Role of FGF21 and Leptin for the Diagnosis of Metabolic Health in Children with and without Obesity.

Obesity and unfavorable metabolic profiles increase the risk for cardiovascular complications in adults. Although it is important to distinguish different metabolic health states at an early stage, there are limited data on the related value of biomarkers in childhood. We aimed to identify biomarkers for the detection of different metabolic health states in children with and without obesity. The serum levels of metabolic regulators (fibroblast growth factor 21 [FGF21], leptin, adiponectin and insulin-like growth factor binding protein 1) and vascular indices (flow-mediated dilation [FMD] and carotid intima-media thickness) were assessed in 78 children. Differences between the metabolically healthy and unhealthy state within children with normal weight (MHN vs. MUN), and within children with overweight/obesity (MHO vs. MUO) were investigated; the discriminatory power of the biomarkers was studied. Both MUN and MUO groups expressed altered lipid and glucose homeostasis compared to their healthy counterparts. The metabolic unhealthy state in children with normal weight was linked to higher FGF21 levels which had good discriminatory ability (area under the curve [AUC]: 0.71, 95% CI: 0.54-0.88; p = 0.044). In overweight/obese children, leptin was increased in the metabolically unhealthy subgroup (AUC: 0.81, 95% CI: 0.68-0.95; p = 0.01). There was a decrease in FMD indicating worse endothelial function in overweight/obese children versus those with normal weight. Distinct states of metabolic health exist in both children with normal weight and overweight/obese children. FGF21 and leptin may help to identify the metabolic unhealthy state in children with normal weight and in overweight/obese children, respectively, early in life.

Prolonged QT Interval in Athletes: Distinguishing between Pathology and Physiology.

BACKGROUND: The physiological QT prolongation in athletes is expected to widen the gray zone between physiology and pathology of QT, increasing the diagnostic challenges encountered in athletes with QT prolongation. SUMMARY: According to international recommendations for electrocardiogram in athletes, further evaluation for long QT syndrome (LQTS) is indicated in male athletes with corrected QT (QTc) ≥470 ms and in female athletes with QTc ≥480 ms. Apart from QTc ≥500 ms, diagnostic challenges arise in borderline cases of QTc prolongation, where further clinical investigations are needed to be performed to clarify whether LQTS exists. Clinical diagnostic investigations, including exercise testing, are more readily available, convenient, and easily interpretable, as well as less costly than genetic testing for LQTS. The main findings on exercise testing that are suggestive of LQTS can be the paradoxical prolongation of QTc during exercise and QTc ≥480 ms at fourth min of recovery. KEY MESSAGES: Exercise testing appears to have an important role in the diagnostic evaluation of athletes with prolonged QT interval, when genetic testing is not available.

Evolution of electrocardiographic abnormalities and arrhythmias in adult patients with beta-thalassemia major during a short-term follow-up.

OBJECTIVE: Adult beta-thalassemia major (TM) patients exhibit electrocardiographic abnormalities and cardiac autonomic dysfunction. We aimed to investigate the evolution of electrocardiographic abnormalities and arrhythmias in TM patients during a 12-month follow-up period. METHODS: Forty-seven adult TM patients (median age: 36 years, 57% men) without overt heart failure were studied. We examined 12-lead electrocardiograms, 24-hour electrocardiographic Holter recordings, and treadmill exercise stress tests at baseline and after 12 months. Conventional electrocardiographic measurements, as well as contemporary indexes of depolarization and repolarization/dispersion of repolarization (QRS fragmentation; T peak-to-end; T peak-to-end/QT) were assessed. Moreover, we examined markers of autonomic dysfunction such as heart rate variability, and heart rate recovery after exercise testing. RESULTS: The electrocardiographic markers of atrial/ventricular depolarization and repolarization, as well as indexes of autonomic imbalance, were not significantly changed. However, the recorded supraventricular ectopic beats increased significantly. Paroxysmal atrial fibrillation (PAF) detection was greater in 12 months (4/47 at baseline vs. 8/47 at 12 months; P=0.38). However, 5/8 patients who were diagnosed with PAF at the second examination did not have the arrhythmia at the initial evaluation. Thus, PAF was present in a total of 9/47 (19%) TM patients. Notably, 3/9 of the patients were asymptomatic. The mean duration of PAF was 5±2 minutes and the mean number of these episodes was 8±2. CONCLUSION: TM patients have repolarization and autonomic function abnormalities that do not significantly change during a 12-month follow-up period. However, supraventricular ectopy and AF burden further evolve.

