The effect of overweight/obesity on diastolic function in children and adolescents: A meta‐analysis

Summary Left ventricular diastolic function (LVDF) is an important marker of early cardiovascular remodelling, which has not been well summarized in young people with overweight/obesity. Weighted, random‐effects regression was used to determine the strength of associations of both body mass index (BMI) and homeostatic model assessment of insulin resistance (HOMA‐IR) with LVDF measures, adjusting for age and sex. Six databases were searched after PROSPERO registration (CRD42020177470) from inception to July 2020 for studies that compared LVDF between overweight/obesity and control groups aged ≤24 years, yielding 70 studies (9983 individuals). Quality and risk of bias were assessed using NHLBI tools, with scores of good, fair, and poor for 6, 48, and 16 studies, respectively. Increased BMI was associated with worse LVDF in all measures except early mitral inflow deceleration time, with septal early diastolic tissue peak velocity to late diastolic tissue peak velocity ratio having the strongest association (n = 13 studies, 1824 individuals; r = −0.69; P < 0.001). Elevated HOMA‐IR was also associated with worse LVDF. Although we could not determine the causality of reduced LVDF in young people, our findings should aid the development of paediatric guidelines for the assessment of LVDF and support further work to address the longitudinal consequences of childhood obesity and IR on LVDF.

obesity-related deaths. 3 Abnormalities of left ventricular diastolic function (LVDF) are major contributors to such CVD, with >80% of diastolic heart failure (HF) patients being overweight or obese. 4 LVDF describes the ability of the left ventricle (LV) to fill with blood during diastole, which completes in four stages: (I) isovolumic relaxation; (II) rapid filling; (III) diastasis; and (IV) left atrium (LA) contraction ( Figure 1).
Numerous physiological parameters influence LVDF, including the rate of early myocardial lengthening in diastole, and thus filling, which is determined by a combination of active (energy-utilizing) and passive forces. Impaired LVDF includes a number of pathological processes, including impaired relaxation, increased myocardial stiffness, and elevated LA pressure (LAP).
An array of interrelated indices obtained by echocardiography or cardiovascular magnetic resonance (CMR) exist to indirectly assess LVDF. Although these are all subject to influence by the factors described above, there is evidence that some measures may be better at differentiating particular elements of LV diastolic dysfunction (LVDD) than others. For example, some measures are less influenced by LAP.
Tissue Doppler imaging (TDI) measures longitudinal myocardial motion at the basal septum or lateral ventricular wall in response to inflow. TDI measures differ from conventional Doppler ultrasound measures of transmitral blood flow velocity because they assess longitudinal rather than global compliance of the ventricle, and are less influenced by LV loading conditions. [5][6][7] It has been suggested that these differences may improve their ability to detect early LVDD, 7 particularly in conditions such as obesity where volume overload occurs.
The chronic volume overload and metabolic abnormalities of obesity are associated with progressive LVDD and eventual diastolic HF, through impairment of myocardial relaxation and passive LV properties. 8 Detection methods for LVDD in adults are well-established, 9 but it is unclear which measures best detect the earliest stages of LVDD and would, therefore, be most suitable in adolescents and particularly in those with OW/Ob. Reliable early detection is important as LVDD reversibility is still potentially achievable and lifestyle habits may be less fixed than in adulthood.
Although there are many studies of LVDF in children with obesity, diverse methods and group definitions have made it difficult to adequately summarize findings by conventional meta-analysis, with study heterogeneity being identified as the main limiting factor in earlier attempts. 10,11 Nevertheless, statistical synthesis should be possible, given that most studies share common measures of adiposity and LVDF. This would confirm whether or not OW/Ob is associated with impaired LVDF at a young age, which is yet to be clearly established.
Although most studies focus on measures of adiposity, a significant number have addressed other cardiometabolic risk factors (CMRFs), such as insulin resistance (IR), [12][13][14] that often accompany OW/Ob and may directly impair LVDF. Where data allow, we aimed to assess the relationships of these other CMRFs with LVDF.
In this systematic review and meta-analysis, our aims were to determine in a population of children and adolescents: (1) the extent to which OW/Ob is associated with various measures of LVDF; (2) measures of LVDF which are most strongly associated with OW/Ob and; (3) the associations of IR and other CMRFs with LVDF measures.

