Subclinical Impairment of Left Ventricular Function assessed by Speckle Tracking in Type 2 Diabetic Obese and Non-Obese Patients: Case Control Study.

Objectives: Type 2 diabetes mellitus (DM) and obesity are an independent risk factor for cardiovascular diseases, so early prediction of LV dysfunction carries better prognosis. So our aim was to assess the subclinical LV dysfunction in type 2 diabetic obese and non-obese patients using two-dimensional speckle tracking echocardiography (2DSTE). Materials and
Methods: We studied 93 patients, including two groups of 31 each with type 2 diabetes mellitus (T2DM), divided by body mass index (BMI), and 31 non-diabetic non-obese controls. All these subjects underwent two-dimensional Echo (2DE) imaging with analysis of conventional parameters of systolic and diastolic function, as well as speckle tracking echocardiography s (STE) analysis of LV global and regional longitudinal strain.
Results: We reported significant inter-group differences in parameters of diastolic function, but no significant differences in ejection fraction or fractional shortening. Nevertheless, we found significant differences in strain, which we interpreted as evidence of subclinical systolic dysfunction.
Conclusion: 2DSTE is better than basic echocardiographic measurements in assessment of subclinical LV dysfunction in type 2 diabetic obese and non-obese patients which can be used to predict cardiomyopathic changes in the earlier course of type 2 DM and start earlier treatment with better prognosis. Copyright:

INTRODUCTION

Type 2 diabetes and obesity are an independent risk factor for cardiovascular diseases, so early prediction of LV dysfunction carries better prognosis. Type 2 diabetes is identified as a risk factor for cardiovascular events.[1]

Cardiovascular complications are the leading causes of morbidity and mortality in the type 2 DM population. Type 2 DM can lead to disharmony in cardiac structures and functions with absence of coronary artery disease and without affecting blood pressure, which is known as diabetic cardiomyopathy.[2]

Although hyperglycemia is a primary key player in the pathogenesis, a number of other mechanisms were reported to play a role in etiology, such as changes in free acid metabolism, increased apoptosis, activation of the renin-angiotensin system, autonomic neuropathy, stem cell defect, and increased oxidative stress among others. All these underlying pathogenesis conditions change the cardiac structure and may lead to cardiac fibrosis.[3]

Cardiomyopathic changes in the earlier course of type 2 DM are known as a state of preserved LV ejection fraction (HFpEF) with abnormalities in diastolic functions. It is known that HFpEF is not an objective tool in the evaluation of systolic functions. Therefore, subclinical LV systolic dysfunction may not be recognized at that stage. Conventional echocardiographic parameters are not able to demonstrate subclinical LV dysfunction.[4]

Tissue Doppler imaging and Doppler speckle tracking-based strain imaging were more sensitive in measuring LV functions than EF. Two-dimensional (2D) strain imaging is used for the quantitative assessment of global and segmental LV function from 2D images.[5]

Speckle tracking echocardiography (STE) is the procedure of choice, compared with tissue Doppler imaging because it eliminates angle dependency and the need of high frame rates. Moreover, when compared with magnetic resonance imaging as a bedside tool, it is a cheap and readily available procedure.[6]

So, this study aimed to assess the subclinical LV dysfunction in type 2 diabetic obese and non-obese patients using two-dimensional speckle tracking echocardiography (2DSTE).

MATERIALS AND METHODS

The present case–control (non-experimental) study was conducted from December 2018 to June 2020 at our Hospital's Cardiology department. The protocol was approved by the University Institutional Review Board, which confirmed that all methods were performed in accordance with the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research. Informed written consent was obtained from all participants.

The study group comprised 93 consecutive patients divided into three groups according to body mass index (BMI) based on the Guidelines of the World Health Organization, which stated that overall obesity is defined as a BMI of ≥25 kg/m2) as follows:

Group I: This group included 31 patients had a known history of type 2 diabetes mellitus with obesity (BMI ≥ 25kg/m2).

Group II: This group included 31 patients had a known history of type 2 diabetes mellitus without obesity (BMI < 25 kg/m2).

Group III (Control): This group included 31 age- and sex-matched healthy individuals with BMIs of 18.5–24.5 kg/m2, showing an absence of diabetes, hypertension, and coronary heart disease and in whom there is no evidence of preexisting cardiac disease on conventional electrocardiography, transthoracic echocardiography, and laboratory examinations.

Eligibility criteria

Inclusion criteria

All individuals with type 2 diabetes mellitus with or without obesity and agreed to participate in the study.

Exclusion criteria

Patients with established CAD and apparent LV wall motion abnormalities, patients with LV systolic dysfunction (EF <50%), patients with cardiac rhythm or conduction disturbances such as atrial fibrillation or artificial pacing or bundle branch block, patients with concomitant moderate or severe mitral regurgitation, aortic stenosis and aortic regurgitation, patients with poor acoustic windows, hypertensive patients and age >40 years old.

Study methodology

The subjects who fulfilled the inclusion criteria had been enrolled in this case–control study and subjected to: careful history taking, thorough clinical examination, standard 12 lead electrocardiogram, basic echocardiographic measurements, measurement of the 2D strain by speckle tracking.

