Childhood obesity is increasing worldwide and is associated with hypertension, increased insulin resistance, dyslipidemia and cardiovascular complications, resulting in high morbidity and mortality.1,2 It is known that altered energy metabolism due to an imbalance in the sympathoadrenal system has a crucial underlying role in the development of obesity. In addition, increased catecholamine secretion and altered reactions to stressors have been shown in obesity.3,4

Heart rate variability (HRV) is defined as beat-to-beat variability in heart rhythm and its measurement is a noninvasive and trustworthy method for assessment of cardiac autonomic function.4–6 Reduced HRV is associated with sudden cardiac death. Houlguin et al.7 reported that supplementation with omega-3 fatty acids caused a significant increase in HRV components in elderly individuals, which was associated with improved cardiac autonomic tone. In a meta-analysis of randomized, double-blind, placebo-controlled clinical trials, Mozaffarian et al.8 demonstrated that fish oil reduced heart rate, probably due to alterations in the automaticity or responsiveness of the sinus node and reductions in systemic vascular resistance. Although a few studies have reported impaired autonomic nervous system activity in obese children,5 there is no research showing the relationship between blood free fatty acids and HRV in the obese pediatric group. We aimed to assess cardiac autonomic function using HRV, as well as a possible relationship between HRV parameters and levels of erythrocyte membrane fatty acids (EMFAs), in obese children.

A total of 48 obese patients – 28 (58.3%) male, mean age 11.95±2.42 years, and 36 healthy controls, 20 (55.5%) male, mean age 12.48±2.27 years – were included in the study (Table 1). There were statistically significant differences between the obese and control groups in BMI (p<0.001), BMI standard deviation (p<0.001), waist/hip ratio (p=0.016), systolic BP (p=0.020) and diastolic BP (p=0.008), but not in age (p=0.311) or gender (p=0.531).

There were significant differences between the obese and control groups in terms of triglycerides (p=0.001), HDL (p<0.001), fasting insulin (p=0.001) and HOMA-IR (p=0.001), while no significant differences were found regarding fasting glucose (p=0.295), total cholesterol (p=0.912) or LDL cholesterol (p=0.237) (Table 1).

Erythrocyte membrane omega-6 fatty acid levels were as follows: linoleic acid (C18:2n6), arachidonic acid (C20:4n6) and dihomo-gamma-linolenic acid (C20:3n6), 48.37±9.64 μg/ml, 58.58±11.12 μg/ml and 6.69±2.24 μg/ml, respectively, in the obese group and 43.90±9.47 μg/ml, 60.31±10.27 μg/ml and 6.36±2.03 μg/ml, respectively, in the control group. Levels of these fatty acids in the obese group were not significantly different from those in the control group (p=0.053, p=0.485 and p=0.502, respectively).

Levels of erythrocyte membrane omega-3 fatty acids – icosapentaenoic acid (C20:5n3) and docosahexaenoic acid (C22:6n3) – were lower in the obese group (3.63±1.83 μg/ml and 10.96±5.62 μg/ml, respectively) than in the control group (16.89±3.46 μg/ml and 13.72±3.66 μg/ml, p<0.001 and p=0.012, respectively) (Table 2).

Mean NN was 699.95±94.03 ms in the obese group and 752.16±72.41 ms in controls (p=0.007). The time-domain HRV parameters RMSSD, SDNN index, NN50 and pNN50 were lower in the obese group (61.43±28.94 ms, 69.12±24.03 ms, 22424.50±11600.56 and 24.96±14.04, respectively) than in the control group (84.08±38.37 ms, 86.13±27.32 ms, 29133.69±14255.94 and 34.84±14.38, respectively) (p=0.003, p=0.003, p=0.020 and p=0.023, respectively). LF and HF values were 26.61±6.37 normalized units (nu) and 17.41±10.23 nu in the obese, compared to 30.00±6.62 nu and 23.38±14.06 nu in controls (p=0.020 and p=0.028, respectively). Other HRV parameters including SDNN and SDANN among time-domain parameters and LF/HF ratio among frequency-domain parameters were similar in the obese and control groups (Table 3).

In Pearson correlation analysis in the obese group, linoleic acid, arachidonic acid, BMI standard deviation, triglycerides and HDL showed a linear correlation with one or more HRV parameter, and age, eicosapentaenoic acid, systolic and diastolic BP had a correlation with mean heart rate (Figure 1 and Tables 4 and 5).

Figure 1.

Scatterplots of correlation analysis between parameters of heart rate variability and variables affecting them in the obese group. LF: low-frequency component; SD: standard deviation; TG: triglycerides.

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In linear regression analysis, age, dihomo-gamma-linolenic acid, linoleic acid, arachidonic acid, BMI standard deviation, systolic blood pressure, triglycerides, low-density lipoprotein and HDL had a moderate effect on heart rate variability (Table 6).

To the best of our knowledge, this is the first study to investigate a possible relationship between EMFAs and HRV as an indicator of cardiac autonomic function in obese children. In this study, we determined that HRV parameters were decreased in obese children, implying impairment of sympathovagal balance and parasympathetic tone. We demonstrated lower erythrocyte membrane omega-3 fatty acids levels in obese children than in healthy children, and EMFA levels presented a correlation with one or more HRV parameters or with mean heart rate. In addition, we showed that EMFAs including linoleic acid, eicosapentaenoic acid and arachidonic acid, BMI, triglycerides, and HDL also had an effect on HRV parameters.

