Loss of ADAMTS19 causes progressive non-syndromic heart valve disease.

Valvular heart disease is observed in approximately 2% of the general population1. Although the initial observation is often localized (for example, to the aortic or mitral valve), disease manifestations are regularly observed in the other valves and patients frequently require surgery. Despite the high frequency of heart valve disease, only a handful of genes have so far been identified as the monogenic causes of disease2-7. Here we identify two consanguineous families, each with two affected family members presenting with progressive heart valve disease early in life. Whole-exome sequencing revealed homozygous, truncating nonsense alleles in ADAMTS19 in all four affected individuals. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype. Expression analysis using a lacZ reporter and single-cell RNA sequencing highlight Adamts19 as a novel marker for valvular interstitial cells; inference of gene regulatory networks in valvular interstitial cells positions Adamts19 in a highly discriminatory network driven by the transcription factor lymphoid enhancer-binding factor 1 downstream of the Wnt signaling pathway. Upregulation of endocardial Krüppel-like factor 2 in Adamts19 knockout mice precedes hemodynamic perturbation, showing that a tight balance in the Wnt-Adamts19-Klf2 axis is required for proper valve maturation and maintenance.

Punch-out lesion following regression of a large left ventricular outflow rhabdomyoma.

Abstracts We report the case of a patient with rhabdomyoma of the left ventricular outflow tract, causing severe obstruction at birth. The tumour regressed completely by 6 years of age, leaving a punch-out lesion. The potential for spontaneous regression of these tumours and the formation of a myocardial lesion following rhabdomyoma regression are discussed.

Interleukin-6 and N-terminal pro-brain natriuretic peptide cord blood levels in premature infants: correlations with perinatal variables.

BACKGROUND: Elevated cord blood levels of interleukin-6 and N-terminal pro-brain natriuretic peptide were associated with neonatal complications; however, simultaneously obtained values have not been compared to date. OBJECTIVES: To study the association of cord blood levels of IL-6 and NT-proBNP with perinatal variables of premature infants and examine the relationship between the obtained values. METHODS: Cord blood IL-6 (89 samples) and NT-proBNP (66 samples) levels obtained from infants delivered before 32 weeks of gestation were analyzed for associations with perinatal variables and possible correlation between both samples. RESULTS: Lower gestational age, no antenatal exogenous steroids, low Apgar scores at 1 minute and delivery at a high birth order, were all associated with more infants having elevated IL-6 levels (P = 0.02, P = 0.03, P = 0.03 and P = 0.001, respectively). None of the infants with necrotizing enterocolitis (n=6) had high IL-6 levels (P = 0.01). Increased NT-proBNP levels were associated with low Apgar scores at 1 minute (P = 0.01) and the presence of clinical chorioamnionitis (P = 0.06). Controlling for gestational age, a weak positive correlation was demonstrated between IL-6 and NT-proBNP levels in infants of 24-27 weeks gestational age (R2 = 0.151, P = 0.08), but not among the more mature infants. CONCLUSIONS: Although both IL-6 and NT-proBNP values were significantly associated with low I minute Apgar scores, our results do not support utilization of these cord blood levels as the sole tool to predict neonatal outcome.

N-terminal pro-B-type natriuretic peptide as a marker of bronchopulmonary dysplasia in premature infants.

We performed an observational pilot study of plasma concentrations of N-terminal pro-B-type natriuretic peptide (BNP) in premature infants with a diagnosis of bronchopulmonary dysplasia (BPD) at 4 weeks of age and after 1 month of conventional therapy. Thirty-four premature infants born before 34 weeks' gestational age without cardiac or infectious diseases were included. Serum NT-pro-BNP was measured in all neonates at 4 weeks of age. In infants with the diagnosis of BPD (n = 11), measurements were repeated at 6 and 8 weeks of age under conventional treatment. Specific clinical characteristics were collected prospectively. Baseline NT-pro-BNP concentrations were high in healthy premature infants compared with previously reported healthy neonates, and significantly higher in those who developed BPD. There was a significant correlation between concentrations of NT-pro-BNP and severity of respiratory distress as assessed by several methods. The concentrations of NT-pro-BNP decreased significantly over time in BPD infants. Premature infants have high concentrations of NT-pro-BNP at 1 month of age. NT-pro-BNP concentrations are significantly higher in BPD infants and decline over time. NT-pro-BNP concentrations correlate with clinical severity of respiratory disease.