Standard 12-lead electrocardiogram

For assessment of cardiac rhythm and features suggesting chamber enlargement and coronary artery disease (CAD).

Basic echocardiographic measurements

Echocardiography was performed using the commercially available system (Vivid E9, General Electric, 2013) ultrasonography machine with an M4S transducer. Patients were monitored through a single-lead electrocardiogram. The left atrial diameter, left atrial volume [Figure 1], left ventricular end-systolic and end-diastolic diameters, the relative wall thickness, left ventricular mass index, left ventricular fractional shortening percentage, the thickness of the interventricular septum, and the posterior wall (PW) were measured according to the recommendations of the 2016 American Society of Echocardiography (ASE) guidelines. The LV ejection fraction (LVEF) was calculated by Simpson's biplane method of disks and M mode at the tips of mitral valve leaflets in parasternal long-axis view [Figure 2].

Figure 1

LA volume in 2 and 4 chamber views: LA volume index: (41.60 ml/m2). LA = Left atrial

Figure 2

EF Simpson's Method: EF (61%), LVESV: (35ml) and LVEDV: (89 ml). EF = Ejection fraction, LVEDV = Left ventricular diastolic volume, LVESV = Left ventricular systolic volume

The transmitral flow velocity was obtained from apical 4C view with the pulsed-wave Doppler method. After measuring the peak early (E) and late (A) diastolic velocities and deceleration time (DT), the ratio of early to late diastolic mitral inflow velocities (E/A) was calculated [Figure 3]. Mitral annulus velocities were obtained using pulsed tissue Doppler imaging from the apical 4C view [Figure 4], by placing the sample volume at the junction of the LV wall with the septal mitral annulus. The ratio of early diastolic mitral inflow velocity to early diastolic annular velocity (E/e') was calculated.

Figure 3

Pulsed wave Doppler on mitral valve: Peak early mitral inflow velocity (e): (52 cm/s), peak late mitral inflow velocity: (55 cm/s), E/A ratio:(0.95), deceleration time (274 ms) and average E/E′(6.57)

Figure 4

(Rt. Panel) TDI on septal mitral annulus: septal E× (6.7 cm/s) and (Lt. Panel) TDI on lateral mitral annulus: lateral E′(9.1 cm/s)

Diastolic dysfunction was defined and graded according to the 2016 ASE Guidelines of E/A ratio, E/e', TR velocity and left atrial volume as follows:

Stage 1: Abnormal filling pattern is the delayed relaxation that results in a reversed E/A ratio (E/A <1), being the earliest stage of heart disease.

Stage 2: Abnormalities in both relaxation and compliance and is known as pseudo normalization because of an apparently normal E/A ratio (E/A >1).

Stage 3: Restrictive filling pattern found in patients with severely compromised LV compliance and elevated ventricular filling pressures, reflecting an advanced stage of the disease.

Measurement of the two-dimensional strain by speckle tracking

2D echocardiography images (transmit/receive 1.9/4.0 MHz) were obtained from LV apical 3C, 4C, and 2C views with frame rates of 50–90 frames/s. Digital data were stored and analyzed offline. LV endocardial surface was traced manually, and the speckle tracking width was modified to cover the whole LV wall thickness to obtain curves Figure 5.

Figure 5

LV strain by speckle tracking in 3 chamber view anterior septum peak longitudinal strain (basal [−15%], mid [−18%] and apical [−24%]), inferolateral wall peak longitudinal strain (basal [−16%], mid [−18%] and apical [−23%]). (i) Average peak longitudinal strain of anterior septum: (−19%). (ii) Average peak longitudinal strain of inferolateral wall: (−19%). LV = Left ventricle

Speckle tracking analysis begins by manually tracing the endocardial border at the end-systolic frame in counterclockwise direction starting from the right-hand mitral annulus in each 3 apical views by a point; thereafter, the machine displays the epicardial line 10 mm outside the created endocardial outline that manually adjusted and rechecked approximately to the epicardium. The software then automatically divides the LV into six equidistant segments (apical, mid, and basal) and accepts segments of good tracking quality and rejects poorly tracked segments, allowing the observer to manually override his decisions.

According to visual assessments of the tracking quality, peak systolic strain was calculated for each of the 17 segments. The global longitudinal strain (GLS) was calculated from the average of 17 LV segments values Figure 6. Because GLS normally varies with age, sex, and LV loading conditions, defining abnormal GLS is not straightforward. However, in adults, GLS <-16% (sic) is abnormal, GLS > -18% (sic) is normal, and GLS -16% to -18% is borderline.

Figure 6

Speckle tracking bull's eye: Global longitudinal strain equals − 17.6

Statistical analysis

Data analysis was performed using the software SPSS software statistical package for social science version 22 (SPSS, Inc. Chicago, IL, USA). Quantitative variables were described using their means and standard deviations. Categorical variables were described using their absolute frequencies and were compared using Chi-square test. Kolmogorov–Smirnov (distribution-type) and Levene (homogeneity of variances) tests were used to verify assumptions for use in parametric tests. To compare the means of more than two groups, one-way ANOVA test was used and when P-< 0.05, least significant difference (LSD) comparison was recruited to compare mean of certain group with another and was adjusted for multiple comparisons. The Kruskal–Wallis test was used to compare continuous quantitative data of more than two groups when data are not normally distributed. The level of statistical significance was set at 5% (P < 0.05). The highly significant difference was present if P ≤ 0.001.

