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Paediatrics
Original research
Endothelial Peripheral Arterial Tonometry (Endo-PAT 2000) use in paediatric patients: a systematic review
  1. Jenny Hayden1,
  2. Gill O’Donnell1,
  3. Isabelle deLaunois2,
  4. Clodagh O'Gorman3,4
  1. 1Department of Paediatrics, University Hospital Limerick, Limerick, Ireland
  2. 2University of Limerick, Limerick, Ireland
  3. 3Paediatrics, Graduate Entry Medical School, University of Limerick, Limerick, Ireland
  4. 4University Hospital Limerick, Dooradoyle, Limerick, Ireland
  1. Correspondence to Dr Jenny Hayden; jennyhayden40{at}gmail.com

Abstract

Objectives Endo Peripheral Artery Tonometry (EndoPAT-2000) is a non-invasive technology for measuring endothelial dysfunction (ED). The reactive hyperaemia index (RHI) is resulted and is low when ED is present. We aim to synthesise the literature on paediatric ED that used Endo-PAT analysis.

Design A comprehensive systematic review was conducted from January 2015 to March 2021. The databases included Cochrane, MEDLINE EBSCO, EMBASE (Ovid), PUBMED and CINAHL EBSCO. Exclusion criteria were: (1) If a study used a different device, for example, (2) If the study had no results. Inclusion criteria were: (1) Published in the English, (2) more than 50% of study subjects were in the paediatric age range, (3) data relevant to paediatric age range children could be extrapolated from all data, where not all study subjects were children.

Results Following the removal of duplicates, 156 articles were initially identified. Following exclusion, 50 articles were included for review. We have subdivided these papers into different systems for ease of reference and have reported our findings in six tables: patients with type 1/2 diabetes, obesity, cardiovascular, respiratory, psychiatric conditions and miscellaneous diseases. For each, the study design, population, control group (if available), RHI results and conclusions were reported.

Conclusions A number of papers using Endo-PAT for children with various chronic diseases have evidence of ED. However, in many cases, there has only been a single cohort study using Endo-PAT. Further studies are required to validate these findings and to help characterise the cardiovascular risk profile of children with chronic disease. Further studies are also required that will characterise more completely the cardiovascular risk profile of these children.

Consensus on other vascular risk markers that could be included in future studies is ideal and if accomplished, this would facilitate meta-analyses of studies of relatively rare conditions.

  • Paediatrics
  • Community child health
  • Paediatric endocrinology
  • Education & training (see Medical Education & Training)
  • Change management
  • Organisational development

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjopen-2022-062098

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    Strengths and limitations of this study

    • Comprehensive systematic review to synthesise the literature on endothelial dysfunction using Endo Peripheral Artery Tonometry (Endo-PAT) in paediatric patients.

    • All study types were reviewed and even the studies without results but were relevant were included in our discussion.

    • In many cases, there has only been a single cohort study using Endo-PAT for a particular disease.

    • Separate paediatric results were obtained where possible from studies with combined adult and paediatric data; however, some papers were of poor quality and had limited results available.

    • Only papers from January 2015 to March 2021 were included in our review.

    Introduction

    Endothelial dysfunction (ED) is an early predictor of cardiovascular disease.1 Negative alterations in endothelial physiology, also known as ED, cause the endothelium to lose its ability to promote vasodilation, fibrinolysis and antiaggregation.2 It is the beginning of atherosclerosis formation, which can lead to plaque progression and luminal narrowing.3 There is an imbalance between vasodilation and vasoconstriction, abnormal reactive oxygen species and nitric oxide (NO) bioavailability.2 ED is a complication of cardiovascular risk factors such as smoking, hypercholesterolemia, hypertension, hyperglycaemia and family history of premature atherosclerosis. ED can be caused by oxidative stress with loss of vasoactive or inflammatory homeostasis within the body’s vascular system. It may be secondary to mechanical stimuli, for example, increased intraluminal pressure within the blood vessel or metabolic factors such as hormones (oestrogen’s vasodilation action).4

