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The recommendations of the Association for European Paediatric and Congenital Cardiology for basic training in paediatric and congenital cardiology required to be recognised as a paediatric cardiologist by the Association for European Paediatric and Congenital Cardiology are described below. Those wishing to achieve more advanced training in particular areas of paediatric cardiology should consult the training recommendations of the different Association for European Paediatric and Congenital Cardiology Working Groups available on the Association for European Paediatric and Congenital Cardiology website (www.aepc.org) and the respective publications 1–6. The development of training requirements is the responsibility of the Educational Committee and the Association for European Paediatric and Congenital Cardiology Council in collaboration with the Working Groups of the Association for European Paediatric and Congenital Cardiology. Trainees should be exposed to all aspects of general paediatric and congenital cardiology from fetal life to adolescence and adulthood. Centres performing generalised and specialised work in paediatric and congenital cardiology should be committed to deliver postgraduate training. At each training institute, trainers should be appointed to supervise and act as mentors to the trainees. Association for European Paediatric and Congenital Cardiology will provide basic teaching courses to supplement the training process.

Percutaneous pulmonary valve implantation (PPVI) allows treatment of both pulmonary valve stenosis and regurgitation ([1][1]). Originally used only in stenotic conduits through Melody Transcatheter Pulmonary Valve (Medtronic, Minneapolis, Minnesota) implantation ([2][2]), with the advent of larger

The early detection of perinatal brain damage in preterm and term newborns (i.e. intraventricular hemorrhage, periventricular leukomalacia and perinatal asphyxia) still constitute an unsolved issue. To date, despite technological improvement in standard perinatal monitoring procedures, decreasing the incidence of perinatal mortality, the perinatal morbidity pattern has a flat trend. Against this background, the measurement of brain constituents could be particularly useful in the early detection of cases at risk for short-/long-term brain injury. On this scenario, the main European and US international health-care institutions promoted perinatal clinical and experimental neuroprotection research projects aimed at validating and including a panel of biomarkers in the clinical guidelines. Although this is a promising attempt, there are several limitations that do not allow biomarkers to be included in standard monitoring procedures. The main limitations are: (i) the heterogeneity of neurological complications in the perinatal period, (ii) the small cohort sizes, (iii) the lack of multicenter investigations, (iv) the different techniques for neurobiomarkers assessment, (iv) the lack of consensus for the validation of assays in biological fluids such as urine and saliva, and (v), the lack of reference curves according to measurement technique and biological fluid. In the present review we offer an up-to-date overview of the most promising developments in the use of biomarkers in the perinatal period such as calcium binding proteins (S100B protein), vasoactive agents (adrenomedullin), brain biomarkers (activin A, neuron specific enolase, glial fibrillary acidic protein, ubiquitin carboxyl-terminal hydrolase-L1) and oxidative stress markers.

Objective: To analyze the more recent outcomes of fetuses with different laterality defects.Material and methods: Out of 1508 fetuses with congenital heart disease (CHD) diagnosed by echocardiograp...

Background Perinatal asphyxia is a major cause of mortality and morbidity in neonates: The aim of the present study was to investigate, by means of longitudinal assessment of urinary S100B, the effectiveness of hypothermia, in infants complicated by perinatal asphyxia and hypoxic-ischemic encephalopathy. Methods We performed a retrospective case-control study in 108 asphyxiated infants, admitted to nine tertiary departments for neonatal intensive care from January 2004 to July 2017, of whom 54 underwent hypothermia treatment and 54 did not. The concentrations of S100B protein in urine were measured using an immunoluminometric assay at first urination and 4, 8, 12, 16, 20, 24, 48, 72, 96, 108 and 120 h after birth. The results were correlated with the achievement of S100B levels within normal ranges at 72 h from hypothermia treatment. Routine laboratory parameters, longitudinal cerebral function monitoring, cerebral ultrasound and neurologic patterns were assessed according to standard protocols. Results Higher S100B concentrations were found in hypothermia-treated infants in both moderate (up to 12 h) and severe (up to 24 h) hypoxic-ischemic encephalopathy. S100B levels returned to normal ranges starting from 20 h of hypothermia treatment in moderate and from 36 h in severe hypoxic-ischemic encephalopathy. Conclusions The present results offer additional support to the usefulness of longitudinal neuro-biomarkers monitoring in asphyxiated infants treated by hypothermia. The pattern of S100B concentrations during hypothermia supports the need for further investigations aimed at reconsidering the time-window for patient recruitment and treatment, and the optimal duration of the cooling and rewarming phases of the hypothermia procedure.

Congenital heart disease (CHD) affects 6–8 per 1,000 of newborn infants. As a result of advances in cardiac surgery and clinical management, survival of patients with CHD has significantly improved over the last decades. Nowadays, it is estimated that 85% of children will survive to adulthood. Imaging is a crucial component to the multidisciplinary management of these patients. Techniques are required both to characterize anatomical structures and their functional status in order to improve management, evaluate the consequences of interventions, and help guide prognosis. Therefore, assessment for CHD requires a multimodality approach where a variety of imaging techniques should be used in a complementary fashion looking for sensitivity, accuracy, reproducibility, and cost-effectiveness, while minimizing harm to the patients.