Association of fibroblast growth factor 21 with metabolic syndrome and endothelial function in children: a prospective cross-sectional study on novel biomarkers.

PURPOSE: Metabolic and cardiovascular disease prevention starting in childhood is critical for reducing morbidity later in life. In the present study, the association of novel biomarkers with metabolic syndrome (MS) and vascular function/structure indices of early atherosclerosis in children was investigated. METHODS: This was a prospective study of 78 children (8-16 years of age) grouped based on the presence or absence of MS. The serum biomarkers investigated included fibroblast growth factor 21 (FGF21), leptin, adiponectin, and insulinlike growth factor binding protein-1 (IGFBP1). Endothelial function and carotid atherosclerosis were assessed based on brachial artery flow-mediated dilation (FMD) and carotid intima-media thickness, respectively. RESULTS: Children with MS (n=12) had higher levels of FGF21 (median [interquartile range]: 128 [76-189] pg/mL vs. 60 [20-98] pg/mL, P=0.003) and leptin (18.1 [11-34.8] pg/mL vs. 7.5 [1.9-16.5] ng/mL, P=0.003), and lower levels of IGFBP1 (1.5 [1.2-2.1] ng/mL vs. 2.3 [1.5-6] ng/mL, P=0.028) compared with children without MS. FMD inversely correlated with FGF21 (Spearman rho= -0.24, P=0.035) and leptin (rho= -0.24, P=0.002) in all children. The best cutoff value of FGF21 levels for MS diagnosis was above 121.3 pg/mL (sensitivity/specificity, 58/86%). Only FGF21 was significantly associated with the presence of MS after adjustment for body mass index, age, and sex (odds ratio per 10 pg/mL increase: 1.10 [95% confidence interval, 1.01-1.22]; P=0.043). CONCLUSION: Increased FGF21 levels were associated with the presence of MS and worse endothelial function in children. Larger studies are needed to evaluate the potential value of FGF21 as a biomarker that could predict future metabolic/cardiovascular disease at an early stage.

The impact of dyslipidemia on early markers of endothelial and renal dysfunction in children.

BACKGROUND: Dyslipidemia has been associated with endothelial dysfunction in childhood. Impairment of renal function has been demonstrated in dyslipidemic adults. OBJECTIVE: The aim of this study was to assess markers of early endothelial and renal dysfunction in dyslipidemic children. METHODS: This was a cross-sectional study of 100 children with dyslipidemia and 100 age- and sex-matched control subjects without dyslipidemia aged 7-16 years. Renal dysfunction was assessed by measurement of serum creatinine and cystatin C levels, urinary beta 2-microglobulin levels, urinary albumin to creatinine (Alb:Cr) ratio, and by the estimated glomerular filtration rate (eGFR), based on serum creatinine or cystatin C. Endothelial dysfunction and early vascular changes were evaluated by ultrasound assessment of flow mediated dilation (FMD) of the brachial artery, and carotid intima-media thickness (cIMT), respectively. RESULTS: The markers of early renal dysfunction showed no difference between the dyslipidemic children and control subjects except for the urinary Alb:Cr ratio that was higher in the dyslipidemic children (median, 0.007 mg/mg vs 0.005 mg/mg, p = 0.004). The urinary Alb:Cr ratio was positively correlated with the triglyceride to high-density lipoprotein cholesterol ratio (r = 0.28, p = 0.013). FMD values were lower in the dyslipidemic children than in the control subjects (8.504 ± 4.73% vs 10.535 ± 4.35%, p = 0.004), but cIMT did not differ between groups. This decrease in FMD values was evident in children aged ≥10 years. FMD was independently associated with the level of lipoprotein (a) (beta = -0.29, p = 0.01). CONCLUSION: Among markers of endothelial and renal dysfunction investigated, FMD was found to be lower and the urinary Alb:Cr ratio higher in children with dyslipidemia.