    Damaged endothelium can release a cascade of substances which pose a risk of thrombosis, inflammation and ultimately atherosclerosis.5 ED in paediatric populations has been associated with several conditions including type 1 diabetes (T1D), type 2 diabetes (T2D), renal impairment, obesity and metabolic syndrome.6–9 In patients with T2D, obesity and metabolic syndrome, insulin resistance is one of the most important factors contributing to ED.9 Metabolic syndrome is a proinflammatory state where dyslipidaemia, hyperuricemia and hypertension occur and can predispose to ED.10

    ED can progress to atherosclerosis which is a chronic condition that poses severe risk of certain diseases, including coronary artery disease, stroke and peripheral arterial disease. If detected early and specific patient modifications are made, the progression to permanent vessel damage may be halted. ED can be detected by invasive techniques assessing the coronary vessels or by non-invasive techniques via the peripheral circulation. The gold-standard test would use coronary angiography and assess response to vasodilators. However, this is not feasible in practice as a screening tool, especially in paediatrics.

    This review highlights the variety of conditions that Endothelial Peripheral Artery Tonometry (Endo-PAT) can be useful in paediatric patients. This systematic review will add to other reviews of endothelial function assessments in paediatric populations as it includes further studies and an increasing variety of paediatric conditions as well.11

    Endo-PAT 2000

    Endo-PAT 2000 is a non-invasive technology for measuring ED developed by Itamar Ltd. Non-invasive pneumatic probes which are placed on the both index fingers, which continuously records pulse wave amplitude. A blood pressure cuff is inflated to occlude blood flow and response after deflation is recorded. The reactive hyperaemic index (RHI) is resulted following this mini-ischaemic stress to the vessel. The pulse wave amplitude (PWA) is measured and computes an RHI result automatically. RHI is calculated as the ratio of average PWA divided by the average amplitude during the equilibration period. To compensate for any systemic changes, this ratio is normalised to a concurrent signal from the contralateral finger.

    Numerous studies in both adult and paediatric literature reveal Endo-PAT’s excellent reproducibility and reliability.12–14 However, RHI has limitations as a reliable method for defining ED, especially in paediatric patients due to the metabolic changes children go through throughout childhood, including growth and puberty. There is no RHI cut-off value in paediatric patients. In ED, the RHI is low and pulse amplitude is high. PAT also provides results on the peripheral augmentation index (PAT-AIx). Bonetti et al report a RHI of <1.35–1.49 as indicative of coronary ED in adults.14 15

    Prior to Endo-PAT, ED had been assessed by flow-mediated vasodilation (FMD). FMD uses an ultrasound to assess the change in brachial artery diameter in response to increased flow after a period of vascular occlusion by a blood pressure cuff and is highly dependent on NO bioavailability. ED is identified by less vasodilatation (reduced FMD) of the brachial artery. FMD is technically challenging to perform, user dependent and requires training. FMD results macroblood vessel reactivity, whereas Endo-PAT results micro, which may account for the challenges in comparing the two techniques. Endo-PAT is easier to set up, is automated and less user dependent. It can be used at the patient’s bedside, without extensive training required of the operator. Wilk et al reported that RHI correlated with FMD (r=0.35, p<0.01); however, there are other studies which have not reported a correlation between the two techniques.16

    Objective

    A systematic review was conducted on the use of Endo-PAT 2000 in paediatric populations in assessing the risk of ED, with the aim of synthesising the literature, to determine a cohort of paediatric patients at high risk of ED and who may benefit from screening.

    Methods

    A comprehensive systematic review was conducted to identify publications that investigated Endo-PAT 2000. All papers published from January 2015 to March 2021 in paediatric populations age birth to 16 years of age were analysed.

    The following scientific databases were searched: The Cochrane Database, MEDLINE EBSCO, EMBASE (Ovid), PUBMED and CINAHL EBSCO. The search was limited by to English studies. The search was limited by type of subjects (human), date (2015 to March 2021) and included all study types. Snowballing method was used. Authors of joint adult and paediatric papers were contacted by email to obtain separate paediatric data.

