1- INTRODUCTION

Diabetes Mellitus Type I (DMT1) is a highlighted endocrine and digestion issue (1) and is an insusceptible framework affliction with a solid hereditary part including all ages and races (2) specially children (3). The frequency of Diabetes Mellitus (DM) is evaluated as 387 million people that DMT1 accounted for 5-10% of it, in different areas (4). In Iran, the prevalence extended from 7.7% in 2005 to 8.7% in 2007 and it is proceeding due to issues such as financial weight, lifestyle changes and social protection (5). A strong association exists between DM and Cardiovascular Diseases (CVD) with a predominant reason for mortality (6). CVD death rate in diabetic patients tends to be about twice as much as that of non-diabetic (7) and DM patients with extreme lipids profiles being more at risk in contrast to those with typical lipids profiles. In this regard, Noori et al. (8) revealed that children with DMT1 who had high low-thickness lipoproteins (LDL) cholesterol are most at CVD hazard compared to those with low LDL. Thus, it appears to be essential to focus on lipids variations from the norm so as to diminish cardiovascular disorders at early ages (7).  Lipids abnormality, more observed in diabetes patients with poor control, indicated an ordinary level or marginally diminished triglycerides and LDL-cholesterol level. In addition, expanded HDL cholesterol levels decline the danger of CVD (9). In spite of the fact that, the specific results of these changes on the improvement of cardiovascular diseases in diabetes are yet obscure, subjective anomalies of lipoproteins are observed in patients with type I diabetes, even in good glycemic control and these variations from the norm are not completely clarified by hyperglycemia and may be due to the marginal hyperinsulinemia related to the internal course of insulin organization (1). Echocardiography is a basic symptomatic tool and method to show heart utilitarian oddities in chronic diseases such as; thalassemia, diabetes and celiac. The most notable method is the conventional echocardiography which has offered improved quality pictures, and has extended the affectability of echocardiography on the disclosure of subclinical ventricular complications (8). Along these lines, the present examination is expected to survey the progress in regular echocardiographic findings due to changes in lipids profiles in children with DMT1.

2- MATERIALS AND METHODS

2-1. Study design

This case-control study performed on192 children, including 96 healthy and 96 with diabetes mellitus type I. The investigation was conducted in Ali Asghar Pediatric Hospital, Zahedan, the capital city of Sistan & Baluchestan province, Iran. The examination was run in two centers in collaboration with endocrinology and cardiology between March 2018 and April 2019.

2.2- Sampling

Sample size was calculated from the following formula;

Where, Zα=1.96, Zβ=0.84 and r =1. For the parameters of Myocardial Performance Index (MPI), the mean value extracted was 0.29 and 0.27 for the patients and controls, respectively (10). Utilizing the referenced parameters in the mentioned equation gave us 96 subjects in each group.

2-3. Inclusion and Exclusion Criteria

DMT1 patients either symptomatic or asymptomatic were included in the study. The disease of diabetes was confirmed by the clinical manifestations such as polyuria, polydipsia and weight loss along with the laboratory measures such as fasting blood glucose > 125, random blood glucose>200 mg/dl. Exclusion criteria were the ages higher than 18 years, documented evidence of other cardiac diseases like cardiomyopathy, valvular heart disease, congenital heart disease, and myocarditis, as well as the features of hypothyroidism, uremia, and random blood sugar > 140 mg/dL for both groups.

