Epicardial fat thickness in infants of diabetic mothers

Abstract

BACKGROUND:

Epicardial fat thickness (EFT) in adults and children has been related to the metabolic syndrome and other cardiovascular risk factors; however, scarce studies have evaluated it in infants of diabetic mothers (IDM) in whom, alterations in the thickness of the interventricular septum have been reported. This study compares the EFT in IDM versus infants of non-diabetic mothers (INDM) and its association with others echocardiographic parameters.

METHODS:

We performed a cross sectional study in 93 infants (64 IDM and 29 INDM). To evaluate EFT dimensions, an echocardiogram was performed within the first 24h of extrauterine life in both groups. In diabetic mothers, HbA1c was also determined.

RESULTS:

There was no significant difference in birth weight between the groups although gestational age was lower in IDM. The EFT (3.6 vs. 2.5 mm, p < 0.0001), the interventricular septum thickness (IVST) (6.2 vs. 5.2 mm, p < 0.0001) and the IVST / left ventricle posterior wall (1.3 vs. 1.1, p = 0.001) were higher in the IDM; while the left ventricular expulsion fraction [LVFE] (71.1 vs. 77.8; p < 0.0001) was lower than in the INDM, respectively. We found a positive correlation between EFT with IVST (r = 0.577; p = 0.0001), LVPW (r = 0.262; p = 0.011), IVST/LVPW index (r = 0.353; p = 0.001), and mitral integral early velocity (r = 0.313; p = 0.002), while a negative correlation with LVFE was observed (r = –0.376; p = 0.0001).

CONCLUSIONS:

The EFT is higher in IDM than in INDM. It was positively related with echocardiographic parameters of left ventricular thickness and negatively with left ventricular ejection function.

Keywords

Epicardial fat infants of diabetic mothers left ventricular mass

1 Introduction

The requirement of intensive care in infants of diabetic mother (IDM) in the first days of life has diminished because of the adequate metabolic control in the mother [1]. However, despite the advances in perinatal medicine, IDM have a high risk for developing perinatal complications, congenital malformations, and in long term, metabolic syndrome [2, 3].

For many years, asymmetrical septal hypertrophy and hypertrophic cardiomyopathy (HCM) have been reported as the result of insulin and others growth factors that stimulate the heart of infants in diabetic mothers [4]. Recently, it has been described that the overcharged of fatty acids at cardiac level, specifically at epicardial fat (EF) specially studied in adults, is an early contributor in the diastolic dysfunction, similar to alterations found in HCM. EF is a visceral and a metabolically active fat depot in anatomical and functional contiguity with the myocardium and the coronary arteries [5, 6]. It produces adipokines and chemokines, which have paracrine and vasocrine effects, playing an important role between the association of obesity and coronary disease [6, 7]. Although, it has been considered as local energy source in high demand situations, EF is also a defense against hypothermia and ischemia, and a secretor of anti-inflammatory molecules like adiponectin and adrenomedullin [8 –10]. In pathological conditions such as obesity or diabetes mellitus, it is able to liberate pro-inflammatory and proaterogenic molecules, but the equilibrium between the protector and harmful effects of this adipose tissue is not clear [11]. A higher epicardial fat thickness (EFT) has been found in pregnant women with gestational diabetes and in their fetus than in non-diabetic mothers and their fetus [12]. The objective of this study was to compare the EFT in IDM versus infants of non-diabetic mothers (INDM) and its association with other echocardiographic parameters.

2 Methods

We performed a cross sectional study in 93 infants (64 IDM and 29 INDM) in the General Hospital, Leon, Mexico. Infants with diagnosis of congenital heart disease or respiratory diseases in their medical chart review were excluded. None of these neonates showed metabolic or other acute complications that needed extended hospitalization or re-hospitalization during the first 28 days of life.

2.1 Measurements

In both groups the gestational age was calculated according to Capurro’s method [13]. Intrauterine growth curves were used to classify and select eutrophic patients as those found among 10 and 90 percentiles.

In IDM semiquantitative glycemia was determined in a routine protocol with capillary glycaemia at 30, 60 and 120 minutes of life according to STABLE program recommendations, and then each 6–8 h according to glucose levels and the health state of the newborn [14].