RESULTS

Demographic data and clinical characteristics

There were no statistically significant difference between the studied groups regarding age (P = 0.142), sex (P = 0.157), mean heart rate (P = 0.173), mean systolic blood pressure (P = 0.057), and mean diastolic blood pressure (P = 0.056) [Table 1].

Table 1

Comparison between the studied groups regarding demographic data and clinical characteristics

Parameter	Groups (n=31)			Test
	DM obese (Group I)	DM nonobese (Group II)	Healthy control (Group III)	χ 2	P
Age
Mean±SD	32.94±5.56	28.74±9.35	30.32±9.53	1.995	0.142
Range	20-40	16-40	12-40
Gender
Female	14 (45.2)	13 (41.9)	20 (64.5)	3.699	0.157
Male	17 (54.8)	18 (58.1)	11 (35.5)
HR (b/m)
Mean±SD	74.39±9.39	79.81±8.77	78.77±16.29	1.79	0.173
Range	53–102	70–106	57–115
SBP (mmHg)
Mean±SD	128.87±6.42	129.52±3.95	125.97±7.46	2.954	0.057
Range	110-135	120-135	110-135
DBP (mmHg)
Mean±SD	76.13±6.42	75.97±4.73	72.9±6.3	2.978	0.056
Range	60-90	70-80	60-85

P<0.05 is statistically significant, χ2=Chi-square test, DM=Diabetes mellitus, HR=Heart rate, SBP=Systolic blood pressure, DBP=Diastolic blood pressure, SD=Standard deviation

Conventional echocardiography measurements

Left ventricular wall thickness

There was a statistically significant difference between the studied groups as regards mean inter-ventricular septum thickness. On LSD comparison, the control group (Group III) had the lowest thickness as compared to Group I and Group II (P = 0.004) Table 2.

Table 2

Comparison between the studied groups regarding left ventricular wall thickness measured by echocardiography

Parameter	Groups (n=31)			Test		LSD
	DM obese (Group I)	DM nonobese (Group II)	Healthy control (Group III)	F	P
IVS thickness (mm)
Mean±SD	9.06±1.46	8.81±1.99	7.58±1.91	6	0.004*	P1=0.574 P2=0.009* P3=0.002*
Range	6-13	6-12	1-11
PWT (mm)
Mean±SD	8.48±1.5	6.77±1.18	7.52±1.39	12.286	<0.001**	P1=<0.001** P2=0.035* P3=0.006*
Range	6-12	6-9	6-11
RWT (mm)
Mean±SD	0.339±0.06	0.287±0.029	0.31±0.05	8.972	<0.001**	P1=<0.001** P2=0.065 P3=0.021*
Range	0.22-0.46	0.24-0.32	0.23-0.49
LVMI (g/m2)
Mean±SD	86.95±28.26	75.22±18.3	70.12±15.54	5.039	0.008*	P1=0.003* P2=0.351 P3=0.034*
Range	47.04-119.95	42.36-119.39	46-118.02

*P<0.05 is statistically significant, **P≤0.001 is statistically highly significant. F=One-way ANOVA. P1=The difference between DM obese and DM nonobese groups, P2=The difference between DM nonobese and control groups, P3=The difference between DM obese and control group. DM=Diabetes mellitus, SD=Standard deviation, LSD=Least significant difference, IVS=Inter-ventricular septum thickness, PWT=Posterior wall thickness, RWT=Relative wall thickness, LVMI=Left ventricular mass index

There was highly significant statistical difference between the studied groups as regard mean left ventricular posterior thickness. On LSD comparison, the type 2 DM obese group (group I) had the highest thickness as compared to group II and group III (P < 0.001).

There was a highly statistically significant difference between the studied groups as regards the mean relative wall thickness. On LSD comparison, Group I had the highest thickness as compared to Group II and Group III (P < 0.001).

There was highly significant statistical difference between the studied groups as regard mean left ventricular mass index where type 2 diabetic obese group (Group I) had the highest value (P = 0.008).

Left ventricular and left atrial dimensions

There were no statistically significant differences between the studied groups regarding mean left ventricular end-diastolic diameter (P = 0.303), and mean left ventricular end-systolic diameter (P = 0.627) [Table 3].

Table 3

Comparison between the studied groups regarding left ventricular and left atrial dimensions measured by echocardiography

Parameter	Groups (n=31)			Test		LSD
	DM obese (Group I)	DM nonobese (Group II)	Healthy control (Group III)	F	P
LVEDD
Mean±SD	49.13±4.02	49.55±6.86	47.48±5.31	1.211	0.303
Range	41-59	41-62	38-60
LVESD
Mean±SD	31.87±4.15	30.94±5.96	30.81±3.75	0.47	0.627
Range	21-39	25-41	22-39
LAD
Mean±SD	42.45±8.23	36.87±6.6	35.19±5.21	9.703	<0.001**	P1=0.002* P2=0.334 P3=<0.001**
Range	27-54	28-48	25-45

*P<0.05 is statistically significant, **P≤0.001 is statistically highly significant. F=One-way ANOVA. P1=The difference between DM obese and DM nonobese groups, P2=The difference between DM nonobese and control groups, P3=The difference between DM obese and control group. DM=Diabetes mellitus, SD=Standard deviation, LSD=Least significant difference, LVEDD=Left ventricular diastolic diameter, LVESD=Left ventricular systolic diameter, LAD=Left atrial dimension

There was highly significant statistical difference between the studied groups regarding mean left atrial diameter. The type 2 diabetic obese group (Group I) had the highest value (P <0.001).

