Endothelial impairment evaluation by peripheral arterial tonometry in pediatric endocrinopathies: A narrative review

Table 1 Study characteristics for reactive hyperemic index-Endopat 2000 in different pediatric type 1 diabetes mellitus populations

Ref.	Study design	Aim of study	Population: age mean ± SD or median (range); n [F/M]	Control group: age mean ± SD or median (range); n [F/M]	RHI result: mean ± SD or median (range)	Outcomes
Mahmud et al[51], 2006	RA	Determinate whether a gender contrast in a preclinical stage of atherosclerosis, or endothelial dysfunction, is present in pediatric diabetic patients.	T1DM Children for at least 1 yr, no microalbuminuria or retinopathy: 14.2 ± 1.3, n = 20 [8/12]	Healthy children without a family history of hypercholesterolemia: 14.1 ± 1.5, n = 20 [8/12]	1.85 ± 0.45 vs 1.95 ± 0.32 (diabetic vs controls)c. 1.61 ± 0.32 vs 1.93 ± 0.28 (male diabetic vs male controls)b. 2.21 ± 0.35 vs 1.99 ± 0.38 (female diabetic vs female controls)c. 1.93 ± 0.28 vs 1.99 ± 0.38 (male vs female control groups)c. 1.61 ± 0.32 vs 2.21 ± 0.35 (male vs female diabetic groups)b.	T1DM adolescents males worse RHI compared with similarly aged T1DM females and healthy gender and age matched controls. T1DM females had higher BMI and were more sexually mature.
Haller et al[48], 2007	RA	Assess the ability of RHI to serve as a surrogate marker of endothelial dysfunction in children with T1DM.	T1DM Children with disease > 1 yr: 14.4 ± 1.5, n = 44 [22/22]	Healthy children, non- smokers and without a family history of medical premature CVD or hyperlipidemia: 14.1 ± 1.5, n = 20 [8/12]	1.63 ± 0.5 vs 1.95 ± 0.3 (diabetic vs controls)a.	RHI lower in diabetic population. In this study children with T1DM had significantly higher mean systolic BP, mean total cholesterol and mean HDL compared to controls. No significant differences in age, BMI, diastolic BP, LDL or triglycerides were observed between the 2 groups.
Mahmud et al[49], 2008	RA	Evaluate the effect of a high-fatmeal on RHI in adolescents with T1DM.	T1DM Children with disease > 2 yr, no retinopathy or nephopathy: 14.6 ± 1.75, n = 23 [9/14]	Healthy children: 14.7 ± 1.95, n = 23 [9/14]	Pre-meal RHI, T1DM vs controls, 1.78 ± 0.4 vs 2.06 ± 0.4a. Post.meal RHI, T1DM vs controls, 1.45 ± 0.3 vs 1.71 ± 0.3a.	RHI lower in diabetic population in a fasting state and after a high-fat meal compared with controls. The change in RHI was similar in the 2 groups.
Palombo et al[54], 2011	RA	To compare large artery structure and function indexes, endothelial function and regenerating capacity between T1DM adolescent and healthy age-matched controls. Association of different vascular measures with EPCs, glyco-metabolic control and AGEs, sRAGE and adiponectin levels were searched.	T1DM patients without retinopathy, microalbuminuria and neuropathy, pharmacological treatment (other than insulin). 18 ± 2, n = 16 [5/11]	Healthy children: 19 ± 2, n = 26 [11/15]	2.0 ± 0.5 vs 1.8 ± 0.6 (T1D vs controls)c. 1.5 ± 0.4 vs 2.2 ± 0.8 (T1D with HbA1c 7.5% vs T1d with HbA1c < 7.5%)a.	T1DM adolescents higher central pulse pressure (PP), Augmentation Index (AI), carotid femoral pulse wave velocity, local carotid wave speed, common carotid artery intima-media thickness. RHI reduced only in T1DM patients with 7.5% (P < 0.05). In the overall population, EPCs were an independent determinant of carotid IMT (together with adiponectin), while fasting plasma glucose was an independent determinant of carotid wave speed, AI and central PP.
