Abstract Background Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given ...that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon (IFN)-α/β immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3 , a potent inducer of IFNs, were proposed to underlie AVM. Objectives This study sought to evaluate the hypothesis that human genetic factors may underlie AVM in previously healthy children. Methods We tested the role of TLR3-IFN immunity using human induced pluripotent stem cell-derived cardiomyocytes. We then performed whole-exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral causes. Results We found that TLR3- and STAT1 -deficient cardiomyocytes were not more susceptible to Coxsackie virus B3 (CVB3) infection than control cells. Moreover, CVB3 did not induce IFN-α/β and IFN-α/β-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-α did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3- or IFN-α/β-related genes. Surprisingly, we found that homozygous but not heterozygous rare variants in genes associated with inherited cardiomyopathies were significantly enriched in AM-AVM patients compared with healthy individuals (p = 2.22E-03) or patients with other diseases (p = 1.08E-04). Seven of 42 patients (16.7%) carried rare biallelic (homozygous or compound heterozygous) nonsynonymous or splice-site variations in 6 cardiomyopathy-associated genes ( BAG3 , DSP , PKP2 , RYR2 , SCN5A , or TNNI3 ). Conclusions Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections in children.
Background The arterial switch operation (ASO) for transposition of the great arteries requires transfer of the coronary arteries from the aorta to the proximal pulmonary artery (neoaorta). This is ...complicated by variable coronary anatomy before transfer. In 8% to 10% of cases, there is evidence of late coronary stenosis and/or occlusion, often with catastrophic clinical consequences. The mechanism of such complications has not been well studied. Methods and Results We analyzed 190 consecutive high-resolution computed tomographic scans from the ASO procedure (patients aged 5-16 years) and found 17 patients with significant (>30% up to occlusion) coronary lesions (8.9%); all were later confirmed by conventional angiography. The left main coronary artery was abnormal in 9 patients (ostium in all), the left anterior descending artery in 3, the circumflex in 2, and the right coronary artery in 3 patients. Using multiplanar and 3-dimensional reconstructions of the coronary arteries, aorta, and pulmonary artery, we identified the commonest mechanisms of coronary abnormalities. For the left main and left anterior descending artery, anterior positioning of the transferred left coronary artery (between 12 and 1 o'clock on the neoaorta) appeared to predispose to a tangential course of the proximal left coronary artery promoting stenosis. All circumflex lesions occurred in Yacoub type D coronaries where a long initially retroaortic artery was stretched by its new positioning behind an enlarged neoaorta. Right coronary artery lesions occurred only in cases in which the reimplantation site was very high above the right coronary sinus with potential compression from the main pulmonary artery bifurcation immediately above. Conclusions Thus detailed multiplanar computed tomographic scanning can elucidate the mechanisms of late coronary complications after the ASO. Understanding these aspects could help to improve surgical technique to minimize the risk of late coronary obstructions.
Abstract Background Pre-natal diagnosis of congenital heart disease (CHD) allows anticipation of urgent neonatal treatment and provides adequate information to the parents on cardiac outcomes. ...Objectives This study sought to analyze the discordances between expert fetal cardiac diagnosis and final diagnosis of CHD and their impact on neonatal and long-term care strategies. Methods We included 1,258 neonates with a pre-natally diagnosed CHD and 189 fetopsies following termination of pregnancy at our tertiary center over a 10-year period. Pre-natal echocardiographic and final diagnoses were compared. Results For live births, we identified 368 (29.3%) discordances between pre- and post-natal diagnoses. The pre-natal diagnosis was different from the post-natal diagnosis in 36 cases (2.9%) and partially different with a major impact on neonatal treatment of the CHD in 97 cases (7.7%). In 235 cases (18.7%), the diagnosis was partially different with no impact on neonatal planned treatment. The discordances had a negative impact on late care strategy in 62 cases (4.9%): more complex CHD that was unsuitable for biventricular repair, leading to unplanned compassionate care, additional surgery or increase of the complexity level of the Aristotle score. A positive impact was found in 31 cases (2.5%): less complex CHD that allowed biventricular repair, fewer surgical procedures, or decrease of the complexity of the Aristotle score. For 275 patients (21.9%), there was no impact on late care strategy. Of the 872 terminations of pregnancy and intrauterine fetal deaths, 189 fetopsies were available: 16 (8.5%) different diagnoses, 27 (14.3%) major differences, and 60 (31.7%) minor differences. Conclusions Correcting fetal cardiac diagnosis after birth can lead to significant changes in neonatal (10.6%) and late (7.4%) care strategies. Tools should be developed to try to improve the accuracy of pre-natal diagnosis of CHD. Clinicians should be cautious when predicting required treatment and outcomes during pre-natal counseling.
Idiopathic pulmonary arterial hypertension (IPAH) remains a progressive fatal disease. Palliative Potts shunt has been proposed in children displaying suprasystemic IPAH.
A retrospective multicenter ...study was performed to evaluate Potts shunt in pediatric IPAH.