| METHODS
The protocol for this review was registered with PROSPERO International Prospective Register of Systematic Reviews (identifier CRD42020177470). This review was completed in accordance with the PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. 15 3 | CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW

| Types of studies
Cross-sectional studies, controlled intervention studies, and pre-post studies that examined the association of childhood and adolescent F I G U R E 1 Stages of diastole and echocardiography measures of diastolic function. Stage I-isovolumic relaxation (IVR) which occurs after aortic valve closure and before mitral valve opening, as left ventricle (LV) pressure falls rapidly until it reaches left atrial pressure, prompting mitral valve (MV) opening; Stage II-rapid filling, where the MV is open and blood is suctioned towards the apex of the LV from the left atrium (LA), which occurs as the myocardium lengthens during falling LV pressure; Stage III-diastasis, after initial filling where LA and LV pressures equalize and flow ceases; Stage IV-LA contraction, which generates an additional pressure gradient that drives more blood into the LV. A wave indicates late mitral inflow peak velocity; a 0 , late diastolic tissue peak velocity; DT, E wave deceleration time; E wave, early mitral inflow peak velocity; e 0 , early diastolic tissue peak velocity; IVRT, isovolumic relaxation time OW/Ob with LVDF were included. Inclusion was limited to full-text articles reported in English and published in peer-reviewed journals.
We excluded studies published in grey literature sources and conference or meeting abstracts without a full text.

| Types of participants
Individuals aged <18 years were included in accordance with the international definition of childhood. Additionally, individuals aged 10-24 years were included and defined as adolescents in accordance with the widest accepted definition to ensure that articles that used this definition were not rejected. 16 It has been suggested that this definition of adolescence corresponds best with contemporary features of adolescent growth and social role transitions. 16 Almost every study used individual criteria to define their OW/Ob and control groups. Furthermore, the pathological group in some studies was obesity only while others included overweight in this group. In other studies, overweight was grouped with normal weight as a control group.
Therefore, study-specific group definitions are reported in the results, but were ignored in the meta-analysis as this heterogeneity did not allow for meaningful group-based comparisons.     (1987 to present). The reference lists of included studies, as well as pertinent reviews, 10,11,18 were also searched, yielding four further studies. [19][20][21][22] The final search was completed on 11th July 2020.

| Data extraction and management
Data were extracted by one author using a pre-defined form and verified for completeness and correctness by two other authors. The following data were extracted: (1) study characteristics and methods; (2) subject/group demographics; (3) homeostatic model assessment of insulin resistance (HOMA-IR) results; (4) measures of LVDF and their results, and where applicable; (5) correlation statistics with adiposity and/or CMRF measures.

| Assessment of risk of bias in included studies
Four authors independently executed quality assessment of the included studies and any discrepancies were resolved by discussion.

Modified versions of the Study Quality Assessment Tools by the
National Heart, Lung, and Blood Institute (NHLBI) were used to assess study quality and risk of bias. 23 Scores of "good" (least risk of bias), "fair" (susceptible to some bias) and "poor" (significant risk of bias) were given to each study based on study design and implementation.
Studies that were scored as "poor" overall but were otherwise methodologically sound (e.g. correctly reported LVDF measures and reported BMI, age, and sex) were included in the meta-analysis. A sensitivity analysis was completed to ensure that these studies did not influence the results. Furthermore, details of how these tools assess quality and risk of bias are given in the Supporting Information.

| Data synthesis
Measures of LVDF were transformed into standard units of measurement where necessary. Mean ± standard deviation (SD) were calculated from alternative descriptions of central tendency and dispersion e.g. median, using the recommended Cochrane tools (Supporting Information). 17, 24

