Left Ventricular Hypertrophy in Obese Children

Childhood obesity is one of the most troubling health conditions worldwide, and it is associated with many diseases that eventually lead to serious morbidities and mortality in adulthood, such as insulin resistance, type 2 diabetes mellitus, high blood pressure, dyslipidemia, obstructive sleep apnea and subsequent renal, and liver and cardiovascular diseases. Cardiovascular disease carries the most risk of all of the long-term outcomes of obesity because it is associated with serious complications in adult life, such as heart failure, acute coronary syndrome, and premature sudden death. This review aims to address childhood obesity as a worldwide health concern and focuses on the cardiovascular risk and adverse outcomes associated with this condition. This review presents details of obesity-related cardiac structural and functional changes, such as left ventricular hypertrophy (LVH) and dysfunction, respectively. A search of multiple medical databases was performed, and the results yielded many studies related to pediatric left ventricular hypertrophy; seventeen studies were found on left ventricular hypertrophy in obese children from 1980 to 2015. Most of these studies demonstrated that obesity and its comorbidities are important predictors for left ventricular hypertrophy in the pediatric age group. Furthermore, weight reduction is an important measure to reverse these structural changes and reduce the associated risks.


Introduction
Childhood obesity is one of the most troubling health conditions worldwide [1]. The association of this condition with many diseases that eventually lead to serious morbidities and mortality in adulthood makes it a challenging public health concern. Morbidities include insulin resistance, type 2 diabetes mellitus, high blood pressure, dyslipidemia, obstructive sleep apnea and subsequent renal, liver and cardiovascular diseases. Obesity is also a risk factor for multiple cancers in adults [2][3][4].
The prevalence of childhood obesity has increased significantly in recent years, and it has become an epidemic in certain areas. The recent WHO Global Database on Child Growth and Malnutrition report states "in the year 2013, an estimate of 42 million children under the age of five around the world are either overweight or obese" [5]. In addition to that, the prevalence of obesity is increasing in all childhood ages, including both males and females of different ethnicities, [6]. Obesity is most often caused by a disturbance in energy balance, which occurs when a child embraces a sedentary life style with decreased physical activity, increased caloric intake, or both. Other factors, such as hormonal, psychosocial, medical and genetic factors, also contribute to the development of obesity but to a much lesser extent.
Classification of childhood obesity as "overweight" or "obese" is determined using the body mass index (BMI) of the child compared to the average BMI for children of the same sex and age rather than the fixed parameters used in the adult index. These measurements are plotted on the growth charts displayed in Figures 1 and 2.
The Center of Disease Control and Prevention defines 'overweight' as "a BMI at or above the 85 th percentile and below the 95 th percentile for children and teens of the same age and sex". 'Obesity' is defined as "a BMI at or above the 95 th percentile for children and teens of the same age and sex".
Body mass index is calculated as the child's weight in kilograms divided by the square of his\her height in meters. Many studies reported that obese children are more likely to turn into obese adults [7]. This

The metabolic effect of childhood obesity
Childhood obesity may lead to many metabolic disturbances, including insulin resistance and subsequent type 2 diabetes mellitus, abnormal lipid profiles and fatty infiltration of the liver. This condition may produce a state of hormonal dysregulation and chronic inflammation because of the association of an increased percentage of adipose tissue and elevated inflammatory cells and cytokines. Obesity also contributes to vascular hemostasis irregularities, reproductive abnormalities and unusual immune responses [9,10].

Dyslipidemia
Children with increased body weight tend to exhibit an abnormal lipid profile. Increased body fat directly elevates lipid parameters [11]. Abnormalities that are classically observed in these populations are elevated triglyceride and decreased high-density lipoprotein (HDL) levels [12]. Low-density lipoprotein (LDL) levels may be normal or high.