Review shows that lipid disorders are associated with endothelial but not renal dysfunction in children.

AIM: We undertook this review to assess the effects of lipid metabolism abnormalities on endothelial and renal function in children. METHODS: A search of relevant literature published in English from January 1988 to May 2018 was performed, and this included randomised controlled trials, observational cohort studies, systematic reviews and case reports. RESULTS: The search process identified 2324 relevant studies and 29 were finally included. Noninvasive ultrasound markers of endothelial dysfunction, such as flow-mediated dilation and carotid intima-media thickness, were impaired in children with dyslipidaemia. Dietary interventions and statin therapy reversed the effects of dyslipidaemia on endothelial function in children. Most data from adult studies failed to prove a causative relationship between dyslipidaemia and renal disease progression or a beneficial effect of lipid-lowering treatment on renal outcomes. The limited paediatric data did not indicate dyslipidaemia as an independent risk factor for renal dysfunction, which was mainly estimated by cystatin C levels or proteinuria. Therefore, further investigation is needed to clarify a potential relationship. CONCLUSION: In view of limited available paediatric evidence, dyslipidaemia may be adversely associated with endothelial function. However, the association between lipid metabolism disorders and renal function in childhood needs to be further investigated.

Autonomic responses during acute myocardial infarction in the rat model: implications for arrhythmogenesis.

Background Autonomic responses participate in the pathophysiology of acute myocardial infarction, but their precise time course remains unclear. Here, we investigated the autonomic activity and ventricular tachyarrhythmias in conscious, unrestrained rats post-infarction. Methods The left coronary artery was ligated in 12 Wistar rats, and six rats were sham operated, followed by 24-h electrocardiographic recording via implanted telemetry transmitters. Sympathetic activity was assessed by detrended fluctuation analysis and vagal activity by time- and frequency-domain analysis of heart rate variability. The duration of the ventricular tachyarrhythmias was measured, and voluntary motion served as a marker of heart failure. Results In sham-operated rats, heart rate and sympathetic activity remained low, whereas vagal activity rose progressively after the fourth hour. Post-ligation, medium-sized antero-septal necrosis was observed, reaching ~20% of the left ventricular volume; tachyarrhythmias were frequent, displaying a bimodal curve, and motion counts were low. Vagal activity decreased early post-ligation, coinciding with a high incidence of tachyarrhythmias, but tended to rise subsequently in rats with higher motion counts. Sympathetic activity increased after the third hour, along with a second tachyarrhythmia peak, and remained elevated throughout the 24-h period. Conclusions Vagal withdrawal, followed by gradual sympathetic activation, may participate in arrhythmogenesis during acute myocardial infarction.

Local conduction during acute myocardial infarction in rats: Interplay between central sympathetic activation and endothelin.

We investigated the effects of autonomic dysfunction and endothelin on local conduction and arrhythmogenesis during myocardial infarction. We recorded ventricular tachyarrhythmias, monophasic action potentials, and activation sequences in wild-type and ETB-deficient rats displaying high endothelin levels. Central sympathetic inputs were examined after clonidine administration. Clonidine mitigated early and delayed arrhythmogenesis in ETB-deficient and wild-type rats, respectively. The right ventricular activation delay increased in clonidine-treated ETB-deficient rats and slightly decreased in wild-type rats. The left ventricular voltage rise decreased in all groups, whereas the activation delay increased mainly in clonidine-treated ETB-deficient rats. Central sympathetic activation and endothelin modulate ischemia-induced arrhythmogenesis. Ischemia alters excitability, whereas endothelin impairs local conduction, an action partly counterbalanced by central sympathetic activity.

