Vasculopathy In Children Research Articles

Inflammatory Cytokines, Endothelial Function, and Chronic Allograft Vasculopathy in Children: An Investigation of the Donor and Recipient Vasculature After Heart Transplantation.

Chronic allograft vasculopathy (CAV) limits the lifespan of pediatric heart transplant recipients. We investigated blood markers of inflammation, endothelial dysfunction, and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from pediatric heart transplant recipients for markers of inflammation and endothelial activation. The systemic vasculature was investigated using brachial artery flow-mediated dilatation and carotid artery intima-medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima-media thickness (mIMT) > 0.5 mm was used to define significant CAV. Forty-eight children (25 male) aged 8-18 years were enrolled in the study. Patients were a median (interquartile range) 4.1 (2.2-8.7) years after transplant. Patients had increased levels of circulating IL6 (3.86 [2.84-4.95] vs. 1.66 [1.22-2.63] p < 0.0001), vascular cell adhesion molecule 1 (539 [451-621] vs. 402 [342-487] p < 0.001), intracellular adhesion molecule 1 305 (247-346) vs. 256 (224-294) p = 0.002 and thrombomodulin (7.1 [5.5-8.1] vs. 3.57 [3.03-4.71] p < 0.0001) and decreased levels of tumor necrosis factor-α, E selectin, and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum thrombomodulin. Posttransplant thrombomodulin levels are elevated after transplant but significantly lower in those with mIMT > 0.5 mm. This suggests that subclinical inflammation is present and that natural anticoagulant/thrombomodulin activity is important after transplant.

Soluble Fas/FasL ratio as a marker of vasculopathy in children and adolescents with sickle cell disease

ObjectivesSickle cell disease (SCD) is characterized by chronic inflammation due to ischemic tissue damage, accentuated during acute complications. Fas and its ligand (FasL) are members of tumor necrosis factor receptor superfamily and a major pathway for induction of apoptosis. Fas/FasL interactions may be related to augmentation of inflammatory response. We assessed the levels of sFas and sFasL in 35 children and adolescents with SCD compared with 35 healthy controls in relation to hemolysis, iron overload, sickle vasculopathy including kidney disease. MethodsSCD patients, in steady state and asymptomatic for pulmonary hypertension, were studied stressing on hydroxyurea therapy, serum ferritin, urinary albumin creatinine ratio (UACR), high-sensitivity C-reactive protein (hs-CRP) and sFas/sFasL levels. ResultssFas/sFasL ratio was significantly higher in patients compared with controls. sFas/sFasL ratio was elevated in patients with pulmonary hypertension, nephropathy and those who had history of frequent sickling crisis or serum ferritin ⩾2500. SCD patients treated with hydroxyurea had lower sFas/sFasL ratio than untreated patients. sFas/sFasL ratio was positively correlated to transfusion index, white blood cells, hs-CRP, serum ferritin and UACR. The cutoff value of sFas/sFasL at 8.75pg/mL could differentiate SCD patients with and without nephropathy while the cutoff value at 22pg/mL could differentiate SCD patients with and without pulmonary hypertension risk with high sensitivity and specificity. ConclusionsFas/sFasL ratio may be considered as a marker for vascular dysfunction in SCD patients and is related to inflammation, iron overload and albuminuria level. Thus, it may be a reliable method to assess renal impairment in SCD.

Delayed hemorrhage after surgery and radiation in suprasellar pilocytic astrocytomas

Delayed intracranial hemorrhage is a rare complication of treatment for central nervous system tumors. This may be secondary to malignant transformation of the tumor or vasculopathy related to radiation therapy (RT). While most reports on radiation-induced vasculopathy in children with optic pathway gliomas are associated with ischemic complications, there are only two reports of hemorrhagic complications in these patients. In both cases, the hemorrhage was asymptomatic and remote from the site of the original tumor but within the field of irradiation. We describe a female patient who underwent surgery for an optico-chiasmatic pilocytic astrocytoma (PA) at the age of 12 followed by RT at the age of 17 for tumor progression. The patient was followed with serial magnetic resonance imaging (MRI) scans showing marginal regression and no subsequent evidence of tumor recurrence, including the most recent MRI done only 6 months before the latest presentation. She then developed a symptomatic intratumoral hemorrhage at the age of 32 for which she underwent emergent surgery. To our knowledge, this is the first report of a nonaneurysmal-delayed hemorrhage within the site of previous surgery, several years after RT for a suprasellar PA. We review literature on delayed vasculopathy following the treatment of pediatric optic pathway gliomas and discuss the possible mechanisms of hemorrhage in our case. These long-term follow-up outcomes add significant insight and have implications in patient management.