Insulin resistance and the metabolic syndrome
Weiss et al. [13] defined childhood metabolic syndrome as a cluster of potent risk factors that present during childhood and significantly increase the likelihood of developing type 2 diabetes mellitus, atherosclerosis and subsequent cardiovascular disease in adults. This cluster of risk factors includes hypertension, hyperlipidemia, insulin resistance and obesity. The most significant impact of these factors is shown to be on the adult population, but the sequence of events that lead to the development of the cardiovascular disease begins during childhood.
Many studies demonstrated that obesity is the cornerstone of the development of childhood metabolic syndrome [14,15]. Weiss et al. also reported that the prevalence of metabolic syndrome was directly proportional to the severity of obesity. Metabolic syndrome is observed in up to 50 % of severely obese children and adolescents. The International Diabetes Federation provided more comprehensive criteria to define childhood metabolic syndrome based on the age of the child (table 3).
A local hospital-based study was conducted in Saudi Arabia at King Abdulaziz University hospital [16] to determine the prevalence of metabolic syndrome in overweight and obese Saudi children from 2 to 18 years of age. A total of 173 of the 387 participants exhibited hyperinsulinism (44.7 %), 55 children exhibited metabolic syndrome (14.29 %) and 35 children had type 2 diabetes mellitus (9.04 %). This study concluded that metabolic syndrome and type 2 diabetes mellitus were prevalent in overweight and obese children. Early management of obesity, with a hope of prevention, is vital to maintain optimal health and prevent unnecessary complications.

Childhood obesity and blood pressure
Recent studies reported that childhood hypertension was prevalent in overweight and obese children. Some studies stated that childhood obesity was the most relevant risk factor to essential high blood pressure in children [17][18][19] other risk factors included family history of hypertension and ethnicity. Hypertension in children is categorized based on the normal distribution of blood pressure in children of the same age and sex. Normal blood pressure is defined as "systolic and diastolic blood pressure that is less than the 90 th percentile for sex, age, and height on at least three separate occasions". Stage 1 hypertension is "Systolic and/or diastolic BP between the 95th percentile and 5 mmHg above the 99 th percentile or if in adolescents the BP exceeds 140/90 mmHg even <95 th percentile". Stage 2 hypertension is "Systolic and/or diastolic BP ≥ 99 th percentile plus 5 mmHg" [20]. High blood pressure is a serious condition that leads to dreadful adverse outcomes, such as cardiovascular accidents, heart failure, renal failure, seizures, and encephalopathy, if left unmanaged.
Weight is strongly associated with blood pressure, which supports the importance of weight loss on reducing elevated blood pressure. Weight loss is one of the most effective measures in the management and prevention of hypertension and its complications. Clarke et al.

Ref. Sample Date Outcome
Dušan et al. [36] 103 obese subjects aged 9 to 19 years 2015 LVH was found in 10 % of subjects Pieruzzi et al. [44] 526 obese children aged 6 to 15 years 2015 Obesity was significantly associated with diastolic dysfunction and correlated with concentric hypertrophy of the left ventricles (P < 0.001) Stephen et al. [41] 201 children and adolescents from 6 to 17 years old 1995 Lean body mass is a significant predictor for left ventricular mass. The prevalence of LVH in hypertensive children was higher (44.5 %) compared to children with normal blood pressure (9.1 %).
Stephen et al. [39] 201 children and adolescents from 6 to 17 years old 1995 The variance of left ventricular mass explained by the model was 77 %. Systolic blood pressure explained only 0.5 % of the variance.

Fat mass and distribution
Pieruzzi et al. [44] 526 obese children aged 6 to 15 years 2015 Waist circumference z-scores were significantly associated diastolic dysfunction.
Daniels et al. [49] 123 children and adolescent aged 9 to 17 years 1999 There was a significant correlation between fat percentage and fat distribution with left ventricular mass (r=0.37).  [21,22] used a 10-year retrospective observational study and reported that any weight change directly affected blood pressure. Weight gain led to elevations in blood pressure, and weight loss helped in reduction of blood pressure.