Left ventricular and left atrial volumes

There were no statistically significant differences between the studied groups regarding mean left ventricular end-diastolic volume (P = 0.588), and mean left ventricular end-systolic volume (P = 0.347) Table 4.

Table 4

Comparison between the studied groups regarding left ventricular and left atrial volumes measured by echocardiography

Parameter	Groups (n=31)			Test		LSD
	DM obese (Group I)	DM nonobese (Group II)	Healthy control (Group III)	F/KW	P
LVEDV (ml)
Mean±SD	90.03±16.42	83.29±30.64	86.9±27.92	0.534	0.588	-
Range	61-117	54-143	40-167
LVESV (ml)
Mean±SD	34.77±8.75	31.13±12.82	31.4±10.75	1.07	0.347	-
Range	16-55	16-55	15-58
LAV (ml)
Mean±SD	53.19±11.22	49.45±16.88	48.19±25.41	6.27	0.043*	P1=0.225 P2=0.175 P3=0.014*
Range	33-82	24-78	19-154

*P<0.05 is statistically significant, F=One-way ANOVA. P1=The difference between DM obese and DM nonobese groups, P2=The difference between DM nonobese and control groups, P3=The difference between DM obese and control group. DM=Diabetes mellitus, SD=Standard deviation, LSD=Least significant difference, LVEDV=Left ventricular diastolic volume, LVESV=Left ventricular systolic volume, LAV=Left atrial volume

There was a statistically significant difference between the studied groups regarding mean left atrial volume. On LSD comparison, the difference is only significant between diabetic obese and control groups (P = 0.043).

Left ventricular ejection fraction and fractional of shortening

There were no statistically significant differences between the studied groups regarding mean left ventricular EF by Teicholz method (P = 0.068), mean left ventricular EF by Biplane method (P = 0.722), and mean left ventricular fraction of shortening (P = 0.32) Table 5.

Table 5

Comparison between the studied groups regarding ejection fraction and fraction of shortening by echocardiography

Parameter	Groups (n=31)			Test
	DM obese (Group I)	DM nonobese (Group II)	Healthy control (Group III)	F	P
EF (Teicholz) (%)
Mean±SD	61.71±6.4	62.87±2.54	64.97±6.55	2.772	0.068
Range	52-80	60-70	61-76
EF (biplane) (%)
Mean±SD	62.26±3.66	62.32±3.72	64.97±4.36	0.327	0.722
Range	54-70	53-70	54-70
FS (%)
Mean±SD	35.1±5.58	36.35±5.22	37.1±4.64	1.165	0.32
Range	26-48	30-46	29-46

F=One-way ANOVA. DM=Diabetes mellitus, SD=Standard deviation, EF=Ejection fraction, FS=Fraction of shortening

Left ventricular diastolic function indices

There was highly statistically significant difference between the studied groups regarding mean peak early mitral inflow velocity. On LSD comparison, Group I had the lowest value as compared to Group II and Group III (P < 0.001) Table 6.

Table 6

Comparison between the studied groups regarding diastolic function indices

Parameter	Groups (n=31)			Test		LSD
	DM obese (Group I)	DM nonobese (Group II)	Healthy control (Group III)	F	P
Peak early mitral inflow velocity E
Mean±SD	69±18.27	81.48±9.75	86.1±17.37	9.962	<0.001**	P1=0.002* P2=0.248 P3=<0.001**
Range	46-122	71-96	58-128
Peak late mitral inflow velocity A
Mean±SD	68.35±19.75	77.81±16.12	67.39±24.03	2.512	0.087
Range	36-125	50-92	28-126
Deceleration time
Mean±SD	247.23±51.68	229.52±39.13	179.65±20.62	24.682	0.002*	P1=0.079 P2=<0.001** P3=<0.001**
Range	150-397	150-322	150-200
E/A ratio
Mean±SD	1.062±0.41	1.089±0.343	1.406±0.495	6.422	0.002*	P1=0.8 P2=0.004* P3=0.002*
Range	0.5-2.43	0.71-1.7	0.7-2.63
Peak mitral annual velocity Eˋ
Mean±SD	10.19±3.37	12.61±4.13	14.57±3.5	10.991	<0.001**	P1=0.011* P2=<0.001** P3=0.0239*
Range	4-19	7-19	8-21
E/Eˋ
Mean±SD	7.14±2.66	7.035±2.02	6.325±1.967	1.893	0.157
Range	3.87-16.17	4.7-10.5	3.7-11.8

*P<0.05 is significantly significant, **P≤0.001 is statistically highly significant. F=One-way ANOVA. P1=The difference between DM obese and DM nonobese groups, P2=The difference between DM nonobese and control groups, P3=The difference between DM obese and control group. DM=Diabetes mellitus, SD=Standard deviation, LSD=Least significant difference

There was no statistically significant difference between the studied groups regarding mean peak late mitral inflow velocity (P = 0.087).