    The database search was repeated several times using the combinations of keywords, Medical Subject Headings (MeSH) terms and filters (child: birth-16 years). The following MeSH terms or key words were used for searching: Peripheral arterial tonometry, PAT test, endopat, adolescent, ado*, child, paediatric, pediatric, preschool, schoolboy, schoolgirl, boy, girl, teen, toddler, infant, baby.

    Exclusion criteria were: (1) if a study used a different device, for example ‘Watch-PAT’ and (2) if the study had no results. Inclusion criteria were: (1) published in the English; (2) more than 50% of study subjects were in the paediatric age range; (3) data relevant to paediatric age range children could be extrapolated from all data, where not all study subjects were children. A child was defined as up to 16 years, and this is consistent with PubMed’s definition of a child, where data relevant to children could not be extrapolated from the whole data set, the study authors were contacted for additional information prior to study inclusion or exclusion.

    Patient and public involvement

    No patient involved.

    Data collection and analysis

    A total of 290 articles were obtained via the online database search (figure 1: flow diagram). Following removal of duplicates, 158 articles remained. The second screening was conducted by ‘Rayyan-systematic review software’. Two further duplicate articles were removed, with 156 remaining for review.

    Figure 1
    Figure 1

    Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 flow diagram of systematic search for Endo-PAT 2000 in paediatric populations. *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers).**If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools. From Page et al.86 EndoPAT-2000, Endo Peripheral Artery Tonometry.

    Two independent authors separately performed a blind screen on the 156 abstracts. Sixty-five articles were initially excluded based on title or abstract: 37 adult studies, 18 ‘PAT’ did not represent peripheral arterial tonometry (eg, prism adaptation test, psychosocial assessment tool), 6 Watch-PAT, 2 sleep studies and 2 had no results available.

    The remaining 91 articles were analysed viewing full-text articles for further information. A further 20 were excluded as they did not fit inclusion criteria or have results to report. Some of these articles that included Endo-PAT 2000 in paediatrics did not have results for the systematic review but had conclusions that were relevant to the paper were referenced in the Results section.

    Twenty-eight authors of studies including both adults and paediatric patients were contacted two times by email to gather separate information on the paediatric participants. Twenty authors did not reply and were, thus, excluded. Eight authors replied: three providing results, four unable to give separate paediatric data and one author’s research was on adult patients so was excluded. Three of the articles whose authors replied with data were included in our review. Four studies were obtained via snow balling searching.

    A total of 50 articles were included in our results and are represented in tables 1–6. For each eligible study, the following data were reported: author, year of publication, design of the study, population studied, control group (if available), RHI results.

    View this table:
    Table 1

    Total of 11 studies included

    View this table:
    Table 2

    Endo-PAT 2000 in paediatric patients who are overweight (OW)/obese (14 studies)

    View this table:
    Table 3

    Endo-PAT 2000 in paediatric patients with cardiac and vascular conditions (seven studies)

    View this table:
    Table 4

    Endo-PAT 2000 in paediatric patients with respiratory conditions (four studies)

    View this table:
    Table 5

    Endo-PAT 2000 in paediatric patients with psychiatric conditions (four studies)

    View this table:
    Table 6

    Endo-PAT 2000 in paediatric patients with other miscellaneous paediatric conditions (10 studies)

    Results

    Endothelial dysfunction in paediatric diabetes mellitus patients

    Five studies involve only T1D patients (table 1). 2-fifth studies reported lower RHI results in the T1D group.17 18 One study which included only adolescent patients reported RHI negatively correlates with impaired metabolic control and subclinical signs of autonomic neuropathy.17 They concluded that good metabolic control (haemoglobin A1c (HbA1c) ≤7.5%) and regular physical activity might be protective against ED. One study reports an improved RHI result with an alpha-lipoic acid and antioxidant diet.19 Nadeau et al reported no significant RHI change with metformin overall but some improvement in overweight T1D men.20 Barber et al report suboptimal glycaemic control causes early atherosclerosis.18 One study noted an improvement in RHI post-vitamin D supplementation in T1D patients with vitamin D deficiency.21