The role of biomarkers in the early detection of anthracycline-induced cardiotoxicity in children: a review of the literature.

Anthracycline-induced cardiotoxicity can cause serious health problems for an increasing number of children surviving childhood malignancies. Early detection of cardiac failure is critically important for the prevention and management of anthracycline-induced cardiotoxicity. The aim of this research was to determine the role of biomarkers in the early detection of anthracycline-induced cardiotoxicity in children. A literature review is presented of studies regarding the use of the biomarkers B-type natriuretic peptide (BNP), N-terminal pro-BNP (NT-pro-BNP), cardiac troponin T (cTnT), and cardiac troponin I (cTnI) in relation with anthracycline-induced cardiotoxicity in children. Six of 14 studies in children showed a significant relation between elevated biomarkers BNP, NT-pro-BNP, and cTnT and cardiac dysfunction. Six studies, although small, suggest that BNP, NT-pro-BNP, and cTnT might be useful markers in the early detection of anthracycline-induced cardiotoxicity.

N-terminal-proB-type natriuretic peptide as a marker for acute anthracycline cardiotoxicity in children.

BACKGROUND: Anthracyclines are widely used in the treatment of pediatric cancer but their use is associated with cardiotoxicity. The cardiotoxic effect may become clinically apparent many years after therapy, and no reliable method exists for early detection of cardiac damage while the patient is receiving the drug. The natriuretic peptides have been established as markers for anthracycline-induced cardiotoxicity in adults and markers for cardiac dysfunction in children. We examined whether N-terminal proB-type natriuretic peptide (NT-proBNP) may be used as a marker for anthracycline-induced cardiotoxicity in children. METHODS: Twenty-three consecutive pediatric patients with newly diagnosed cancer were enrolled in this study. All patients received anthracycline-containing chemotherapy. Fifty-four age-matched children served as controls. Serial measurements of plasma NT-proBNP levels were taken before and after each anthracycline-containing course. Echocardiograms were performed before initiation of treatment and at the end of the study. RESULTS: Plasma levels of NT-proBNP were within normal limits before treatment and increased significantly only after the first anthracycline dose (from 150+/-112 to 327+/-321 pg/mL, mean+/-SD, P=0.02) and not after subsequent doses. This increase was attributed mainly to a subgroup of patients who received more than 25 mg/m of doxorubicin. In 14 patients (61%), the highest NT-proBNP level occurred after the first anthracycline dose. All patients had normal echocardiograms and none developed heart failure. CONCLUSIONS: NT-proBNP increases significantly after the first anthracycline course in a subset of pediatric cancer patients. This increase is not associated with clinical or echocardiographic evidence of cardiac dysfunction. Anthracyclines may be more cardiotoxic in the first course than in subsequent courses. Longer follow-up of these patients is necessary to determine whether NT-proBNP can be used as an early marker for anthracycline-induced cardiotoxicity.

Risk factors for cardiovascular disease in children and young adults after renal transplantation.

Despite good outcomes in pediatric renal transplantation, life expectancy is reduced, mostly as a result of accelerated atherosclerosis. A comprehensive evaluation of cardiac status and risk factors for cardiovascular disease was performed in 60 patients after renal transplantation (age 3 to 29 yr; mean 15.8). Posttransplantation diabetes was diagnosed in 7%. Half of the patients did not engage in any physical activity, and this was associated with increased body mass index. Uncontrolled hypertension was found in 13% of patient, and 53% were on antihypertensive medications. BP index was associated with left ventricular mass index (LVMI). Dyslipidemia was relatively uncommon, with hypercholesterolemia found in 15% and elevated LDL cholesterol found in 10% of patients. Hyperhomocysteinemia was frequent (58%); in most patients, it was not due to folate or B(12) deficiency. Lipid and homocysteine abnormalities were associated with cyclosporine therapy. Echocardiography demonstrated normal LVMI in 93% of patients, although LVMI was higher than in healthy control subjects. Cardiac troponin I was normal in all patients, but N-terminal pro-brain natriuretic peptide was elevated in 35% and was associated with LVMI and renal function. Although present cardiac status is relatively normal in pediatric renal transplantation patients, cardiac risk factors are common, and strategies to prevent cardiovascular disease need to be developed.