Background Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM). Cardiac magnetic resonance (CMR) detects replacement fibrosis (RF) through late gadolinium enhancement (LGE) and interstitial fibrosis (IF) in apparently unscarred myocardium by T1 mapping-derived increased extracellular volume (ECV). Differently from LGE, to date only few small studies have explored the clinical significance of IF in HCM and a correlation between IF and diastolic dysfunction (DD) has been proposed. However, DD detection is challenging in this population since the accuracy of standard echocardiographic parameters is controversial, especially in presence of left ventricular outflow tract obstruction (LVOTO). Left atrial (LA) dysfunction is associated with high left ventricular (LV) filling pressures and may represent an early marker of DD in HCM. Purpose To explore the correlation between IF and LA dysfunction in HCM patients with preserved systolic function. Methods 93 consecutive HCM patients with preserved EF underwent a standard CMR scan. Semi-automatic threshold-based quantification of ventricular volumes, function and mass was performed. LA volumes (LAV) and function were evaluated by CMR feature-tracking (FT) analysis. The three atrial phasic functions were analyzed: (i) passive strain (εe), (ii) active strain (εa) and (iii) total strain (εs). LGE was quantified using the standard deviations (SDs) method (≥4 SDs). IF was assessed by T1 mapping-derived ECV quantification in remote myocardium (r-ECV). A matched group of 15 healthy subjects (HS) served as controls. Results Compared to HS, HCM patients showed increased LAV (LAV max: HS 39±9ml, HCM 59±20 ml; LAV min: HS 16±4 ml, HCM 34±17 ml; p0.05). HCM patients with increased r-ECV showed significantly impaired LA function in terms of all three strain parameters vs. normal r-ECV group (HCM r-ECV Conclusions In HCM patients increased r-ECV correlates with LA dysfunction, hinting towards a possible role for IF in determining altered LV relaxation and DD. LA strain in controls and HCM ECV groups Funding Acknowledgement Type of funding source: None

Background T1 mapping is emerging as a powerful tool in cardiac magnetic resonance (CMR) to evaluate diffuse fibrosis. However, right ventricular (RV) T1 mapping proves difficult due to the limited wall thickness in diastolic phase. Several studies focused on systolic T1 mapping, albeit only on the left ventricle (LV). Purpose To estimate intra- and inter-observer variability of native T1 (nT1) mapping of the RV, and its correlations with biventricular and pulmonary function in patients with congenital heart disease (CHD). Material and Methods In this retrospective, observational, cross-sectional study we evaluated 36 patients with CHD, having undergone CMR on a 1.5-T scanner. LV and RV functional evaluations were performed. A native modified look-locker inversion recovery short-axis sequence was acquired in the systolic phase. Intra- and inter-reader reproducibility were reported as complement to 100% of the ratio between coefficient of reproducibility and mean. Spearman ρ and Mann–Whitney U-test were used to compare distributions. Results Intra- and inter-reader reproducibility was 84% and 82%, respectively. Median nT1 was 1022 ms (interquartile range [IQR] 1108–972) for the RV and 947 ms (IQR 986–914) for the LV. Median RV–nT1 was 1016 ms (IQR 1090–1016) in patients with EDVI ≤100 mL/m2 and 1100 ms (IQR 1113–1100) in patients with EDVI >100 mL/m2 ( P = 0.049). A significant negative correlation was found between RV ejection fraction and RV–nT1 (ρ = −0.284, P = 0.046). Conclusion Systolic RV-nT1 showed a high reproducibility and a negative correlation with RV ejection fraction, potentially reflecting an adaptation of the RV myocardium to pulmonary valve/conduit (dys)-function.

Background The increased use of antidepressant treatment during pregnancy occurred without firm evidence on safety/efficacy. The present study investigated the correlation among S100B and paroxetine blood levels with the occurrence of short-term post-natal neurological abnormalities. Methods We conducted a cross-sectional study in 50 pregnant women using paroxetine because of depression and in 150 controls. Standard laboratory parameters and S100B were measured at seven monitoring time-points (maternal blood: T1, 16–20 wks; T2, 27–30 wks; T3, 35–40 wks; T4, at delivery; amniotic fluid, T5; venous and arterial cord blood, T6-T7). Paroxetine levels were measured at T1-T6. Neurological outcome was set at 7th day from birth. Results Higher S100B concentrations at T1-T7 were found in the paroxetine-treated group. S100B correlated with paroxetine blood levels. The paroxetine/S100B ratio cut-off of 1.31 at T2 achieved sensitivity 100%, specificity 96.5% and positive/negative predictive values 87.5–100, respectively, as a single marker to predict adverse neonatal neurological outcome. Conclusions The present study offers additional support to the usefulness of longitudinal S100B and drug level monitoring in depressed pregnant women and in the early detection of cases at risk for short-term neurological abnormalities. Results open the way at further investigations correlating antidepressant drugs and neurobiomarkers in the maternal bloodstream.