To evaluate the EFT, in the entire group of infants, an echocardiogram without sedation of the participants was carried out within the first 24 hours of extrauterine life by a pediatric cardiologist. Bidimensional Doppler studies were made with a Phillips HD11XE equipment, using an 8 MHz transductor. The echocardiogram was registered in all the evaluated subjects, while they laid in supine position. The left ventricle systolic function was evaluated using the following echocardiographic parameters in M mode: interventricular septum thickness (IVST), dimensions of the left ventricle and thickness of the posterior wall of the left ventricle (PWLV). Also measurements of hemodynamic state of neonates such as blood velocities were evaluated. Conventional echocardiography measurements were obtained through two dimensionally guided modes according to the recommendations of the American Society of Echocardiography [15]. Asymmetrical septal hypertrophy (ASH) was considered in case of IVST > 6 mm [4, 16]. The EFT was measured in the free wall of the right ventricle from the parasternal view of the long axis. It was identified as a free echo space in the precardiac layers in the bidimensional echocardiography, and it thickness was measured perpendicularly in the free wall of the right ventricle by the end of diastole during 3 cardiac cycles according to Iacobellis et al. [17]. Of the lack of definite value considered normal for EFT in neonates, we decided to use the highest value registered in the control group.

All diabetic mothers were classified according to the ADA criteria [18], and the degree of metabolic control was valued by determining the glycosylated hemoglobin (HbA1C) levels within the first 24 postpartum hours, considering adequate control when HbA1C was < 6%, but the ADA considers that target may be relaxed to < 7%(53 mmol/mol) if necessary to prevent hypoglycemia.

2.2 Ethical aspects

The study was evaluated by the local ethical committee of the General Hospital. For all patients, an informed consent letter signed by the parents was obtained after the information of the study including its objective and risks of participation.

2.3 Sample size and statistical analysis

Considering a correlation of 0.3 between EFT with interventricular septum thickness (IVST) and left ventricule fraction ejection (LVFE), 65 patients were needed for an α= 0.05 and β= 0.20 according to the MedCalc software. Descriptive statistics was carried out to evaluate the demographic variables. The comparison of quantitative and qualitative parameters between IDM and INDM was performed using the two sample t test and squared chi test, respectively. In case of non-normal distribution of continuous variables, U-Mann-Whitney test was performed. Pearson's correlation test was used to value the correlation between different echocardiographic parameters and EFT. A p value < 0.05 is considered significant. Statistical analysis was performed in the Statistics software.

3 Results

No difference in sex distribution, weight, and size was observed between groups. However, gestational age was lower in IDM and born more frequently by cesarean than in the control group (Table 1).

Table 1
General characteristics of infants of diabetic and non-diabetic mothers

Variables Infants of diabetic mothers n = 64 Infants of non-diabetic mothers n = 29 P value

Sex (M/F) 38/26 15/14 0.471

Gestational age (Weeks) 37.9±1.0 38.8±2.3 0.013

Weight (Kg) 3.1±0.36 3.1±0.43 0.691

Size (cm) 49.2±2.3 49.3±0.43 0.929

Cesarean delivery 42(65.6%) 8(27.5%) 0.003

HbA1c in mothers 6.3±0.79 % –

Variables	Infants of diabetic mothers n = 64	Infants of non-diabetic mothers n = 29	P value
Sex (M/F)	38/26	15/14	0.471
Gestational age (Weeks)	37.9±1.0	38.8±2.3	0.013
Weight (Kg)	3.1±0.36	3.1±0.43	0.691
Size (cm)	49.2±2.3	49.3±0.43	0.929
Cesarean delivery	42(65.6%)	8(27.5%)	0.003
HbA1c in mothers	6.3±0.79 %	–

Forty-eight (75%) mothers in the diabetic group of neonates showed gestational diabetes, 15 (23.43%) type 2 diabetes and only one (1.56%) type 1 diabetes. During the study, 46 (71.85%) of them were exclusively on diet control, 13 received insulin (20.31%) plus diet, and 5 received insulin and metformin plus diet (7.81%). We identified that 34 (53.12%) mothers in this group showed HbA1C > 6%. Furthermore, the highest value was 9.6%in only one mother as an outlier value, and 10 (15.62%) showed HbA1C≥7%.