Detection of Cerebral Vasculopathy by Transcranial Doppler in Children With Neurofibromatosis Type 1.

Neurofibromatosis type 1 is characterized by nerve sheath neurofibromas associated with a number of additional clinical features, including cerebrovascular disease. The aim of this study was to use transcranial Doppler as a screening method for identifying cerebral vasculopathy in children with neurofibromatosis type 1. Forty children with neurofibromatosis type 1, aged 5 to 18 years old, were examined by transcranial Doppler. Patients presenting with hemodynamic features of arterial stenosis/occlusion on transcranial Doppler underwent magnetic resonance angiography to confirm the findings. Magnetic resonance angiography was performed on 4 children who exhibited a transcranial Doppler hemodynamic pattern indicative of cerebral vasculopathy. Among these cases, 2 presented internal carotid artery stenosis/occlusion, 1 had bilateral middle cerebral artery stenosis, and 1 presented a normal magnetic resonance angiography result. Transcranial Doppler can be used routinely in the investigation of cerebrovascular disease in neurofibromatosis type 1 patients, where magnetic resonance angiography can be subsequently applied to confirm the diagnosis, further contributing to the prevention of cerebrovascular events.

G6PD deficiency and absence of α-thalassemia increase the risk for cerebral vasculopathy in children with sickle cell anemia.

The aim of this study was to test the association between hematological/genetic factors and cerebral vasculopathy in children with sickle cell anemia (SCA). A group with cerebral vasculopathy (VASC) was composed of children who had stroke (n = 6), silent infarct (n = 11), or an abnormal transcranial Doppler (n = 5). Eighty-four patients had neither positive history of stroke or silent infarct, nor abnormal transcranial Doppler (NORM group). An intermediate group (COND; n = 15) was composed of SCA children with a conditional transcranial Doppler. Biological analyses were performed on samples obtained at steady state and before the beginning of any chronic treatment. The comparisons of the three groups demonstrated a protective effect of α-thalassemia against cerebral vasculopathy through its effects on hemoglobin and reticulocyte levels. Moreover, we observed higher frequency of G6PD deficiency in the VASC group compared with the other groups. Our study confirms the key role of α-thalassemia and G6PD status in the pathophysiology of cerebral vasculopathy in SCA children.

How I manage cerebral vasculopathy in children with sickle cell disease.

Sickle cell disease induces specific brain alterations that involve both the macrocirculation and the microcirculation. The main overt neurovascular complications in children are infarctive stroke, transient ischaemic attack and cerebral haemorrhage. Silent cerebral infarction, cognitive dysfunction and recurrent headache are also common. Cerebrovascular disease selectively affects children with the HbSS or HbS-β(0) genotypes (i.e. sickle cell anaemia). The incidence of stroke peaks between 2 and 5years of age (1·02/100 patient-years) and increases with the severity of the anaemia. Most strokes can be prevented by annual transcranial Doppler screening from 2 to 16years of age and providing chronic blood transfusion when this investigation shows elevated blood-flow velocities. The role for hydroxycarbamide in children with abnormal transcranial Doppler findings is under investigation. After a stroke, chronic blood transfusion is very strongly recommended, unless haematopoietic stem cell transplantation can be performed. Routine magnetic resonance imaging shows that more than one-third of children have silent cerebral infarction, which is associated with cognitive impairments. Screening for silent infarcts seems legitimate, since their presence may lead to supportive treatments. The role for more aggressive interventions such as hydroxycarbamide or chronic blood transfusion is debated.

Cerebral vasculopathy in children with sickle cell anemia.

