Tetralogy of Fallot (TOF) (OMIM #187500) is the most frequent conotruncal congenital heart defect (CHD) with a range of intra- and extracardiac phenotypes. TBX5 is a transcription factor with well-defined roles in heart and forelimb development, and mutations in TBX5 are associated with Holt-Oram syndrome (HOS) (OMIM#142900). Here we report on the screening of 94 TOF patients for mutations in TBX5, NKX2.5 and GATA4 genes. We identified two heterozygous mutations in TBX5. One mutation was detected in a Moroccan patient with TOF, a large ostium secundum atrial septal defect and complete atrioventricular block, and features of HOS including bilateral triphalangeal thumbs and fifth finger clinodactyly. This patient carried a previously described de novo, stop codon mutation (p.R279X) located in exon 8 causing a premature truncated protein. In a second patient from Italy with TOF, ostium secundum atrial septal defect and progressive arrhythmic changes on ECG, we identified a maternally inherited novel mutation in exon 9, which caused a substitution of a serine with a leucine at amino acid position 372 (p.S372L, c.1115C>T). The mother's clinical evaluation demonstrated frequent ventricular extrasystoles and an atrial septal aneurysm. Physical examination and radiographs of the hands showed no apparent skeletal defects in either child or mother. Molecular evaluation of the p.S372L mutation demonstrated a gain-of-function phenotype. We also review the literature on the co-occurrence of TOF and HOS, highlighting its relevance. This is the first systematic screening for TBX5 mutations in TOF patients which detected mutations in two of 94 (2.1%) patients.

Since the spread of COVID-19, pediatric patients were initially considered less affected by SARS-COV-2, but current literature reported subsets of children with multisystem inflammatory syndrome (MIS-C). This study aims to describe the cardiac manifestation of SARS-COV-2 infection in a large cohort of children admitted to two Italian pediatric referral centers. Between March 2020 and March 2021, we performed a cardiac evaluation in 294 children (mean age 9 ± 5.9 years, male 60%) with active or previous SARS-COV-2 infection. Twenty-six showed ECG abnormalities: 63 repolarization anomalies, 13 Long QTc, five premature ventricular beats, two non-sustained ventricular tachycardia, and one atrial fibrillation. In total, 146 patients underwent cardiac biomarkers: NT-proBNP was elevated in 57, troponin in 34. An echocardiogram was performed in 98, showing 54 cardiac anomalies: 27 left-ventricular dysfunction, 42 pericarditis, 16 coronaritis. MIS-C was documented in 46 patients (mean age 9 ± 4.8 years, male 61%) with cardiac manifestations in 97.8%: 27 ventricular dysfunctions, 32 pericarditis, 15 coronaritis, 3 arrhythmias. All patients recovered, and during follow-up, no cardiac anomalies were recorded. Our experience showed that cardiac involvement is not rare in children with SARS-COV-2, and occurred in almost all patients with MIS-C. However, patients’ recovery is satisfactory and no additional events were reported during FU.

The effects of breathing depth in attenuating induced bronchoconstriction were studied in 12 healthy subjects. On four separate, randomized occasions, the depth of a series of five breaths taken soon (ϳ1 min) after methacholine (MCh) inhalation was varied from spontaneous tidal volume to lung volumes terminating at ϳ80, ϳ90, and 100% of total lung capacity (TLC). Partial forced expiratory flow at 40% of control forced vital capacity (V part) and residual volume (RV) were measured at control and again at 2, 7, and 11 min after MCh. The decrease in V part and the increase in RV were significantly less when the depth of the five-breath series was progressively increased (P Ͻ 0.001), with a linear relationship. The attenuating effects of deep breaths of any amplitude were significantly greater on RV than V part (P Ͻ 0.01) and lasted as long as 11 min, despite a slight decrease with time when the end-inspiratory lung volume was 100% of TLC. In conclusion, in healthy subjects exposed to MCh, a series of breaths of different depth up to TLC caused a progressive and sustained attenuation of bronchoconstriction. The effects of the depth of the five-breath series were more evident on the RV than on V part, likely due to the different mechanisms that regulate airway closure and expiratory flow limitation. deep breath; airflow obstruction; partial forced expiratory flow; residual volume SEVERAL STUDIES HAVE DOCUMENTED the ability of reversing induced airway narrowing by deep breaths in healthy humans (4, 5, 7, 14, 18, 23-25, 31, 35, 38). This effect has been inferred from the increase in forced expiratory flows or the decrease in airway resistance or residual volume (RV) when a full lung inflation was taken after exposing the airways to a constrictor agent. This phenomenon is basically absent or modest in asthma and chronic obstructive pulmonary disease and may contribute to explain the degree of airway hyperresponsiveness (2,4,5,14,(23)(24)(25). The understanding of the mechanisms regulating airway tone in healthy conditions becomes central to the knowledge of the pathophysiology of obstructive lung diseases. All studies have so far focused on the effects of deep breaths taken to total lung capacity (TLC), but little is known about the effects of submaximal inspirations. The only few studies that addressed this issue were conducted in animals after exposing the airways or isolated airway smooth muscle to a constrictor agent and documented a progressive decrease in airway resistance or decrease in airway smooth muscle force with gradual increments of the depth of lung inflations (11, 32).The present study was conducted in healthy humans to examine the effects on airway function of a series of five breaths of variable depth taken soon after inducing airway narrowing by methacholine (MCh). It was intended to address three main questions. First, is induced airway narrowing progressively attenuated by increasing the amplitude of the breaths, or is there a threshold for the effects of lung inflation to become apparent? Second, f...

Our results confirm that even patients treated with a median anthracycline dose of 240 mg/m(2) (range 100-490) are at considerable risk of exhibiting subclinical cardiac dysfunction that, however, does not seem to alter the physiologic response of the cardiovascular system to dynamic exercise.

Cardiovascular magnetic resonance (CMR) and computed tomography (CCT) are advanced imaging modalities that recently revolutionized the conventional diagnostic approach to congenital heart diseases (CHD), supporting echocardiography and often replacing cardiac catheterization. Nevertheless, correct execution and interpretation require in-depth knowledge of all technical and clinical aspects of CHD, a careful assessment of risks and benefits before each exam, proper imaging protocols to maximize diagnostic information, minimizing harm. This position paper, written by experts from the Working Group of the Italian Society of Pediatric Cardiology and from the Italian College of Cardiac Radiology of the Italian Society of Medical and Interventional Radiology, is intended as a practical guide for applying CCT and CMR in children and adults with CHD, wishing to support Radiologists, Pediatricians, Cardiologists and Cardiac Surgeons in the multimodality diagnostic approach to these patients. The first part provides a review of the most relevant literature in the field, describes each modality's advantage and drawback, making considerations on the main applications, image quality, and safety issues. The second part focuses on clinical indications and appropriateness criteria for CMR and CCT, considering the level of CHD complexity, the clinical and logistic setting and the operator expertise.