| Statistical analysis
Analysis was completed using STATA (version 16.1, StataCorp, College Station, TX). Although group data are reported in study descriptions, the marked heterogeneity in the mean BMI of control and OW/Ob groups across studies limited our ability to do a conventional, group-based meta-analysis reliably. To overcome this, mean (SD) BMI values for all groups, regardless of how those groups were defined by authors, were used to assess continuous associations of BMI with LVDF measures, using weighted, random-effects linear regression. These models were adjusted for age and sex to account for their known effect on BMI. These models also took account of the fact that some group means (e.g. a normal and an obesity group) were drawn from the same study. Each study was treated as a unique level in the random-effects regression, allowing the pairwise differences within studies to be captured by the model without reliance on specific group definitions. This enabled estimation of the linear relationships of BMI with multiple measures of LVDF and their relative strength, giving insight into which measurements may be most useful for early detection of impaired LVDF.
F I G U R E 2 Flow diagram of study identification, screening, eligibility and inclusion/exclusion. Echo indicates echocardiography; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; n, number of studies; OB, obese; OW, overweight. a Exclusion criteria and reasons can be found in the Supporting Information HOMA-IR values were similarly used to assess continuous associations with LVDF measures, using weighted, random-effects linear regression. These models were also adjusted for age and sex.
To account for individual study size and measure variance, each group estimate in the random-effects regression models was weighted using the inverse-variance method (1/standard error [SE] 2 ). 17 The SE of each measure was calculated using the SD and N reported for each group.
Histogram plots were used to assess normality of variables. Any non-normally distributed variables were transformed into normal distributions using the Tukey Ladder of Powers using the transformation with the smallest chi-squared value. Measures were further transformed to their z-scores (LVDFz, BMIz and HOMA-IRz), to allow correlation coefficients (r) to be calculated. Fisher's z-test was used to compare the strength of these correlations with the strongest association as a reference (Supporting Information). Robust z-scores, which do not depend on parametrically distributed data, were also calculated (Supporting Information) and the analyses were repeated to check that non-parametric distributions were not responsible for the findings. The brand of echocardiography machine was further included as a variable in repeat analyses to determine whether differences in technologies influenced the strength of relationship to LVDF measures. A sensitivity analysis was completed by repeating the analysis but excluding any studies reported as "poor". A further sensitivity analysis was completed by excluding any study that included participants older than the American Academy of Paediatrics definition of adolescence (11-21 years). 25 The r 2 and adjusted r 2 were reported for each model, and effect sizes, SE, 95% confidence intervals (CI), z-statistic, and P-value were reported for each independent variable in the models. P < 0.05 was considered statistically significant.  Abbreviations: A wave, late mitral inflow peak velocity; a 0 , late diastolic tissue peak velocity; BMI, body mass index; DT, E wave deceleration time; E wave, early mitral inflow peak velocity; e 0 , early diastolic tissue peak velocity; E/A, E wave/A wave ratio; E/e 0 , E wave/e 0 ratio; e 0 /a 0 , e 0 /a 0 ratio; IVRT, isovolumic relaxation time.
F I G U R E 3 Distribution of body mass index (BMI) in control (red) and overweight/obese (blue) groups included in the meta-analysis. Groups were defined as per the definitions in individual studies. A normal distribution curve was generated using the reported sample size (N), mean BMI, and BMI standard deviation. Significant overlap of BMI distributions between groups and marked variability of distributions within groups highlights that it was not possible to perform traditional group-based meta-analysis reliably One study that assessed LVDF by CMR was identified but was excluded from the systematic review due to different ages of participants between groups. The number of studies and number of participants for each LVDF measure are reported in Table 1. Of these, 6 studies were scored as good, 48 as fair, and 16 as poor for quality and risk of bias (Table S1). Mean age, percentage of males, and mean BMI ranged from 8.9 to 18.4 years-of-age, 0-100%, and 15.8-60.0 kg/m 2 , respectively. There was marked heterogeneity in groupdefinitions, with >20 definitions identified for groups with OW/Ob groups and > 20 for control groups (Table S1). Furthermore, there was marked overlap of BMI between control and OW/Ob groups and marked dispersion of BMI within groups across studies, presenting a major challenge to the reliable use of conventional group-based metaanalysis ( Figure 3).

