A case series on the potential effect of omega-3-fatty acid supplementation on 24-h heart rate variability and its circadian variation in children with attention deficit (hyperactivity) disorder
Attention deficit disorder with and without hyperactivity (ADHD) in children is associated with decreased 24-h heart rate variability (HRV). Previous research has shown that supplementation of omega-3-fatty acid increases HRV. Here, we aimed to investigate whether the supplementation of omega-3-fatty acids would increase 24-h HRV in an uncontrolled case series of children with ADHD. HRV was recorded in 18 children and adolescents (age 13.35 ± 2.8 years) before and after omega-3 supplementation. Preliminary results indicate that omega-3 supplementation in children with AD(H)D may reduce mean heart rate and increase its variability. Future studies would do well to implement randomized, placebo-controlled designs with greater methodological rigor.
KeywordsHeart rate variability ADHD Vagal activity Circadian variation Omega-3
It has previously been shown that untreated children with attention deficit disorder with and without hyperactivity [AD(H)D] exhibit decreased 24-h heart rate variability [HRV] assessed via Holter ECGs (Buchhorn et al. 2012), albeit absence of altered HRV in short-term resting state recordings (Koenig et al. 2017). Autonomic imbalance, reflected by decreased HRV, is an important indicator of an enhanced cardiovascular morbidity and mortality risk in adults (Wulsin et al. 2015) as well as children and adolescents (Farah et al. 2014; Vrijkotte et al. 2015). Ongoing debate in the AD(H)D literature predominantly focuses on the proarrhythmogenic side effects of psycho-stimulants (Triedman and Alexander 2010) and not on the well-known enhanced cardiovascular risk in patients with psychiatric disease (Neylon et al. 2013).
Nutritional intake of omega-3-fatty acids has a potential positive impact on cognition (Cooper et al. 2015) and emotional dysregulation (Cooper et al. 2016; Messamore and McNamara 2016) associated with AD(H)D, although the existing evidence is mixed (Chang et al. 2017). The DOLAB study showed low blood long-chain omega-3 fatty acids in children with poor cognitive performance and behavior (Montgomery et al. 2013). Several prospective randomized controlled trials support the supplementation of omega-3-fatty acids in children with AD(H)D to improve cognition (Gow et al. 2015; Widenhorn-Müller et al. 2014). Beneficial effects on inattention in AD(H)D and healthy children (Bos et al. 2015) and other psychopathologies across the lifespan have also been reported (Sinn et al. 2010, 2012). However, other studies showed that omega-3-fatty acid supplementation effects cognition only in patients with reduced omega-3 levels (Hawkey and Nigg 2014). Further, omega-3 fatty acids might improve cardiovascular function in children with AD(H)D and thereby reduce the associated cardiovascular risk, but more research is needed on this topic (Simopoulos 2008).
Previous research has shown that the supplementation of omega-3-fatty acid increases HRV (Carney et al. 2010; Christensen 2011; O’Keefe et al. 2006; Romieu et al. 2005). Here, drawing on routine clinical data from a pediatric cardiology department, we aimed to illustrate potential effects of omega-3-fatty acid supplementation on 24-h HRV in children with AD(H)D, based on a case series. We assumed that children with AD(H)D would show increased 24-h HRV and reduced heart rate (HR) after omega-3-fatty acids supplementation.
Patients and procedures
A total of 18 cases, children and adolescents (age 13.35 ± 2.8 years; size 156.8 ± 16.4 cm; weight 50.2 ± 16.7 kg; BMI 20.0±4.1), who were referred to the outpatient clinic for pediatrics of the Caritas Hospital Bad Mergentheim between the years 2010–2016 were identified based on clinical files. Patients with a diagnosis of AD(H)D, made by an external child psychiatrist according ICD-10 diagnostic criteria, were referred to the pediatric cardiology department for evaluation. All patients and their parents were informed about the multimodal therapy for AD(H)D (medications and behavioral therapy) and the possibility to supplement with omega-3-fatty acids. Of the cases included for analysis, some used omega-3 prior to stimulant treatment (n = 4); some after termination of stimulant treatment because of the occurrence of side effects (n = 4); and the majority used omega-3 to reduce the cardiovascular risk during stimulant treatment (n = 10). If the supplementation was not covered by health insurance, patients usually purchased different products based upon 1–2 g fish oil per day from discounters.
Hour ECG and analysis of heart rate variability
Two 24-h Holter ECGs were recorded. One before supplementation with omega-3-fatty acids and a second one after 143.7 days on average (range 42–490 days). Given the large variance in days between assessments due to the naturalistic design of the study, potential outcome effects were addressed in later analysis. A two-channel Holter monitor (Pathfinder, Spacelabs, Germany) was used for recording, while the children followed their normal daily routines. All Holter recordings were reviewed by an experienced cardiologist and were edited to validate the system’s QRS labeling. Measures of HRV were calculated using inter-beat intervals between adjacent R-peaks. The Holter ECGs were analyzed as average values from the entire 24 h of analyzable data and additionally for circadian rhythm analysis as mean hourly values with regard to the time of day. Measurement and interpretation of HRV parameters in the current sample were standardized according to the Task Force Guidelines (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology 1996). A minimum of 23 h of analyzable data and minimally 95% of analyzable RR intervals were required for the data to be included. The presentation focuses on three parameters,1 including heart rate (mean RR intervals) and one time-domain (the square root of the mean of the sum of squared differences between adjacent RR intervals (RMSSD)) and one frequency-domain (high-frequency HRV via fast Fourier transformation over the frequency of 0.15–0.4 Hz) measure of vagally mediated HRV.