2-4. Measurements

2-4.1. Echocardiography measures

Both groups went under conventional echocardiography (M mode and 2D) by a cardiologist, using My Lab 60 instrument with 3-8-MHz transducers (made in Italy). The values of all necessary echocardiographic parameters, namely Ejection Fraction (EF), Fractional Shortening (FS), velocity of the blood flow through the heart valves, as well as the Ejection Time (ET), peak A velocity (A), peak E velocity (E), Myocardial Performance Index (MPI), peak E (early mitral and tricuspid valve flow velocity) /peak A (late mitral and tricuspid valve flow velocity) velocity (E/A ratio), isovolumic relaxation time (IVRT), Isovolumic Contraction Time (ICT) of both sides were measured with pulsed Doppler echocardiography. The sample volume was positioned at the tips of the tricuspid and mitral valve leaflets in the apical four chamber view to enable the measurement of (a): the time interval between the start and the end of trans-mitral and trans tricuspid flow. The sample volume was thereafter relocated to the left ventricular outflow tract just below the aortic valve (apical five-chamber view) so as to measure (b): the left ventricular ejection time. The right ventricular outflow velocity pattern was also recorded from the parasternal short-axis view with the Doppler sample volume positioned just distal to the pulmonary valve for the measurement of (b). Myocardial Performance Index (MPI/Tei Index) was calculated as a-b/b = (ICT + IRT)/ET (11). The left ventricular mass index (LVMI) was calculated by the following formula: LVM (g) = 0.8 (1.04 (((LVDD + PWD + IVSD)³ -LVDD ³))) + 0.6; and LVMI (g/m²) = LVM / 2.7 (11) and relative wall thickness was also calculated from RWT = 2 PWD/ LVDD formulae.

2-4.2. Lipids profiles

Patients were tested for their lipids profiles of cholesterol (CHO) mg/dl, high density lipoprotein (HDL) mg/dl, low density lipoprotein (LDL) mg/dl, and triglyceride (TG) mg/dl. Abnormal lipids profile was defined as CHO >200 mg/dl, HDL < 40 mg/dl, LDL >130 mg/dl, and TG >150 mg/dl (1).

2-4.3. Diabetic measures and duration of diabetic state

The cardiac functions in our patients were categorized based on hemoglobin A1c (HbA1c) and duration of diabetic state.

1. a) HbA1c:

The level of HbA1c reflects glycemic control. HbA1c is the mean blood glucose concentration during the 3 months preceding the measurement. Higher values indicate higher blood glucose levels, and therefore, more poorly controlled diabetes. Laboratory results of HbA1c assays in the blood samples are conducted as part of the patients’ regular outpatient visit. The normal range on this assay is 4.0-6.1%. For the purposes of this study, we considered good control to be an HbA1c < 7%, and poor control to be an HbA1c ≥ 7%. (11).

1. b) Duration of the diabetic state

The diabetic duration is considered as the time between the disease onset based on the diagnosed time by the pediatric endocrinologist and the time of referring to the pediatric cardiologist for performing conventional echocardiography.

The patients were classified into groups according to their diabetic duration based on the cut point of 4 years.

2-4.4. Anthropometric measurements

The height and weight of children were measured by an experienced expert using the standard equipment. The recumbent length for children under 2 years were graded using a flat wooden table; and their weight measurements were performed by the use of the balance weights Mika with the error probability of 100gr, and then their BMIs were calculated [Weight (Kg) / Height (m²)].

2-5. Ethical Considerations

Informed consent was obtained from all individual participants included in the study after the study approval. The study was approved as a project proposed (ID-code: 7230) to the Children and Adolescent Health Research Center by the Ethics Committee of Zahedan University of Medical Sciences, Zahedan, Iran.

2-6. Statistical Analysis

Data was analyzed via SPSS 18.0 (SPSS Inc, Chicago, IL, USA). Descriptive statistics were presented in mean ±SD. Comparisons between DMT1 subjects and the controls were performed using t-test and Mann-Whitney U test; and when more than two groups were to be compared, the One-way Analysis of Variance and Kruskal –Wallis tests were used based on normality of the variable data distribution. The correlations between the variables were calculated using Pearson’s correlation. P < 0.05 was considered significant.