    Six studies focused on type 2 diabetes (T2D) and impaired glucose tolerance or ‘pre-diabetes.’ Tomsa et al note a link between insulin resistance and obesity by utilising Endo-PAT.22 They also noted that RHI is higher if HbA1c is less than 5.5%.22 Two studies compare on non-alcoholic fatty liver disease (NAFLD), T2D and pre-diabetes patients.23 24 If dysglycemia, NAFLD is associated with worse endothelial function. Circulating FGF-21 levels are elevated in obese youth with NAFLD and are associated ED and, therefore, may be a biomarker for ED.24 Bartz et al report urine albumin creatinine ratio may be an early marker of ED independent of glycaemia.25 Endothelial dysfunction (EDF) may mediate the link between obesity-related insulin resistance and early microalbuminuria.25 Kochummen et al reported a mean RHI in obese adolescents without diabetes was similar to T1D and T2D patients.26 One study noted an improvement in RHI-post vitamin D supplementation in T1D patients with vitamin D deficiency.21 Another study noted that lower vitamin D concentrations are associated with lower insulin sensitivity and worse endothelial function.27

    EDF and obesity

    Fourteen studies describe the use of Endo-PAT 2000 in overweight or obese patients (table 2). Studies included measurement of the following parameters: body mass index (BMI), T1D, T2D, gender, pubertal stage, age, blood pressure values, NAFLD, obstructive sleep apnoea (OSA), insulin, plasma glucose levels, inflammatory markers (urinary markers, CNP, micro-RNA-126, E-Selectin). In numerous studies, RHI was significantly lower in obese groups.7 26 28–34 ED may mediate the link between obesity-related insulin resistance and early microalbuminuria.25 Exercise and diet control improve glycolipid metabolism.35 Two studies by Czippelova et al did not find a lower RHI in obese groups, but recommended further studies.36 37 Noma et al38 report the beneficial effects of exercise in paediatric patients and is an important message in reducing future endothelial complications.38 Fusco et al noted preclinical microvascular changes in obese patients compared with controls using LDF but noted no RHI change.39

    EDF in cardiac and vascular conditions

    Seven studies report the use of Endo-PAT and cardiovascular conditions (table 3). Lower RHI is seen with patients with familial hypercholesterolaemia.40 Studies assess ED in patients with systemic lupus erythematosus (SLE) and Henoch Schonlein purpura (HSP).8 41 42 Negishi et al43 used Endo-PAT to compare Fontan survivors and healthy controls. The Fontan patients were aged 15–2 years. Mean RHI 0.56±0.26 in Fontan patients and 0.78±0.31 in controls (p=0.09). RHI in Fontan patients was associated with diastolic blood pressure, heart rate and HbA1c level.43 Endothelial function in Fontan patients was associated with abnormal glucose tolerance and arterial stiffness and, therefore, concluded that glucose regulation might be a potential target to improve ED in this cohort. Nozaki et al44 assessed ED in conduit and resistance arteries and used FMD and Endo-PAT in paediatric patients with repaired coarctation of aorta.44

    EDF in respiratory conditions

    Four studies used Endo-PAT in respiratory conditions (table 4). Augusto et al noted an increased augmentation index (AIx) without changes in RHI in asthmatic patients.45 One study reported an improvement in sleep-disordered breathing post weight loss and also, endothelial function significantly improved after weight loss.46 Two studies report children with OSA compared with habitual snorers are at increased risk for ED.47 48 Frequent wakening due to obstructive respiratory events may be a risk factor for ED in OSA.

