Longitudinal evaluation of Endothelial Function in Children with Type 1 Diabetes Mellitus. A long term follow up study.
Lorenzo Iughetti1, Rosario Rossi2 , Barbara Predieri1, Patrizia Bruzzi1, Viviana Dora Patianna1, Annamaria Salvini1, Maria Grazia Modena2.
Departments of Paediatric1 and Cardiology2 University of Modena and Reggio Emilia Modena, Italy.
Running title: Endothelial Function in Children with Diabetes
Address correspondence and reprint request: Lorenzo Iughetti., MD, PhD
Department of Pediatrics
University of Modena and Reggio Emilia Via del Pozzo, 71. 41100 Modena, Italy
Tel. 0039 059 4225382 Fax 0039 059 4224583 e-mail: [email protected]
Abstract
Type 1 diabetes (T1DM) with the increased risk to develop atherosclerosis predisposes to cardiovascular disease. In childhood the cardiovascular risk may be evaluated studying endothelial function, assessed by a noninvasive ultrasound technique, namely flow-mediated dilation (FMD) of the brachial artery. The aim of this study was to longitudinally evaluate the longitudinal modifications in the endothelium–dependent function in children with T1DM. We included in the study 32 T1DM patients (14 girls and 18 boys; aged 11.6 ± 3.3 years), that developed the disease 49.0 ± 39.5 months ago. FMD and blood samples were obtained from all patients at baseline (time 0) and after a follow-up of at least 2 years (time 1). FMD was also evaluated in 45 healthy controls (22 boys, 23 girls) aged 10.1 ± 2.9 years. The re-assessment of FMD 1 showed a dramatic impairment of endothelial function: FMD lower than at baseline in 24 out of 32 patients (75% of the entire population) respect to 50% found at the begging of the study. No correlation was found between FMD and pubertal status, lipid profile, glycated hemoglobin (HbA1c) or duration of T1DM. Males had a more important impairment of FMD than females. The glycemic control, assessed by the HbA1c values, was always considered “appropriate” both at baseline and during follow-up.
Because endothelial dysfunction appears earlier in diabetic children, they are at high risk to develop atherosclerosis. The ultrasound assessment of FMD might be a useful tool for cardiovascular risk stratification of pediatric patients with T1DM.
Key words: type 1 diabetes mellitus, flow mediated dilation, glycosilated hemoglobin control, atherosclerosis.
Abbreviations: T1DM, type 1 diabetes mellitus; CHD, coronary heart disease; FMD, flow-mediated dilation; ED, endothelial dysfunction; DCCT, The Diabetes Control and Complications
Trial; EDIC, Epidemiology of Diabetes Interventions and Complications; HbA1c, glycated hemoglobin; BAD, brachial artery diameter; NO, nitric oxide;
INTRODUCTION
It is well known that type 1 diabetes mellitus (T1DM) is associated with an increased risk for coronary heart disease (CHD). Patients with T1DM have, in fact, 2- to 4-fold increased risk of developing atherosclerotic-related events (1). This is due to macro- and micro-angiopathy (2), demonstrated, in subclinical way, in diabetic children in form of impaired endothelial function (3-5). In this respect, flow-mediated dilation (FMD) of the brachial artery, as first demonstrated by Celermajer (6), represents a marker of endothelium-dependent function and it is a non-invasive method, based on ultrasound, for detecting early functional and subclinical atherosclerotic changes in the arterial wall.
The Diabetes Control and Complications Trial (DCCT) and its follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) studies, showed that the risk of micro- and macro-vascular complications linked to T1DM is related to the long-term glycemic control (7-8). Moreover, from DCCT it emerged that in the intensive arm of the study the mean value of glycated hemoglobin (HbA1c) was 8,1% (9), demonstrating that, even with intensive insulin treatment, the majority of children with T1DM are unable to maintain a near-normal glycemic control. On this basis, it is evident that subjects with T1DM, since childhood, are at highest risk of developing subsequent micro- and macro-vascular complications. Because vascular complications of diabetes are not yet clinically evident in diabetic children, surrogate markers for CHD are needed to check the efficacy of treatment (10).
Aim of our study was to longitudinally evaluate the endothelium-dependent vasodilation in children and adolescents with T1DM to understand if there should be any better or worse change and to clear if clinical or laboratory data can be correlated to modifications.
