Diabetic cardiomyopathy has been characterized by an early impairment of left ventricular (LV) longitudinal function as opposed to preserved LV radial function.
Conventional echocardiography and longitudinal (ϵ L ) and radial (ϵ R ) systolic strain assessed by speckle-tracking imaging were obtained in 114 type 2 diabetic patients and 88 age-matched controls.
LV ejection fraction was similar in diabetic patients and controls. The presence of subclinical LV systolic dysfunction in diabetic patients was demonstrated by lower values of midwall fractional shortening (18% ± 3% vs 20% ± 3%, P = .006), ϵ L (-19% ± 3% vs –22% ± 2%, P < . 001), and ϵ R (50% ± 16% vs 56% ± 12%, P = .003) compared with controls. On multivariate analysis, factors predicting strain values were diabetes ( P = .001) and gender ( P = .001) for ϵ L and diabetes ( P = .003) for ϵ R .
Diabetic patients without overt heart disease display subclinical alteration of both radial and longitudinal LV systolic function even after adjustment for blood pressure, age, and body mass index.
Diabetes mellitus (DM) may alter cardiac structure and function independently of underlying coronary artery disease or hypertension. This diabetic cardiomyopathy is characterized by a long silent phase of progressive left ventricular (LV) remodeling before contractile dysfunction, increased myocardial stiffness, and onset of heart failure symptoms.
Many clinical, echocardiographic, and magnetic resonance imaging studies have demonstrated various functional defects in the hearts of patients with DM, ranging from subtle alteration in diastolic function to overt systolic dysfunction or to impaired myocardial reserve in response to inotropic stimuli or exercise. Most of these echo studies used tissue Doppler imaging (TDI) that has also been proven to detect subclinical myocardial dysfunction in community surveys. Specially, LV longitudinal systolic dysfunction has been well demonstrated in individuals with DM without overt coronary artery disease and normal standard echocardiography. However, radial systolic function has been less investigated in this population. Indeed, only few studies assessed radial function with controversial results. The majority of these studies suggest that radial function was increased or preserved to compensate longitudinal function alteration. Of note, these studies compared diabetic patients with healthy but overweight subjects, which might have introduced biases to the interpretation of the LV function abnormalities because obesity by itself affects both systolic and diastolic function. In regard to the underlying pathogenesis of diabetic cardiomyopathy, we rather hypothesized a parallel decrease of radial and longitudinal systolic function than a selective decrease in longitudinal function compensated by an increase in radial function.
To test this hypothesis, we evaluated myocardial function by speckle-tracking imaging (STI), which enables the assessment of myocardial deformation or strain during the cardiac cycle by automatic tracking of myocardial segments. Indeed, as opposed to TDI, strain measurement using STI is independent of the insonation angle, therefore allowing complete evaluation of all myocardial segments.
Therefore, we specifically compared radial and longitudinal LV systolic function assessed by STI in a population of asymptomatic and uncomplicated patients with type II DM with an age-matched group of controls without any cardiovascular risk factor susceptible to influence myocardial function. In addition, to avoid the potential influence of gender and weight, two subgroups of patients and controls were paired regarding age, gender, and body mass index (BMI) for comparison.
Materials and Methods
Population and Study Protocol
We prospectively enrolled 114 consecutive patients with type 2 DM, referred to the outpatient clinic department of Louis Pradel Hospital (Lyon, France) between February 2006 and March 2008, and 88 age-matched healthy controls, previously enrolled in the Asklepios cohort between October 2002 and October 2004.
The study inclusion criteria of patients with type 2 DM were as follows: age between 35 and 60 years; oral antidiabetic or insulin treatment; no symptoms, sign, or history of heart disease; LV ejection fraction (LVEF) > 55% assessed by the modified Simpson’s biplane method and absence of regional LV wall motion abnormalities; and no myocardial ischemia as assessed by a normal exercise stress test or stress echocardiography within the month before inclusion. Exclusion criteria were absence of sinus rhythm, history of cardiomyopathy or coronary artery disease, valvular heart disease, severe renal failure defined as creatinine clearance < 30 mL/min, echocardiographic images unsuitable for quantification, type 1 DM, severely uncontrolled DM defined as glycated hemoglobin >12% or glycemia > 3 g/L, and uncontrolled blood pressure at rest.
Controls were eligible if they conformed to following criteria: age ≥ 40 years, never smokers, systolic blood pressure < 140 mm Hg, diastolic blood pressure < 85 mm Hg, no drug treatments for hypertension, nondiabetic and normal fasting glycemia (glycemia < 110 mg/dL), triglycerides < 150 mg/dL, total cholesterol < 230 mg/dL, low-density lipoprotein cholesterol < 160 mg/dL, high-density lipoprotein cholesterol > 38.5 mg/dL, and serum creatinine < 1.25 mg/dL.
Then, among these two populations, we selected two subgroups of 42 patients with DM and controls to obtain strictly paired data on the basis of the following variables: age, gender, and BMI.
The study protocol was approved by the local ethics committee of Louis Pradel Hospital, Lyon, and University of Ghent, and all subjects gave written informed consent.
