The role of inflammatory biomarkers in CHD-associated pulmonary hypertension in children.

OBJECTIVE: The present study aims to identify the role of inflammatory markers such as C-reactive protein, interleukin-6, and fractalkine in CHD-associated pulmonary hypertension in children. METHODS: This is a prospective review of 37 children with CHD-related pulmonary hypertension, 21 children with congenital heart defects, and 22 healthy children. RESULTS: Serum C-reactive protein and interleukin-6 levels were significantly higher in the children with CHD-related pulmonary hypertension (respectively, p=0.049 and 0.026). Serum C-reactive protein concentrations correlated negatively with ejection fraction (r=-0.609, p=0.001) and fractional shortening (r=-0.452, p=0.007) in the pulmonary hypertension group. Serum fractalkine concentrations correlated negatively with ejection fraction (r=-0.522, p=0.002) and fractional shortening (r=-0.395, p=0.021) in the children with pulmonary hypertension. Serum interleukin-6 concentrations also correlated negatively with Qs (r=-0.572, p=0.021), positively with Rs (r=0.774, p=0.001), and positively with pulmonary wedge pressure (r=0.796, p=0.006) in the pulmonary hypertension group. A cut-off value of 2.2 IU/L for C-reactive protein was able to predict pulmonary hypertension with 77.5% sensitivity and 77.5% specificity. When the cut-off point for interleukin-6 concentration was 57.5 pg/ml, pulmonary hypertension could be predicted with 80% sensitivity and 75% specificity. CONCLUSION: Inflammation is associated with the pathophysiology of pulmonary hypertension. The inflammatory markers C-reactive protein and interleukin-6 may have a role in the clinical evaluation of paediatric pulmonary hypertension related to CHDs.

Biomarker and shear stress in secondary pediatric pulmonary hypertension

Background/aim: Endothelial dysfunction, tissue damage, inflammation, and microthrombosis are involved in the pathogenesis of pulmonary hypertension (PH), which may be present as a complication of congenital heart diseases. This study aims to identify how indicators of endothelial dysfunction (shear stress), tissue damage (brain natriuretic peptide and troponin T), inflammation (C-reactive protein (CRP)), and microthrombosis (D-dimer and von Willebrand factor) are altered in children with congenital left-to-right shunting. Materials and methods: This is a review of 25 children who developed PH due to congenital left-to-right shunting, 40 children who underwent corrective surgery for congenital left-to-right shunting, and 40 healthy children.Results: Serum brain natriuretic peptide (BNP), CRP, and CA-125 levels were significantly increased and shear stress was significantly decreased in children with PH (P = 0.001, P = 0.044, P = 0.012, and P = 0.011). A BNP level of >225 pg/mL had a sensitivity of 95.3% and specificity of 92.4%, whereas a CRP level of >2.2 IU/L had a sensitivity and specificity of 87.5%, and a CA-125 level of >35 IU/mL had a sensitivity of 92.2% and a specificity of 90.4% for PH. Shear stress of <2.5 dyn/cm2 had a sensitivity of 84.8% and specificity of 92.9%.Conclusions: A combination of BNP, CRP, CA-125, and shear stress might be used to predict the development of PH during follow-up of children with congenital left-to-right shunting.

The effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirements in a pediatric population.