3- RESULTS

The study was conducted on 192 subjects composed equally of diabetic and healthy children. The children had a sex distribution of 52.6% and 47.4% for boys and girls, respectively.  From among the patients, 47.9% were boys when this rate was 57.3% for controls with similar sex distribution in patients and controls (X²=1.692, p= 0.193). Mean age of the participants was 10.82± 3.15 years, such that the patients and controls had 10.87±3.46 and 10.77±2.82 years, respectively.

Table 1 demonstrates the normality distribution of study variables among the participants. Table 2 shows that the right and Left DT, (p<0.001), aorta diameter in diastole (p=0.005) and aorta diameter in systole (p=0.011) were higher in patients when ET (p<0.001), EF (p<0.021), left E/A (p=0.019), LAs /Aos (p=0.001), FS (p=0.014) were higher in controls. MPI was significantly higher in the patients (p=0.001).

Table 3 shows the comparisons between the study variables in diabetic children based on HbA1C groups (cut off point= 7%).  Patients with poorly controlled glucose had higher levels in LVMI and left DT significantly (p<0.05).

Table 4 presents the comparisons based on the diabetes duration. In children with longer period diabetes, HbA1c was significantly higher (p=0.008), LA diameter in systole / aortic diameter in systole was significantly lower (p=0.042), LVMI significantly decreased (p=0.005), right AT significantly increased (p=0.047), IVSD significantly decreased (p=0.028), PWD significantly decreased (p=0.036), and right E/A decreased significantly (p=0.050).

Table 5 shows the comparisons based on CHO changes in diabetic children.  The changes of CHO were based on the level of 200 mg/dl, in which the normal patients had < 200mg/dl of CHO. In patients with abnormal CHO EF (p=0.015), the levels of FS (p=0.014), Left E/A(p=0.024), LAd/Aod(p=0.008), LAs/Aos(p=0.001), left ET (p<0.001), and PWD(p=0.039) were higher and the echocardiography findings of the right deceleration time(p<0.001), aortic diameter in diastole(p=0.002), aortic diameter in systole (p=0.013), Left MPI (p=0.001) and left DT(P,0.001) were lower, significantly.  Regarding the lipids profile changes, LDL and HDL both increased in patients with an abnormal status of CHO (p<0.05).

Table 6 compares the cardiac findings based on LDL changes in diabetic children. LDL > 130 mg/dl was considered abnormal. In patients who had abnormal values of LDL, the aorta diameter in diastole (p=0.002), right DT (p<0.001), and aorta diameter in systole (p=0.010) were significantly lower. However, the ejection fraction (p=0.010) and fractional shortening (p=0.009) were higher in patients with abnormal LDL values, left MPI (p=0.001) was lower, Left E/A (p=0.026) and LAd / Aod (p=0.017) were higher, LAs/Aos (p=0.001) ,  left ejection time (p<0.001) and PWD(p=0.047) were higher; and in final, the left deceleration time (p<0.001) was lower, significantly.  The lipids profile of HDL increased in patients with an abnormal status of LDL (p<0.001).  The results indicated that the echocardiography findings did not change by TG variation in the patients but the CHO increased in patients with an abnormal status of TG levels (p<0.001). Those patients who had abnormal values of HDL, had higher left MPI (p=0.023) when left ejection time (p=0.015) was lower in patients with abnormal HDL. TG increased in patients with a normal status of HDL (p<0.001).

4- DISCUSSION

The results of the study revealed that he left DT, aorta diameter in diastole and aorta diameter in systole were higher in patients, while ET, EF, left E/A, LAs /Aos, and FS were higher in controls. The left MPI was also higher in patients. Patients with poor glycemic control had higher LVMI and left DT. Children with longer periods of diabetes had an increase in HbA1c, right AT, and a decrease in LA diameter in systole / aortic diameter in systole, LVMI, IVSD, PWD, and right E/A. The results also indicated that patients with an abnormal status of CHO, had higher values  of EF, while their FS, left E/A, LAd/Aod, LAs/Aos, left ET, PWD and right DT, aortic diameter in diastole, aortic diameter in systole, Left MPI and left DT had lower values. In addition, the LDL and HDL both increased in patients with an abnormal status of CHO. The diabetic children with an abnormal LDL had lower AoD, right DT, AoS, and left MPI and left DT, while the parameters of EF, ES, left E/A, Lad/Aod, LAs/Aos, left ET, PWD and RWT had higher values. The echocardiography findings did not change by TG variation. The patients with abnormal values of HDL, had higher left MPI while their left ET was lower.

