Left ventricular remodeling patterns in children with metabolic syndrome

Veronica ESANU1, Ina PALII1, Veronica MOCANU3, Lorina VUDU2, Valeriu ESANU1, 1Department of Pediatrics, Nicolae Testemitanu State University of Medicine and Pharmacy, Republic of Moldova 2Department of Endocrinology, Nicolae Testemitanu State University of Medicine and Pharmacy, R. of Moldova 3Department of Morpho-functional Sciences Pathophysiology, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania


INTRODUCTION
Metabolic syndrome (MS) is considered a recent major health problem, although scientific advances and therapeutic strategies have provided lots of opportunities for its management. It gets even more important if it occurs in children since the therapeutic possibilities in pediatric patients are quite limited due to the considerable side effects and/or no sufficient studies so far.
Metabolic syndrome is a pediatric pathology, leading to several early disorders, including cardiovascular disease (CVD) (1), showing an increased risk due to its early onset and duration. The prevalence rate varies between 10% and 84%, depending on the geographical region, environment, individual demographic characteristics (gender, age, race, and ethnic origin), as well as other criteria used for its defining (2). In terms of gender, most studies show a higher frequency in males (3,4), whereas the differences also vary depending on the age gaps, being higher in males than adolescent females (10.9% vs 6.29%), subsequently being reversed in adulthood (18% vs 20% at the age of 20-39 years and 42% vs 51% at the age ≤ 60 years) (5).
Pediatric MS correlates with cardiac structural and geometrical changes, leading to a cardiac pathological remodeling, which is considered a substrate for developing heart failure, being also a strong predictor of arrhythmia, characterized by an impaired heart function (systolic and diastolic) and an early risk of sudden death (6).
While considering the aforementioned arguments and the impact of childhood health on further adult health, we considered to choose the following research on left ventricular remodeling patterns in children with MS, that will contribute to the opening of new perspectives for identifying a single and effective approach, as well as for preventing cardiovascular complications of this syndrome, based on IDF criteria adapted for children, to reduce the morbidity and mortality rates at a young age.