OBJECTIVE: The aim was to investigate the frequency of genetic polymorphisms of cytochrome P4502C9 (CYP2C9) and vitamin K epoxide reductase complex subunit1 (VKORC1) and determine the effect of these polymorphisms on warfarin dose requirements in pediatric patients. METHODS: Fifty-eight pediatric patients with cardiac disease, thrombophilia, or other conditions, taking a stable warfarin dose, aged 0.2-18 years, and with international normalized ratio (INR) between 2 and 3 and 149 healthy children as a control group were included in this prospective, observational study. Patients receiving drugs that interact with warfarin, having chronic liver or renal disease, obesity, or thyroid dysfunctions were excluded. Polymerase chain reaction (real time and restriction fragment length polymorphism) was used to analyze the CYP2C9*2, CYP2C9*3, and VKORC1 polymorphisms. The ideal warfarin dose was calculated according to the patient's age, height, and the presence of CYP2C9*2, CYP2C9*3, and VKORC1 genetic polymorphisms. The mean daily administered doses and ideal doses were compared. Analysis of variance, Student's t-test, logistic regression analysis, and Pearson's correlation analysis were used for statistical analyses. RESULTS: The frequency of the CYP2C9 and VKORC1 genetic polymorphisms was determined as CYP2C9*1/*1 (54.6%), *1/*2 (16.4%), *1/*3 (24.2%), *2/*3 (2.9%), *3/*3 (1.9%), wild-type VKORC1 (26.6%), heterozygote alleles (52.7%), and mutant alleles (20.8%). Patients with allelic variants were found to require lower warfarin doses, and a 64.5% correlation was found between the calculated ideal doses and the administered warfarin doses. CONCLUSION: Considering CYP2C9 and VKORC1 genetic polymorphisms prior to commencing warfarin treatment will make it easier to reach target INRs and reduce the rate of complications.

Magnetic resonance imaging in pediatric pulmonary hypertension.

The present study aims to determine the efficacy and reliability of cardiovascular magnetic resonance imaging in establishing the diagnosis and prognosis of pulmonary hypertension in children. This is a retrospective comparison of 25 children with pulmonary hypertension and a control group comprising 19 healthy children. The diagnosis of pulmonary hypertension was made when the mean pulmonary artery pressure was ≥25 mmHg by catheter angiography. The children with pulmonary hypertension had significantly lower body mass indices than did the healthy children (P=0.048). In addition, the children with pulmonary hypertension had significantly larger main pulmonary artery diameters and ascending aortic diameters (both P=0.001) but statistically similar ratios of main pulmonary artery diameter-to-ascending aortic diameter. If the main pulmonary artery diameter was ≥25 mm, pediatric pulmonary hypertension was diagnosed with 72% sensitivity and 84% specificity. In the event that the ratio of main pulmonary artery diameter-to-ascending aorta diameter was ≥1, pediatric pulmonary hypertension was diagnosed with 60% sensitivity and 53% specificity. When compared with children who had New York Heart Association functional class II pulmonary hypertension, the children with functional class III pulmonary hypertension had significantly larger main (P=0.046), right (P=0.036), and left (P=0.003) pulmonary arteries. Cardiovascular magnetic resonance imaging is useful in the diagnosis of children with pulmonary hypertension. Pediatric pulmonary hypertension can be diagnosed with high sensitivity and specificity when the main pulmonary artery diameter measures ≥25 mm.

Left-to-Right Shunt with Congenital Heart Disease: Single Center Experience.

Objective. The objective of this study was to determine the frequency of pulmonary arterial hypertension (PAH) in congenital heart disease (CHD) with an isolated, large left-to-right shunt and to indicate the factors in the development of PAH. Methods. The pressure measurements in the cardiac chambers and the calculations based on the Fick's principle were compared among 3 separate groups of patients, respectively, with PAH, with hyperkinetic pulmonary hypertension (HPH), and with neither PAH nor HPH. Results. PAH was diagnosed in 30 (12.3%) patients, HPH in 35 (14.4%), while 177 (73.1%) were free of either. The highest risk for the development of PAH was found in the presence of perimembranous ventricular septal defect. A statistically significant difference was seen among these groups as to their left atrial pressure (p = 0.005) and the mean pulmonary arterial pressure (PAPmean; p < 0.001). While a correlation was present between RpI on one hand and age on the other (p = 0.014), a multiple linear regression could not evidence any correlation among age (p = 0.321), gender (p = 0.929). Conclusion. Our findings do not allow establishing a correlation between the duration of the high pulmonary flow and pulmonary vascular resistance increase or PAH development in isolated left-to-right shunts with congenital heart diseases.

