Clinically evident diabetes-related vascular complications are rare in childhood and adolescence. However, early functional and structural abnormalities may be present a few years after the onset of the disease. This article is protected by copyright. All rights reserved.

ISPAD Clinical Practice Consensus Guidelines 2018: Microvascular and macrovascular complications in children and adolescents

High Density Lipoproteins (HDLs) have long been considered as "good cholesterol," beneficial to the whole body and, in particular, to cardio-vascular health. However, HDLs are complex particles that undergoes dynamic remodeling through interactions with various enzymes and tissues throughout their life cycle, making the complete understanding of its functions and roles more complicated than initially expected. In this review, we explore the novel understanding of HDLs' behavior in health and disease as a multifaceted class of lipoprotein, with different size subclasses, molecular composition, receptor interactions, and functionality. Further, we report on emergent HDL-based therapeutics tested in small and larger scale clinical trials and their mixed successes.

https://www.zora.uzh.ch/id/eprint/199141/1/fcvm-07-00039.pdf

High Density Lipoproteins: Metabolism, Function, and Therapeutic Potential.

We examined the temporal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT) with the risk of overweight/obesity and elevated blood pressure (BP)/hypertension. We studied 3862 adolescents aged 17.7 years from the Avon Longitudinal Study of Parents and Children, followed-up for 7 years. cfPWV and cIMT were measured by ultrasound. Total and trunk fat mass and lean mass were assessed by dual-energy X-ray absorptiometry. Body mass index and BP were measured. Data were analyzed using logistic regression, linear mixed-effect, and cross-lagged structural equation models, with covariate adjustments. Among 1719 male and 2143 female participants, higher cfPWV at 17.7 years was associated with the risk of elevated systolic BP/hypertension (odds ratio, 1.20 [1.02-1.41]; P=0.026), elevated diastolic BP/hypertension (1.77 [1.32-2.38]; P<0.0001), body mass index-overweight/obesity (1.19 [1.01-1.41]; P=0.041), and trunk fat mass overweight/obesity (1.24 [1.03-1.49]; P=0.023) at 24.5 years. Higher cIMT at 17.7 years had no associations with obesity and elevated BP at follow-up. cfPWV progression was directly associated with 7-year increase in systolic BP (effect estimate 16 mm Hg [9-24]; P<0.0001) and diastolic BP (28 mm Hg [23-34]; P<0.0001). cIMT progression was directly associated with the 7-year increase of all adiposity measures and diastolic BP. In the temporal analysis, baseline cfPWV was directly associated with follow-up systolic and diastolic BP, however, baseline BP was unassociated with follow-up cfPWV. cfPWV but not cIMT was bidirectionally associated with adiposity. Obesity and hypertension prevention from adolescence may require developing novel approaches to mitigate arterial stiffness.

https://www.ahajournals.org/doi/pdf/10.1161/HYPERTENSIONAHA.121.18449

Effects of Arterial Stiffness and Carotid Intima-Media Thickness Progression on the Risk of Overweight/Obesity and Elevated Blood Pressure/Hypertension: a Cross-Lagged Cohort Study.

Background: A large yet heterogeneous body of literature exists suggesting that endothelial dysfunction appears early in type 1 diabetes, due to hyperglycemia-induced oxidative stress. The latter may also affect vascular smooth muscles (VSM) function, a layer albeit less frequently considered in that pathology. This meta-analysis aims at evaluating the extent, and the contributing risk factors, of early endothelial dysfunction, and of the possible concomitant VSM dysfunction, in type 1 diabetes.
Methods: PubMed, Web of Sciences, Cochrane Library databases were screened from their respective inceptions until October 2019. We included studies comparing vasodilatory capacity depending or not on endothelium (i.e., endothelial function or VSM function, respectively) in patients with uncomplicated type 1 diabetes and healthy controls.
Results: Fifty-eight articles studying endothelium-dependent function, among which 21 studies also assessed VSM, were included. Global analyses revealed an impairment of standardized mean difference (SMD) (Cohen's d) of endothelial function: −0.61 (95% CI: −0.79, −0.44) but also of VSM SMD: −0.32 (95% CI: −0.57, −0.07). The type of stimuli used (i.e., exercise, occlusion-reperfusion, pharmacological substances, heat) did not influence the impairment of the vasodilatory capacity. Endothelial dysfunction appeared more pronounced within macrovascular than microvascular beds. The latter was particularly altered in cases of poor glycemic control [HbA1c > 67 mmol/mol (8.3%)].
Conclusions: This meta-analysis not only corroborates the presence of an early impairment of endothelial function, even in response to physiological stimuli like exercise, but also highlights a VSM dysfunction in children and adults with type 1 diabetes. Endothelial dysfunction seems to be more pronounced in large than small vessels, fostering the debate on their relative temporal appearance.

https://hal.univ-lille.fr/hal-02569246/document

Early Endothelial Dysfunction in Type 1 Diabetes Is Accompanied by an Impairment of Vascular Smooth Muscle Function: A Meta-Analysis.