Prolonged intra-myocardial growth hormone administration ameliorates post-infarction electrophysiologic remodeling in rats.

Experimental studies indicate improved ventricular function after treatment with growth hormone (GH) post-myocardial infarction, but its effect on arrhythmogenesis is unknown. Here, we assessed the medium-term electrophysiologic remodeling after intra-myocardial GH administration in (n = 33) rats. GH was released from an alginate scaffold, injected around the ischemic myocardium after coronary ligation. Two weeks thereafter, ventricular tachyarrhythmias were induced by programmed electrical stimulation. Monophasic action potentials were recorded from the infarct border, coupled with evaluation of electrical conduction and repolarization from a multi-electrode array. The arrhythmia score was lower in GH-treated rats than in alginate-treated rats or controls. The shape and the duration of the action potential at the infarct border were preserved, and repolarization-dispersion was attenuated after GH; moreover, voltage rise was higher and activation delay was shorter. GH normalized also right ventricular parameters. Intra-myocardial GH preserved electrical conduction and repolarization-dispersion at the infarct border and decreased the incidence of induced tachyarrhythmias in rats post-ligation. The long-term antiarrhythmic potential of GH merits further study.

Intra-myocardial growth hormone administration ameliorates arrhythmogenesis during ischemia-reperfusion in rats.

Growth hormone, currently under evaluation for the prevention of left ventricular remodeling post-myocardial infarction, displays antiarrhythmic properties in the acute setting. However, it is uncertain whether these actions are retained after ischemia/reperfusion. Using implanted telemetry transmitters, we examined the effects of prolonged, intra-myocardial growth hormone administration in conscious rats. During a 24-h observation period, ventricular tachyarrhythmias and sympathetic activation were attenuated in treated rats, whereas infarct-size was unchanged. These findings call for further study on the antiarrhythmic effects of growth hormone and on the underlying mechanisms.

Electrocardiographic abnormalities and arrhythmic risk markers in adult patients with beta thalassemia major.

BACKGROUND: There seems to be a significant arrhythmia burden in ß-thalassemia major (TM) patients without overt cardiomyopathy. Apart from conventional electrocardiographic (ECG) and arrhythmic risk markers we studied novel markers of ventricular repolarization and autonomic imbalance both at rest and after exercise testing. METHODS: We studied 47 adult TM patients without systolic heart failure and 47 age and sex-matched healthy control subjects. The median age of the studied population was 36 [32-43] years, 57% men. Baseline demographic and clinical characteristics were recorded while 12-lead electrocardiograms, 24-hour ECG Holter recordings, and treadmill exercise stress tests were analyzed. RESULTS: TM patients exhibited increased QTc intervals in both 12-lead ECG recordings and in 24-hour Holter recordings. In addition, they had increased indexes of ventricular repolarization heterogeneity such as QT dispersion, and T peak-to-end/QT ratios. Furthermore, TM patients had decreased indexes of heart rate variability while the heart rate recovery after exercise was significantly attenuated compared to controls. Also, they had increased P wave and QRS duration while the QRS fragmentation was very prevalent. Finally, premature atrial extrasystoles and paroxysmal atrial fibrillation episodes were more frequent in TM patients. CONCLUSIONS: TM patients with preserved left ventricular systolic function have several ECG abnormalities including alterations in ventricular depolarization and repolarization. Also, cardiac autonomic dysfunction is evident in 24-hour ECG monitoring as well as in the recovery phase after exercise testing. The prognostic value of specific arrhythmic risk indexes in this setting remains to be elucidated.

Fibroblast growth factors in cardiovascular disease: The emerging role of FGF21.