[Bilateral pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension: the youngest case in our region]. / Kronik tromboembolik pulmoner hipertansiyon nedeniyle uygulanan iki tarafli pulmoner tromboendarterektomi: Bölgemizdeki en küçük olgu.

The insertion of ventriculoatrial (VA) shunts for the treatment of hydrocephalus is associated with the development of chronic thromboembolic pulmonary hypertension (CTEPH). Chronic thromboembolic pulmonary hypertension occurs in patients with recurrent or chronic pulmonary embolism, and is a rare but, potentially devastating disease in children. Pulmonary thromboendarterectomy (PTE) is an important curative therapy for patients with CTEPH. Herein, we present a case of a 14 year-old male patient with CTEPH that developed after a VA shunt procedure. After successful PTE, systolic pulmonary artery pressure was decreased from 75 mmHg to 30 mmHg. PTE is recommended in the pediatric CTEPH population.

Doppler tissue imaging provides an estimate of pulmonary arterial pressure in children with pulmonary hypertension due to congenital intracardiac shunts.

OBJECTIVE: The aim of this study is to determine the relationship between the cardiac catheterization findings and pulsed-wave (PW) Doppler and Doppler tissue imaging (DTI) in pulmonary arterial hypertension patients with congenital heart disease with intracardiac shunts. DESIGN AND PATIENTS: The present study aims to determine the relationship between the cardiac catheterization findings and PW Doppler and Doppler tissue imaging (DTI) in patients who have pulmonary arterial hypertension patients due to congenital heart disease with intracardiac shunts. Echocardiographic measurements were performed at the catheter angiography laboratory with concurrent catheterization. Left and right ventricle inflow velocities were recorded with PW Doppler and DTI studies. Maximum tricuspid regurgitation velocity (TS) was recorded in cases with measurable levels by continuous-wave Doppler. Moreover, the correlations among the echocardiographic values and invasive hemodynamic measures such as systolic pulmonary arterial pressure (PAPsystolic), mean pulmonary arterial pressure (PAPmean), diastolic pulmonary arterial pressure (PAPdiastolic) and pulmonary vascular resistance index (PVRI) were evaluated. RESULTS: A negative correlation was found between TE'/TA' and PAPsystolic, PAPdiastolic and PAPmean (P = 0.008, r = -0.480; P = 0.001, r = -0.584; P = 0.001, r = -0.567, respectively). ME/ME' was also found to be negatively correlated with PAPdiastolic, PAPmean and PVRI (P = 0.002, r = -0.556; P = 0.005, r = -0.502; P = 0.027, r = -0.411, respectively). The concurrent use of TE'/TA' (cut-off value <2.6) and TS had a sensitivity of 79% and a specificity of 93% for distinguishing between patients with healthy controls. CONCLUSION: When used in conjunction with conventional methods, TE'/TA' has the highest sensitivity and specificity in distinguishing between patients and healthy controls.

Assessment of pulmonary arterial hypertension and vascular resistance by measurements of the pulmonary arterial flow velocity curve in the absence of a measurable tricuspid regurgitant velocity in childhood congenital heart disease.

This study aimed to determine mean pulmonary arterial pressure (PAPmean) and pulmonary vascular resistance (PVR) using transthoracic echocardiography (TTE) measurements of the pulmonary artery flow velocity curve in children with pulmonary arterial hypertension (PAH) and congenital heart disease when the tricuspid regurgitant velocity (TRV) is not sufficient. This study enrolled 29 congenital heart disease cases with pulmonary arterial hypertension and 40 healthy subjects followed at our center. The mean age was 66.9 ± 77.9 months in the patient group and 76.3 ± 62.1 months in the control group. A positive correlation was found between TRV and systolic pulmonary arterial pressure (r = 0.394, p = 0.035, 95% confidence interval [CI] = 0.032-0.665), whereas a negative correlation was found between corrected acceleration time (AcTc) and PAPmean (r = -0.559, p = 0.002, 95% CI = -0.768 to -0.242). Furthermore, a negative correlation was found between parameters TRV and AcTc (r = -0.383, p = 0.001, 95% CI = -0.657 to -0.019). Based on the cutoff criterion of 124 ms for AcTc, sensitivity was found to be 79.3% and specificity to be 77.5% in distinguishing between the PAH patients and the healthy control patients (receiver operating characteristic [ROC] area under the curve [AUC] = 0.804, 95% CI = 0.691-0.890, p < 0.0001). The sensitivity and specificity of the concomitant use of AcTc and/or TRV were found to be 90 and 73%, respectively, in distinguishing between the PAH patients and the the healthy control patients. The data obtained by TTE also can be appropriate for measuring PAPmean, PVR, and the vasoreactivity test and for determining the priority of implementing cardiac catheterization even if there is no measurable TRV value.