To investigate changes in 24-h HRV recordings taken pre- and post-omega-3 supplementation, a threefold approach was chosen. First, the overall 24-h means of all indices were compared using paired t test for dependent samples. Second, mixed linear regression analyses were used to investigate main effects of supplementation (baseline versus omega-3) over repeated measures (main effect: hourly means) on all indices. To adjust for the time difference between repeated measures, we further tested such effect but found no significant influence of the variance in days between assessments. Third, we used a cosine function analysis approach (trigonometric linear regression) to model differences in circadian variation patterns and graphically display them. In a first step, three individual-level cosine function parameters were estimated for each individual 24-h time series to quantify the following circadian variation pattern (CVP) parameters: MESOR (the rhythm adjusted 24-h mean level), amplitude (the distance between MESOR and the highest maximum value of the cosine curve), and acrophase (the phase shift of amplitude from a given reference time point when the highest oscillation is reached). In a second step, these parameters were subjected to mixed linear regression models to estimate the impact of omega-3 supplementation on MESOR, amplitude, and acrophase. Accordingly, time (baseline versus omega-3) differences were graphically illustrated using predicted values and the corresponding 95% CI of the standard errors of the prediction. All analyses were performed using Stata/SE (Version 14.1; StataCorp LP, College Station, TX, US) with alpha set to .05. Graphs were prepared using GraphPad Prism (version 6.0, GraphPad Software Inc., USA).
Means of HRV indices at baseline and after omega-3 supplementation
The present case series, drawing on routine clinical data, aimed to elucidate potential effects of omega-3 supplementation on long-term recordings of HRV in children with AD(H)D. While the study has major methodological shortcoming, this case series indicates that omega-3 supplementation in children with AD(H)D may reduce mean heart rate and increase its variability on a variety of time- and frequency-domain measures. Analysis or recordings collected before and after omega-3 supplementation revealed changes in measures of the overall mean HRV and measure of amplitude in mean RR and RMSSD.
Reduced HRV is an important marker of enhanced cardiovascular risk (Thayer et al. 2010). Only a few studies in children with AD(H)D to date have included cardiovascular endpoints. The majority of the existing studies addressed the association of cardiovascular adverse events and stimulant treatment (Dalsgaard et al. 2014). Stimulants have been reported to increase resting heart rate and elevate systolic blood pressure compared to placebo in adults with AD(H)D (Mick et al. 2013).
However, the present case series has several limitations that need to be addressed in future research. First, we studied a relatively small sample of children and adolescents from a naturalistic clinical sample using routine data, referred to a pediatric cardiology department, who were not characterized in detail. In particular, a lack of standardized psychiatric assessment and information about child and adolescent psychiatric and psychotherapeutic treatment limit the generalizability of the findings, as other treatments may underlie the increase in HRV. This includes a lack of standardized reporting of AD(H)D symptom severity before and after omega-3 supplementation. Further, the supplementation of omega-3 fatty acids was not standardized by any means (i.e., exact compound, dose, duration of supplementation).
We were not able to gain information on the EPA/DHA content and dose of the used brands of supplements and therefore are not able to determine whether appropriate doses of EPA/DHA have been taken and whether the ratio between EPA and DHA was appropriate. Further, we cannot rule out potential effects of combined stimulant treatment, as some patients used omega-3 prior to stimulant treatment, some after termination of stimulant treatment, and some during stimulant treatment. Future studies would do well to implement randomized, placebo-controlled designs and adhere to a strict protocol with respect to the measurement point of HRV, as we cannot rule out any other factors (i.e., changes in lifestyle habits such as physical activity) potentially influencing HRV. Further, we did not measure red blood cell PUFA levels, prohibiting any conclusion with respect to the compliance with omega-3 supplementation, or a potential dose–response relation between omega-3 intake and changes in HR or HRV. Albeit these methodological limitations and shortcomings, the case series illustrates preliminary empirical data, illustrating that HRV may be an interesting biological marker that may be used to assess effects of omega-3 supplementation in ADHD. Longitudinal trials assessing the potential of omega-3-fatty acid supplementation to improve the risk of arrhythmias (London et al. 2007) and hypertension (Buchhorn and Christian 2014) in children with AD(H)D are warranted.
The selection of parameters was limited during the review process. Upon request, the authors provide additional data on the standard deviation of RR intervals (SDNN), the percentage of pairs of adjacent RR intervals differing by more than 50 ms (pNN50), very low frequency (VLF, < .04 Hz), and low frequency (LF, .04–.15 Hz) HRV.
JK and MNJ are supported by a Physician-Scientist-Fellowship provided by the Medical Faculty of Heidelberg University.
Compliance with ethical standards
Conflict of interest
The authors have no conflict of interest, real or perceived, to declare.
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