| Objective 1-The association of OW/Ob with measures of LVDF
Objective 1 was to determine the association of OW/Ob with LVDF. This was done by meta-analysis and by systematic review.
A small subset of papers addressed this question directly as a study outcome and the findings of these are summarized in Note: Associations that were statistically significant (P < 0.05) are represented by bold 95% confidence intervals (CI). Fisher's z-test, which accounts for sample size, was used to compare the strength of the correlation coefficients (r) with the strongest association, septal (sep) e 0 /a 0 , as a reference. Larger values of Fisher's z indicate that correlation coefficients are more likely to be statistically different (less strongly associated) with respect to the reference association. Those that were significantly different (P < 0.05) are marked with an a . Tissue Doppler imaging (TDI) measures are reported as an average of recordings from the septal and lateral wall (lat) of the left ventricle, and individually as sep and lat. Abbreviations: A wave, late mitral inflow peak velocity; a 0 , late diastolic tissue peak velocity; b, unstandardized regression coefficient; BMI, body mass index; DT, E wave deceleration time; E wave, early mitral inflow peak velocity; e 0 , early diastolic tissue peak velocity; E/A, E wave/A wave ratio; E/e 0 , E wave/e 0 ratio; e 0 /a 0 , e 0 /a 0 ratio; IVRT, isovolumic relaxation time.
DT (r = 0.158). The latter did not become statistically significant after such normalization. Repetition of the analyses using robust z-scores or with adjustment for the type of echocardiography machine used in each study made no meaningful difference to the results (not shown). Sensitivity analyses to exclude poor quality studies also made no meaningful difference to the results. Sensitivity analyses to exclude studies with adolescents aged >21 years made no overall meaningful difference to the results. However, averaged e 0 /a 0 ratios were no longer significantly associated with BMI (Table S3).

| Systematic review
Forty-three studies eligible for systematic review reported matching LVDF measures to those included in the meta-analysis ( Figure 4). 19

| Objective 2-Comparison of measures of LVDF
Standardized r coefficients are reported in Table 2 and S4. BMI was most strongly associated with septal e 0 /a 0 ratio after adjustment for age and sex. Septal TDI measures were more strongly associated with BMI than lateral or averaged equivalents. Other TDI measures of LVDF, especially those including a 0 peak velocities, were more strongly associated with BMI than conventional measures of mitral inflow peak velocities (e.g. early mitral inflow peak velocity [E wave]). Associations of BMI with E wave peak velocity, E wave/late mitral inflow peak velocity ratio (E/A ratio), and DT were significantly weaker than that of septal e 0 /a 0 (Table 2), suggesting inferiority for early detection of reduced LVDF in childhood and adolescent OW/Ob.

| Meta-analysis
A small subset of papers addressed the association between HOMA-IR and LVDF directly as a study outcome and the findings of these are summarized in the Supporting Information.
Evidence of reduced LVDF with increasing levels of HOMA-IR are reported in Table 3 and S6. The strongest association was with averaged E wave peak velocity/e 0 peak velocity ratios (E/e 0 ratio).
Other TDI measures of LVDF and IVRT were more strongly associated with HOMA-IR than conventional measures of mitral inflow velocities. E wave peak velocity, DT, septal e 0 peak velocity, and lateral a 0 peak velocity were not associated with HOMA-IR. Associations of HOMA-IR with measures of LVDF were not statistically different than that of averaged E/e 0 ratios (  We also provide evidence that IR, as indicated by HOMA-IR, is associated with reduced LVDF.

| LVDF in childhood and adolescent OW/Ob
We conclude that elevated BMI in childhood and adolescence is adversely associated with all measures of LVDF, apart from DT, and support these findings with a systematic review. Primarily, we showed impaired longitudinal myocardial motion of the LV, identified by lower e 0 peak velocities and e 0 /a 0 ratios, and higher a 0 peak velocities is associated with raised BMI.
LVDD begins with impaired relaxation and decreased ventricular "suction" in early filling, advancing to increased LV stiffness and elevated LAP, then high LAP and a non-compliant LV, before becoming irreversible. In advanced LVDD, LA size increases markedly and symptoms of diastolic HF appear. In our analysis, we identified reduced myocardial motion in early diastole (e 0 ) in those with greater BMI. As  Abbreviations: A wave, late mitral inflow peak velocity; a 0 , late diastolic tissue peak velocity; b, unstandardized regression coefficient; CI, confidence interval; DT, E wave deceleration time; E wave, early mitral inflow peak velocity; e 0 , early diastolic tissue peak velocity; E/A, E wave/A wave ratio; E/e 0 , E wave/e 0 ratio; e 0 /a 0 , e 0 /a 0 ratio; HOMA-IR, homeostatic model assessment of insulin resistance; IVRT, isovolumic relaxation time.
a There was an insufficient number of studies on septal E/e 0 to be included in the analysis.