    EDF and psychological conditions

    Four studies report the use of Endo-PAT in psychiatric conditions (table 5). Potential limitations in this area are self-reported methods for detecting psychological distress of children, for example, in the LOOK longitudinal study.49 Naiberg et al50 used retinal vascular photography as a proxy for cerebral microvasculature, and Endo-PAT to assess cardiovascular and neurocognitive burden in adolescents with bipolar disorder (BD).50 In the BD group, better endothelial function was associated with higher arteriovenular ratio (r=0.375, p=0.041). Olive 51 published ‘The emerging field of paediatric psycho-cardiology’ highlighting the importance of the childhood origins of adult cardiovascular disease (CVD).51 This article highlights that psychological distress can influence CVD risk, directly by physiological change that can negatively impact the integrity of the cardiovascular system.

    EDF and other paediatric conditions

    Childhood cancer survivors

    There is evidence of ED in cancer survivors (table 6).52 Chemotherapy causes cardiomyocyte damage and also negatively affects endothelial function. Broberg et al53 utilised Endo-PAT in childhood cancer survivors and noted a lower RHI in this cohort compared with controls.53 Broberg et al identified one-third of cancer survivors (31.2%) compared with 8% of controls (p=0.02) had ED in their study.54 They concluded this may be a useful screening tool of cardiovascular disease in asymptomatic cancer survivor patients. Pao et al55 assessed the relationship between blood pressure and ED using Endo-PAT in haematopoietic stem cell transplant recipients. Hypertension on ambulatory blood pressure monitoring (p= 0.045) and blunted nocturnal dipping (p= 0.04) were associated with a lower Endo-PAT scores.55

    Autoimmune conditions

    Children with autoimmune diseases may have a high tendency to develop ED which was highlighted in a study using a novel technique.56 Atherosclerosis is an emerging cause of morbidity and mortality in patients with rheumatological conditions such as juvenile idiopathic arthritis, SLE and dermatomyositis. Borenstein-Levin et al assessed a cohort with autoimmune conditions compared with controls: 29% in the study group had ED compared with 6% (p<0.05).56 Chang et al noted nocturnal blood pressure (BP) non-dipping is associated with ED in SLE patients highlighting a potential role for ambulatory BP monitoring in these patients(table 3).8

    Metabolic diseases

    Yano et al research in Fabry disease patients demonstrated that early diagnosis of ED can help determine the timing of initiating enzyme replacement therapy.57 Utilising RH-PAT as a screening tool for early renal involvement may be helpful as it may detect abnormalities even prior to microalbuminuria.58 This can provide guidance on enzyme replacement therapy which is required to prevent irreversible progressive renal failure. Al Jasmi et al research in mitochondrial diseases reported that arginine or citrulline supplementation may improve ED, which provides evidence that these amino acids may be therapeutic (table 6).59

    Inflammatory bowel disease:

    One study (table 6) highlights that IBD patients had lower RHI compared with controls.60 Petr et al61 provided evidence of increased ED in children with Crohn’s disease compared with healthy controls.61 RHI values were significantly lower in the patients with Crohn’s than controls (p<0.05).

    Infectious diseases

    Dirajlal-Fargo et al used Endo-PAT to assess ED in HIV patients (table 6).62 63 Perinatally acquired HIV patients appear to have higher levels of ED (RHI 1.34 (1.20, 1.42) compared with controls (1.52 (1.27, 1.80) (p< 0.01)).63 The pathogenesis of severe Plasmodium vivax malaria is poorly understood. ED and reduced NO bioavailability characterise severe falciparum malaria. Barber et al64 identified that endothelial function was impaired in proportion to disease severity. Those with severe vivax malaria, mild-moderate infection and healthy controls: median RHI 1.49, 1.73, and 1.97 respectively (p=0.018).64 ED in this cohort was associated with reduced L-arginine bioavailability, which may contribute to microvascular pathogenesis.

    Discussion

    To our knowledge, this study is the first to conduct a rigorous systematic review of published and presented literature on the results of RHI as measured by Endo-PAT 2000 as a measure of EDF in children and adolescents. One of the benefits of RHI as a measure of ED is that it is an easy test to conduct, is well-tolerated by children and adolescents and it can be performed at the point of care.