Blood samples were taken for biochemical analysis of renal function, electrolytes, triglycerides, total, and high-density lipoprotein cholesterol. In patients with type 2 DM, glycated hemoglobin and microalbuminuria were also measured.
All subjects were fasting, had refrained from smoking for 6 hours, and were screened for active infection/inflammation. Serum parameters were measured using commercial reagents according to the manufacturers’ recommendations on a Modular P automated system (Roche Diagnostics, Mannheim, Germany).
Resting transthoracic echocardiography was performed in patients with DM and controls, using a similar commercially available ultrasound system (Vivid 7, GE Medical Systems, Oslo, Norway). All echographic acquisitions were digitally stored in raw data format from at least three consecutive heart beats for off-line analysis (EchoPAC, GE-Vingmed, Horten, Norway), which was performed in Louis Pradel Hospital (LE, CB).
LV end-diastolic and end-systolic diameters, wall thicknesses, and LV fractional shortening (FS) were measured from the M-mode images of the parasternal long-axis view according to the recommended criteria. LV mass was determined by Devereux’s formula and indexed to body surface area. Midwall fractional shortening (FSm) was measured as previously described. LV volumes and LVEF were calculated from the apical views using the modified Simpson’s biplane method. Left atrium area was measured in apical four-chamber view by planimetry.
LV end-diastolic sphericity index was assessed on apical four-chamber view and calculated as the ratio of the minor axis to the major axis length of the LV.
By using pulsed-wave Doppler, stroke volume was determined. For diastolic function, mitral inflow velocities, peak early diastolic velocity (E), peak late diastolic velocity (A), E/A ratio, E-wave deceleration time (mDT), and isovolumic relaxation time (IVRT) were measured. Annular early diastolic velocity (é) was assessed at the septal site of the mitral annulus using pulsed-wave TDI to calculate E/é ratio.
STI analysis was performed using a dedicated software package (EchoPAC, GE-Vingmed) from apical and parasternal short-axis views as previously described. Peak systolic radial strain was measured on short-axis view at the papillary muscles level, and longitudinal systolic strain was measured on apical four-chamber view (frame rate: 76 fps). From an end-systolic frame, the endocardial border was manually traced. Then, the epicardial border was automatically detected by the software and the region of interest was manually adjusted to include the entire myocardial wall. Thus, the software tracked the contour throughout the entire cardiac cycle frame by frame. The quality of tracking was verified and the region of interest was modified and corrected by the observer if judged necessary to obtain optimal tracking. The software automatically divided the LV walls into six segments and calculated strain values.
From the short-axis view, radial strain was assessed from the six mid-segments of the anteroseptal, anterior, anterolateral, inferolateral, inferior, and inferoseptal walls. From the apical four-chamber view, longitudinal strain was assessed from the basal, mid, and apical segments of the inferoseptal and anterolateral walls. Then, the average of radial and longitudinal segmental strain values was calculated for each patient and presented as ϵ R and ϵ L , respectively.
To define reproducibility, 18 patients with DM (corresponding to 108 segments for the longitudinal strain measurement and 108 segments for the radial strain measurement) were randomly selected. In these patients, STI analysis was repeated 3 months apart by the same observer and was performed by a second blinded observer. Intraobserver and interobserver variability were calculated as the absolute difference divided by the average of the two measurements for each parameter.
Statistical analysis was performed using SPSS 15.0.1 (SPSS Inc, Chicago, IL). Normally distributed data were expressed as mean ± standard deviation, data deviating from normality were expressed as median (interquartile range), and categoric variables were expressed as percentages. Baseline data in the two groups were compared by means of the unpaired t test for continuous variables and the chi-square test for categoric variables. Data in the two subgroups, age, gender, and BMI-paired controls, were compared by means of the paired t test. Multivariate analyses were performed with continuous variables whenever possible, using stepwise linear regression ( P in = .05; P out = .10). Confounders were prespecified on the basis of biological plausibility and prior published data, and identified using univariate regression analysis. Independent parameters contributing to the difference in ϵ R and ϵ L between the two groups were identified through univariate analysis using the Student t test followed with a multivariate regression analysis. Variables with a P value < .05 on univariate analysis were included in multivariate analysis. A P value < .05 was adopted to consider the significant association between variables and the difference in ϵ R and ϵ L observed between the two groups.