PATIENTS AND METHODS
Patients
We studied thirty-two children and adolescents with T1DM [14 girls and 18 boys, aged 11.6 ± 3.3 years (range: 3.15 – 20.0)], with T1DM duration of 49.0 ± 39.5 months (range 3 – 170); and forty-five age-matched healthy control children [23 girls, 22 boys, aged 10.1 ± 2.9 years; (range: 4 – 21 )] Ethical Board of Pediatric Department approved the protocol study and informed consent to participate to the study was obtained from the patient/patients’ parents.
In all included subjects height, weight, pubertal staging, laboratory and ultrasonographic study were evaluated at baseline (Time 0) and after a period >2 years (Time 1).
The clinical characteristics of the patients are reported in Table 1 and 2. All subjects were normal weight and none had other acute or chronic diseases. Thyroid hormones, hepatic and renal functions were normal. All diabetic patients were taking no medications other than insulin; none had retinopathy, demonstrated by fundoscopic examination, nor microalbuminuria, measured by overnight albumin excretion rate. Subjects with hypertension or history of smoking were excluded from the study.
Methods
Height was measured to the nearest 0.1-cm with a wall-mounted stadiometer (Harpenden, Crymych; UK). Body weight was measured to the nearest 0.1-kg and body mass index (BMI) was obtained from the weight in kg/height in meters squared and expressed as Z-score with respect to
chronological age (CA).
Pubertal development was determined using the grading system defined by Tanner for pubic hair (PH) and breast (B) (11).
After an overnight fast, each subject underwent blood sample collection in the morning before insulin administration and the ultrasound test. Serum total cholesterol (TC), high-density lipoprotein
cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) plasma concentrations were measured by standard enzymatic methods.
Fasting plasma glucose level was measured by the hexokinase spectrophotometry method (Synchron system, Beckman Instruments, US) and HbA1c was determined by high performance liquid chromatography (Variant Analyser, Bio-Rad).
All children and adolescents underwent an ultrasonographic study, in order to evaluate endothelial-dependent vasodilation, using the determination of the FMD of the brachial artery. To reduce the interobserver intersession coefficient of variation, one single, experienced vascular ultrasonographer performed all exams. The study was performed in the morning, between 07.00 and 08.00 a.m. after an overnight fast and before the administration of morning insulin. The study of the brachial artery was performed in all participants by means of an Acuson 128 XP/10 mainframe (Acuson, Mountain View, California) with a 7.0-MHz linear array transducer. The technique for assessing FMD has been described in detail elsewhere (6,10,12-14). Briefly, FMD was assessed in the subject’s right arm in the recumbent position after a 15-min equilibration period in a temperature-controlled room (22°C to 25°C). Each subject had fasted the previous night for at least 12 h. The artery was longitudinally imaged approximately 5 cm proximal to the antecubital crease, and brachial artery diameter (BAD) was measured at end-diastole. After the baseline resting scan, a pneumatic cuff placed at the level of the mid-forearm (proximal to the target artery) was inflated until no blood flow was detected through the brachial artery with the Doppler probe, and this pressure was held for 5 min. Increased flow was then induced with sudden cuff deflation and a continuous scan was performed for 1 min. For the reactive hyperemia scan, BAD measurements were taken 45 to 60 s after cuff deflation. FMD was calculated from the diameters as (reactive hyperemia - baseline)/baseline percent.
Statistics
All results are reported as the mean ± standard deviation (S.D.). Non parametric statistical analysis (STATISTICA™ software, StatSoft Inc., Tulsa, OK, USA) was performed using Mann-Whitney’s U test to compare Time 0 imaging findings among T1DM and control groups, Wilcoxon test for paired samples to evaluate statistical differences between basal and longitudinal clinical, laboratory and imaging findings inside T1DM group. Spearman’s correlation was also performed to analyze relationship among variables. Moreover, a multiple regression was performed using the following models:
1.
FMD Time 0a. age, sex, pubertal status, height SDS, BMI SDS, and duration of disease b. TC, HDL-C, LDL-C, TG, glycemia, HbA1c
2.
FMD Time 1a. age, sex, pubertal status, height SDS, BMI SDS, and duration of disease b. TC, HDL-C, LDL-C, TG, glycemia, HbA1c
A P value below 0.05 was considered statistically significant.
RESULTS
Clinical data
Table 1 shows the clinical characteristics of patients with T1DM compared to healthy controls. No significant differences were found.