The diabetes cardiomyopathy is defined as the cardiovascular damage in diabetic patients, which is characterized by myocardial dilatation and hypertrophy, as well as a decrease in the systolic and diastolic functions of the left ventricle, and its presence is independent of the coexistence of ischemic heart disease or hypertension (12).  DMT1 predicts a broad range of later health problems including an increased risk of cardiovascular morbidity and mortality; and may even begin in childhood (13). Nonetheless, Ferranti et al. (14) expected that cardiac disorders do not occur during childhood, even in the setting of DMT1 with lipids profile abnormalities.  Atabek et al. (13) reported that the total cholesterol, triglycerides and LDL-cholesterol were slightly higher in diabetic children than in healthy controls. Endogenous insulin production reduces vascular complications and improves glucose control that may have a beneficial effect on CVD risk in the long period due to a favorable lipids profile. As children enter into adolescence, increasing the good glycemic control may lead to improvements in lipids levels (15), such that the risk of CVD will decrease (13).

Noori et al. (11) conducted a study on cardiac functions in diabetic children. They found that the left and right DTs were higher in patients, and the left and right peak E velocity were lower; the left ET decreased in patients and left MPI increased.

Table-1: Test of normality of the study variables in the participants

Table-2: Comparing the study variables between the children with Diabetes type I and the controls

Table-3: comparing the study variables between the two groups of children with Diabetes type I; Good (45 children) and poor control (51 children)

Table-4: comparing the study variables in children with Diabetes type I based on Duration of diabetes

Table-5: Comparing the study variables between the type I diabetic children with normal and abnormal CHO

Table-6: Comparing the study variables between the type I diabetic children with normal and abnormal LDL

Ozdemir et al. (16) found that the left and right MPI were higher, and LV, RV and ET were lower in children with diabetes.  Abd-El Aziz et al. (10) evaluated the cardiac functions in children with diabetes and concluded that the diameter of aorta, left LA, IVSS, LVPW, LVDD and LVDs were higher, while FS was lower. They also demonstrated that the patients had lower E and A wave velocity in right and left. All these results confirmed the findings of the present study.