Sickle cell anemia (SCA)-associated cerebral vasculopathy and moyamoya is a unique entity reflecting the abnormal interactions between sickled red blood cells (RBCs) and the cerebral arterial endothelium. Endothelial injury, coagulation activation, and the inflammatory response generated by sickled RBCs are implicated in the development of cerebral vasculopathy, but the pathophysiology remains incompletely understood. SCA-specific screening and treatment guidelines have successfully reduced the incidence of overt strokes in this high-risk population. However, despite aggressive hematological management, many children with cerebral vasculopathy due to SCA have progressive vasculopathy and recurrent strokes; therefore, more effective therapies, such as revascularization surgery and curative hematopoietic stem cell transplant, are urgently needed.

Systemic Effects of Intracoronary Nitroglycerin during Coronary Angiography in Children after Heart Transplantation

Coronary spasm during coronary angiography for vasculopathy in children can be prevented by the intracoronary administration of nitroglycerin. We reviewed the anesthesia and catheterization reports and charts for pediatric transplant recipients who underwent angiography from 2005 through 2010. Correlation analysis was used to study the relation of post-injection systolic blood pressure (SBP) to nitroglycerin dose. Forty-one angiographic evaluations were performed on 25 patients (13 male and 12 female). Mean age was 9.9 ± 3.2 years (range, 3.3-16.1 yr). The mean total dose of nitroglycerin was 2.93 ± 1.60 µg/kg (range, 1-8 µg/kg). There was a significant drop between the baseline SBP (mean, 106 ± 21.6 mmHg) and the lowest mean SBP before nitroglycerin administration (78 ± 13.2, P <0.0001, paired t test). There was no significant additional change in SBP (mean after nitroglycerin administration, 80.7 ± 13.1 mmHg; P = 0.2). There was a significant drop in lowest heart rate between baseline (109 ± 16.5 beats/min) and before nitroglycerin administration (89 ± 14.3 beats/min; P <0.0001, paired t test). There was no significant additional change in heart rate (mean heart rate after nitroglycerin, 84 ± 17.7 beats/min; P = 0.09). There were 2 interventions for SBP before nitroglycerin and 2 after nitroglycerin. One child experienced a transient ST-T-segment change during angiography after nitroglycerin. In the highest dose range, the additional decrease in SBP was 7.2 mmHg (P=0.03). Routine intracoronary nitroglycerin administration in this dose range produced no significant changes in SBP or heart rate in children.

Diagnosis and management of coronary allograft vasculopathy in children and adolescents.

Coronary allograft vasculopathy remains one of the leading causes of death beyond the first year post transplant. As a result of denervation following transplantation, patients lack ischaemic symptoms and presentation is often late when the graft is already compromised. Current diagnostic tools are rather invasive, or in case of angiography, significantly lack sensitivity. Therefore a non-invasive tool that could allow early diagnosis would be invaluable.This paper review the disease form its different diagnosis techniques,including new and less invasive diagnostic tools to its pharmacological management and possible treatments.

Detection and Grading of Coronary Allograft Vasculopathy in Children With Contrast-Enhanced Magnetic Resonance Imaging of the Coronary Vessel Wall

Coronary allograft vasculopathy is the leading cause of late death after heart transplantation in children. It is poorly detected by conventional angiography. Intravascular ultrasound is invasive and costly. This study shows that magnetic resonance imaging (MRI) late gadolinium enhancement (LGE) of the coronary vessel wall can detect and grade coronary allograft vasculopathy. Twenty-four children (10 male; age range, 9-17 years) underwent coronary angiography, intravascular ultrasound, and MRI. Maximal intimal thickness and mean intimal index were recorded. MRI included coronary magnetic resonance angiogram and LGE vessel wall imaging with 1.5 T (n=12) and 3.0 T (n=12). Ten healthy control subjects also underwent LGE MRI. Mean time posttransplantation was 5.5 years (range, 0.25-14 years). Seven patients had Stanford grade IV coronary allograft vasculopathy on intravascular ultrasound, 3 of whom had angiographic disease. Maximal intimal thickness and mean intimal index were 0.73±0.50 mm and 20.9±10.6%, respectively. On MRI, mean diameter of enhancement of vessel wall was 6.57±4.91 mm, and mean enhancement index (indexed to vessel lumen size) was 1.10±1.72. The control group showed little or no LGE. Correlation of LGE with maximal intimal thickness using the Pearson coefficient was 0.80 (P<0.001) and with mean intimal index was 0.92 (P<0.001). An MRI diameter >7.5 mm gave 86% sensitivity and 93% specificity. LGE scores correlate well with traditional intravascular ultrasound measures. These promising early results encourage larger-scale clinical studies to investigate whether LGE MRI will allow closer follow-up and better prevention of coronary allograft vasculopathy in children.