EFT, IVST and IVST/LVPW were higher in IDM, while left ventricular fraction ejection (LVFE) was lower than in INDM (Table 2). The ASH frequency in IDM was 45.3 %, and in 3.4%of the control group.

Table 2

Echocardiographic parameters in infants of diabetic and non-diabetic mothers

Variables	Infants of Diabetic mothers n: 64	Infants of Non-Diabetic mothers n: 29	P value
EFT (mm)	3.6±0.67	2.5±0.30	< 0.0001
IVST (mm)	6.2±0.92	5.2±0.66	< 0.0001
LVPW (mm)	4.8±0.68	4.6±0.78	0.103
IVST/LVPW	1.3±0.21	1.1±0.15	0.001
LVFE (%)	71.1±4.0	77.8±6.1	< 0.0001
LVSD (mm)	9.4±1.4	9.7±1.1	0.425
LVDD (mm)	15.3±2.6	16.0±1.4	0.187
SF (%)	38.3±4.7	39.1±5.5	0.455
PASP (mmHg)	19.8±3.3	19.9±2.6	0.898

EFT: Epicardial Fat Tickness, IVST: Interventricular Septum Thickness, LVPW: Left Ventricle Posterior Wall, LVFE: Left Ventricle Fraction Ejection, LVSD: Left Ventricle Systolic Diameter, LVDD: Left Ventricle Diastolic Diameter, SF: Shortening Fraction of the Left Ventricle, PASP: Pulmonary Artery Systolic Pressure.

No difference in EFT was found in neonates according to the different type of DM in their mothers. Because of the lack of definite value considered normal for EFT in neonates, we decided to use the highest value in the control group, which was 3.3 mm. According to this, we identified that 10 (66.6%) IDM with Type 2 diabetes, and 28 (58.3%) IDM with gestational diabetes showed high EFT values. In the unique case of IDM with type 1 diabetes, EFT value was exactly 3.3 mm. No correlation was observed in EFT values in neonates and HbA1c in their mothers (r = 0.061; p = 0.937).

Aortic peak velocity and pulmonary integral velocity were lower, while mitral integral early velocity was higher in IDM than in INDM (Table 3).

Table 3

Valvular velocities in infants of diabetic and non-diabetic mothers

Variables	Infants of Diabetic mothers n:64	Infants of Non-Diabetic mothers n:29	P value
Mitral Peak Early Velocity (m/s)	0.61±0.10	0.60±0.13	0.679
Mitral Integral Early Velocity (m/s)	0.41±0.08	0.36±0.06	0.009
Tricuspid Peak Early Velocity (m/s)	0.64±0.16	0.67±0.09	0.328
Tricuspid Integral Early Velocity (m/s)	0.38±0.13	0.43±0.06	0.056
Aortic Peak Velocity (m/s)	0.80±0.16	0.91±0.08	0.001
Aortic Integral Velocity (m/s)	0.56±0.14	0.59±0.07	0.268
Pulmonary Peak Velocity (m/s)	0.85±0.14	0.90±0.12	0.065
Pulmonary Integral Velocity (m/s)	0.58±0.13	0.67±0.11	0.002

We found a significant positive correlation between EFT with IVST, LVPW, IVST/LVPW index, and mitral integral early velocity, while a negative correlation with LVFE was observed (Table 4).

Table 4

Correlation between epicardial fat thickness with other ecocardiographic variables in the entire group

	IVST	LVPW	IVST/LVPW	LVFE	Mitral Integral Early Velocity
EFT	0.577	0.262	0.353	–0.376	0.313
	p = 0.0001	p = 0.011	p = 0.001	p = 0.0001	p = 0.002

EFT: Epicardial Fat Tickness, IVST: Interventricular Septum Thickness, LVPW: Left Ventricle Posterior Wall, LVFE: Left Ventricle Fraction Ejection.

