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Copyright ©The Author(s) 2021.
World J Diabetes. Jun 15, 2021; 12(6): 810-826
Published online Jun 15, 2021. doi: 10.4239/wjd.v12.i6.810
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], 2006RADeterminate 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], 2007RAAssess 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], 2008RAEvaluate 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], 2011RATo 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], 2013CSSTo search a difference in RHI between w T1DM adolescents and controlsT1DM 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], 2015CSTo evaluate prevalence of early EF, measured by RHI < 1.67 in T1DM cohort, at baseline and after a a 1 yr follow-upT1DM 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 controls1.26 ± 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], 2015RATo evaluate the effect of alpha-lipoic acid on ED in T1DM youth, a 6-month, double- blind, randomized controlled trialT1DM 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], 2018RATo evaluate the effect of Vit. D supplementation on EF by RHI measurementT1DM 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.
Table 2 EndoPat 2000 in pediatric population with metabolic syndrome
Ref.
Design
Aim of the study
Population: age in years; mean ± SD or median (range)
Control group: age in years; mean ± SD or median (range)
RHI reported in arbitrary units. If RHI not specified, we reported p trend or positive/negative relation with parameters examined
RHI outcomes
Dongui et al[58], 2019QRSImpact of diet and exercise on microvascular functionSedentary OB Age 12-18, n = 57 [F/M = 0/57]Healthy NW Age 12-20, n = 10 [F/M 0/10]OB 1.43 (0.35) vs CG 1.67 (0.36)a. After exercise OB vs CGa. OB Pre-exercise vs Post-Exercisea.RHI higher in CG. In OB RHI improved after 6 wk of diet and exercise.
Pareyn A et al[59], 2015CSSAssessment of EF in OB/OW adolescentsOW/OB Age 14.7, n = 27 [F/M 11/16]NW Age 15.5, n = 25 [F/M 13/12]NW 1.88 (1.7-2.4) vs OW 1.5 (1.3-1.9)a. Positively with agea and tanner stagea. Negatively with diastolic BPa. With BGL, insulin lipid profilec.RHI lower in OB/OW adolescents. RHI improved with age and Tanner stage. RHI decreased with higher diastolic BP. RHI not related with lipid, IR, BGL and gender. RHI inversely related with baseline pulse amplitude.
Agarwal et al[60], 2013CSSAssessment of EF in OB/NW adolescentsOB Age 15.3 (0.4) years, n = 37 [F/M 26/11]NW Age 14.9 (0.6), n = 14 [F/M 9/5]OB 1.7 (0) vs NW 1.9 (0.1)a. OB IGR 1.63a. Other values reported like p trend.RHI lower in obese adolescents. RHI negatively related with BMI, WC, BGL, HOMA-IR, Leptin, TNF, hs-CRP. No relationship with lipid profile and BP.
Mahmud et al[61], 2009RAEvaluation of EF in OB adolescents with impaired ISOB with HOMA-IR 5.4 Age 13.4 (1.7), n = 26 [F/M 10/16]NW, healthyAge 14 (1.4), n = 51 [F/M 21/30]OB 1.5 (0.4) vs NW 2 (0.4)b. Other values reported like p trend.EF lower in OB and negatively related with adiposity, TG, LDL and Tot-Chol. RHI improved with age. RHI not correlated with Leptin, IR or gender.
Tomsa et al[62], 2016CSSComparing EF to body fat, IS, BGL and CIM in dysglicemic and OW adolescentsOW with NGT, n = 25, OW with IGT n = 19, OW with T2D but HB1Ac < 8% n = 16; Age 15.5 (0.2) Total n = 60 [F/M 37/23]NW Age 15.5 (0.2), n = 21 [F/M 9/12]BMI 30.91.2 (0) vs BMI 30.41.5 (0) vs BMI 26.72.0 (0)p trenda. Negatively with WC, BGL, TNF, PAIa, leptinb. Positively with age and insulin sensitivitya. BP, lipid profilec. For exact values see reference.RHI lower in OB and T2DM. RHI negatively related with percentage body fat, WC, Leptin, TNF-alpha, BGL. RHI positively related with age and. RHI not related with BP and lipid profile.