Central Nervous System Vasculopathy in HIV-Infected Children Enrolled in the Pediatric AIDS Clinical Trials Group 219/219C Study.

Central nervous system (CNS) vasculopathy has been reported in human immunodeficiency virus-infected (HIV+) adults and children. In children, it often presents with HIV encephalopathy, stroke, or intracerebral aneurysms. The etiology, incidence, and risk factors of HIV-associated CNS vasculopathy in children are unknown. We identified HIV+ children with a diagnosis of vasculopathy or other cerebrovascular events among children enrolled between 1993 and 2004 in 2 prospective, multicenter cohort studies. Demographic and laboratory data, history of antiretroviral use, and signs, symptoms, and diagnostic studies pertaining to the CNS event were reviewed. Among the 3338 HIV+ children, 51 had diagnoses that suggested CNS vasculopathy. Of these, 12 (24%) were included in this analysis, after excluding those with alternative diagnoses and those from closed sites. Among these 12, 4 (33%) were female, 4 (33%) were white, and 10 (83%) had perinatal HIV. Their average age at the event was 10.8 years with a median CD4 count of 22 cells/mm(3) and median HIV-1 viral load of 94 304 copies/mL. Fifty-eight percent of subjects had a history of opportunistic infections before the CNS event. Fifty percent had cerebral aneurysms on imaging. The overall incidence among HIV+ subjects was 3.4 cases per 10 000 person-years (95% confidence interval, 1.8-6.0). CNS vasculopathy in HIV+ children is uncommon but more common than in the general pediatric population. Cerebral aneurysms are the most common manifestation. Although the pathogenesis remains unclear, older children and those with low CD4 counts and high HIV viral loads are at the highest risk.

5′UTR Repeat Polymorphisms of the BMPR2 gene in Children with Pulmonary Hypertension associated with Congenital Heart Disease

The mutations of bone morphogenetic protein receptor type 2 (BMPR2) in patients with idiopathic pulmonary hypertension has been well defined. We investigated the occurrence of BMPR2 mutation and genetic polymorphisms in children with pulmonary hypertension associated with congenital heart disease (aPH/CHD) and correlated with the pulmonary haemodynamic and vasoreactivity. BMPR2 mutation/polymorphisms were determined in 30 aPH/CHD children. All children underwent cardiac catheterisation to obtain baseline haemodynamic data. The 5'UTR containing promoter region and all the exons [1-13] of BMPR2 gene were genotyped for possible genetic variants that may be related to the aPH/CHD. None of our 30 patients (median-age 90 months) with aPH/CHD (mean PAP 48±17mmHg, PVR 6.7±4.2WUm(2)) has had any BMPR2 mutation. Fifteen of them had single nucleotide polymorphism, rs1061157 and/or 5'UTR-polymorphism, specifically GGC repeat variant in seven patients; AGC repeat variant in one patient; and nine base pairs duplication (CTTCTTCGG) in one patient. The GGC repeat ≥13 was found in three out of six of children with aPH/CHD with normal PVR vs. two out of 24 children with aPH/CHD with high PVR. The odd ratio between these two subgroups of aPH/CHD is 0.09 (95% CI 0.02-0.34). In our cohort, there was no BMPR2 mutation in children with aPH/CHD while nine out of 30 of them have 5'UTR repeat polymorphisms. Our data suggests the occurrence of GGC repeat ≥13 at the 5'UTR region may have some protective effect towards pulmonary vasculopathy in children who have been exposed to high pulmonary blood flow due to CHD.