Elevated homocysteine and asymmetric dimethyl arginine levels in pulmonary hypertension associated with congenital heart disease.

Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality among patients with congenital heart disease (CHD). This study was designed to determine biomarker levels in patients with PAH associated with CHD (PAH-CHD) and CHD patients without PAH and to investigate the relationship of these potential biomarkers with hemodynamic findings. In this prospective single-center study, patients with CHD were analyzed according to the presence or absence of PAH and compared with healthy control subjects. Cardiac catheterization and echocardiographs were performed. Plasma homocysteine, asymmetric dimethyl arginine (ADMA), and nitric oxide (NO) levels were determined by enzyme-linked immunosorbent assay. Homocysteine and ADMA levels were higher in the PAH-CHD group (n = 30) than among CHD patients with left-to-right shunting but no PAH (n = 20; P < 0.001) and healthy control subjects (n = 20; P < 0.001). There was no difference in NO levels. Cyanotic PAH-CHD patients had significantly higher homocysteine than acyanotic patients in the same group. No correlation was shown between echocardiographic/hemodynamic parameters and homocysteine, ADMA, and NO levels. Homocysteine and ADMA levels are increased in patients with PAH-CHD. These parameters have the potential to be used as biomarkers in the diagnosis and follow-up evaluation of patients with PAH-CHD. However, large, multicentered prospective studies are required to facilitate routine use of these biologic markers in the clinical setting.

Quantitative evaluation of right ventricle function by transthoracic echocardiography in childhood congenital heart disease patients with pulmonary hypertension.

INTRODUCTION AND OBJECTIVE: The present study aims to quantitatively evaluate the right ventricle (RV) function by means of transthoracic echocardiography in normal children and childhood congenital heart disease patients with pulmonary hypertension. PATIENTS AND METHODS: This study was conducted in a cohort including 40 healthy children and 30 pediatric patients with pulmonary hypertension who were diagnosed under close surveillance at the study center between October 2009 and November 2010. RESULTS: Statistically significant differences were found between the patient and control groups for the right ventricle myocardial performance index (RVMPI), the left ventricle myocardial performance index (LVMPI), the tricuspid valve systolic flow velocity (Ts), the ratio of systolic pulmonary artery pressure to the right ventricle outflow tract systolic flow velocity time integral (sPAP/RVOT VTI), and the ratio of systolic pulmonary artery pressure to right ventricle outflow tract systolic flow velocity time integral × heart rate (sPAP/[RVOT VTI×HR]). When the children were divided into three groups based on their pulmonary vascular resistance significant differences emerged that predicted an increasing severity of RV dysfunction. Significant differences were also observed for the RVMPI, the LVMPI, and the Ts as well as for echocardiographic pulmonary flow (Qp) and systemic flow (Qs). DISCUSSION: The present study demonstrates that echocardiographic parameters can be used for the quantitative detection of RV dysfunction in childhood congenital heart disease patients with high pulmonary artery pressure (systolic, diastolic, and mean) or pulmonary vascular resistance.

Persistent left superior vena cava: experience of a tertiary health-care center.