    Weaknesses of the paper include the quality of the papers are limited and varied; 11 are conference abstracts that had little information available on methods or results and have limited analysis. Observational studies are also limited in research value. Many are case-control studies which are not as valuable as randomised controlled trials (RCT). Only four studies are RCTs. The studies cannot be compared for a meta-analysis as most are not RCT level research of high enough quality. Therefore, the conclusions drawn from many of these studies are limited. There are also limitations of RHI as reliable method for defining ED. There is no defined RHI cut-off value in paediatric populations. Moreover, there may be significant findings in studies in the grey literature or in conference presentations that were not included, for example, in the studies where 25 authors did not respond to emails. Only papers from 2015 to March 2021 were included. Many of the papers did not include other factors that would be important in a cardiovascular assessment of children, for example, family history, cholesterol and blood pressure parameters and BMI and standardised BMI measurements. So, in many studies, it cannot be excluded that there were confounding variables affecting the ED score. Regardless, this study indicates that there are a significant number of published paediatric papers that indicate the presence of ED in children as young as 8 years old.

    Strengths of the paper include a comprehensive literature search including contacting authors by email for separate paediatric results in studies with combined adult and paediatric data. All study types were reviewed and even the studies without results but had interesting points were included in our discussion. Also, we do not think that this paediatric Endo-PAT review has been done before. Our results highlight that Endo-PAT has benefits including point-of-care and ease of conduct of test for assessor.

    The potential future role of Endo-PAT for paediatric patients may be an adjunct tool in screening for cardiovascular risk factors. If atherosclerosis is identified early, it can be halted in its process in certain conditions. There is huge potential for its use in diabetic patients. Improving glucose control can protect endothelial function. Persistent high sugars can impair endothelial function via oxidative stress and production of free radicals.2 Lower insulin sensitivity poses a risk of diabetic nephropathy.9 Microangiopathic renal damage increases oxygen consumption and increases resistance in the afferent arterioles. Shah et al report T2D patients have greater vascular thickness and stiffness and worse endothelial function compared with obese and lean children.65 This is raising concern that adolescents with T2D are already at risk of developing early-onset cardiovascular disease.

    Diabetic microangiopathy can result in retinopathy, neuropathy and peripheral vascular neuropathy. Subclinical evidence of these complications can be seen in paediatric patients, especially in those with poor glycaemic control. Unfortunately, there have been reports of T2D paediatric patients diagnosed with microangiopathic complications, particularly nephropathy.66 This early endothelial damage can be linked with increased morbidity and mortality.67 Moreover, new onset diabetes after transplantation is characterised by insulin resistance and T2D.68 Endo-PAT has multiple benefits in obesity as it can identify if early ED is present and, therefore, strategies to reverse or halt this process can be made (table 2).7 30 37

    In recent decades, the number of childhood cancer survivors is increasing.69 Treatments used such as haematopoietic stem cell transplantation have increased risk of cardiovascular disease.70 71 Following chemotherapy, radiotherapy, immunosuppressive treatments, the risk of insulin resistance has been noted.72 With advances in treating malignant paediatric conditions there are long term complications emerging in survivors. High-dose chemotherapy including anthracyclines, alkylating agents and vinca alkaloids may disrupt the substances on the surface of the endothelium and impair its ability to dilate and constrict. Moreover, total body radiation poses a risk by damaging the elastic matrix. Heart disease in long-term cancer survivors is 5–10 times higher than their siblings.72 Brouwer et al73 studied cancer survivor patients after potential cardiovascular toxic treatment (eg, anthracyclines, platinum) and/or radiotherapy and noted a higher risk of ED compared with sibling controls.73 Jehlicka et al74 used Endo-PAT and noted acute lymphoblastic leukaemia patients had lower RHI compared with controls (1.57±0.50, 1.96±0.63; p≤0.05).74

    Turner syndrome (TS) patients have increased cardiovascular risk factors, which predispose to cardiac and cerebrovascular complications.75 A case–control study on TS patients noted a statistically significant increase in RHI in growth hormone-treated girls.76 There are countless other paediatric syndromes with risk of ED that could benefit from screening.