Magnetic resonance angiography‐defined intracranial vasculopathy is associated with silent cerebral infarcts and glucose‐6‐phosphate dehydrogenase mutation in children with sickle cell anaemia

Silent cerebral infarct (SCI) is the most commonly recognized cause of neurological injury in sickle cell anaemia (SCA). We tested the hypothesis that magnetic resonance angiography (MRA)-defined vasculopathy is associated with SCI. Furthermore, we examined genetic variations in glucose-6-phosphate dehydrogenase (G6PD) and HBA (α-globin) genes to determine their association with intracranial vasculopathy in children with SCA. Magnetic resonance imaging (MRI) of the brain and MRA of the cerebral vasculature were available in 516 paediatric patients with SCA, enrolled in the Silent Infarct Transfusion (SIT) Trial. All patients were screened for G6PD mutations and HBA deletions. SCI were present in 41·5% (214 of 516) of SIT Trial children. The frequency of intracranial vasculopathy with and without SCI was 15·9% and 6·3%, respectively (P<0·001). Using a multivariable logistic regression model, only the presence of a SCI was associated with increased odds of vasculopathy (P=0·0007, odds ratio (OR) 2·84; 95% Confidence Interval (CI)=1·55-5·21). Among male children with SCA, G6PD status was associated with vasculopathy (P=0·04, OR 2·78; 95% CI=1·04-7·42), while no significant association was noted for HBA deletions. Intracranial vasculopathy was observed in a minority of children with SCA, and when present, was associated with G6PD status in males and SCI.

Intima media thickness in children undergoing dialysis

Uremic vasculopathy, including vascular calcification, increases the risk for cardiovascular disease and mortality in chronic kidney disease (CKD) patients. We have investigated the prevalence and factors associated with vasculopathy in children undergoing peritoneal dialysis (PD) or hemodialysis (HD) in a single center. Common carotid intima media thickness (cIMT) and its relation with demographics, biochemical parameters and medication was analyzed in 60 patients (mean age 12.9 ± 3.4 years; 27 girls) treated with PD (n = 31) or HD (n = 29) for 34 ± 34 months. Patients were divided into two groups: normal cIMT and increased cIMT. Mean levels of calcium, phosphate and calcium/phosphate product were in the normal range, the but parathyroid hormone level, 729 ± 670 pg/mL, was higher than the National Kidney Foundation Kidney Disease Outcome Quality Iniative (K/DOQI) recommendations. Twenty-nine patients had increased cIMT, which was associated with time on dialysis of >2 years, hypercalcemia, higher daily dose of calcitriol and HD (vs. PD). In the multivariate analysis, accounting for time on dialysis, HD persisted as a risk for increased cIMT. The prevalence of increased cIMT in children on dialysis is similar to that reported in adults with CKD and increased with time on dialysis. HD was associated with increased cIMT, independently of time on dialysis; however, the results should be interpreted with caution due to the possible impact of confounding factors. These results underline the need to monitor and, if possible, prevent and treat increased cIMT in children on dialysis.

Cerebral Vasculopathy in Children With Neurofibromatosis Type 1

Cerebral vasculopathy is an important but underrecognized complication of neurofibromatosis type 1. Over a 10-year period, we retrospectively assessed the prevalence, clinical manifestations, management, and outcome of cerebral vasculopathy in children with neurofibromatosis type 1. Magnetic resonance imaging (MRI) of the brain was performed on 78% of the patients (312/398) of which 46% (143/312) had magnetic resonance angiography of the intracranial arteries; 4.8% (15/312) had cerebral vasculopathy. Approximately half were asymptomatic at presentation; none had neurologic deficits. Cerebral vasculopathy included moyamoya changes (7) and stenosis/occlusion of major intracranial arteries (8). On follow-up (mean 4 years), 2 patients developed radiologic progression; 1 was treated with aspirin alone, whereas another underwent revascularization surgery. Although cerebral vasculopathy in neurofibromatosis type 1 may be asymptomatic at presentation, there may be radiologic and clinical progression leading to morbidity and mortality. Magnetic resonance angiography should be considered with brain MRI for early detection and timely intervention of cerebral vasculopathy.

136 Central Aortic Stiffness, Hypertension and Coronary Allograft Vasculopathy in Children

The purpose of this study is to investigate whether central arterial stiffness in children is related to the extent of coronary allograft vasculopathy (CAV).