There was a statistically significant difference between the studied groups regarding mean DT. On LSD comparison, Group III had the lowest value as compared with Group I and Group II (P = 0.002).

There was a statistically significant difference between the studied groups regarding the mean E/A ratio. On LSD comparison, (Group III) had the highest value as compared to Group I and Group II (P = 0.002).

There was a highly statistically significant difference between the studied groups regarding mean mitral annular velocity. On LSD comparison, the difference is significant between every two individual groups, where Group I had the lowest velocity, while Group III had the highest velocity (P < 0.001).

Speckle tracking measurements

Peak longitudinal strain of each segment of the left ventricle

There was statistically significant difference between the studied groups regarding the mean peak longitudinal stain of the inferior septum. On LSD comparison, the difference is significant only between Group I and Group III (P = 0.003) [Figures 5, 6 and Table 7].

Table 7

Comparison between the studied groups regarding peak longitudinal strain of each segment measured by speckle tracking

PLS	Groups (n=31)			Test		LSD
	DM obese (Group I)	DM nonobese (Group II)	Healthy control (Group III)	F	P
Inferior septum
Mean±SD	−18.62±3.306	−19.73±2.419	−21.032±2.753	6.045	0.003*	P1=0.098 P2=0.074 P3=0.001**
Range	−24.6-−11	−24.6-−17	−31-−18
Lateral wall
Mean±SD	−19.26±5.517	−20.41±4.866	−21.5±3.671	1.734	0.182
Range	−32-−7	−27.3-−14	−29.6-−13.3
Inferior wall
Mean±SD	−19.59±4.692	−18.94±1.76	−22.45±3.127	9.133	<0.001**	P1=0.456 P2=<0.001** P3=0.001**
Range	−28-−11.6	−22-−16	−30-−16
Anterior wall
Mean±SD	−17.09±4.418	−20.26±3.01	−21.25±3.662	10.421	<0.001**	P1=<0.001** P2=0.305 P3=0.001**
Range	−25.3-−4.6	−24.6-−17	−30-−14
Inferolateral wall
Mean±SD	−17.019±4.418	−15.48±3.796	−19.813±3.314	8.829	<0.001**	P1=0.145 P2=<0.001** P3=0.009*
Range	−25.3-−4.6	−24.6-−17	−30-−14
Anterior septum
Mean±SD	−16.01±4.661	−17.52±2.58	−18.57±3.926	3.527	0.034*	P1=0.124 P2=0.279 P3=0.01*
Range	−22-−6.5	−22.5-−13.5	−26.3-−10.5

*P<0.05 is significantly significant, **P≤0.001 is statistically highly significant. F=One-way ANOVA. P1=The difference between DM obese and DM nonobese groups, P2=The difference between DM nonobese and control groups, P3=The difference between DM obese and control group. DM=Diabetes mellitus, SD=Standard deviation, LSD=Least significant difference, PLS=Peak longitudinal strain

There was no statistically significant difference between the studied groups regarding the mean peak longitudinal strain of the lateral wall (P = 0.182).

There was highly significant statistical difference between the studied groups regarding mean peak longitudinal strain of anterior wall. On LSD comparison, type 2 diabetic obese group had the least value (P< 0.001).

There was a highly statistically significant difference between the studied groups regarding the mean peak longitudinal strain (LS) of the anterior wall. On LSD comparison, the diabetic obese group had the least value (P < 0.001).

There was a highly statistically significant difference between the studied groups regarding the mean peak LS of the inferolateral wall. On LSD comparison, Group III had the highest value as compared to Group II and Group I (P < 0.001).

There was a statistically significant difference between the studied groups regarding the mean peak LS of the anterior septum. On LSD comparison, the difference is significant only between Group I and Group III (P = 0.034).

Global longitudinal strain of left ventricle

The mean GLS of LV was 18.04 ± 3.526% in Group I (ranging from − 25.2 – [−10.8]), while it was −19.49% ± 2.38% in Group II (ranging from − 23.1 – [−16.4]) and was − 21.27% ± 2.5% in Group III (ranging from − 26.4 – [−16.4]), with statistically significant difference between the studied groups. On LSD comparison, Group III had the highest value as compared to Group I and Group II (P = 0.001) Table 8.