BACKGROUND: The aim of this study was to assess the prevalence of persistent left superior vena cava (PLSVC) in patients with all types of congenital heart defects and to determine the congenital heart anomalies accompanying PLSVC. METHODS: The present study is based on a retrospective review of 1205 children who consecutively underwent cardiac catheterization from 2000 to 2007. In order to determine the existence of PLSVC, all the subjects routinely underwent superior vena cava (SVC) injection during angiography at the catheter laboratory of the study center. RESULTS: The prevalence of PLSVC was computed to be 6.1% for the present study population. Transthoracic echocardiography was able to detect PLSVC in 32 children (2.6%) whereas angiography diagnosed PLSVC in 74 children (6.1%). The mean age of the patients with PLSVC was 40.09 ± 50.21 months. A communication between the right and left SVC was determined in 27% of the children who were diagnosed with PLSVC after angiography was performed (20 out of 74). A statistically significant association was present between PLSVC and other congenital cardiac anomalies, including ventricular septal defect (n= 42, 56.8%), atrial septal defect (n= 31, 41.9%), pulmonary stenosis (n= 19, 25.7%), atrioventricular septal defect (n= 10, 13.5%), patent ductus arteriosus (n= 6, 8.1%) and cor triatriatum (n= 3, 4.1%). CONCLUSION: Transthoracic echocardiography usually visualizes dilated coronary sinus in association with PLSVC. However, SVC injection should be performed in patients undergoing angiography so that morbidity and mortality related with persistent left superior vena cava can be avoided during cardiovascular surgery.

Serum and pulmonary vascular endothelial growth factor/receptors and haemodynamic measurements in cyanotic congenital heart disease with decreased pulmonary blood flow.

Tetralogy of Fallot is the most common cyanotic congenital heart disease with decreased pulmonary blood flow. Right-to-left shunt and infundibular pulmonary stenosis in this disease lead to a decrease in arterial O(2) saturation. Hypoxia is a strong stimulus for angiogenesis; however, the reason for insufficiency in the pulmonary vascular growth in patients despite chronic arterial hypoxia is still not known. This study was planned considering that the impairment in vascular endothelial growth factor-receptor relationship or the vascular endothelial growth factor-receptor deficiency in the pulmonary vascular bed during development may cause insufficiency of pulmonary vascular growth. A total of 24 patients were grouped as cyanotic - including 13 patients with tetralogy of Fallot - and acyanotic - including 11 patients with left-to-right shunt lesions. During cardiac catheterisation, vascular endothelial growth factor measurements were performed; and oxygen saturations, pressures, and haemoglobin levels were measured. Perioperative lung biopsy for vascular endothelial growth factor receptors was performed in the cyanotic group. Vascular endothelial growth factor of the aorta was higher in the acyanotic group. There was a significant negative correlation between vascular endothelial growth factor levels and aortic O(2) saturation in the cyanotic group (p < 0.05). Vascular endothelial growth factor tissue staining was negative in 11 out of 13 (84.6%) patients. KDR/Flk-1 receptor was positive in four out of 13 (30.7%) patients; Flt-1 receptor was positive in six out of 13 (46.1%) patients. Vascular endothelial growth factor values were found to be lower than those of the acyanotic patients in this study. Low serum vascular endothelial growth factor levels of the cyanotic group, in spite of the hypoxia, demonstrated the importance of studying vascular endothelial growth factor tissue levels and vascular endothelial growth factor receptors in these patients.

An unusual case of heterotaxy and polysplenia syndrome associated with hemiazygous continuation of the left-sided vena cava inferior, dilated azygous vein and large venous ectasia.

We report a 13-year-old male patient with heterotaxy and polysplenia syndrome associated with hemiazygous continuation of the left-sided vena cava inferior, dilated azygous vein, and large venous ectasia. This is the first report of heterotaxy and polysplenia syndrome associated with this particular venous arrangement.

Cardiac troponin T in children with acute rheumatic carditis.

