiography
Three-dimensional imaging was performed from the apical position using a commercial scanner (1.5–4.0 MHz, 4V-D, Vivid E9; GE Medical Systems, Waukesha, WI) with a fully sampled matrix-array transducer. Electrocardiograms were recorded simultaneously during the examinations. The width of the angle was adjusted to ensure that acquisitions consisted of six wedge-shaped volumes, and six consecutive cardiac cycles were recorded during a single breath-hold. Furthermore, the temporal and spatial resolutions of images were optimized by decreasing the depth and adjusting the sector width as much as possible while retaining the entire left ventricle within the pyramidal volume. As a result, the volume rate of acquisition ranged from 24 to 45 frames/sec. All echocardiographic images were obtained by an experienced echocardiographer according to a standard protocol and analyzed online by another experienced echocardiographer blinded to the clinical data of the subjects.
All images were analyzed using an online cardiovascular analysis system. The LV endocardial and epicardial borders (including both end-diastolic and end-systolic phases) were automatically detected by the analysis system. The endocardial border and myocardial thickness could be manually adjusted after automatic detection if necessary. Then, the system automatically performed segmental strain analysis through an entire cardiac cycle and provided continuous values of global and segmental strain, including global longitudinal strain (GLS), global circumferential strain (GCS), global area strain (GAS), and global radial strain (GRS), for all 17 segments simultaneously ( Figure 1 ). End-systolic and end-diastolic LV volume, mass, and sphericity index were generated automatically. If more than two segments were untrackable after adjustment, the patient was excluded because of inadequate image quality.
In the parasternal long-axis view, the thickness of the interventricular septum and the LV posterior wall were measured at end-diastole, while LV diameters were measured at both end-diastole and end-systole. All these parameters were indexed to body surface area.
For the assessment of diastolic function, the early (E) and late (A) diastolic peak velocities of mitral inflow as well as the deceleration time of the E wave were measured using pulsed-wave Doppler. The early (Em) and late (Am) diastolic peak velocities of the septal mitral annulus were measured using a pulsed-wave DTI spectrum. The E/A ratio, Em/Am ratio, and E/Em ratios were calculated.
Clinical Assessment
Biochemical analyses including total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglyceride, were performed using standard laboratory techniques in all subjects. In patients with type 2 DM, HbA 1c was measured <2 weeks before the echocardiographic evaluation. Patients with DM were then divided into two groups, those with controlled DM (HbA 1c < 7%, n = 31) and those with uncontrolled DM (HbA 1c ≥ 7%, n = 37).
Intraobserver and Interobserver Reproducibility
Three-dimensional speckle-tracking echocardiographic measurements were repeated in 20 randomly selected subjects. Intraobserver reliability assessment was performed ≥1 week apart by the same observer on the same echocardiographic images in a random order, while interobserver reproducibility assessment was carried out by another independent observer. Both observers were blind to previous measurements and unaware of the clinical data of the patients in this study.
Statistical Analysis
Statistical analysis was performed using SPSS version 16.0 (SPSS, Inc., Chicago, IL). Continuous data are presented as mean ± SD, except that the duration of DM or hypertension is presented as the median value. Frequencies are expressed as percentages. Student’s t test or one-way analysis of variance with post hoc least significant difference test was used as appropriate for comparisons of continuous data between the study groups. Fischer’s exact or χ 2 tests were used in comparisons of categorical data between groups. Independent determinants of subclinical myocardial systolic dysfunction in patients with DM were examined using multivariate backward stepwise linear regression. P values < .05 were considered statistically significant.
Reproducibility was assessed using intraclass correlation coefficients (ICCs) along with absolute differences, expressed as percentages of the mean of repeated measurements, and clinical significance was categorized as follows: good, ICC ≥ 0.75; moderate, 0.4 ≤ ICC < 0.75; and poor, ICC < 0.4.