Cardiac allograft vasculopathy in children — treatment challenges

Cardiomyopathy in children accounts for greater than 50% of the cases of end-stage cardiac disease leading to heart transplantation in children. While early survival is excellent, late survival is limited with an average graft half-life of approximately 15 years in children. Cardiac allograft vasculopathy is a not uncommon complication of transplantation and is the leading cause of late graft loss and retransplantation in pediatric populations. Studies of the United Network of Organ Sharing database and the Pediatric Heart Transplant Study group report rates of coronary vasculopathy that increase from 5% at 2 years to 35% at 10 years. Coronary artery vasculopathy is a complex process caused by both immune mediated endothelial dysfunction and vascular changes as well as typical cardiovascular risk factors. Unfortunately, despite vigilant surveillance protocols, new onset graft dysfunction and sudden cardiac death can be the presenting symptoms of new disease. In recent years multiple medical and adjuvant therapies have been studied in relation to potential management to minimize this disease process. Further research and collaborative multi-center trials will be the most effective means of developing strategies for the prevention and treatment of coronary vasculopathy in pediatric heart transplant patients.

Uraemic vasculopathy in children with chronic kidney disease: prevention or damage limitation?

Since the inception of pediatric dialysis programmes nearly 50years ago, there have been vast improvements in both the technology and expertise in the care of children with chronic kidney disease (CKD). Nevertheless, children on dialysis continue to have a significantly higher mortality than their healthy peers and cardiovascular disease (CVD) is the most common cause of death in this group. Chronic kidney disease is described as the "perfect storm" of risk factors for CVD development, and vascular calcification is a highly regulated cell-mediated process with several promoters and inhibitors of calcification. CVD begins early in the course of CKD and there is an independent and graded association between cardiovascular morbidity and renal decline. Also, it is shown that once vascular damage and calcification begin, they progress inexorably in the uraemic milieu and may only be partially reversed after successful transplantation. Thus, preventing the development of CVD is key, and early identification and management of specific CVD-related risk factors should begin from the early stages of CKD. While the vasculopathy of childhood CKD is clearly multifactorial, clinical, epidemiological and cell biology studies provide converging evidence pointing to the role of dysregulated mineral metabolism as an important modifiable risk factor in the development of vascular calcification. In this review we focus on the role of calcium, phosphate, parathyroid hormone and vitamin D in ectopic vascular calcification, and discuss the role of screening, early intervention and management of established vascular calcification.

Incidence of vasculopathy in children with hypothalamic/chiasmatic gliomas treated with brachytherapy

External brain irradiation in children can cause cognitive decline, endocrine dysfunctions and second malignancies. A rare complication is cerebral vasculopathy, which occurs most often in patients with neurofibromatosis type 1. Interstitial radiotherapy using transient Iodine-125 implants is a radiotherapy option, called brachytherapy, offering excellent survival rates, but little is known on treatment-related morbidity, especially long time vascular changes. Thirteen children with low-grade hypothalamic gliomas, four of them with neurofibromatosis type 1, were diagnosed and treated at the University Hospital Freiburg, Germany. They belong to a larger group of 44 children with suprasellar low-grade gliomas, treated with transient Iodine-125 seeds and include those who attended all routine follow-up examinations in Freiburg. After written informed consent from the parents or caregivers all patients underwent magnetic resonance imaging with angiographic techniques in 2001, 3 to 13 years after treatment. Six out of 13 revealed cerebral vasculopathies, only one of them revealed symptoms of intermittent cerebral ischemia. Neurofibromatosis type 1 was present in one affected patient. The aetiology of the cerebral vascular changes is not fully understood so far. Tumour encasement, surgical damage and brachytherapy may contribute as a single risk factor or in combination. To get more information, we recommend MRA for artery vasculopathy at follow-up in all patients with suprasellar brain tumours irrespectively to their former treatment or presence of cerebrovascular symptoms.

Transcranial Doppler Series Part V: Specialty Applications

ABSTRACT.Transcranial Doppler (TCD) is well known for its usefulness in diagnosing vasospasm in patients with subarachnoid hemorrhage and vasculopathy in children with sickle cell disease. However, there are some lesser known TCD studies. Bubble studies detect right to left shunts. Head rotation studies evaluate for extrinsic compression of the vertebral arteries. CO2 challenge and breath holding studies evaluate vasomotor reserve. Reactive hyperemia studies help diagnose subclavian steal. Emboli monitoring detects any particulates that might be present in the cerebral blood flow.