Introduction

Cardiovascular disease (CVD) is becoming more prevalent due the growing incidence of childhood obesity [28]. Obese children are predisposed to the development of subclinical cardiovascular alterations early in life [11] and to an increased cardiovascular morbidity and mortality in adulthood [11, 25, 36].

Several studies have shown that obese children present several cardiometabolic risk factors, such as high blood pressure, dyslipidemia, and liver steatosis, already during the prepubertal period [13, 23, 34]. In addition, obese children show early signs of impaired vascular function, such as increased carotid intima–media thickness, arterial stiffness and decreased flow-mediated dilation [16, 23]. Many metabolic and inflammatory factors are involved in the pathogenesis of vascular changes in obese children. In particular, insulin resistance has been proposed as a key link between adiposity and the associated cardiovascular risk, because it mainly participates in the development of vascular endothelial dysfunction [9]. Under physiological conditions, insulin signaling in the endothelial cells results in vasodilation via increased nitric oxide production and bioavailability. In contrast, in conditions of insulin resistance, there is an impaired insulin signaling which leads to vasoconstriction and vascular proliferation, therefore contributing to endothelial dysfunction [33]. During the last years, several studies have focused on the relationship between obesity and potential abnormalities in cardiac structure and function [11]. Adults with severe forms of obesity show a cardiomyopathy attributed to chronic overload, left ventricular (LV) hypertrophy, and ventricular dysfunction [21, 40, 43]. Even milder forms of obesity have been associated with abnormalities in cardiac function and structure [40], which, although often subclinical, represent predisposing factors for increased CVD morbidity and mortality [11].

Some studies performed in obese youth have shown that subclinical cardiac alterations can be detected even at an early age [6, 12, 19, 26, 27, 29, 41]. However, data on the association between childhood obesity and morphological and functional changes in the heart have often reported contrasting findings. In addition, little is known on the potential association between early cardiac alterations and metabolic abnormalities in obese children when compared to healthy normal weight peers.

The aim of this study was to evaluate early cardiac structural and functional abnormalities in obese children and adolescents compared to normal weight controls and the potential association with metabolic alterations, in particular with insulin resistance.

Patients and methods

Study population

The study population included 30 obese and 15 normal weight children and adolescents (Table 1).

Table 1 Clinical and biochemical characteristics of the study population
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Obese children were consecutively recruited from patients attending the Pediatric Endocrinology Clinic of the Department of Pediatrics, University of Chieti, Italy. The inclusion criteria of the case group were age between 6 and 17 years, obesity (body mass index [BMI] > 95th percentile for age and sex), being otherwise in good health, and not affected by any chronic disease. The control group was recruited from children attending the pediatric outpatient clinics for a general check after 1–2 weeks from a previous admission to our pediatric ward for minor diseases (mainly gastroenteritis and trauma). At the time of assessment, these children were in good general health with complete resolution of the original disease. The inclusion criteria of the control group were age between 6 and 17 years, normal weight (BMI between 5th and 85th percentile for age and sex), being otherwise in good health, and not affected by any chronic disease. None of the patients were taking any medication, and none had a history of smoking or alcohol consumption.

At the beginning of the study, a complete physical examination, including anthropometric measurements (height, weight, BMI, and waist circumference [WC]), was performed, and basal blood pressure was measured in all children. Fasting blood samples were collected to measure glucose and insulin levels, lipid profile (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides [TG]), and asymmetric dimethylarginine (ADMA). Homeostasis model assessment of insulin resistance (HOMA-IR) was used as a surrogate index of insulin resistance, and it was calculated as follows: [fasting insulin (mU/l) × fasting glucose (mmol/l) / 22.5] [35].

Doppler two-dimensional echocardiographic assessments were performed in all subjects.

The study was approved by the local ethics committee. Written informed consent was obtained from all parents and oral consent from all children.

Anthropometric measurements

Body weight was determined to the nearest 0.1 kg, and height was measured with Harpenden stadiometer to the nearest 0.1 cm. BMI and WC were used as indexes of adiposity. BMI was calculated as the weight in kilograms divided by the square of the height in meters and was converted in standard deviation scores (SDS) using published reference values for age and sex for the Italian population [8]. WC was measured at its smallest point between iliac crest and rib cage.

Blood pressure

Systolic (SBP) and diastolic (DBP) blood pressure were measured twice from the right arm after 10 min of rest in the supine position by using a calibrated sphygmomanometer and averaged. The cuff size, which was selected on the length and circumference of upper arm, was as large as possible without the elbow skin crease obstructing the stethoscope.