    Furthermore, in cardiac diseases and postcardiac surgery, Endo-PAT has been proven useful in multiple studies (table 3).44 75 77 Dietz et al’s78 systematic review and metanalysis on peripheral ED in Kawasaki disease, report coronary arterial aneurysms had higher surrogate markers for cardiovascular disease risk.78 This may indicate that these patients should be monitored for CVD in adulthood; however, significant heterogeneity was noted. Endo-PAT has been shown to be beneficial postoperatively in Fontan survivors and comparing surgical techniques like in the ‘The LOVE-COARCT study’ (Long-term Outcomes and Vascular Evaluation After Successful Coarctation of the Aorta Treatment).79–81

    With the rising premature population, Endo-PAT may prove useful in this cohort. Harris et al82 assessed cardiovascular outcomes for those born with very low birth weights (VLBW) <1500 g. The VLBW cohort (n=229; 71% of survivors) and term-born controls (n=100) were assessed at age 26–30 years. The VLBW cohort had lower RHI compared with controls.82 Endo-PAT is also used in haematological conditions. Sivamurthy et al83 reported lower RHI in the majority sickle cell disease in a paediatric population (1.53 and 1.71; p value 0.032). RHI was not normal in children with chronic transfusions or hydroxyurea.83

    The psychological studies in our paper raise an interesting link between the vascular system and the psychiatric diagnoses. Retinal vascular calibre was shown to be associated with endothelial function in BD patients and it has been suggested that it may be used as an assessment tool in this cohort.

    Finally, many paediatric autoimmune conditions are linked with ED.8 56 In patients with SLE, ED may occur from impaired clearance of apoptotic cells, oxidative stress or B cell activation with different circulating autoantibodies.42 Regular ED assessment in SLE patients has been recommended due to risk of subclinical atherosclerosis.42 Moreover, several factors may impact microvascular function in children, for example, puberty, which is of particular interest in our paediatric review. Bhangoo et al report improved RHI in correlation with an increase in Tanner stages and postulated that this may be due to sex steroids.84 If Endo-PAT is used in research in adolescents, age, sex and tanner staging must be taken in account when reporting RHI results.85

    Conclusion

    There are a number of papers in the paediatric literature describing ED at young ages using Endo-PAT. However, in many cases, there has only been a single cohort study using Endo-PAT. Further studies are required to validate these findings. Additionally, longitudinal studies are required to evaluate how this ED may change as the child ages and their chronic conditions change. Further studies are also required that will characterise more completely the cardiovascular risk profile of these children with chronic disease. Consensus on other vascular risk markers that could be included in future studies is ideal and if accomplished, this would facilitate meta-analyses of studies of conditions with relatively rare conditions.

    The establishment of a threshold RHI for normal or abnormal would be helpful if it correlated well with clinical outcomes. This might be achieved in the future either by meta-analysis of the literature, if outcomes are measured and reported in a standardised manner, or by the conduct of a prospective longitudinal study that follows RHI in childhood to adulthood along with identification of cardiac outcomes. The latter would by its nature require to be a long-term study and would require a repeated iterative process to establish the threshold of normal for RHI, as a continuous variable. Therefore, a meta-analysis may be preferable. In the short term, a systematic approach to cardiovascular risk assessments should be promoted.

    Data availability statement

    Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

    Ethics statements

    Patient consent for publication

    Ethics approval

    Not applicable.

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    Footnotes

    • Contributors All authors contributed to the initial search strategy. Id performed the online database search. JH and CO'G are responsible overall for the content of the paper and JH is the guarantor of the work. JH and GO'D separately performed a blind screen of the abstracts and analysed the papers. GO'D contacted the authors of joint adult and paediatric papers to obtain separate paediatric data. JH wrote the initial manuscript that was revised by CO’G. All authors reviewed the manuscript prior to submission.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.