MATERIAL AND METHODS
The purpose of the research: to study the left ventricular remodeling patterns in children with metabolic syndrome.
General design and study population. The study project was carried out within the IMPH IMC, at the Department of Pediatrics of the Pediatric Cardiology Clinic, to which 161 children were admitted, aged from 10 to 17 years 11 months and 29 days, from both urban and rural areas, the patients being selected electively during the 2016 -2019 period. An observational analytical cohort study was planned to achieve the research purpose.
The research comprised several stages. The 1 st stage included 145 children (out of 161 participants, 16 ineligible), who were selected based on the inclusion/exclusion criteria, and made up the research group according to the following criteria: the age of 10 -17 years 11 months and 29 days (inclusive); with abdominal obesity (waist circumference (WC) ≥ 90 th percentile (7)); the child's parent or guardian consent, as well as children's assent (age ≥ 14 years) on research participation; being a citizen of the Republic of Moldova; ability to effectively communicate with the researcher; ability to understand and follow the study requirements; sufficient understanding in signing the informed agreement and written assent.
The study exclusion criteria for the patients were the following: secondary obesity: endocrine, genetic and neurological type, having a suggestive clinical examination, confirmed by specialized examinations; secondary high blood pressure: renal, endocrine, neurogenic, drug -induced, etc., patients having a suggestive clinical examination, confirmed by specialized examinations; acute conditions, whether or not accompanied by fever, whether or not undergoing treatment; chronic respiratory, cardiovascular, gastrointestinal, renal, neurological, endocrine, etc., disorders, whether or not undergoing treatment; the child's parents or legal representative disagreement, child's refusal to participate in the research, with a difficult ultrasound window, low compliance, patient's refusal to be included in the study.
The selected participants underwent a complex examination, which included: filling in a specific questionnaire (food and physical activity survey), the clinical examination on systems, laboratory testing for lipid status (total cholesterol (TCh), triglycerides (TG), high-density cholesterol (HDLc)), the glucose (Glu) spectrum (basal glucose, oral glucose tolerance test (OGTT)selectively) and uric acid.
Following the clinical and paraclinical findings, the 2 nd stage included the respondent's selfdivision into 2 groups, by using the criteria of MS according to the Consensus of the IDF adapted for children [1], namely: the research group (L1) -53 de children with MS (including 3 -5 criteria) and control group (L0) -92 children without MS (including 1 -2 criteria). The ratio of the study groups was 1:2. Subsequently, subjects from both groups were investigated by transthoracic echocardiography.
The 3 rd stage included a comparative study of the two groups, in terms of lifestyle, symptoms, demographic, anamnestic and biochemical profile, cardiac function and morphology, etc., as well as a statistical analysis of the obtained results. Practical conclusions and recommendations, based on the obtained results, were traced out at the 4 th stage of the study.
All the participants were selected and informed about the research stages, being enrolled only by personal informed consent, following a detailed explanation of the requirements and procedures of necessary investigations by discussing with each subject individually. All the procedures were performed, based on children's parent and legal representative consent, as well as on written assent of children ≥ 14 years old. They were not paid and have not suffered any financial costs for participation.
Ethical considerations. The study complied with the international standards of medical ethics, developed by the Declaration of Helsinki, regarding confidentiality and personal data protection of the participants. The research was approved by the Research Ethics Committee of State University of Medicine and Pharmacy Nicolae Testemitanu (report no. 59 of 03.06.2016). The resulting data were revealed only to the concerned participant, the personal data of each subject were not used and will not be used for any other purpose. The study applied the following research methods: historical, comparative, biostatistics ones, and others.
Metabolic syndrome. MS was defined according to the IDF consensus definition of metabolic syndrome in children (8): WC≥90 th percentile or adult cut-off if lower, plus any two of the following four factors: TG≥1.7 mmol/L, HDLc<1.03 mmol/L, BP systolic ≥130 and diastolic ≥85 mmHg (> 95 th percentile for age, height, and sex), Glu≥5.6 mmol/L (If≥5.6 mmol/L (or known T2DM) recommend an OGTT) for age group 10 -<16 years, and use existing IDF criteria for adults: central obesity (defined as WC≥94 cm for Europid men and ≥ 80cm for Europid women, with ethnicity specific values for other groups) plus any two of the following four factors: TG≥1.7mmol/L or specific treatment for high TG, reduced HDLc: <1.03mmol/L in males and <1.29 mmol/L in females, or specific treatment for low HDLc, systolic BP≥130 mmHg or diastolic BP≥85 mmHg or treatment of previously diagnosed Arterial Hypertension, and Glu≥5.6 mmol/L or known T2DM for age group >16 years.
Left ventricular geometry pattern. To define the LV geometry pattern, we measured the myocardial mass index by M-mode echocardiography using the Devereux formula and normalized to height 2,7 , as well as the relative wall thickness (RWT) defined as LV wall thickness + septal thickness relative to the internal dimensions of the LV. The LVH was diagnosed by cutoff value utilized in adults (51 g/m) corresponding to the 97.5 th percentile in children (9). The LV geometric patterns (normal, eccentric or concentric LV hypertrophy, and concentric LV remodeling) were calculated according to the left ventricular mass index (LVMI) and RWT. All echocardiographic measurements were conducted using the Toshiba Aplio 300, MODEL TUS-A300 Cardiac Ultrasound Machine, by a specialized sonographer, who was unaware of the patients' diagnosis.
Covariates. Apart from standard biochemical parameters to confirm the diagnosis of MS, uric acid level, and LDLc (TCh -HDLc -TG/5), were determined in every patient. All blood specimens were taken after an overnight fasting. Additional clinical evaluation included medical history, lifestyle questionnaire, anthropometric measurements, physical examination, etc.
Statistical analysis. The data collected from the primary material were introduced into the electronic database, whereas the statistical processing was performed using the Statistical Package for the Social Sciences (SPSS) version 20.

RESULTS
According to the inclusion and exclusion criteria, there was formed a general group, including 145 participants, of which 36.6% (53 pts) children with MS (research group) and 63.4 % (92 pts) children with non-MS (control group). Gender groups were divided into 55.9% boys (81 pts) and 44.1% girls (64 pts) of the total number of enrolled children. MS was present in 39.5% (32 pts) boys vs 32.8% (21 pts) girls, and non-MS in 60.5% (49 pts) boys vs 67.2% (43 pts) girls (χ2=0.69; p>0.05). Also, there were selected 5 factors of MS (according to the IDF consensus, adapted for children). The first factor (F1) -obesity, was recorded in 100% (145 pts) of cases in order of prevalence (it might be because children included in the study exhibited WC ≥ 90 th percentile), the second factor (F2) found in 47.6% (69 pts) of cases, showed low values of HDLc and the third factor (F3), found in 25.5% (37 pts) of cases, which were defined by high TG was named the lipidic factor. The fourth factor (F4), recorded in 42.8% (62 pts) of cases with high BP values (BP systolic and/or BP diastolic), was called the blood pressure factor, and the fifth factor (F5), reported in 7.6% (11 pts) of cases with higher than normal blood Glu levels, was related to carbohydrate metabolism, is less prevalent.
The assessment of pediatric MS was also performed by detecting the components and their association. The prevalence of cases with defined MS was assessed using clustering patterns, which was estimated according to the number of criteria (tab.1).
Depending on the number of MS criteria, a normal LV geometry appearance was found in