Biochemical analyses

Plasma glucose levels were determined by using the glucose oxidase method, and plasmatic insulin levels were measured with two-site immunoenzymetric assay (AIA-PACK IRI; Tosoh, Tokyo, Japan). Total cholesterol, HDL-C, and TG were measured with an enzymatic–calorimetric test. LDL-C was derived according to the Friedewald equation (low-density lipoprotein cholesterol = total cholesterol − high-density lipoprotein cholesterol − triglycerides / 5). The TG/HDL ratio was also calculated as an emerging marker of cardiovascular risk [16].

Levels of human serum ADMA were determined by enzyme-linked immunosorbent assay kit (Cusabio Biotech Co., LTD, Catalog No. CSB-E09298h, People’s Republic of China), according to the manufacturer’s protocols [17]. The minimum detectable dose of human ADMA was less than 2 ng/ml. The intra-assay coefficient of variation was <8 %, and the inter-assay coefficient of variation was <10 %.

Echocardiography

All echocardiographic measurements were performed with Acuson Sequoia, whereas tissue Doppler was performed with Philips Sonos 500. Standard views from the parasternal long and short axis and apical four-chamber views were used. Echocardiographic images were obtained with the subject in the left partial decubitus position. The LV internal dimensions and septal and posterior wall thickness were measured at the end of the diastole and the end of the systole from two-dimensional target M-Mode echocardiographic tracings in the parasternal long axis, according to the criteria of the American Society of Echocardiography. Relative wall thickness (RWT) was calculated as (diastolic posterior wall thickness + diastolic interventricular septum thickness) / LV diastolic diameter (LVDD). LV mass was calculated using Devereux’s method [20].

Left atrial (LA) size assessment was performed by two-dimensional four-chamber view, at end-systole just before the mitral valve opens, and included cranio-caudal diameter, latero-lateral diameter, atrial area, and volume. LA area was measured tracing planimetry of atrial endocardial border and major-axis dimension; atrial volume was measured according to area/length method using planimetered area and minor-axis dimension [volume = 8 × (A1)^2/3p × (L)]. Images were optimized to avoid foreshortening and obtain clear endocardial border delineation.

LA and LV geometric parameters were indexed by dividing height in meters to the allometric power of 2.7 (h2.7), as previously suggested by De Simone et al. [18].

Pulsed Doppler measurements of LV filling were obtained in the apical four-chamber view, with the Doppler beam aligned perpendicularly to the plane of the mitral annulus, and the sample volume was placed between the tips of the mitral leaflets. Three consecutive beats obtained during quiet respiration were acquired for calculating peak early wave (E) and peak late wave (A) velocities and the E wave deceleration time.

The Doppler cursor was placed parallel to mitral inflow, and maximal velocity was measured with the sample volume at the mitral valve leaflet tips. The mitral peak of E (early filling) and A (late filling) waves, E/A ratio, and deceleration time (DcT) of the E wave velocity were measured. Tissue Doppler imaging was performed to acquire mitral annular diastolic myocardial velocities by setting the sample point at the lateral and septal sides of the mitral annulus in the apical four-chamber view (septal and lateral early diastolic mitral annular velocity (Em) and late diastolic mitral annular velocity (Am), in cm/s), and E′/A′ ratio and LV filling index E/Em ratio were calculated in accordance with recent guidelines [31, 37].

All reported measurements represent the average of three consecutive cardiac cycles obtained by a single experienced pediatric cardiologist, with a validated training in cardiac ultrasound. In order to assess the reproducibility of the assessments, a random sample of five obese children and three control children was reassessed by a second cardiologist. The inter-observer correlation was good being between 0.88 and 0.94 for the different cardiac parameters.

Statistical analysis

All data were expressed as mean ± SD or median (interquartile range), unless otherwise stated. P values <0.05 were considered statistically significant. All calculations were made with the computer program Statistical Package for the Social Science (SPSS) version 17.0 (SPSS Inc., Chicago, IL, USA). Not normally distributed variables were log transformed before data analysis. Differences between the two study groups in continuous variables were tested by an unpaired t test, whereas differences in categorical variables were assessed by χ 2 test or Fisher’s exact test. Analysis of covariance was used to allow adjustments for potential confounders, such as pubertal stage and sex, followed by Bonferroni test when more than two groups were compared.

Linear regression analysis was performed to assess the potential associations of cardiac geometry and function parameters with demographic and clinical/biochemical data.

Results

Clinical and metabolic characteristics

The study population included 30 obese and 15 normal weight children. The two groups were comparable for age, sex distribution, and height, whereas, as expected, weight, BMI, and WC were higher in obese compared to control children. SBP SDS was also higher in obese than in normal weight children (Table 1).

Obese children showed higher values of LDL-C, TG, and TG/HDL ratio and lower levels of HDL-C, compared to normal weight children. ADMA levels were also higher in obese children than in their normal weight peers (Table 1).