Table 8

Comparison between the studied groups regarding global longitudinal strain findings measured by speckle tracking

GLS	Groups (n=31)			Test		LSD
	DM obese (Group I)	DM nonobese (Group II)	Healthy control (Group III)	F	P
GLS
Mean±SD	−18.04±3.526	−19.49±2.38	−21.27±2.5	7.988	0.001**	P1=0.138 P2=0.016* P3=0.001**
Range	−25.2-−10.8	−23.1-−16.4	−26.4-−16.4

*P<0.05 is significantly significant, **P≤0.001 is statistically highly significant. F=One-way ANOVA. P1=The difference between DM obese and DM nonobese groups, P2=The difference between DM nonobese and control groups, P3=The difference between DM obese and control group. DM=Diabetes mellitus, SD=Standard deviation, LSD=Least significant difference, GLS=Global longitudinal strain

DISCUSSION

Type 2 diabetes is identified as a risk factor for cardiovascular events. Obesity is one of the most important concerns of the 21st century, and it is considered to be a major public health issue worldwide.[1]

Developments in echocardiographic speckle tracking allow the quantification of myocardial deformation in longitudinal, radial, and circumferential dimensions which are based on frame-by-frame tracking of echo-dense speckles within the myocardium and subsequent measurement of LV deformation.[7]

Patients with early diabetic cardiomyopathy often have evidence of global diastolic dysfunction but preserved systolic function, as reflected by a normal LVEF. Compared with LVEF, myocardial velocity and strain analysis are more sensitive indexes of LV function and have been demonstrated to be abnormal in patients with type 2 diabetes mellitus (DM). In patients with evidence of early systolic impairment, a prompt aggressive treatment of both conditions should be recommended to allow a real prognostic benefit.[8]

We found no statistically significant differences between the studied groups regarding age and gender. These findings came in agreement with Wang et al.[9] This could be due to all we had age and gender matched groups and patients more than 40 years old were excluded from our study.

There was no statistically significant difference between the studied groups regarding heart rate. These findings came in agreement with Wang et al.[9] that showed no statistical difference among the three groups regarding heart rate this could be due to all patients with cardiac rhythm or conduction disturbances were excluded from our study.

There were no statistically significant differences between the studied groups regarding systolic blood pressure and diastolic blood pressure. These findings came in agreement with Conte et al.[10] But, it was different from Wang et al.[9] who found that diastolic blood pressure was significantly higher in type 2 diabetics with overall obesity compared with the other two groups, this may due to elevated vascular resistance caused by excess adipose tissue and higher artery stiffness in type 2 diabetic obese group that increases diastolic blood pressure. This could be due to all hypertensive patients were excluded from our study.

Conventional echocardiography revealed that there were statistically significant differences between the studied groups regarding left ventricular wall thickness including interventricular septum thickness and posterior wall thickness (PW), the type 2 DM obese group (Group I) had the highest thickness as compared to type 2 diabetic non obese (Group II) and the healthy control group (Group III). These findings came in agreement with Wang et al.[9] who found that type 2 diabetic subjects with overall obesity had significantly thicker LV walls. This could be due to accumulation of lipid in or around myocytes in type 2 diabetic obese patients as well as increased afterload due to elevated vascular resistance caused by excess adipose tissue and higher artery stiffness that acts as a pressure overload against the heart leading to increased LV wall thickness.

There were statistically significant difference between the studied groups regarding left ventricular mass index, where type 2 diabetic obese group (group I) had the highest value as compared to group II and group III. These findings came in agreement with Conte et al.[10] This could be due to increased wall thickness in type 2 diabetic obese patients and the expanded intravascular volume present in obesity that may cause LV eccentric hypertrophy.

There was no statistically significant difference between the studied groups regarding left ventricular end-diastolic diameter (LVEDD). This could be due to the balance between increased wall thickness and LV mass in type 2 diabetic obese patients and the expanded intravascular volume present in obesity, so there is no significant difference between the studied groups regarding left ventricular end-diastolic diameter.

These findings were different from Conte et al.[10] who found that LVEDD was significantly lower in type 2 diabetic obese group (Group B) versus type 2 diabetic non obese (Group A). This could be due to overall-obesity diabetic patients with higher blood volume and a more active adipose metabolism required more oxygen, and they had to rely mainly on increasing stroke volume to meet these needs, leading to LV overload and LV dilatation.

There were statistically significant difference between the studied groups regarding left atrial diameter, where type 2 diabetic obese group (group I) had the highest value as compared to group II and group III. These findings came in agreement with Wang et al.[9] who found that type 2 diabetic subjects with overall obesity had significantly larger left atrium. This could be due to increased wall thickness and LV mass in type 2 diabetic obese patient that may lead to diastolic dysfunction and left atrial dilatation.

There were statistically significant difference between the studied groups regarding left atrial volume, where type 2 diabetic obese group (Group I) had the highest value as compared to Group II and Group III. These findings came in agreement with Conte et al.[10] This could be due to increased LV wall thickness and LV mass in type 2 diabetic obese patient that may lead to diastolic dysfunction, left atrial dilatation and increased left atrial volume.

The type 2 diabetic obese (Group I) had lower mitral annular velocity E′ values compared to Group II and Group III with statistical significance between Group I that had the lowest velocity and Group III that had the highest velocity. These findings came in agreement with Wang et al.[9] who found that type 2 diabetic subjects with overall obesity had significantly impaired E' velocity compared with controls. This could be due to increased wall thickness and LV mass in type 2 diabetic obese patient that interfere with myocardial relaxation during diastole and reduced mitral annular velocity E'.