Results
Clinical Characteristics
Clinical characteristics of the two DM groups and the control group are summarized in Table 1 . No statistical differences was found in gender, age, body mass index, heart rate, blood pressure, and the prevalence, duration, and treatment of hypertension among the three groups (all P values > .05). However, low-density lipoprotein and total cholesterol levels were significantly greater in patients with uncontrolled DM than in the other two groups. Although the level of HbA 1c was significantly lower in the controlled DM group than in the uncontrolled DM group (6.1 ± 0.5 vs 9.1 ± 1.4%, P < .001), the duration of DM, complications, and medications showed no significant differences between the two groups ( P > .05).
| Controls | Controlled DM | Uncontrolled DM | ||
|---|---|---|---|---|
| Parameter | ( n = 63) | ( n = 31) | ( n = 37) | P value (controlled DM vs uncontrolled DM) |
| Age (y) | 58 ± 10 | 61 ± 9 | 60 ± 10 | .455 |
| Men | 30/63 (48%) | 15/31 (48%) | 21/37 (57%) | .290 |
| Body mass index (kg/m 2 ) | 23.9 ± 3.7 | 25.2 ± 3.1 | 24.4 ± 3.6 | .869 |
| Heart rate (beats/min) | 74 ± 13 | 72 ± 12 | 76 ± 15 | .290 |
| Systolic BP (mm Hg) | 129 ± 12 | 129 ± 8 | 128 ± 8 | .708 |
| Diastolic BP (mm Hg) | 77 ± 7 | 77 ± 5 | 76 ± 9 | .566 |
| Total cholesterol (mmol/L) | 3.8 ± 0.7 | 4.0 ± 0.8 | 4.2 ± 0.8 ∗ | .222 |
| LDL cholesterol (mmol/L) | 2.0 ± 0.5 | 2.1 ± 0.6 | 2.3 ± 0.6 ∗ | .144 |
| HDL cholesterol (mmol/L) | 1.4 ± 0.6 | 1.3 ± 0.5 | 1.2 ± 0.4 | .791 |
| Triglycerides (mmol/L) | 1.2 ± 0.5 | 1.2 ± 0.5 | 1.4 ± 0.6 | .305 |
| HbA 1c (%) | — | 6.10 ± 0.53 | 9.12 ± 1.40 | <.001 |
| DM duration (y) | — | 7 (4–13) | 8 (5–16) | .262 |
| Hypertension | 28/63 (44%) | 15/31 (48%) | 17/37 (46%) | .340 |
| Hypertension duration (y) | 6 (1–15) | 6 (4–18) | 3 (1–6) | .082 |
| DM complications | ||||
| Peripheral vascular disease | — | 3/31 (10%) | 5/37 (14%) | .679 |
| Retinopathy | — | 6/31 (19%) | 8/37 (22%) | .239 |
| Neuropathy | — | 2/31 (6%) | 2/37 (5%) | .326 |
| Diabetic treatment | ||||
| Diet therapy | — | 3/31 (10%) | 3/37 (8%) | .892 |
| Insulin | — | 19/31 (61%) | 23/37 (62%) | .754 |
| Metformin | — | 6/31 (19%) | 7/37 (19%) | .556 |
| Sulfonylureas | — | 3/31 (10%) | 5/37 (14%) | .256 |
| Cardiovascular medications | ||||
| ACE inhibitors | 28/63 (44%) | 15/31 (48%) | 17/37 (46%) | .688 |
| β-blockers | 15/63 (24%) | 8/31 (26%) | 8/37 (22%) | .398 |
| Diuretics | 16/63 (25%) | 8/31 (26%) | 10/37 (27%) | .772 |
Echocardiographic Characteristics
Echocardiographic characteristics of the study groups are shown in Table 2 . The three groups had similar LV end-systolic and end-diastolic volumes, diameters, LVEFs, and sphericity indices (all P values > .05). End-diastolic interventricular septal thickness and end-diastolic posterior wall thickness were significantly greater in patients with DM than in controls. As a result, LV end-diastolic mass index was also higher in patients with DM. However, no significant differences were found between the two DM groups.