Biochemical data
At the first evaluation (time 0) diabetic patients showed an HbA1c value of 8.0 1.0 % and normal lipids levels. After 30.3 ± 7.4 months of follow-up (time 1), the metabolic control of T1DM did not change significantly (Table 2).
At time 0, FMD in controls was significantly higher than in diabetic children and adolescents: 12.8 6.7 % vs. 6.4 10.6 %, respectively; 95% (p = 0.006; Figure 1).
The re-assessment of FMD at time 1 revealed a dramatic impairment of this parameter: the FMD values resulted; in fact, lower than at baseline in 25 of 32 (78.1%) patients. Only 3 patients significantly improved FMD value (Figure 2).
Conversely, the worsening of FMD was significantly higher in males than in females (Table 3; Figure 3).
At baseline the mean value of FMD resulted 3.45 11.8% in the group of T1DM patients with HbA1c < 7.5% vs. 6.49 10.9% (p = 0.495) in patients with HbA1c > 7.5%
Using Spearman correlation we only found a significant correlation between FMD and sex (p = 0.002) while no relation was demonstrated between FMD and fasting glucose plasma levels, HbA1C, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and diabetes duration, both at time 0 and after follow-up (Figure 4).
The same results were found using multiple linear regression: at baseline we did non demonstrated significant relation between FMD and clinical or laboratory data; the second model including data at follow up confirm that sex is the more important parameter than influence FMD values (p=0.029; =0.470).
DISCUSSION
The present study demonstrates that an impaired endothelial function is common in T1DM children and adolescents respect to healthy age-matched controls, already few years after the onset of diabetes. Moreover, our longitudinal results underlines that FMD rapidly impaired despite a glycemic control comparable with the control of patients in the active arm of DCCT.
A cardiovascular event is rare in early childhood, but risk factors are present in pediatric age, predicting CHD in adulthood (15-17). The impairment of endothelial function in patients with T1DM was demonstrated firstly in adults, and subsequently confirmed in adolescents. Donaghue et al (18) suggested, for example, that in adolescents with T1DM a large vessel diameter was the most
common damage. Meeking et al (19) clearly showed that endothelial dysfunction is a potent prognostic factor for the development of renal damage; and Singh et al (20) demonstrated that the alteration of FMD precedes structural vessel abnormalities. On this basis, our results suggest that the evaluation of endothelial dysfunction in diabetic patients could have a predictive importance to precociously individuate vascular damage.
The duration of disease should represent an important factor in the deterioration of FMD, both in adults and in adolescents (20, 21). Our data, however, don’t support this hypothesis, lacking any significant correlation between FMD and diabetes duration. The reason of this apparent discrepancy is that in our patients the duration of disease is relatively short, and correlation between diabetes duration and endothelial dysfunction become apparent with a longer duration of the disease, as previously suggested (21-23).
Regarding the differences between males and females about endothelial dysfunction, it was already reported in the literature (24-26). In general, women have a vasomotor activity (mediated of endothelium) greater than that of males of the same age. There are many hypotheses on the reason for which this happens. First of all, females have less body surface area, a lower BMI and a lower arterial diameter. This is the crucial point that, in our opinion, may explain the observed differences. Mizia-Stec et al have demonstrated, in fact, that the brachial artery diameter well correlates with the amount of FMD % (25). Even in our case the diameter of the brachial artery is significantly different in males respect to females. Another hypothesis takes into account the age of our patients, occurring near to the puberty age. At this stage of life women acquire the ability to produce large amounts of estrogen, which are known as agents that can improve endothelial function (27).
The average HbA1c in our patients with T1DM (both at baseline and after follow up) is lower than the HbA1c of young patients noted in the invasive therapy arm of the DCCT, but this better glycemic control did not protect our patients from a lower endothelial function than our control subjects. It has been suggested that the alteration of endothelial function was related to the degree of
diabetes control expressed by the levels of HbA1c (28), but this correlation is was absent both in our and in others studies (20-23).
Lipids alterations play a major role in determining the progression of atherosclerosis, so it is reasonable to suppose a correlation between lipids concentration and FMD. Recent data have demonstrated better endothelial function in adults with CHD who have LDL levels < 80 mg/dL, when compared with those with LDL between 80 and 100 mg/dL (29). In our study the lipid profile apparently doesn’t significantly influence FMD, as could be suggested by the absence of any significant correlation between cholesterol and triglycerides levels and FMD. However, the few studies in children and adolescent with T1DM have shown contrasting results. While Singh et al (20) showed a significant negative relationship between FMD and both total and LDL-cholesterol, Suys et al (30) demonstrated that FMD has no correlation with LDL-cholesterol.