Table 1 summarizes the clinical and biological characteristics of the age-matched diabetic and control populations. As a result of the selection of a low-risk control population, BMI was lower in the control group compared with the DM group. Mean duration of DM was 11 ± 7 years. In the DM group, 21% (24/114) were smokers, 38% (43/114) were treated for systemic hypertension, and 25% (28/114) were treated for hypercholesterolemia. Antidiabetic treatment consisted of metformin in 74% (84/114), sulfonylureas in 47% (54/114), and glitazones in 22% (25/114); insulin was combined in 42% (48/114). In addition, the other medical treatments included statins in 46%, angiotensin-converting enzyme inhibitors in 26%, angiotensin II antagonists in 23%, calcium-blockers in 18%, and beta-blockers in 4%. Mean systolic and diastolic blood pressure, and heart rate were well within the normal range in both groups, although it was slightly higher in patients with type 2 DM than in controls. In addition, patients with DM had higher glycemia and triglyceride plasma levels compared with controls.
|DM group |
(n = 114)
(n = 88)
|Age (y)||52.0 ± 4.5||51.7 ± 2.6||.59|
|BMI (kg/m 2 )||29 ± 5||24 ± 3||.0001|
|sBP (mm Hg)||128 ± 14||120 ± 9||.0001|
|dBP (mm Hg)||77 ± 10||74 ± 6||.02|
|HR (bpm)||75 ± 12||63 ± 8||.001|
|Glycemia (mmol/L)||8.6 ± 3.0||4.9 ± 0.4||.0001|
|Glycated hemoglobin (%)||7.7 ± 1.4||NA|
|Total cholesterol (mmol/L)||4.72 ± 1.1||5.11± 0.54||.001|
|Triglycerides (mmol/L)||1.60 ±1.10||0.81 ± 0.26||.0001|
|High-density lipoprotein cholesterol (mmol/L)||1.23 ± 0.40||1.74 ± 0.24||.0001|
|Low-density lipoprotein cholesterol (mmol/L)||2.72 ± 0.91||2.97 ± 0.53||.01|
|Microalbuminuria (mg/L)||19.1 (17.4-54.4)||NA|
Table 2 summarizes the standard echocardiographic parameters. LV diameters and LV mass index were similar in the two groups. However, LV sphericity index was slightly higher in the DM group than in controls. Conventional parameters of LV systolic function (LVEF and FS) did not significantly differ between the two groups. However, FSm was significantly lower in patients with DM than in controls. LV relaxation was delayed in patients with DM as evidenced by lower E/A, longer IVRT and mDT, and higher E/é ratio. IVRT was still higher in patients with DM even after adjustment for heart rate and systolic blood pressure. In addition, left atrium area was significantly higher in patients with DM than in controls.
|DM group |
(n = 114)
(n = 88)
|LVEDD (mm)||49 ± 5||48 ± 4||.32|
|LVESD (mm)||29 ± 4||29 ± 4||.39|
|LVEDVi (mL/m 2 )||45 ± 1||43 ± 1||.77|
|LVESVi (mL/m 2 )||15 ± 5||14 ± 5||.13|
|LVM index (g/m 2 )||84 ± 18||80 ± 19||.12|
|LV sphericity index||0.53 ± 0.07||0.51 ± 0.6||.03|
|FS (%)||40 ± 6||41 ± 8||.86|
|FSm (%)||18 ± 3||20 ± 3||.006|
|LVEF (%)||67 ± 6||68 ± 7||.12|
|LA area (cm 2 )||17 ± 3||14 ± 3||<.0001|
|E/A||1.1 ± 0.2||1.2 ± 0.2||<.001|
|mDT (ms)||225 ± 52||180 ± 27||<.0001|
|IVRT (ms)||82.7 ± 11.0||74.2 ± 10.5||<.0001|
|E/é||10.9 ± 3.6||7.7 ± 1.7||<.0001|
|Stroke volume (mL)||79.0 ± 15.7||78.1 ± 15.8||.34|
Radial and Longitudinal Function Assessed by Speckle-Tracking Imaging
STI analysis was feasible in all the patients included in the study. An example of STI analysis is shown in Figure 1 . Intraobserver variability was 5.0% for longitudinal strain and 6.5% for radial strain, whereas interobserver variability was 5.3% for longitudinal strain and 7.0% for radial strain.
Segmental values of radial and longitudinal strain are shown in Table 3 , and systolic function parameters are shown in Figure 2 . Almost all segments showed a significant decrease in both radial and longitudinal strain values in the DM group compared with controls. As a result, both ϵ L (-19% ± 3% vs -22% ± 2%; P < . 001) and ϵ R (50% ± 16% vs 56% ± 12%; P = .003) were significantly lower in the DM group than in controls.
|DM group |
(n = 114)
(n = 88)
|Radial (ϵ R , %)|
|Anteroseptal||44 ± 16||52 ±14||.001|
|Anterior||47 ± 17||54 ± 14||.004|
|Anterolateral||50 ± 18||57 ± 14||.009|
|Inferolateral||54 ± 18||59 ± 15||.069|
|Inferior||54 ± 17||59 ± 17||.64|
|Inferoseptal||49 ± 17||56 ± 16||.009|
|ϵ R (%)||50 ± 16||56 ± 12||.003|
|Longitudinal (ϵ L , %)|
|Base||-16 ± 4||-19 ± 3||<.001|
|Mid||-18 ± 4||-20 ± 3||<.001|
|Apex||-23 ± 5||-24 ± 4||.19|
|Base||-19 ± 5||-22 ± 4||<.001|
|Mid||-18 ± 4||-21 ± 3||<.001|
|Apex||-21 ± 6||-23 ± 4||<.001|
|ϵ L (%)||-19 ± 3||-22 ± 2||<.001|