We examined the temporal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT) with the risk of overweight/obesity and elevated blood pressure (BP)/hypertension. We studied 3862 adolescents aged 17.7 years from the Avon Longitudinal Study of Parents and Children, followed-up for 7 years. cfPWV and cIMT were measured by ultrasound. Total and trunk fat mass and lean mass were assessed by dual-energy X-ray absorptiometry. Body mass index and BP were measured. Data were analyzed using logistic regression, linear mixed-effect, and cross-lagged structural equation models, with covariate adjustments. Among 1719 male and 2143 female participants, higher cfPWV at 17.7 years was associated with the risk of elevated systolic BP/hypertension (odds ratio, 1.20 [1.02-1.41]; P=0.026), elevated diastolic BP/hypertension (1.77 [1.32-2.38]; P<0.0001), body mass index-overweight/obesity (1.19 [1.01-1.41]; P=0.041), and trunk fat mass overweight/obesity (1.24 [1.03-1.49]; P=0.023) at 24.5 years. Higher cIMT at 17.7 years had no associations with obesity and elevated BP at follow-up. cfPWV progression was directly associated with 7-year increase in systolic BP (effect estimate 16 mm Hg [9-24]; P<0.0001) and diastolic BP (28 mm Hg [23-34]; P<0.0001). cIMT progression was directly associated with the 7-year increase of all adiposity measures and diastolic BP. In the temporal analysis, baseline cfPWV was directly associated with follow-up systolic and diastolic BP, however, baseline BP was unassociated with follow-up cfPWV. cfPWV but not cIMT was bidirectionally associated with adiposity. Obesity and hypertension prevention from adolescence may require developing novel approaches to mitigate arterial stiffness. 

Effects of Arterial Stiffness and Carotid Intima-Media Thickness Progression on the Risk of Overweight/Obesity and Elevated Blood Pressure/Hypertension: a Cross-Lagged Cohort Study

Objectives This study characterized the determinants of carotid intima-media thickness (cIMT) in a large (n > 4,000) longitudinal cohort of healthy young people age 9 to 21 years. Background Greater cIMT is commonly used in the young as a marker of subclinical atherosclerosis, but its evolution at this age is still poorly understood. Methods Associations between cardiovascular risk factors and cIMT were investigated in both longitudinal (ages 9 to 17 years) and cross-sectional (ages 17 and 21 years) analyses, with the latter also related to other measures of carotid structure and stress. Additional use of ultra-high frequency ultrasound in the radial artery at age 21 years allowed investigation of the distinct layers (i.e., intima or media) that may underlie observed differences. Results Fat-free mass (FFM) and systolic blood pressure were the only modifiable risk factors positively associated with cIMT (e.g., mean difference in cIMT per 1-SD increase in FFM at age 17: 0.007 mm: 95% confidence interval [CI]: 0.004 to 0.010; p  Conclusions Subtle changes in cIMT in the young may predominantly involve the media and represent physiological adaptations as opposed to subclinical atherosclerosis. Other vascular measures might be more appropriate for the identification of arterial disease before adulthood.

/pdf/determinants-of-intima-media-thickness-in-the-young-the-2e68c5xhpc.pdf

Determinants of Intima-Media Thickness in the Young: The ALSPAC Study

AIMS High-density lipoprotein (HDL) function may be altered in patients with chronic disease, transforming the particle from a beneficial vasoprotective molecule to a noxious pro-inflammatory equivalent. Adolescents with Type 1 diabetes often have elevated HDL, but its vasoprotective properties and relationship to endothelial function have not been assessed. METHODS AND RESULTS Seventy adolescents with Type 1 diabetes (age 10-17 years) and 30 age-matched healthy controls supplied urine samples for the measurement of early renal dysfunction (albumin:creatinine ratio; ACR), blood samples for the assessment of cardiovascular risk factors (lipid profiles, HDL functionality, glycaemic control, and inflammatory risk score), and had their conduit artery endothelial function tested using flow-mediated dilation (FMD). HDL-c levels (1.69 ± 0.41 vs. 1.44 ± 0.29mmol/L; P < 0.001), and glycated haemoglobin (HbA1c) (8.4 ± 1.2 vs. 5.4 ± 0.2%; P < 0.001) were increased in all patients compared with controls. However, increased inflammation and HDL dysfunction were evident only in patients who also had evidence of early renal dysfunction (mean ± standard deviation for high-ACR vs. low-ACR and healthy controls: inflammatory risk score 11.3 ± 2.5 vs. 9.5 ± 2.4 and 9.2 ± 2.4, P < 0.01; HDL-mediated nitric-oxide bioavailability 38.0 ± 8.9 vs. 33.3 ± 7.3 and 25.0 ± 7.7%, P < 0.001; HDL-mediated superoxide production 3.71 ± 3.57 vs. 2.11 ± 3.49 and 1.91 ± 2.47nmol O2 per 250 000 cells, P < 0.05). Endothelial function (FMD) was impaired only in those who had both a high inflammatory risk score and high levels of HDL-c (P < 0.05). CONCLUSION Increased levels of HDL-c commonly observed in individuals with Type 1 diabetes may be detrimental to endothelial function when accompanied by renal dysfunction and chronic inflammation.

/pdf/elevated-high-density-lipoprotein-in-adolescents-with-type-1-37qmlfnoia.pdf

Elevated high-density lipoprotein in adolescents with Type 1 diabetes is associated with endothelial dysfunction in the presence of systemic inflammation.

The study was supported by a grant from Diabetes UK (09/0003859). P.H.T. was financially supported by Academy of Finland (decision 130171); The Diabetes Research Foundation, Finland; Foundation for Pediatric Research, Finland; The Alma and K. A. Snellman Foundation, Oulu, Finland; and The Finnish Medical Foundation.

/pdf/clustering-of-cardio-metabolic-risk-factors-in-parents-of-1ahpguyass.pdf

H Nguyen

Papers

Determinants of Intima-Media Thickness in the Young: The ALSPAC Study

Elevated high-density lipoprotein in adolescents with Type 1 diabetes is associated with endothelial dysfunction in the presence of systemic inflammation.

Clustering of cardio-metabolic risk factors in parents of adolescents with type 1 diabetes and microalbuminuria.

Determinants of arterial intima and media thickness in young adults