Repair of anomalous pulmonary artery with interposition graft: midterm results.

Anomalous pulmonary artery arising from the aorta is a rare congenital anomaly. The midterm results of repair of this malformation by Gore-Tex graft interposition were examined in 5 patients: 3 with anomalous right pulmonary artery and 2 with anomalous left pulmonary artery from the ascending aorta. Echocardiography was adequate in 4 cases for diagnosis, planning the operation, and follow-up. Angiography was needed for diagnosis in one case where the echocardiographic findings were unclear. The mean follow-up period was 4 years. One patient with tracheoesophageal fistula and cardiac malformation died 2 months after the operation due to multi-organ failure. Three patients needed re-operation because of graft narrowing, and one was without problems 5.2 years postoperatively. In anomalous pulmonary artery from the ascending aorta, repair should be performed as early as possible to prevent pulmonary hypertensive changes. When the anomalous pulmonary artery cannot be anastomosed directly to the main pulmonary artery, an interposition graft can be placed safely without cardiopulmonary bypass. With appropriate follow-up, this can be a satisfactory solution, although it carries the risk of re-operation due to graft narrowing.

Evaluating the risk of tuberous sclerosis in cases with prenatal diagnosis of cardiac rhabdomyoma.

OBJECTIVE: To evaluate the prenatal parameters that increase the risk of tuberous sclerosis in prenatal management of fetal cardiac tumors suspected as rhabdomyoma. METHODS: The study was a retrospective survey of 18 documented cases in which cardiac rhabdomyoma was suspected during pregnancy. The following parameters were evaluated as possible risk factors associated with tuberous sclerosis: tumor size, isolated or multiple, and family history of tuberous sclerosis. RESULTS: Eighteen documented cases in which cardiac rhabdomyoma was found during pregnancy were evaluated. Of these cases, seven (39%) had proven tuberous sclerosis and 11 were found to be non-associated tuberous sclerosis tumors. When combining the present data with previous series, cases with diagnosis of tuberous sclerosis had equal mean tumor size to those with normal outcome. Family history of tuberous sclerosis in the presence of cardiac rhabdomyoma almost invariably ended with tuberous sclerosis (86%). All other cases with diagnosis of tuberous sclerosis and no family history had all multiple cardiac tumors. CONCLUSION: The present data suggest that 39% of in utero suspected cardiac rhabdomyoma would have tuberous sclerosis. Family history and multifocality remain the strongest predictors of tuberous sclerosis, whereas size of the cardiac tumor can not reliably be used to predict tuberous sclerosis in prenatal counseling.

Jagged1 gene mutation for abdominal coarctation of the aorta in Alagille syndrome.

Congenital cardiac defects such as peripheral pulmonary stenosis are well described in Alagille syndrome (AGS), which is transmitted in an autosomal dominant inheritance. Haploinsufficiency of the Jagged1 (JAG1) gene has been shown to cause AGS. Abdominal coarctation is an uncommon vascular congenital anomaly which has been described only three times in AGS. Recently, expression of the Jagged1 gene has been found in the developing heart and in multiple associated vascular structures, including the descending aorta. Mutation analysis of the Jagged1 gene in this fourth reported patient with coarctation of the abdominal aorta in AGS and right subclavian stenosis identified a mutation deletion (1485 Del CT). This agrees with the Jagged1 expression studies and suggests that coarctation of aorta may be a component of AGS.