Early detection of risk factors for enhanced primary prevention and novel therapies for treating the chronic consequences of cardiovascular disease are of the utmost importance for reducing morbidity. Recently, fibroblast growth factors (FGFs) have been intensively studied as potential new molecules in the prevention and treatment of cardiovascular disease mainly attributable to metabolic effects and angiogenic actions. Members of the endocrine FGF family have been shown to increase metabolic rate, decrease adiposity, and restore glucose homeostasis, suggesting a multiple metabolic role. Serum levels of FGFs have been associated with established cardiovascular risk factors as well as with the severity and extent of coronary artery disease and could be useful for prediction of cardiovascular death. Furthermore, preclinical investigations and clinical trials have tested FGF administration for therapeutic angiogenesis in ischemic vascular disease, demonstrating a potential role in improving angina and limb function. FGF21 has lately emerged as a potent metabolic regulator with multiple effects that ultimately improve the lipoprotein profile. Early studies show that FGF21 is associated with the presence of atherosclerosis and may play a protective role against plaque formation by improving endothelial function. The present review highlights recent investigations suggesting that FGFs, in particular FGF21, may be useful as markers of cardiovascular risk and may also serve as protective/therapeutic agents in cardiovascular disease.

Arterial hypertension during treatment with triptorelin in a child with Williams-Beuren syndrome.

BACKGROUND: Arterial hypertension (AHT) is a common finding in children with Williams-Beuren syndrome (WBS). Although cardiovascular and renal abnormalities can explain the AHT in some patients with WBS, its etiology is not fully understood and most cases are considered idiopathic. CASE-DIAGNOSIS/TREATMENT: The case is reported of a 10-year-old girl with WBS who developed severe AHT during treatment with triptorelin, a long-lasting gonadotropin-releasing hormone (GnRH) analog, administered because of early normal puberty. Comprehensive diagnostic studies ruled out other known causes of AHT associated with WBS. After discontinuation of triptorelin, the blood pressure remained within the normal range for her age and height with no antihypertensive treatment on long-term follow-up. To the best of the authors' knowledge, this is the first report of AHT associated with triptorelin administration in a child with WBS. CONCLUSIONS: Clinicians should be aware of the possibility, although rare, of AHT developing during triptorelin administration in childhood, specifically in patients at increased risk of AHT, such as those with WBS.

Endothelial dysfunction, but not structural atherosclerosis, is evident early in children with heterozygous familial hypercholesterolemia.

Children with heterozygous familial hypercholesterolemia (heFH) are prone to premature atherosclerosis. Vascular endothelial dysfunction may predict increased cardiovascular risk in children with heFH. The aim of this study was to assess for early functional and structural vascular changes in children with heFH. This cross-sectional study included 30 children with heFH (mean age 12 years) and 30 age- and sex-matched controls. Brachial artery flow-mediated dilation (FMD), carotid intima-media thickness (cIMT), carotid-femoral pulse wave velocity, and large- and small vessel compliance were measured noninvasively. HeFH children exhibited significantly greater total and LDL cholesterol, apolipoprotein B, and lipoprotein (a) levels (p < 0.05 for all) and lower FMD (6.23 ± 3.88 vs. 9.46 ± 4.54 %, p < 0.004) compared with controls. When children were divided in age subgroups, FMD was found to be significantly decreased in heFH compared with control subjects only in ages >10 years (p < 0.05). However, FMD was found to be similarly impaired in heFH children in all age subgroups (two-way analysis of variance, p = 0.39). No differences in other vascular function indices were found. In heFH patients, but not in controls, FMD was inversely correlated with cIMT (r = -0.378, p = 0.036). In conclusion, endothelial dysfunction occurs early in heFH children indicating an increased risk for premature cardiovascular disease and reflecting probably the need for early initiation of anticholesterolemic treatment. Decreased FMD is detected before structural atherosclerotic changes occur.

Noninvasive assessment of pulmonary vascular resistance by Doppler echocardiography.