Our findings also manifested that the diabetic children with an increase in Hb A1c had higher levels in LVMI and left deceleration time but none of their lipids profiles changed. In the same line, M Abd-El Aziz et al. (10) categorized diabetic patients based on HbA1c status (good and poor control) and concluded that all conventional parameters were similar.  Mehravar et al. (17) also confirmed the correlation between HbA1c and cholesterol, TC, LDL and HDL ratio.  In a study by Mostofizadeh et al. (18), dyslipidemia was presented as high as 74.8% among Iranian children with diabetes.  The most common lipids profile abnormality in their study was hypercholesterolemia followed by high LDL. Furthermore, the patients with poorly controlled glucose had a significantly higher LDL in comparison to the well-controlled patients.  The inconsistency of their results with that of the present study might be due to age of the patients. In addition, it may be partly explained by the fact that a single HbA1c may not reflect the overall control of diabetes and might cause insufficient and deceptive information about long-term glycemic control. So, the mean HbA1c value averaged from several time measures instead of a single instantaneous value can provide more accurate information about glycemic control. Rexhepi et al. (19) grouped the diabetic patients in controlled and uncontrolled diabetic dyslipidemia. After comparing some cardiac findings between these two groups, they found no differences between the groups in relation of left ventricular dimensions, the thickness of left ventricular septum and posterior wall, EF, FS, and LVM. The present study revealed that children with longer periods of diabetes had lower LAs / Aos, LVMI, IVSD, PWD and right E/A and had a higher right acceleration time.  Moreover, any of the lipids profiles did not change in duration; though the level of HbA1c was higher in patients with longer durations. In the study by Aderibigbe et al. (21), inconsistent with our findings, a marked decrease was found in the percentage of subjects showing high levels of CHOL, LDL and triglyceride after receiving treatment for 7 years when compared to those who had received treatment for less than 7 years. The dissimilarity might be due to the difference in the time duration considered for the groupings. In this regard, Abd-El Aziz et al. (10) found no significant correlation between the duration of diabetes and the conventional echocardiography findings. However, we found significant changes in some of the parameters including  LA diameter in systole / aortic diameter in systole, LVMI, IVSD, PWD, right E/A, and right acceleration. Abd-El Aziz et al. (10) compared the conventional echocardiography findings between the patients with and without dyslipidemia. They revealed that all the conventional findings were similar except for the left peak a velocity. We, recently, conducted a similar study on Doppler tissue imaging findings (1) and found that the left ICT’ and right S’ were higher in the abnormal status of HBA1c.  All TDI findings were similar in patients with short and long duration. Patients with higher TG had lower values of left A/A’. The patients with abnormal cholesterol had higher right S’, right E’ and right A’ but had lower right E/E’. Right S’ was higher in DMT1 children with abnormal LDLs while their right E/E’ was lower. Any of the DTI findings did not change in line with the HDL changes. Dyslipidemia can serve as an early biomarker for cardiovascular dysfunction in children with TDM1.

4.1- Study limitation

The main limitation of the study was the lack of proper cooperation on the part of the participants, especially the controls.

5- CONCLUSION

In general, the findings demonstrated that the type I diabetes mellitus children with uncontrolled Hb A1c had higher levels in LVMI and left deceleration; furthermore the LA / Ao diameter in systole were lower in and LVMI, IVSD, PWD and right E/A and right acceleration time were higher when the duration of diabetes increased.   The present study revealed that the damage of heart function in systole and diastole such as MPI, ejection fraction and fractional shortening changed by lipids profiles of cholesterol, low-density lipoprotein and high-density lipoprotein when triglyceride changes did not affect the cardiac functions. Therefore, in children with DMT1, the lipid profile have different effects on the conventional echocardiography finding, especially in respect to the systolic and diastolic parameters.

6- ACKNOWLEDGEMENTS

The authors would like to present their deep thanks to the parents of children for their participation in the study.

7- CONFLICT OF INTEREST

The authors would like to declare for no conflict of interest.

8- ABBREVIATIONS

AT: Acceleration Time, DT: Deceleration Time, Aod: Diameter of Aorta in Diastole, LAd: Diameter of LA in Diastole, Aos: Diameter of Aorta in Systole, LAs: Diameter of LA in Systole, ET: Ejection Time, IVSD: Interventricular Septal Dimension in Diastole, LVDD: Left Ventricular end-Diastolic Dimension, PWD: Posterior Wall Dimension in diastole, IVSS: Interventricular Septal dimension  in Systole, LVDS: Left Ventricular end-Systolic Dimension, PWS: Posterior Wall dimension in Systole, EF: Ejection Fraction (calculated in the apical two and four chamber views with Simpson’s apical biplane method), FS: Fractional Shortening, RWT: Relative Wall Thickness, E: peak E velocity, A:  peak A velocity, MPI: Myocardial Performance Index, LVMI: Left Ventricular Mass Index,  TG: Triglycerides  , CHO: Cholesterol, LDL: Low-Density Lipoprotein  , HDL: High-Density Lipoprotein. 

9- AUTHORS’ CONTRIBUTION

Noori designed the study; Teimouri analyzed the data; Noori, Nakhaee and Teimouri wrote the primary version of the manuscript. All Authors agree for the publication of the present manuscript.