Childhood obesity and cardiovascular risk
The presence of obesity in children increases the risk of developing cardiovascular disease during adulthood because of the association between obesity and the development of atherosclerosis (which is the main element of the pathogenesis of this disease). Excess adipose tissue in children often leads to physiological, inflammatory and metabolic disturbances. These dysregulations increase the probability of children exhibiting signs of premature cardiac dysfunction and structural abnormalities in subsequent events. Therefore, obese children may exhibit cardiometabolic patterns that are similar to obese adults [23,24].
Wong et al. [25] defined obesity-related cardiomyopathy as "myocardial disease in obese individual that cannot be explained by diabetes mellitus, hypertension, coronary artery disease or other etiologies".
Recent studies identified obesity as an independent predictor for heart [26,27]. Furthermore, the duration of Obesity is another important predictor for the development of cardiac dysfunction and structural abnormalities, which predisposes children to heart failure in early adulthood [28,29]. Since obese children tend to grow into obese adults, early identification of these cardiovascular changes and weight reduction are important to ensure the reversibility of these changes.

Obesity-related left ventricular hypertrophy (LVH) and cardiac dysfunction
Left ventricular geometry is assessed using echocardiographic measurements. It is classified into the following four groups based on left ventricular mass (LVM) and relative wall thickness (RWT): concentric hypertrophy "increased mass and increased relative wall thickness", eccentric hypertrophy "increased mass and normal relative wall thickness", concentric remodeling "normal mass and increased relative wall thickness", and normal geometry "normal mass and normal relative wall thickness [30] (Figure 3). Left ventricular mass index (LVMI) is calculated by indexing the echocardiographic measurement to height to a 2.7 power. One study of more than 2000 children revealed that "for children above 9 years LVM/height 2.7 values > 40 g/m 2.7 in girls and >45 g/m 2.7 in boys can be considered abnormal because it falls beyond the 95 th percentile of the normal LVMI distribution for age and sex" [31]. Cardiac diastolic function is evaluated using a Doppler echocardiography by measuring the mitral E/A ratio.
Obese children, especially children with severe obesity, exhibit a tendency to develop abnormal left ventricular geometry (left ventricular hypertrophy or relative wall thickness) and cardiac dysfunction [32][33][34]. The underlying pathogenesis is that obese children have increased metabolic activity due to the presence of excess adipose tissue, which leads to increased heart output and total blood volume to meet the metabolic demands. This compensatory process causes the structural changes and cardiac dysfunction that are occasionally observed in obese children [35].
One study of the relative effect of elevated blood pressure and obesity on left ventricular mass demonstrated statistically significant results, which supports the roles of obesity and elevated blood pressure as independent factors that increase the probability of the occurrence of LVH. Data analysis revealed that "obesity OR = 3.26, p<0.001. In addition, high blood pressure showed an OR = 2.92, p<0.001". High blood pressure and obesity together exert an additive effect on the Plus any two of the following four factors: • Raised triglycerides > 1.7 mmol/L • Reduced HDL-cholesterol: <1.03 mmol/L (<40 mg/dL) in males and <1.29 mmol/L (<50 mg/dL) in females, or specific treatment for these lipids abnormalities • Raised blood pressure: systolic Bϑ + 130 or diastolic Bϑ = 85 mm Hg, or treatment of previously diagnosed hypertension • Impaired fasting glycemia (IFG): fasting plasma glucose (FPG)=5.6 ,,ol/L • (> 100 mg/dL), or previosly diagnosed type 2 diabetes WC: waist Circumference; HDL-C: high-density lipoprotein chelostrol; T2DM: type 2 diabetes mellitus; OGTT; oral glucose tolerance test. The IDF Consensus group recognise that these are ethnic, gender and age difference but research is still needed an outcomes to establish risk. Kinik et al. [48] 30 obese children who were matched to a control group 2006 There was a slight correlation between insulin and lipid profile with relative wall thickness of the heart, but when these measures were indexed to height, the study failed to show any correlation.
Relative wall thickness correlates directly to BMI. Other metabolic conditions that are generally associated with obesity, such as waist circumference, insulin resistance, and hyperlipidemia, are also associated with LVH [40]. This is a topic of interest because LVH (among other factors) has been established as an independent risk factor for cardiovascular disease in adults. Multiple data analyses demonstrated that LVMI exhibited the highest independent relative risk for the development of these events in the future [41,42].
Among different left ventricular geometry patterns, concentric hypertrophy is the most prevalent type of LV remodeling observed in obese children, and this pattern in particular is shown to have the worst prognosis. One recent study reported [43] that 40% of obese children had concentric hypertrophy, 40 % had normal geometry, and 20% had eccentric hypertrophy or concentric remodeling. These signs may be present at an early age in obese children, even before 9 years of age. Other studies reported similar results [44,45]. Obesity prevention and early management using weight reduction (conventional or surgical) are important nonpharmacological measures to ameliorate LVM and reverse most cardiac abnormalities that are associated with obesity in children. One study [46] has evaluated morbidly obese adolescents before and after bariatric surgery and demonstrated that the prevalence of concentric LVH improved from 28% pre-operatively to only 3% at follow up. Furthermore, normal LV geometr was more frequently observed from 36% to 79% at follow up, and diastolic function also improved.