Del Ry et al[63], 2016RAC-type Natriuretic Peptide in OW, OB and NW. Relation with RHI and other endothelial markersOW AGE 12.8 (1.6) n = 10; [F/M 5/5]. OB, G 3.5 (1), AGE 12.8 (1.6) n = 45; [F/M19/26].NW, AGE 12.8 (1.4) n = 27; [F/M 14/13]NW 2.1 (0.2) vs OW 1.6 (0.4)a. NW vs OB 1.4 (0.3)b. Negatively with CNPb. Exact values non reported.RHI was significantly lower in OW/OB. CNP negatively related with RHI.
Del Ry et al[64], 2020RANatriuretic peptide network in normal weight and obese adolescents, its relation with RHI.Primary OB Not diabetic, Age 13.3 (0.5) n = 16; [F/M8/8].NW, Age 14.3 (0.4) n = 24; [F/M14/10].NW 2.1 (0) vs OB 1.4 (0)b. Negatively with CNP, hs CRP, diastolic BPb. Exact values non reported.RHI significantly lower in OB.RHI negatively related with hs-CRP, CNP, diastolic BP, fat mass and A1C.
Singh et al[65], 2017RARelation between EF and urinary markersOW and OB Age 13.8 (2.4) n = 43; [F/M 23/20]Healthy NW Age 13.9 (2) n = 20; [F/M 8/12]NW 1.6 (0.1) vs OW 1.66 (0.1)c and OB 1.67 (0.1)c. NW girls 1.9 vs NW boys 1.25b.No correlation between RHI, BMI and urinary markers. RHI higher in NW female adolescents
Czippelova et al[66], 2019RAAssessment of EF in different systemic vascular resistances. Comparing EF to Cardio Ankle Vascular IndexOB No DM or HBP Age 16.4 (2.7) n = 29 [F/M 14/15]NW Age 16.5 (2.6) n = 29 [F/M NR]NW 1.45 (0.3) vs OB 1.4 (0.3)c. Positively with SVRa.No difference between RHI in OB and CG RHI was influenced by vascular tone and resistance. RHI in OB positively related with SVR.
Kochummen et al[24], 2019CSSEvaluation of EF in OB with normal BGL comparing to NW with T1DM1 and OB with T2DMNW with DM1 and OB DM2 Age 12.7 (3.8) n = 41 [F/M 25/16]OB with normal BGL, BP and lipid profile. Age 12.8 (2.7) n = 17 [F/M 9/8]A1C > 10% 1.2 (0.2) vs A1C < 10% 1.7 (0.6)a. Negatively with A1Ca. DM 1.4 (0.5) vs obese 1.4 (0.3)c. T1D 1.4 (0.5) vs T2D1.5 (0.5)c. Female 1.5 (0.5) vs male 1.3 (0.4)a.RHI lower in poorly controlled DM. RHI negatively related with A1C. RHI similar between OB and NW with DM and between DM1 and DM2. RHI lower in males especially in OB without DM.
Bruyndonckx et al[67], 2014CSSEvaluation of EF and correlation with CVRF in childrenOB Age 15.2 (1.4) n = 57NW Age 15.5 (1.5) n = 30NW 2 (0.6) vs OB 2.2 (0.7)c. Lipid, HOMA-IR, BP, hsCRPc.RHI not related with BMI, HOMA-IR, BP, lipid or hsCRP. RHI not homogenous with “Time to peak”.
Tryggestad et al[68], 2012RAEvaluation of vascular function in OB and NW childrenOB Age 13.9 (2.5) n = 62 (F/M 32/30)NW Age 13.3 (3) n = 61 (F/M 30/31)OB vs CGc. Exact values reported for age and BMI ( see reference). Age group 8-12 yr: 1.6-2.0a. Age group 13-18 yr: 2.0-2.5a.RHI similar in OB and CG. RHI improved 0.07 for each year of age in CG. RHI was reduced in older OB. RHI not related with BP and lipid profile.
Fusco et al[69], 2020RAAssessment of precocious microvascular dysfunction in OB adolescentsOB Age 14.1 (2.5), n = 22 [F/M 13/9]NW Age 15.1 (1.5) n = 24 [F/M 11/13]OB 1.8 (0.6) vs CG1.9 (0.5)c. RHI not different between CG and OB. RHI not correlated with LDF (that is impaired in OB).