BACKGROUND: The ratio of tricuspid regurgitation velocity (TRV) to the time-velocity integral of the right ventricular outflow tract (TVIRVOT) has been studied as a reliable measure to distinguish elevated from normal pulmonary vascular resistance (PVR). The equation TRV/TVIRVOT × 10 + 0.16 (PVRecho) has been shown to provide a good noninvasive estimate of PVR. However, its role in patients with significantly elevated PVR (> 6 Wood units [WU]) has not been conclusively evaluated. The aim of this study was to establish the validity of the TRV/TVIRVOT ratio as a correlate of PVR. The role of TRV/TVIRVOT was also compared with that of a new ratio, TRV(2)/TVIRVOT, in patients with markedly elevated PVR (>6 WU). METHODS: Data from five validation studies using TRV/TVIRVOT as an estimate of PVR were compared with invasive PVR measurements (PVRcath). Multiple linear regression analyses were generated between PVRcath and both TRV/TVIRVOT and TRV(2)/TVIRVOT. Both PVRecho and a new derived regression equation based on TRV(2)/TVIRVOT: 5.19 × TRV(2)/TVIRVOT - 0.4 (PVRecho2) were compared with PVRcath using Bland-Altman analysis. Logistic models were generated, and cutoff values for both TRV/TVIRVOT and TRV(2)/TVIRVOT were obtained to predict PVR > 6 WU. RESULTS: One hundred fifty patients remained in the final analysis. Linear regression analysis between PVRcath and TRV/TVIRVOT revealed a good correlation (r = 0.76, P < .0001, Z = 0.92). There was a better correlation between PVRcath and TRV(2)/TVIRVOT (r = 0.79, P < .0001, Z = -0.01) in the entire cohort as well as in patients with PVR > 6 WU. Moreover, PVRecho2 compared better with PVRcath than PVRecho using Bland-Altman analysis in the entire cohort and in patients with PVR > 6 WU. TRV(2)/TVIRVOT and TRV/TVIRVOT both predicted PVR > 6 WU with good sensitivity and specificity. CONCLUSIONS: TRV/TVIRVOT is a reliable method to identify patients with elevated PVR. In patients with TRV/TVIRVOT > 0.275, PVR is likely > 6 WU, and PVRecho2 derived from TRV(2)/TVIRVOT provides an improved noninvasive estimate of PVR compared with PVRecho.

Depressive symptoms and neurocardiogenic syncope in children: a 2-year prospective study.

OBJECTIVE: To evaluate prospectively the relationship between neurocardiogenic syncope (NCS) and depressive symptoms in pediatric patients. METHODS: Forty-five patients (aged 12.3 ± 2.9 years) with NCS (diagnosed as ≥ 1 syncopal episodes with typical symptoms, reproduced by tilt-table testing, in the absence of structural or primary electrical heart disease) were compared with 45 age- and gender-matched control subjects. Assessment was performed at baseline and 2 years thereafter. Depressive symptoms and self-perception profile of participants were evaluated, along with their parents' psychological distress, defensive profile and hostility. Family cohesion and adaptability, as well as the opinion of parents and teachers on children's strengths and difficulties, were also examined. RESULTS: At baseline, patients showed more (P = .008) depressive symptoms than controls, correlating with the number of syncopal episodes, impaired relationship with parents and poor family cohesion. A conservative management strategy of NCS was adopted and psychological counseling was offered, focusing on patients with clinically significant depressive symptoms and their families. During follow-up, depressive symptoms decreased in patients (P < .001), but remained stable in controls. Child-parent relationship, family cohesion and family adaptability improved at follow-up in patients. No recurrent syncope was noted during follow-up and this along with improvement in child-parent relationship were associated with depressive symptoms improvement. CONCLUSIONS: Depressive symptomatology is common in pediatric patients with NCS. Our findings call for additional investigation in larger controlled clinical interventional studies that will enhance understanding of the possible pathophysiological association between depressive symptomatology and NCS in pediatric populations.

Determinants of pulmonary hypertension in patients with Beta-thalassemia major and normal ventricular function.