The type 2 diabetic obese (Group I) had higher E/e' values compared to Group II and Group III but without statistical significance. These findings came in agreement with Wang et al.[9] and Di Bello et al.[11] This could be due to increased LV mass in type 2 diabetic obese patient due to accumulation of lipid in or around myocytes and endothelial dysfunction associated with type 2 diabetes that increases endothelium derived substances such as endothelin and angiotensin II so LV hypertrophy and increased LV filling pressure that increases E/e' values.

There was no statistically significant difference between the studied groups regarding left ventricular EF. These findings came in agreement with Conte et al.[10] who found that EF was similar in the three groups as also PW TDI-derived systolic motion (S) at the mitral level. This could be due to patients with LV systolic dysfunction (EF <50%) were excluded from our study.

But it was different from Wang et al.[9] who found that type 2 diabetic subjects with overall obesity had lower 2D-LVEF compared with the other two groups while no statistical differences were found in ejection fraction between type 2 diabetic subjects without overall obesity and controls. This could be due to toxic effects of fatty acids on the myocardium and endothelial dysfunction that increase release of endothelium-derived substances that have profound effects on myocardial structure and function in type 2 diabetic obese patients.

There was no statistically significant difference between the studied groups regarding left ventricular end-diastolic and systolic volume. This could be due to the balance between increased wall thickness and LV mass in diabetic obese patients and the expanded intravascular volume present in obesity, so there is no significant difference between the studied groups regarding left ventricular end-diastolic and systolic volumes.

These findings were different from Wang et al.[9] who found that diabetic patients with overall obesity had significantly higher EDV and ESV than the other two groups, while no statistical differences were found in LV volume between diabetic patients without overall obesity and controls. This could be due to overall-obesity diabetic patients with higher blood volume and a more active adipose metabolism required more oxygen, and they had to rely mainly on increasing stroke volume to meet these needs, thus likely leading to LV overload and eccentric hypertrophy.

STE revealed that there was a statistically significant difference between the studied groups regarding peak longitudinal stain of each segment of LV except lateral wall, where the healthy control (Group III) had the highest value as compared to type 2 diabetic non-obese (Group II) and type 2 diabetic obese (Group I). These findings also came in agreement with Wang et al.[9] who found that diabetic patients without overall obesity had significantly lower global circumferential strain (CS), global area strain, and global radial strain (RS), as well as markedly lower GLS compared with the control group.

This could be explained by diabetic duration was the only independent predictor for the reduction of GLS and HbA1C also related to GLS. This could be due to longitudinal fibres in the subendocardial layer are more susceptible to ischemia because anatomical features of coronary arteries make the endocardium more vulnerable to ischemia and hypoxia, and these longitudinal fibres have stronger contractility, higher stress, and require more oxygen, making them more easily affected in the early stages of subclinical LV dysfunction. Thus, the longitudinal function would be impaired earlier and more severely. This also may be due to type 2 diabetic obese patients with higher blood volume and a more active adipose metabolism required more oxygen, and they had to rely mainly on increasing stroke volume to meet these needs, thus likely leading to LV overload. Meanwhile, lipid accumulation in the obese patients caused secondary myocardial interstitial hyperplasia. The above changes, combined with the lesions induced by type 2 diabetes, caused more obvious abnormality in cardiac structure and function.

STE revealed that there was a statistically significant difference between the studied groups regarding GLS of LV where the healthy control (Group III) had the highest value as compared to type 2 diabetic non-obese (Group II) and type 2 diabetic obese (Group I). These findings came in agreement with Conte et al.[10] who showed decreased GLS in type 2 diabetic patients. They revealed that in uncomplicated asymptomatic type 2 DM patients, the presence of first degree obesity plays an incremental role in adversely affecting left ventricular function and remodeling.

These findings came in agreement with Conte et al.[10] who showed decreased GLS in diabetes patients. They revealed that in uncomplicated asymptomatic DM patients, the presence of first-degree obesity plays an incremental role in adversely affecting left ventricular function and remodeling. The conventional echocardiographic methods such as the EF and the TDI are not so sensitive to identifying the early LV dysfunction such as the evaluation of GLS by STE. The longitudinal subendocardial fibers dysfunction in type 2 diabetes/obese patients could be derived by the complex interaction between metabolic (diabetes) and hemodynamic/endocrine abnormalities.

These findings also came in agreement with Karagöz et al.,[12] who evaluated subclinical LV dysfunction with STE-based strain measurement and concluded that type 2 diabetic patients were found to have lower longitudinal myocardial mechanics compared with the healthy control group. Circumferential and rotational mechanics were found to be relatively preserved in patients with type 2 DM.

These findings also came in agreement with Wang et al.,[9] who found that GLS in type 2 diabetic subjects with overall obesity was not only markedly lower compared with those in the control group but also significantly lower compared with with those in type 2 diabetic subjects without overall obesity.

These findings also came in agreement with Kibar et al.,[13] who evaluated the effect of obesity on the risk of subclinical LV longitudinal myocardial dysfunction in normotensive obese children by 2DSTE, which is an angle-independent and new technique for studying myocardial deformation. They showed that childhood obesity, in the absence of hypertension, is associated with an altered in the longitudinal LV function by STE. However, LV LS parameters (peak systolic strain and global strain) using 2DSTE were lower in the obese group than the controls. There strain parameters are showing LV systolic dysfunction in obese patients in the early preclinical stage. Furthermore, LV 2D strain parameters for the assessment of regional myocardial dysfunction in obese children may be a new approach to noninvasive methods.