Insulin levels and HOMA-IR values were significantly higher in obese than in normal weight children, whereas there were no differences in fasting glycemia between the two groups (Table 1).

Cardiac geometry and function

Atrial and ventricular size

The results of the echocardiographic assessment are reported in Table 2. LA size was significantly increased in obese compared to normal weight children, as indicated by higher LA cranio-caudal and latero-lateral diameters, LA area, and volume (Table 2 and Fig. 1a, b). These differences were maintained after the normalization of atrial measurements for height2.7.

Table 2 Left cardiac geometry and function
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Fig. 1
figure 1

Comparison of obese vs normal weight children: left atrial area (a), left atrial volume (b), and their association with HOMA-IR, respectively (c, d)

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LV mass index was also increased in obese compared to normal weight children, whereas there were no significant differences in other assessed structural LV parameters, such as PWT, IVS, LVDD, and RWT (Table 2).

Diastolic function

Obese children showed subtle abnormalities in the transmitral flow, characterized by an increased peak early filling velocity E and a prolonged DcT of early transmitral blood flow velocity. No significant differences between the two groups were found in the peak late filling velocity A and in the E/A ratio (Table 2).

Regarding myocardial flow velocities, the only different parameter between obese and control children was lateral Am, which was slightly higher in the obese group. The septal and lateral E/Em ratio, an index of LV filling, was not different between the two groups (Table 2).

Associations between cardiac parameters and clinical/biochemical variables

In a univariate model, LA size parameters were all significantly associated with BMI-SDS and WC, as well as with SBP (Table 3). The association between LA size and BMI-SDS and WC persisted after adjusting for age, pubertal stage, and sex, while the association with SBP lost statistical significance (Table 4, model 1). When including BMI-SDS and WC in the same regression model, only BMI-SDS remained significantly associated with all LA size parameters (data not shown).

Table 3 Associations between cardiac parameters and clinical/biochemical variables
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Table 4 Associations of individual clinical/biochemical variables and cardiac parameters, after adjusting for age, sex pubertal stage (model A), and BMI-SDS (model B)
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In the univariate model, LA size was also associated with HOMA-IR, ADMA, and TG/HDL ratio (Table 3). These associations remained statistically significant after adjusting for age, sex, and pubertal stage (Table 4, model A). When BMI-SDS was added into the regression model (Table 4, model B), HOMA-IR remained significantly associated with LA diameter, area, and volume (Fig. 1c, d), whereas ADMA only reached borderline statistical significance (Table 4, model B).

LV mass was significantly associated with adiposity indexes (BMI-SDS and WC) (Table 3). Significant associations were also found between LV mass and HOMA-IR, although this was not maintained after adjusting for BMI (Table 4).

Peak E was only associated with SBP, but this association was lost after adjusting for age, sex, and pubertal stage (r = 0.143, p = 0.459).

To further explore the effect of HOMA-IR on cardiac parameters, the study population was divided into tertiles of HOMA-IR. In an analysis of covariance, after adjusting for BMI-SDS, a significant trend across HOMA-IR tertiles was found in LA area (adjusted mean ± SD = 11.7 ± 2.4 vs 13.0 ± 2.1 vs 14.7 ± 2.3 cm2, p for trend = 0.01), with a significant difference between the first and last tertiles (p = 0.009) and LA volume (24.7 ± 9.7 vs 29.0 ± 8.5 vs 37.7 ± 9.3 ml, p for trend = 0.005), with again a significant difference between the first and last tertiles (p = 0.006).

Discussion

The present study showed that obese children have an increased LA size and initial alterations in LV geometry and diastolic function when compared to their normal weight peers. Adiposity and insulin resistance were significantly associated with these early cardiac changes.

Increased LA size

Our study showed marked variations in the LA dimension: a clear LA enlargement was observed in obese youth compared to their normal weight peers. In addition, LA size, both in terms of diameters, area, and volume, was independently associated with adiposity indexes, such as BMI and WC. These findings are in line with some previous studies reporting LA enlargement in obese compared to normal weight peers [6, 19, 26, 27, 32, 45]. The present study confirmed that excess body weight is associated with LA enlargement as early as during childhood and adolescence and remarkably in youth without hypertension. This finding is clinically relevant, because in obese adults an increased LA size has been associated with adverse cardiovascular events, including risk for atrial fibrillation, congestive heart failure, and stroke [1, 5, 7, 38].

Increased LV mass and LV diastolic dysfunction

LV mass index was also increased in obese children, and this parameter was independently associated with BMI. This is in line with previous studies where obese and overweight adults and children had increased LV mass even in the absence of arterial hypertension [12, 18, 43]. This finding is clinically relevant because the persistence of the obesity status overtime may lead to the development of hypertension, which in turn may add an additional load for the LV.