BACKGROUND/AIMS: We sought to define the incidence and predictive factors of pulmonary hypertension in ß-thalassemia major. METHODS: We studied 27 consecutive patients (19 male, 38 ± 9 years of age) with ß-thalassemia major. All the patients had normal (left and right) ventricular (systolic and diastolic) function and underwent echocardiographic assessment of pulmonary artery systolic pressure. Univariate regression and discriminant function analyses were used to identify predictive factors of pulmonary hypertension. RESULTS: Pulmonary hypertension was observed in 18.5% of the patients, but clinically significant disease was detected in only 3.7%. A total of 14 (51.8%) patients had been receiving a combined administration of deferoxamine and deferiprone for 7.0 ± 1.3 years. Amidst a large number of variables examined, ferritin levels and delayed onset of chelation therapy were the only predictors of pulmonary hypertension. CONCLUSION: Pulmonary hypertension in ß-thalassemia major is relatively infrequent and generally mild due to improved chelation therapy. The role of hemochromatosis in pulmonary hypertension development merits further study.

Transforming growth factor-ß inhibition and endothelin receptor blockade in rats with monocrotaline-induced pulmonary hypertension.

Transforming growth factor-ß (TGF-ß) inhibition is an investigational therapy for pulmonary arterial hypertension with promising results in experimental studies. The present work compared this approach with endothelin-receptor blockade and evaluated the effects of combined administration. Pulmonary arterial hypertension was induced by single monocrotaline injection (60 mg/kg) in 75 Wistar rats and 15 rats served as controls. Intervention groups consisted of treatment with an antibody against TGF-ß-ligand, bosentan, both or none, initiated four weeks after monocrotaline injection. Right ventricular systolic pressure, pulmonary vascular remodeling, and exercise tolerance were evaluated eight weeks after monocrotaline injection. Either treatment, alone or in combination, lowered mortality. Comparable efficacy was found in the three treatment groups in terms of right ventricular systolic pressure (~45% decrease) and hypertrophy (~30% decrease), as well as exercise capacity. The three treatment groups equally ameliorated pulmonary vascular remodeling, evidenced by decreased vessel-wall thickness (in vessels 50-200 µm) and a smaller number of pre-capillary arterioles (< 50 µm) with a muscularized media. Treatment either with an antibody against TGF-ß or with endothelin receptor blockade are equally effective in experimental pulmonary hypertension. Their combination provides no added benefit, indicating common mechanisms of action.

Changes in vascular function and structure in juvenile idiopathic arthritis.

OBJECTIVE: Chronic inflammatory diseases in adults have been associated with increased cardiovascular risk and impaired vascular function. We aimed to assess the presence of early vascular dysfunction in patients with juvenile idiopathic arthritis (JIA) and investigate the role of inherent inflammatory process of JIA in vascular health. METHODS: Thirty patients with JIA (age range 7-18 years) were compared to 33 age- and sex-matched controls. Endothelial function (brachial artery flow-mediated dilation [FMD]), carotid intima-media thickness (IMT), and arterial stiffness were examined. Endothelial inflammation was assessed by intercellular adhesion molecule 1 (ICAM-1) and P-selectin measurements. RESULTS: Patients with JIA showed decreased FMD compared to controls (P = 0.001), independent of age (P = 0.9 among age subgroups). Baseline differences in erythrocyte sedimentation rate, ICAM-1, and glucose between the 2 groups accounted for the difference in FMD. The presence of systemic JIA was associated with greater IMT compared to patients with oligoarticular disease, polyarticular disease, or controls (P = 0.014, P = 0.069, and P = 0.046, respectively). The difference in IMT between systemic versus oligoarticular/polyarticular JIA was attributed to the following risk factors: age, body mass index, blood pressure, disease activity, and corticosteroids use. There were no differences in arterial stiffness indices between JIA patients and controls or between patients with systemic versus nonsystemic disease. CONCLUSION: Endothelial function is impaired in patients with JIA at a very young age, while IMT is increased only in the presence of systemic JIA. Vascular dysfunction may be partly attributed to the effects of disease-related characteristics (inflammation, disease activity, and medications).