Various studies have been performed investigating autonomic function in obese children and adults. Piccirillo et al.18 reported impairment of sympathetic response in normotensive obese adults and Rossi et al.19 described decreased parasympathetic activity with normal sympathetic tone in obese adults. Zahorska-Markiewicz et al.20 detected increased sympathetic tone in obese adults, while Arone et al.21 found lower parasympathetic activity in obese adults, which was improved with weight loss. Rabbone et al.22 showed that adolescent obesity is characterized by imbalance in cardiac vagal response and sympathovagal tone and increased sympathetic hyperactivity. Similarly, the results of Taşçılar et al.5 indicate parasympathetic withdrawal and sympathetic predominance in obese children. Recently, Farinatti et al.23 showed that parasympathetic HRV indices were lower in obese children compared with healthy children. We also demonstrated sympathovagal imbalance and decreased parasympathetic tone, in agreement with the literature.

One of the best non-invasive techniques for assessing autonomic function is analysis of HRV parameters, the simplest of which is R-R interval (beat-to-beat) variability, and which provide numerical data on the autonomic nervous system.4 However, HRV parameters may be affected by many variables such as age, gender, ethnicity, nutrition, obesity, hyperlipidemia, diabetes, hypothyroidism, heart failure, hypertension, coronary artery disease, chronic obstructive pulmonary disease, renal failure, chronic liver disease and drugs.24 In our study, we excluded obese children with these risk factors to avoid possible confounding effects.

There is an association between insulin levels and HRV. HRV is lower in hypertensive patients with insulin resistance.22 Vinik et al.25 found that even mild hyperinsulinemia can impair circadian rhythms of autonomic activity. Recently, Hillebrand et al.26 reported a relationship between body fat and HRV and concluded that insulin resistance may decrease HRV in these patients. It is possible that visceral obesity increases free fatty acid levels in the portal circulation and reduces hepatic insulin clearance, resulting in hyperinsulinemia.27 Our patients had no insulin resistance but HOMA-IR and fasting insulin levels in the obese group were significantly higher than in controls. However, we found no correlation between HOMA-IR, fasting insulin, and HRV parameters in the obese group, and insulin levels were not predictive of HRV parameters in our study.

It is known that hyperlipidemia and increased plasma free fatty acid levels are common in the obese population and that infusion of free fatty acids into the portal vein can activate the sympathetic nervous system.28,29 Verwaerde et al.30 reported that a sudden increase in plasma free fatty acid levels caused tachycardia due to deterioration of parasympathetic tone in dogs, implying that free fatty acids play a significant role in autonomic activity. Shaltout et al.31 found a significant increase in the LF/HF ratio due to high plasma nonesterified fatty acid levels in rats, indicating a reduction in the vagal component of cardiac autonomic control. Stepniakowski and Egan32 assessed venous distensibility in 58 subjects including obese and lean hypertensives and normotensives. They concluded that obesity reduced venous distensibility, which might have hemodynamic effects. They also assessed dorsal hand vein responses to co-infusion of Intralipid 10% and heparin, raising fatty acids locally, in normal volunteers. The infusion reduced hand vein distensibility, implying that elevated nonesterified fatty acid levels may have potent vascular effects. In our study, triglycerides showed a negative correlation with LF, and HDL presented a positive correlation with LF/HF in the obese group. In addition, LDL, HDL, and triglycerides were risk factors for at least one HRV parameter. In view of these findings, we can state that blood lipid levels in obese children may contribute to sympathovagal imbalance.

Essential fatty acids such as omega-3 and omega-6 play important physiological roles in the cell membrane. It has been shown that lower omega-3 fatty acid levels and a decreased omega-3/omega-6 ratio are associated with various diseases.17,33,34 It has been reported that omega-3 fatty acids improved HRV variables in survivors of myocardial infarction.33 A study revealed that dietary supplementation with fish oil enriched with omega-3 enhances HRV indices and that there is a relationship between omega-3 concentrations in the cell membrane and HRV parameters.7 It has been suggested that omega-3 fatty acids prevent ventricular arrhythmias and sudden cardiac death due to myocardial ischemia by binding to sodium channels, and that omega-3 fatty acids reduce levels of tumor necrosis factor-alpha, interleukin-1 and interleukin-2, which are secreted in the early stage of myocardial ischemia and impair myocardial contraction and increase myocardial damage and reactive oxygen species.33 In addition, Minami et al.35 demonstrated that dietary docosahexaenoic acid increased levels of hippocampal acetylcholine, a vagal neurotransmitter, and prevents imbalance of parasympathetic tone by suppressing proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1β, -6, and -18. Thus, omega-3 free fatty acids have protective effects on myocardial tissue by inhibiting proinflammatory cytokines and on cardiac function via the parasympathetic nervous system. In our study, linoleic acid and eicosapentaenoic acid had a negative correlation with HRV parameters reflecting parasympathetic tone. Arachidonic acid was also negatively correlated with LF, indicating impairment of vagal activity. Moreover, dihomo-gamma-linolenic acid, arachidonic acid and eicosapentaenoic acid had a moderate effect on HRV parameters. Although these findings may have been affected by the relatively small study population, specific features of the patients and possible confounding variables on HRV indices, the outcomes suggest a possible contribution of omega-3 and omega-6 fatty acids to decreased HRV in obese children.

There are some limitations in this study. First, the study population is relatively small. Second, prepubertal children were not included. Third, we could not investigate the effect of EMFAs on cardiac systolic and diastolic function by advanced echocardiographic techniques. Finally, from a statistical standpoint, this study lacks the power to assess causality, and there is the risk of spurious correlations between variables because of multiple statistical testing.

In conclusion, we found impairment of cardiac autonomic function in obese children. Although the exact mechanism of this impairment is still unknown, omega-3 and omega-6 fatty acids contributed to autonomic dysfunction in these obese children. Further studies with larger patient populations are needed to define the precise effect of free fatty acids on cardiac autonomic function in obese children.

The authors declare that this study received no financial support.

The authors have no conflicts of interest to declare.