These findings also came in agreement with Nakai et al.,[14] who measured LS, RS, and CS in asymptomatic type 2 diabetic patients using 2DSTE. They described the first signs of systolic dysfunction following established diastolic dysfunction in type 2 diabetic patients. Although preferential strain reduction was observed in the longitudinal direction, all three-principal strain values were reduced before the development of systolic dysfunction in type 2 diabetic patients. LVEF is not a sensitive indicator for the detection of subclinical systolic dysfunction. The Type 2 diabetes duration was the only independent predictor for the reduction of global LS. 2DSTE has the potential for detecting subclinical LV systolic dysfunction, and it might provide useful information for the risk stratification of an asymptomatic type 2 diabetic population.

This could be due to GLS that reflects the contraction of sub-endocardial fibers which are arranged in a longitudinal manner. These longitudinal fibers had stronger contractility, higher stress, and need more oxygen. In addition, the anatomical features of coronary arteries also made the endocardium more vulnerable to ischemia and hypoxia. Thus, the longitudinal function would be impaired earlier and more severely in a variety of diseases, including type 2 diabetes, leading to impaired LS.

Abdominal obesity was remarkably characterized by abdominal adipose accumulation and increased waist circumference (WC), accounting for a large proportion of the Asian obese population. Type 2 diabetes and abdominal obesity are both parts of the so-called “metabolic syndrome” (MS, mainly including abdominal obesity, hypertension, dyslipidemia, and hyperglycemia), which is associated with an increased risk of cardiovascular morbidity and mortality.[15]

We demonstrated the subclinical impairment of LV function in type 2 diabetic obese and non-obese patients and showed that LV LS measured by 2DSTE was lower in the diabetic obese group (Group I) in comparison to type 2 diabetic non-obese (Group II) and healthy control group (Group III). Previous studies have demonstrated the synergistic effects of multiple MS components on LV function, suggesting that the increasing number of MS criteria can induce progressive LV dysfunction. These findings came in agreement with Gong et al.[16] who reported that LV LS measured by TDI was significantly lower in MS patients with four disorders than in those with three disorders. Meanwhile, Crendal et al.[17] also found similar results using 2DSTE. Furthermore, Almeida et al.[18] found LV CS to be gradually reduced with the increase of MS components, while Tadic et al.[19] observed the unfavorable influence of increased MS risk factors on longitudinal and CSs.

This could be due to endothelial dysfunction that occurs in type 2 diabetic patients, leading to the release of endothelium-derived substances that have profound effects on myocardial structure and function. For example, both endothelin and angiotensin II cause myocardial hypertrophy and increased interstitial connective tissue, and both may also contribute to myocardial apoptosis. Furthermore, obesity predisposes to the toxic effects of fatty acids on the myocardium and the additional detrimental effects of cytokines and angiotensin II released by adipose tissue.

Study limitations

Our study was on a relatively small sample size, the present study was a case–control design; hence, it does not provide prognostic data and we did not follow-up with the patients to assess long-term clinical outcomes. A limitation of the study is the use of BMI alone in type 2 diabetic and non-diabetic patients, it would be interesting to add also the waist-corrected BMI, calculated as WC × BMI, as demonstrated by Antonini-Canterin et al.[20] The wBMI has demonstrated to have the theoretical advantage of taking into account simultaneously the global fat mass and distribution and might be useful for a better cardiovascular risk assessment. Also to add some data on further studies about the laboratoristic examinations to understand if the type 2 diabetes is well controlled and how the uric acid that it is known is associated with early signs of atherosclerosis.[2122]

Clinical implication

Early detection of the subclinical LV dysfunction in type 2 diabetic obese and non-obese patients using 2DSTE is the procedure of choice as a bedside tool; it is a cheap and readily available procedure which predicts cardiomyopathic changes in the earlier course of type 2 DM and start treatment early for better prognosis.

CONCLUSIONS

2DSTE is better than basic echocardiographic measurements in the assessment of subclinical LV dysfunction in type 2 diabetic obese and non-obese patients who predict cardiomyopathic changes in the earlier course of type 2 DM and start earlier treatment with a better prognosis.

Recommendations

Further research is needed to clarify these points on larger sample of patients. Further large–scaled studies are needed to assist the role of speckle tracking in the diagnosis of left ventricular function in patients with type 2 diabetes mellitus. Further investigations are needed to allow the analysis of genetic polymorphisms that characterize this type of patient, in a more comprehensive knowledge of the complex interaction between obesity and type 2 diabetes and with a deeper study of various aspects as the analysis of endocrine and metabolism factors. Further studies are needed for measuring outcome and follow up to predict cardiomyopathic changes. Further studies are needed to include comparison between different population groups as a cohort of patients with obesity but not DM.

Ethical clearance

The protocol was approved by our Zagazig University Institutional Review Board (ZU-IRB#2528/3-12-2016) which confirmed that all methods were performed in accordance with the relevant guidelines and regulations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.