DISCUSSIONS
MS is a clinical condition, which is associated with an increased risk of cardiovascular diseases (10). The present study investigated a welldefined general population, aged between 10-18 years, the prevalence of the MS and that of its contributors, as well as the relationship with non-invasively measured markers of cardiac involvement.
The syndrome was found to have a considerable prevalence in the pediatric population, averaging 36.6% of all subjects aged between 10-18 years, showing greater prevalence among boys (39.5% vs 32.8%), which was similar to previous studies (10).
Regarding the MS-related factors, apart from visceral adiposity present by definition in 100% of cases, high TG (25.5%), high BP (42.8%), and low HDLc (47.6%) values were the most frequently detected.
The assessment of pediatric MS was also performed by detecting the components and their association. The prevalence of cases with defined MS was assessed by using the clustering patterns, being estimated according to a number of criteria. The clusters WC+HDLc+HBP, WC+TG+ HDLc, WC+TG+HDLc+HBP, WC+TG+HBP were the most frequently registered. Obesity cases were found to be associated with dyslipidemia, high BP, and glucose regulation disorders (similar data were found in specialized literature among the adult population, whereas no data were recorded for the pediatric population).
In our study, MS subjects-compared to non-MS had significantly higher values of weight, waist circumference, hip circumference, triglycerides, as well as lower levels of HDL-cholesterol. The anthropometric and biochemical data altogether are the most important features of metabolic syndrome in this present research.
The analysis of cardiac remodeling types showed a higher incidence in pediatric subjects with normal LV geometric appearance -62.1%. The three pathological LV remodeling subtypes (eccentric hypertrophy, concentric hypertrophy, and concentric remodeling) showed a higher rate for concentric LV hypertrophy -27.6%, followed by concentric LV remodeling type -5.5% and eccentric LV hypertrophy -4.8%, which was predominantly found in males, for three positive criteria, and within the following clusters WC+HDLc+HBP, WC+TG+HDLc, WC+TG+HDLc+ Glu, WC+TG+ HDLc+HBP, showing no statistically significant difference (p>0.05; similar data were found in specialized literature among the adult population, whereas no data were recorded for pediatric population).
Finally, during the research, the potential risk of installing remodeling patterns of LV myocardium in children with MS was also estimated, after calculating the necessary indicators. The syndrome was found to be a risk factor, as well as an association between MS and remodeling of the LV myocardium, which has been identified.
Some limitations of this study must be taken into account. The current study included a relatively small number of patients, particularly of subjects aged between 16-18 years, although metabolic syndrome is considered to have a high incidence rate. The main study limitation regarding the patients'enrollment was the fact that we aimed at identifying pediatric subjects with MS from within the Cardiology Clinic. Another reason for a relatively small number of participants was the careful selection of patients, as to obtain an optimal ultrasound window, for an accurate analysis of the echocardiographic data. The short-term MS installation is another study limitation.
2. The analysis of cardiac remodeling types showed a higher incidence in pediatric subjects wi th nor mal left ventricular geometric appearance -62.1%. The three pathological remodeling subtypes (eccentric hypertrophy, concentric hypertrophy, and concentric remodeling) showed a higher rate for concentric left ventricular hypertrophy -27.6%, followed by concentric left ventricular remodeling type -5.5% and eccentric left ventricular hypertrophy -4.8%.

3.
In children aged 10-18 years, metabolic syndrome is a risk factor and has a positive association with the development of left ventricular myocardial remodeling (relative risk=1.7, confidence in-terval=1.3-4.2).

PRACTICAL RECOMMENDATIONS
1. Screening of the metabolic syndrome is recommended in children with abdom inal obesity, aged 10 -18 years in order to detect those cases, who are at risk of developing complications.
2. Echocardiography is recommended to assess the presence of structural remodeling patterns of left ventricular myocardium, which will allow detecting children with metabolic syndrome and those who are at higher risk for developing cardiovascular complications.