Pareyn et al[50], 2013	CSS	To search a difference in RHI between w T1DM adolescents and controls	T1DM children insulin treated for at least one year: 15.8 (14.4 to 16.6), n = 34 [18/16]	Healthy children: 15.5 (13.9 to 16.2, n = 25 [13/12]	1.6 (1.3-2.0) vs 1.9 (1.7-2.4), children with T1DM vs controlsa. 1.3 (1.3-1.7) vs 2.0 (1.7-2.5), female with T1DM vs female controlsa. 1.8 (1.5-2.1) vs 1.8 (1.5-2.3), male with T1DM vs male controlsc.	RHI lower in T1DM, especially in females. No correlation was seen between RHI and BMI SDS, BP SDS, HbA1c, age, disease duration, TG and Tanner stage.
Scaramuzza et al[52], 2015	CS	To evaluate prevalence of early EF, measured by RHI < 1.67 in T1DM cohort, at baseline and after a a 1 yr follow-up	T1DM adolescents with disease duration > 1 yr, Tanner pubertal stage III-V, BMI between 5-95° percentile: 16.2 ± 3.5, n = 73 [25/48]	No controls	1.26 ± 0.22 vs 2.24 ± 0.48, patients with RHI < 1.67 vs patients with RHI > 1.67b. At the 1 yr follow-up in 64/73 patients, the rate of endothelial dysfunction (81.8%) was even higher than the rate recorded at baseline (76.7%).	RHI negatively correlates with impaired metabolic control and subclinical signs of autonomic neuropathy, while positively correlates with regular physical activity. ED progression irrespective of improved metabolic control.
Scaramuzza et al[57], 2015	RA	To evaluate the effect of alpha-lipoic acid on ED in T1DM youth, a 6-month, double- blind, randomized controlled trial	T1DM adolescents for at least 1 yr, aged 12-19 yr, insulin requirement 0.5 U/kg/day, blood glucose checks more the 3 times/day, BMI and BP < 95° percentile, no cardiovascular or inflammatory diseases. 16.3 ± 3.4, n = 71 [29/42], age at baseline.		3 double-blind study arms: 10000 ORAC antioxidant diet + (-lipoic acid, 1.40 ± 0.68 vs 1.72 ± 0.66a (baseline vs after 6 months). 10 000 ORAC antioxidant diet + placebo, 1.39 ± 0.41 vs 1.58 ± 0.40c (baseline vs after 6 months). Controls, 1.58 ± 0.64 vs 1.54 ± 0.42c.	Positive association between alpha-lipoic acid administration and ED parameters.
Deda et al[53], 2018	RA	To evaluate the effect of Vit. D supplementation on EF by RHI measurement	T1DM patients for at least 2 yr and levels of 25-OH-Vit. D < 37.5 nmol/L. 15.7 ± 1.4, n = 31 [19/12]	To account for seasonality of RHI testing, a separate cohort of age, sex and T1DM matched controls was tested in spring and in fall (no significant difference was showed)	After a 4.8 ± 1.3 months Vit. D supplementation RHI improved: 1.83 ± 0.42 vs 2.02 ± 0.68a.	Vit.D supplementation associated with EF improvement and reduced expression of urinary inflammatory markers.

^aP<0.05.

^bP<0.005.

^cP>0.05.

AGEs: Serum levels of advanced glycation end products; CS: Cohort study; CSS: Cross sectional study; CVD: Cardiovascular disease; BMI: Body mass index; BP: Blood pressure; ED: Endothelial dysfunction; EF: Endothelial function; EPCs: Endothelial progenitor cells; F: Female; HbA1c: Hemoglobin A1c; LDL: Low-density lipoprotein; M: Male; ORAC: Oxygen radical absorbance capacity units; RA: Research article; RHI: Reactive hyperemia index; SDS: Standard deviation score; sRAGE: Soluble receptors for AGEs; T1DM: Type 1 diabetes mellitus; TG: Triglycerides.