The most impressive results from our study are those related to the dramatic impairment of the FMD after a relatively short follow-up, especially in males. Because endothelial dysfunction appears earlier (than expected) in diabetic children, they are at high risk to develop atherosclerosis. This impairment of endothelial function, unpredictable on the basis of glycemic control, circulating lipid concentrations, blood pressure values, allows us to assume a more aggressive treatment of T1DM.
We well know that the evaluation of FMD can be influenced by several factors (temperature, diet, menstrual cycle, technicalities) changing day to day with consequent variable results (31).
However, we totally agree with the assumption that FMD is “particularly suited to young individuals” because of they generally present wide vasodilator responses that easily facilitate discrimination of normal and abnormal values (32).
In conclusion, we demonstrated that in few years endothelial function severely impairs in diabetic children and adolescents. We think that the ultrasound assessment of FMD might be a useful tool for cardiovascular risk stratification of pediatric patients with T1DM, at least in a research setting. However, in the approach at diabetic children and adolescent it is time to consider surrogate
methods to examine endothelial function, in order to better understand the impact of the treatment on the vascular status. Further studies are required to individuate both factors involved in the impairment of FMD, and therapeutic interventions with beneficial effects on endothelial function.
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Figure 1 – Flow-mediated dilation (FMD) in diabetic patients (T1DM) and in control subjects (control) at enrollment. In the present figure data are presented showing the median value of FMD (small square), the standard error of mean (great square) and the standard deviation (lines most extreme).
Figure 2 - In the present figure is represented the modifications in flow-mediated dilation (FMD) during follow-up. It is clearly visible as patients who worsen FMD (n = 25; 78.1%) are the majority of our sample (green lines), compared to the minority of patients (n = 7; 21.9%) that improve the same parameter (red lines). The black lines underline the mean value ± SD (lines most extreme) of FMD at baseline (time 0) and at the end of the study (time 1) and the behavior of the same
parameter during follow up.
Figure 3 – Different change of FMD in males and females
Figure 4 – Correlation between FMD and HbA1c and duration of the disease at time 0 (T0) and at follow op (T1).
Table 1: Clinical characteristics of patients with T1DM compared to healthy controls. Parameter T1DM group (n=32) Control group (n = 45) p Age (years) 11.6 ± 3.3 10.1 ± 2.9 0.69 Height (cm) 147.3 ± 18.1 139.9 ± 16.3 0.57 Weight (kg) 44.1 ± 15.3 37.1 ± 12.3 0.10
Body Mass Index (kg/m2) 19.6 ± 2.9 18.4 ± 2.5 0.75
Table 2: Comparison between diabetic patients at baseline and after follow up. Parameter Time 0 (baseline) Time 1 (after a follow-up of 30.3 ± 7.4 months) p Glycemic control
Fasting plasma glucose (mg/dl) 232.1 ± 90.1 232.3 ± 84.4 0.99
HbA1c (%) 8.0 ± 1.0 8.1 ± 1.1 0.31
Duration of diabetes (months) 49.0 ± 39.5 79.4 ± 41.1 0.00 Lipids profile Total cholesterol (mg/dl) 167.6 ± 36.5 166.1 ± 30.9 0.84 HDL cholesterol (mg/dl) 64.8 ± 11.8 66.0 ± 13.3 0.60 LDL cholesterol (mg/dl) 89.3 ± 31.2 93.8 ± 26.1 0.30 Triglycerides (mg/dl) 57.8 ± 21.7 65.8 ± 31.9 0.17 Endothelial function FMD (%) 6.4 ± 10.6 2.6 ± 9.1 0.04
Data are mean value ± one SD or % (n). HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; FMD, flow mediated dilation.
Table 3 : Gender differences in vascular function of our study population.
Parameter
Male Female p
Values at baseline
BAD (mm) 2.9 ± 0.8 2.3 ± 0.7 0.04
FMD (%) 5.3 ± 11.9 7.8 ± 9.1 0.51
BAD (mm) 3.0 ± 0.8† 2.2 ± 0.8† 0.03
FMD (%) - 0.9 ± 8.1* 7.1 ± 8.2† 0.009
* p = 0.043 respect to FMD at baseline † p = NS respect to baseline values