Between 2003 and 2010, 8 children with suprasystemic IPAH and in World Health Organization functional class IV despite medical pulmonary arterial hypertension therapy underwent Potts shunt. Age at IPAH diagnosis ranged from 4 to 180 months (median age, 64 months). Surgical procedure was performed in a mean delay of 41.9±54.3 months (range, 4 to 167 months; median delay, 20 months) after IPAH diagnosis. Mean size of the Potts shunt was 9.25±3.30 mm. Two patients, whose medical pulmonary arterial hypertension therapy had been interrupted just after surgery, died at postoperative days 11 and 13 of acute pulmonary hypertensive crisis. After a mean follow-up of 63.7±16.1 months, the 6 children who were discharged from the hospital were alive. Functional status improved markedly in the 6 survivors, with a World Health Organization functional class I (n=4) or II (n=2) at last follow-up, consistent with significant improvement of 6-minute-walk distance (302±95 m 51%±20% of theoretical values versus 456±91 m 68%±10% of theoretical values; p=0.038) and decrease of brain natriuretic peptide levels (608±109 pg/mL versus 76±45 pg/mL; p=0.035). No Potts shunt was found to be restrictive at last echocardiography.
Palliative Potts shunt constitutes a new alternative to lung transplantation in severely ill children with suprasystemic IPAH, carrying a prolonged survival and persistent improvement in functional capacities.
Objective To better describe the natural history, mode of inheritance, and the epidemiological and clinical features of isolated congenital asplenia, a rare and poorly understood primary ...immunodeficiency. Study design A French national retrospective survey was conducted in hospital pediatric departments. A definitive diagnosis of ICA was based on the presence of Howell-Jolly bodies, a lack of detectable spleen, and no detectable cardiovascular malformation. Results The study included 20 patients (12 males and 8 females) from 10 kindreds neither related to each other nor consanguineous. The diagnosis of ICA was certain in 13 cases (65%) and probable in 7 cases (35%). Ten index cases led to diagnosis of 10 additional cases in relatives. Five cases were sporadic and 15 were familial, suggesting autosomal dominant inheritance. Median age was 12 months at first infection (range, 2-516 months), 11 months at diagnosis of asplenia (range, 0-510 months), and 9.9 years at last follow-up (range, 0.7-52 years). Fifteen patients sustained 18 episodes of invasive bacterial infection, caused mainly by Streptococcus pneumoniae (61%). Outcomes were poor, with 9 patients (45%) dying from fulminant infection. Conclusions ICA is more common than was previously thought, with an autosomal dominant inheritance in at least some kindreds. Relatives of cases of ICA should be evaluated for ICA, as should children and young adults with invasive infection.
Apart from the common alteration in elastic fibers, the other pathological features are not observed in the STAT3-deficient patient. ...interaction between STAT3 and elastin has never been reported. ......this is the first detailed report on a unique and previously uncharacterized vasculopathy associated with STAT3 deficiency.
During the same period, a total of 450 NKX2.5 gene screenings were performed. ...approximately 90% of the genetic analyses were negative. Structural cardiomyopathy was observed in 14 patients (28%) ...(7 left ventricular noncompaction, 4 hypertrophic cardiomyopathy, 2 dilated cardiomyopathy DCM, 1 restrictive/constrictive) with a preserved left ventricular ejection fraction in 44 of 48 patients.
We report 2 cases of fatal rhabdomyolysis in children carrying an LPIN1 mutations preceded by similar electrocardiogram changes, including diffuse symmetrical high-amplitude T waves. Our report ...underlines the severity of this disease and the need for active management of episodes of rhabdomyolysis in a pediatric intensive care unit.
Abstract Background The reversed Potts shunt improves right ventricular(RV) function in patients with suprasystemic pulmonary arterial hypertension(PAH). The proximity of the left pulmonary ...artery(LPA) to the descending aorta(DAo) permits the creation of a transcatheter connection. We sought to assess the safety, feasibility and hemodynamic efficacy of transcatheter Potts shunt(TPS) in children. Methods The TPS procedure was performed using radiofrequency energy for vessel perforation and deployment of a covered stent to connect the DAo and LPA. Procedural details and clinical follow-up data were prospectively collected. Results A TPS was successfully created in 6 children (mean age 11.0±4.2 years) with drug-refractory suprasystemic PAH and deteriorating RV function. All patients exhibited near complete equalization of aortic and pulmonary pressures and improvement in RV contractility within days after TPS placement. Two patients with pre-existing severe biventricular dysfunction and pericardial effusion developed acute low output states immediately after shunt creation due to sudden reductions in LV preload, resulting in cardiac arrest, irreversible brain damage and death. Stent dislodgement and embolization into the iliac artery occurred in one patient. The stent was successfully secured, followed by placement of a second stent at the target location. The procedure was uncomplicated in 4 patients who remain alive after a mean follow-up of 10±2.6 months. Intravenous vasodilator therapy was uneventfully weaned after TPS in 3 patients. Conclusions TPS creation in children is feasible and results in hemodynamic improvement. Further insights into high-risk markers, such as reduced pre-procedural left ventricular function and preload reserves, are important for guiding patient selection.
Safety and Accuracy of 64-Slice Computed Tomography Coronary Angiography in Children After the Arterial Switch Operation for Transposition of the Great Arteries Phalla Ou, David S. Celermajer, Davide ...Marini, Gabriella Agnoletti, Pascal Vouhé, Francis Brunelle, Kim-Hanh Le Quan Sang, Jean Christophe Thalabard, Daniel Sidi, Damien Bonnet One hundred thirty children who had an arterial switch operation in the neonatal period for transposition of the great arteries underwent conventional coronary angiography and 64-slice computed tomography (CT) angiography. The CT was able to assess all ostia and proximal segments of coronary arteries in 126 of 130 children and correctly identified all 12 patients (9.2%) who had significant coronary lesions in invasive angiography. The CT furthermore allowed assessment of the underlying reason for coronary luminal narrowing through demonstration of the exact anatomical relationship to surrounding structures.
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