| Measures with strongest relationship to BMI
We were able to compare the strength of the associations of BMI with different LVDF measures, yielding insight into which measurements are most useful for early detection of impaired LVDF in this context. Myocardial tissue peak velocities assessed by TDI were the LVDF measures that were most strongly associated with BMI. Of these, the strongest association was with the e 0 /a 0 ratio, which is in accord with a study of children with Type 1 diabetes (T1D). 89 These results also coincide with earlier studies of LVDF that identified the e 0 /a 0 ratio as the best marker of early longitudinal compliance abnormalities. 7 Of these two components of LVDF, a 0 was more strongly associated with BMI than e 0 in our analysis. The stronger relationship with a 0 may be explained by this measure being less influenced by volume overload, which is typically seen in obesity. 5 We therefore suggest that measures of both a 0 and e 0 /a 0 should be considered the best markers to identify early impairments of LVDF in children and adolescents with obesity, particularly in the septum.
We found, in general, that TDI peak velocities assessed at the septal mitral annulus were more strongly associated with BMI than the lateral equivalent or their average. Stronger associations of BMI with septal TDI measures may reflect preferential remodelling of the septum prior to similar changes in the lateral myocardium. 59

| Cardiometabolic health and LVDF
IR is associated with cardiovascular events, 13 and contributes to progressive declines in LVDF, independent of confounders. 14 The pathogenesis of IR associated with obesity is described elsewhere in detail, 92

| Standardization of group definitions
Previous studies do not report a standardized measure of obesity that can be compared between studies. We confirm this with >20 definitions identified for both groups with OW/Ob and control groups.
When country-specific BMI z-scores are reported, authors should also report a standardized, global BMI z-score using common, easily accessible tools such as the World Health Organization (WHO) 2007 BMI z-scores. 95 This would allow for the direct comparison between studies and aid future attempts to statistically synthesize data on childhood and adolescent OW/Ob.

| Study strengths and limitations
This work has a number of strengths and potential limitations. Some studies were rejected from the meta-analyses due to insufficient reporting of BMI, HOMA-IR, age and sex. Nevertheless, the results of the systematic review, which was more inclusive, broadly reflected the findings of the meta-analyses, supporting our conclusions. We limited the impact of group selection bias in our meta-analyses by including the pairwise differences between groups within a study as a unique level in the multilevel model but, importantly, ignoring the authors' group definitions in favour of a continuous analysis, using the reported mean BMI instead. Linear regression analyses can be unduly influenced by non-normal distributions, but our results did not differ meaningfully after the normalization of distributions and with repeat analysis using robust z-scores.
Although some studies reported BMI z-scores, it was not possible to construct an analysis using BMI z-scores due to the heterogeneity in the normative data used to calculate BMI z-scores. Any study that defined groups using BMI z-scores and that was not included in the meta-analyses was included in the systematic review.
The marked heterogeneity in definitions of normal weight and OW/Ob required an analytical approach that ignored these group definitions. As a consequence, it was also not possible to analyse whether individual study findings were distributed evenly around the mean effect size and thus less likely to be subject to publication bias. Thus, our study does not address possible publication bias statistically.
However, it should be noted that only data on unpublished studies truly allow for publication bias to be determined and these are not available in this context.

| CONCLUSIONS
This review provides the first evidence by meta-analysis that childhood adiposity, as indexed by BMI, is associated with worse LVDF.
We demonstrate that increased BMI is most strongly associated with septal e 0 /a 0 ratios. These findings should aid the development of paediatric guidelines for the assessment of LVDF, by highlighting the most sensitive measures for early detection of LVDF in children with OW/Ob.
We also demonstrate that increased levels of HOMA-IR are associated with LVDF, which may be particularly useful for understanding the early pathogenesis of LVDD. Further work should address the longitudinal consequences of childhood obesity and cardiometabolic dysfunction with LVDF.