Another key finding of the present study was the detection of subtle abnormalities in some parameters related to LV function, suggestive of an initial impairment of LV diastolic function. In particular, the transmitral flow assessment showed that obese children presented higher E values and DcT, whereas in terms of myocardial flow velocities, there was only a small difference between the two groups in the lateral Am. These findings are in line with those from some previous studies [45] but in contrast with some others, mainly performed in adults with a longer duration of obesity, where a reduced peak E was detected [42, 46]. Duration of obesity has been suggested as a main determinant of cardiac remodeling [2], with longer duration being associated with more evident cardiac morphological and functional abnormalities. This aspect, as well as different degrees of obesity [4], may explain different findings between obese adults and children and contrasting results between studies performed within the pediatric population. The findings of the present study might reflect a specific obesity pattern of alterations associated with an early onset and short duration of obesity.

Impact of insulin resistance on cardiac changes

The abnormal cardiac structural findings of the present study are of particular interest mainly because they emerged from a group of apparently healthy obese youth, in the absence of metabolic alterations, such as dyslipidemia, impaired glucose tolerance/type 2 diabetes, or hypertension, a well-known risk factor for cardiac structure modifications [14]. Particularly, in children with hypertension, excess body weight has been associated with LA size, independently of blood pressure [15], suggesting a potential role of other obesity-related mechanisms, including hyperinsulinemia/insulin resistance [32]. Reduced insulin sensitivity is a common finding among obese children, already during the prepubertal period [9]. This metabolic abnormality is not only a risk factor for future development of type 2 diabetes, but it is also associated with the presence of other cardiometabolic risk factors, such as increased blood pressure, dyslipidemia, and liver steatosis [9]. In obese children, insulin resistance represents also a key link between excess body weight and the associated cardiovascular  risk, being one of the first mechanisms involved in the development of vascular endothelial dysfunction [9] and early vascular alterations, such as increased carotid intima–media thickness [22]. The independent association between insulin resistance and LA enlargement observed in this study highlights another possible negative effect mediated by insulin resistance in the context of obesity. This is supported by previous data from animal and human studies showing a role of obesity-associated insulin resistance in mediating alterations in myocardial metabolism, by acting on fatty acid uptake and oxidation [39]. Previously, several mechanisms have been proposed to explain the association between insulin resistance and cardiac structure [44]. In particular, the most likely ones in our normoglycemic population might be related to the associated hyperinsulinemia and include a growth effect on the cardiac myocytes, altered vascular compliance, matrix remodeling, and increased sodium reabsorption [44].

In the present study, we also assessed potential associations between some selected cardiovascular markers, in particular the TG/HDL ratio and ADMA, and left cardiac size. Recently, there has been growing interest in the role of the TG/HDL ratio as a potential new marker of cardiovascular risk. Previous studies have shown that in obese adults and children, the TG/HDL ratio is associated with insulin resistance and early signs of cardiovascular complications, such as increased intima–media thickness [16, 24]. In contrast, in our study, although this index was increased in obese children, it did not emerge to have an independent effect on cardiac structure, but it may be considered as a surrogate marker of obesity in this setting.

Another finding in the present study was the association between LA size and ADMA levels, although this association was mainly mediated by adiposity. ADMA is an endogenous inhibitor of nitric oxide synthase, and it has been associated with an increased cardiovascular morbidity and mortality in adults [3] and with adverse cardiovascular outcomes even in the pediatric population [10]. In line with our finding, a previous study showed an association between cardiac structure parameters and ADMA, which was mainly explained by an effect of BMI on both variables [30], suggesting that increased ADMA and LA size may be the result of common mechanisms acting in the context of obesity. However, further studies are required to better explore the potential causal relationship between LA size and ADMA.

Some limitations of the present study need to be acknowledged, including in particular the small sample size and the cross-sectional design. However, the study population underwent a large number of echocardiographic parameters including not only geometry but also diastolic function parameters, thus allowing a good cardiac evaluation.

In conclusion, this pilot study suggests that the alterations in cardiac geometry and function previously observed in obese adults also occur in the context of obesity in childhood and adolescence. The finding that LA morphological alterations and only few abnormalities in diastolic function parameters occur in obese children compared with their normal weight peers leads to the hypothesis that obesity has an earlier negative impact on the cardiac geometry and only later can affect also LV diastolic function. These morphological cardiac changes were independently associated with insulin resistance, although future longitudinal studies are required to test a pathogenetic role of insulin resistance.

Overall, these findings suggest that assessing cardiac function and structure may represent an important clinical tool for estimating cardiovascular risk in obese youth. At present, the overtime progression of the detected cardiac abnormalities is unknown. Therefore, follow-up of the study population would be of paramount importance to clarify this issue. A further point to clarify is the correlation between the reported abnormalities during childhood and cardiovascular outcomes during adulthood.