Lipid profile and LVH
An abnormal lipid profile is one of the metabolic disturbances caused by obesity and elevated fat mass. Moreover, it is associated with cardiovascular accidents, and plays a role in the pathogenesis of developing atherosclerosis. However, it is not well known whether a significant relationship between dyslipidemia and LVH exists or the relationship is not more than an indirect association because dyslipidemia is a "comorbidity of obesity". A recent study in Indonesia [47] examined the relationship between lipid profile and LVM in obese adolescents, and the results demonstrated no significant association between lipid profile disturbances with LVM. Another study [48] demonstrated that relative left ventricular wall thickness (intraventricular septum and left ventricular posterior wall thickness) correlated with insulin, very low-density lipoprotein, and triglyceride levels. Data in this area are inconsistent, and further research is needed.

Fat mass and distribution and LVH
In addition to abnormal lipid profile, the percentage of fat and its distribution are also related to LVH. One study demonstrated significant (P<0.05) univariate correlations between fat distribution (central deposition of fat-android pattern) and fat mass with LVM. The correlation coefficient between the android pattern and LVH was equal (r=0.37) [49].

High blood pressure and LVH
Hypertension is an independent predictor for the development of LVH, and LVH is the most prevalent end organ damage in children with hypertension. LVH correlates with the severity of hypertension, and it generally indicates a worse prognosis [50]. Falkner et al. [51] investigated 301 African-American adolescents and reported that "adolescents with higher blood pressure had higher left ventricular mass index (33.2 vs. 38.7 gm/m 2.7, p<0.001) and greater left ventricular hypertrophy". The effect of blood pressure was independent of obesity.
Obesity and high blood pressure promote concentric LV remolding, but this change is more highly associated with high blood pressure than obesity [52,53].

Obstructive sleep apnea and LVH
Obstructive sleep apnea is defined as a complete cessation of airflow for >10s during sleep. The decrease in airflow leads to a fall in oxygen saturation (i.e., nocturnal hypoxemia). Obstructive sleep apnea is associated with obesity. A strong association between obstructive sleep apnea and LVH was reported previously [54]. LVH was observed in 78-88% of adults [55,56] as well as 40% of children with obstructive sleep apnea. "Low nocturnal oxygen saturation" was the strongest independent predictor for LVH compared to other factors, such as systolic BP and BMI (P<0.001) [57,58].

Conclusion
Obesity is one of the most prevalent public health problems worldwide, and it affects nearly one in five children. Obesity is associated with many short-and long-term complications, and it predisposes children to adult onset obesity, cardiovascular-associated morbidities and premature death.
The process of developing this risk begins during childhood because obesity is an independent risk factor for the development of LVH and cardiac dysfunction. Other factors that are generally associated with obesity, such as dyslipidemia, insulin resistance, fat mass distribution, high blood pressure, and nocturnal hypoxemia, are also related to LVH. These factors, especially high blood pressure and nocturnal hypoxemia, exert a synergetic effect with obesity for the development of LVH, which is more common and prevalent when these two conditions coexist.
Obesity prevention and early management using weight reduction (conventional or surgical) are important nonpharmacological measures to ameliorate left ventricular mass and reverse most cardiac abnormalities that are associated with obesity in children.
Future efforts should focus on parents and the public to recognize the health consequences of obesity in young children and adolescents and spread greater awareness of this condition by encouraging everyone to play an active role in the prevention and early management of obesity in the young. Completion of this goal requires a collaborative effort between the medical profession, government and the public.