| Controls | Controlled DM | Uncontrolled DM | ||
|---|---|---|---|---|
| Parameter | ( n = 63) | ( n = 31) | ( n = 37) | P value (controlled DM vs uncontrolled DM) |
| LVEDDI (mm/m 2 ) | 27.0 ± 2.4 | 27.1 ± 2.2 | 27.1 ± 2.8 | .959 |
| LVESDI (mm/m 2 ) | 16.7 ± 2.0 | 16.6 ± 1.7 | 16.8 ± 1.9 | .618 |
| LVEDVI (mL/m 2 ) | 50.0 ± 10.8 | 50.8 ± 9.2 | 49.1 ± 10.4 | .500 |
| LVESVI (mL/m 2 ) | 19.1 ± 5.9 | 19.4 ± 4.7 | 19.2 ± 4.5 | .883 |
| LVEF (%) | 63.0 ± 4.6 | 62 ± 5 | 61 ± 3 | .287 |
| IVSD (mm) | 10.5 ± 1.9 | 11.3 ± 1.4 ∗ | 11.6 ± 1.5 ∗ | .498 |
| PWD (mm) | 9.2 ± 1.1 | 10.3 ± 1.1 † | 10.2 ± 1.0 † | .718 |
| Sphericity index | 0.33 ± 0.08 | 0.35 ± 0.07 | 0.32 ± 0.07 | .185 |
| LV end-diastolic mass index (g/m 2 ) | 86.6 ± 13.0 | 93.9 ± 15.1 ∗ | 93.6 ± 14.2 ∗ | .923 |
| E (cm/sec) | 81.2 ± 23.5 | 84.6 ± 25.7 | 67.8 ± 17.0 ∗ | .003 |
| A (cm/sec) | 79.8 ± 14.1 | 92.1 ± 20.3 ∗ | 93.5 ± 17.9 † | .734 |
| E/A ratio | 1.1 ± 0.5 | 0.9 ± 0.3 | 0.7 ± 0.2 † | .026 |
| DT (msec) | 212 ± 26 | 218 ± 22 | 213 ± 28 | .298 |
| Em (cm/sec) | 7.5 ± 2.2 | 6.1 ± 2.3 ∗ | 5.0 ± 1.2 † | .017 |
| Am (cm/sec) | 9.1 ± 2.1 | 8.6 ± 2.2 | 8.2 ± 1.2 ∗ | .517 |
| Em/Am ratio | 0.9 ± 0.4 | 0.8 ± 0.3 | 0.6 ± 0.2 † | .102 |
| E/Em ratio | 11.2 ± 2.9 | 15.2 ± 6.3 † | 14.2 ± 4.5 ∗ | .346 |
For the assessment of diastolic function, E/A ratios were significantly lower in the uncontrolled DM group than in the other two groups, while no significant difference was found between the controlled DM group and controls. Higher E/Em ratios were observed in patients with DM than in controls, but no significant difference was observed between the two DM groups.
In 3D speckle-tracking echocardiographic analyses, only GLS showed a significant difference between the controlled DM group and control subjects (−17.7 ± 2.6 vs −19.1 ± 3.4, P = .038). Nevertheless, the uncontrolled DM group had decreased peak systolic strains in all the directions (GLS, GCS, GAS, and GRS) compared with controls (−16.2 ± 2.4 vs −19.1 ± 3.4, −16.2 ± 2.7 vs −18.5 ± 3.1, −28.8 ± 3.6 vs −32.9 ± 4.8, and 45.2 ± 8.3 vs 54.4 ± 11.3; all P values < .05) and the controlled DM group (−16.2 ± 2.4 vs −17.7 ± 2.6, −16.2 ± 2.7 vs −18.1 ± 2.9, −28.8 ± 3.6 vs −31.7 ± 4.5, and 45.2 ± 8.3 vs 51.5 ± 10.6; all P values < .05) ( Figure 2 ).
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