Bacha et al[74], 2017CSSComparing EF in hispanic adolescents with and without NAFLDOW with pre diabetes or T2DM with NAFLD Age 15.2 (0.5) n = 23 [F/M 12/11]OW with pre-diabetes or TD2 without NAFLD Age 15.7 (0.4) n = 13 [F/M 3/10]NAFLD 1.4 (0) vs CG 1.7 (0)b.Hepatic fat and AST/ALT levels were inversely related with RHI.
aP< 0.05.
bP< 0.005.
cP> 0.05.
A1C: Glycosylated hemoglobin; AE: Anti-epileptic drugs; CIM: Circulating inflammatory markers; CNP: C-type natriuretic peptide; CSS: Cross sectional study; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; CVR: Cardio vascular risk; CVRF: Cardio vascular risk factors; EF: Endothelial function; HBP: High blood pressure; IGT: Impaired glucose tolerance; IR: Insulin resistance; IS: Insulin sensitivity; LDF: Laser Doppler flowmetry; NW: Normal weight; OB: Obese > 95’cc; OS: Oral steroids; OW: overweight > 85’ cc; NGT: Normal Glucose Tolerance; PM: Psychiatric medications; QRS: Quasi randomized study; RA: Research Article; SVR: Systemic vascular resistance; TG: Triglycerides; Tot-Chol: Total cholesterol; RHI: Reactive hyperemic index; WC: Waist circumference.
Table 3 Study characteristics for reactive hyperemic index-Endopat 2000 in different pediatric endocrine 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)
Outcomes
Bhangoo et al[44], 2011CSSRelation of puberty and sex steroids with endothelial functionHealthy population: Tanner I: 12.1 (0.6), n = 21 [19/2] Tanner II-III: 12.7 (0.7), n = 35 [21/14] Tanner IV-V: 13 (0.7), n = 33 [22/11]Tanner I 1.46 (0.44) vs Tanner II-III 1.71 (0.35)a. Tanner I 1.46 (0.44) vs IV-V 1.92 (0.38)b. Tanner II-III value n.avs IV-V value NAa. F Tanner II-III 1.66 (0.38) vs F IV-V 1.91 (0.29)a. M Tanner I 1.41 (0.35) vs M Tanner II-III 1.78 (0.30)b. M Tanner I vs M Tanner IV-V 1.93 (0.67)a.PAT index positively related with estradiol, DHEAS levels and age.
O’Gorman et al[94], 2012CCSEvaluation of EF in TS, and HC.Turner syndrome: 13.5 (2.4), n = 15 [15/0]. Turner syndrome: GH-untreated 14.3 (2.4), n = 8. Turner syndrome: GH-treated 12.7 (2), n = 7.Healthy children (HC) 14.3 (1.7), n = 15 [15/0]Turner syndrome: 1.64 (0.34) vs HC 2.08 (0.32)b. Turner syndrome: GH-untreated 1.44 (0.26) vs GH-treated 1.86 (0.28)a.PAT index lower in TS indicating impaired EF compared with HC.GH may protect endothelial function in TS.
Ruble et al[78], 2015CCSEvaluation of RHI in ALL survivors, compared with HS.ALL survivors: (0.9), n = 16 [8/8]. HS:13.8 (0.9), n = 16 [6/10].HS: 14.3 (1.7), n = 15 [15/0]ALL survivors 1.54 (0.38) vs HS 1.77 (0.41)a.Poorer vascular health ALL survivors.
Blair et al[77], 2014RCCTEvaluation of flavanoid-rich purple grape juice (compared in RCCT with clear apple juice) on endothelial function, markers of oxidative stress and inflammation in cancer survivors.Cancer survivors (hematopoietic malignancy 50%, solid tumor 50%) 16.4 (13.7–17.2), n = 24 [17/7]Cancer survivors. Before apple juice 1.57 (0.36) vs before grape juice 1.75 (0.52). After apple juice 1.83 (0.47) vs after grape juice 1.75 (0.39). Before grape juice 1.57 (0.52) vs after grape juice 1.75 (0.39).After four weeks of daily consumption of flavanoid-rich purple grape juice, no measurable change in vascular function in young cancer survivors.
aP<0.05.
bP<0.005.
CSS: Cross sectional study; CCS: Case control study; F: Female; GH: Growth hormone; HC: Healthy controls; HS: Healthy siblings; ALL: Acute lymphoid leukemia; M: Male; NA: Not available; RHI: Reactive hyperemic index; RCCT: Randomized controlled crossover trial.