4 Discussion

EFT has emerged as a new marker of cardio-metabolic risk due to its intimate proximity with the myocardium, the coronary arteries and its endocrine-metabolic features [8]. It is consistently associated with metabolic syndrome (MS), and it varies according to the ethnicity and age showing a value < 7 mm in healthy and slim adult subjects [19]. In children 2.5±0.81 mm for non-obese and 5.5±1.98 mm for obese children have been reported, and EFT > 5 mm seems to show a good sensibility to predict MS in children and adolescents [20, 21]. Furthermore, maternal diabetes upsets the intrauterine environment resulting in an excessive growth, high weight at birth, and ASH [22]. It is possible that maternal diabetes since an early stage changes the dimensions of the EFT, because it has been reported higher in diabetic mother fetuses than in the non-diabetic mother fetuses [12, 23]. In our study, EFT was higher in IDM than in INDM as well as the interventricular septum thickness (IVST) and the ASH frequency, as previously identified in IDM or in children with family history of type 2 diabetes mellitus [24].

We found a positive correlation between EFT with IVST, LVPW, IVST/LVPW index, and mitral integral early velocity, while a negative correlation with LVFE was observed. A positive correlation between EFT with IVST and IVST/LVPW has been previously reported by Eren et al. in obese children [25], pointing secondary to the intimate contact of the EFT with the myocardium [20]. Furthermore, secretory products from EFT from patients with T2D have also been shown to depress cardiomyocyte contractile function and fat oxidation, which could explain the negative relationship with LVFE [26]. Nonetheless, we can not only consider a deleterious effect of EFT in neonates, because cardiac cryoprotection due to its thermogenic capacity, resembling that of brown/beige adipocytes has also been reported [27, 28]. So, this higher EFT in IDM could reflect fetal adaptation to the adverse in utero environment [29].

Although some valvular peak and integral velocities were different between groups, all these values are in normal ranges [30]. Furthermore, changes in peak systolic velocities in neonates must consider the loading condition when interpreting the values and the interpretation of diastolic velocities is more challenging because more factors influence the measurement. EFT threshold values are not identified in neonates and it needs to be clarified whether EFT is a clinically relevant risk factor that will improve risk stratification in this population and guide future clinical decision-making. Nonetheless, considering that several studies have shown that EFT is associated with diastolic dysfunction at older age [31 –33], long term studies in this population are desirable, and using E/A ratio, E/e’ ratio, and tissue Doppler echocardiography for diastolic function evaluation.

It has been described that a good prenatal glycemia control, especially in the 3rd trimester can diminish the frequency of neonatal complications, such as macrosomia but not the tendency to cardiac growth and septal hypertrophy [34]. In this study, no association between the maternal diabetes control and the EFT dimensions was found in contrast with fetal EFT in diabetic mothers [35]. As a limitation in our study, only diabetic mothers had HbA1C values, and only eutrophic patients were recruited. We didn’t find any report of hypoglycemia in our patients, the lack of complications is apparently related to the fact we only evaluated eutrophic infants.

Whether an echocardiogram will be performed and include the EFT measure, not enough long term studies can support this recommendation. Even some authors recommend EFT intrauterine monitorization, because it is considered as a novel marker to the fetus exposure to glucose, existing already a nomogram for its intrauterine monitorization [33], and it is considered that this can help to improve the diabetic fetopathy management and diagnosis [25].

The strength in our study lies in the fact that we are the first to report the relationship between EFT with other cardiac parameters in IDM. However, as a limitation of this study, the evaluation of the LV ejection fraction was not performed with modified Simpson method (biplane method), instead of linear measurement. Thus, the present results provide support for more convincing measurements to support our findings and a prospective study to further investigate the association between newborn EFT and adiposity, both in terms of body fat percentage and the metabolic profile and cardiac function in other infant stages of development. Nevertheless, studies including long term following and its change in the medium term and their interactions with factors that have been described as protective such as exclusive breastfeeding, weight control, physical activity, etc., must be carried in this population.

5 Conclusion

EFT was significantly higher in IDM than in INDM and no relationship was found with metabolic control. EFT was positively related with echocardiographic parameters of left ventricular thickness and negatively with left ventricular ejection function.

Disclosure statements

The authors have no conflicts of interest relevant to this article.

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