The existence of cardiac damage in active rheumatic carditis patients is unknown, especially in those without pericarditis. The aim of this study was to determine cardiac myocyte damage using cardiac troponin T (cTnT) measurements in active rheumatic carditis. The levels of creatine kinase MB isoenzyme (CK-MB), cTnT, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), cardiothoracic ratio (CTR), and fractional shortening (FS) were compared using Mann-Whitney U test between 28 patients with active rheumatic carditis and 32 controls (healthy children). Association of cTnT levels with ESR, CRP, and CTR was evaluated with Spearman correlation analysis. ESR, CRP, cTnT levels, and CTR were statistically higher in the patients than in the controls. There were no differences between the groups for CK-MB levels and FS. No relationships were found between cTnT levels and ESR, CRP, and CTR in the patient group. The results of the study suggest that when cTnT levels are within non-pathological range, there is no serious cardiac damage; however, statistically significant increases in cTnT levels may indicate minor damages in patients with active carditis due to acute rheumatic fever.

The role of viral agents in aetiopathogenesis of acute rheumatic fever.

The reason why abnormal immune response exists in acute rheumatic fever is not exactly explained. The influence of co-pathogens like certain viruses were mentioned regarding the initiation of the immunological reaction in acute rheumatic fever patients by several authors since 1970. This study was designed to find the role or effect of some viral infections in the development of rheumatic fever. In this study, 47 cases with acute rheumatic fever (acute rheumatic arthritis, acute rheumatic carditis, and chorea), 20 cases with chronic rheumatic fever, 20 cases with streptococcal pharyngitis, and 20 healthy age- and gender-matched control cases were involved. Serological and molecular tests were made including hepatitis B virus, hepatitis C virus, rubella virus, herpes simplex virus (HSV group 1), and Epstein-Barr virus (EBV). HBsAg, rubella IgM and EBV IgM positivity were not seen in any of patients with rheumatic fever. Although antiHBs seropositivity was higher in the control group, it was not statistically significant (p > 0.05). There was no difference in rubella IgG, HSV IgM seropositivity, either (p > 0.05). EBV DNA was searched by the polymerase chain reaction technique; due to the latent nature of the virus, no significant difference was found between the control group and the other groups (p > 0.05). In this study, no positive correlation could be found to support the synergism theories regarding the streptoccocus infection and viral infections in the development of acute rheumatic fever. Only EBV DNA positivity was found in all acute rheumatic fever cases but not in the control group may lead to further studies with larger series of patients.

[Pediatric pulmonary hypertension and pulmonary arterial hypertension secondary to congenital heart diseases]. / Pediatrik pulmoner hipertansiyon ve dogumsal kalp hastaliklarina bagli bagli pulmoner arteriyel hipertansiyon.

Causes of pulmonary arterial hypertension (PAH) are similar in adults and children. The main difference is that PAH secondary to congenital heart diseases, is the predominant cause in pediatric patients. Persistent pulmonary hypertension of the newborn shows completely different clinical course and pathophysiological mechanisms. It is usually seen in full term babies with a high morbidity and mortality rate. Improved prognosis has been reported with inhaled nitric oxide (NO) and extracorporeal membrane oxygenation therapy in babies hospitalized in well equipped and experienced newborn centers. Primary pulmonary hypertension and familial pulmonary hypertension are rare in pediatric age group because the diagnosis is initially made in adolescence. The incidence of PAH secondary to congenital heart disease is estimated as 1.6 - 12.5 case/million/year. Eisenmenger syndrome is diagnosed in 1% of patients with PAH. Patients with left to right shunts are the main group who develop pulmonary vascular disease if not treated in the early infancy. Some cyanotic congenital heart diseases are also the causes of PAH. The best treatment of patients at risk for the development of pulmonary vascular disease is prevention by early surgical elimination of defects or repairing the anatomy. Treatment options with vasodilating agents like NO, prostaglandin analogs, phosphodiesterase -5 inhibitors and endothelin receptor antagonists are used to improve survival and quality of life. Heart lung or bilateral lung transplantation is the only surgical option for many of these patients. Results of national and international registries will bring valuable epidemiological and prognostic perspectives to pediatric PAH.