Background: Different studies have indicated that thiazide diuretics can increase the risk of developing type 2 diabetes (T2D). Therefore, in this study, we investigated whether switching from hydrochlorothiazide (HCTZ) to amlodipine resulted in ameliorating different cardiovascular and metabolic measures in hypertensive patients with or without T2D. Methods: This study [Diuretics and Diabetes Control (DiaDiC)] was a 6-week, single-blind, single-center randomized controlled trial. The first 20 normal glucose-tolerant, 20 prediabetic, and 20 T2D consecutive patients were randomized to continue the previous antihypertensive treatment with HCTZ (12.5-25 mg/day) or to switch from HCTZ to amlodipine (2.5-10 mg/day). The primary endpoints were the absolute change in 7-day continuous subcutaneous glucose monitoring (CSGM) glycemia, serum uric acid concentrations, and endothelial function [measured as flow-mediated dilation (FMD)]. Other secondary endpoints were investigated, including changes in glycated hemoglobin (HbA(1)c), glycemic variability from 7-day CSGM, and the estimated glomerular filtration rate (eGFR). Results: Amlodipine treatment was associated with a significant reduction in HbA(1)c (P = 0.03) for both 7-day CSGM glycemia (P = 0.01) and glycemic variability (coefficient of variability %: HCTZ +3%, amlodipine -2.8%), and a reduction in uric acid concentrations (P < 0.001), especially in participants with T2D or prediabetes. Following amlodipine treatment, a significant increase in both eGFR (P = 0.01) and FMD (P = 0.02) was also observed. Conclusions: This study demonstrates that the replacement of HCTZ with amlodipine has several metabolic and cardiovascular beneficial effects. However, further intervention studies are necessary to confirm the clinical effects of thiazides, especially in diabetic people and in those at risk of diabetes.

AIM Near-infrared spectroscopy (NIRS) has been proposed to provide reliable information concerning brain oximetry and tissue activation level in the perinatal period. We aimed to investigate whether NIRS brain patterns in healthy preterm (PT) and term (T) infants were gender- and gestational age (GA)-dependent. METHODS We conducted an observational study in 74 newborns, from consecutive singleton pregnancies, of whom 37 were born at term (male: n = 19 female: n = 18) and 37 (male: n = 18 female: n = 19) were PT. Cerebral oximetry (crSO2 ) and fractional tissue oxygen extraction (cFTOE), were recorded on the 5th day from birth. RESULTS crSO2 was significantly higher and cFTOE lower (p

The performance of blood-processing devices largely depends on the associated fluid dynamics, which hence represents a key aspect in their design and optimization. To this aim, two approaches are currently adopted: computational fluid-dynamics, which yields highly resolved three-dimensional data but relies on simplifying assumptions, and in vitro experiments, which typically involve the direct video-acquisition of the flow field and provide 2D data only. We propose a novel method that exploits space- and time-resolved magnetic resonance imaging (4D-flow) to quantify the complex 3D flow field in blood-processing devices and to overcome these limitations. We tested our method on a real device that integrates an oxygenator and a heat exchanger. A dedicated mock loop was implemented, and novel 4D-flow sequences with sub-millimetric spatial resolution and region-dependent velocity encodings were defined. Automated in house software was developed to quantify the complex 3D flow field within the different regions of the device: region-dependent flow rates, pressure drops, paths of the working fluid and wall shear stresses were computed. Our analysis highlighted the effects of fine geometrical features of the device on the local fluid-dynamics, which would be unlikely observed by current in vitro approaches. Also, the effects of non-idealities on the flow field distribution were captured, thanks to the absence of the simplifying assumptions that typically characterize numerical models. To the best of our knowledge, our approach is the first of its kind and could be extended to the analysis of a broad range of clinically relevant devices.

The antioxidants such as polyphenols, especially flavonols, present in large quantitites in cocoa, cause vasodilation, modulate inflammatory markers and cardiovascular health, and possess a range of protective cardiovascular effects. On the other hand, overconsumption of chocolate can lead to tachyarrhythmias, supraventricular tachycardia, atrial fibrillation, ventricular tachycardia and ventricular fibrillation due to its caffeine content. This review describes both the cardioprotective and adverse effects of chocolate and its constituents.

A 73-year-old lady presented to our unit due to shortness of breath and New York Heart Association (NYHA) functional class III. In her previous medical history, she had experienced endometroid ovarian carcinoma, treated medically and surgically, and a previous stroke. Echocardiography showed right

Aims: S100B has been proposed as a consolidated marker of brain damage in infants with congenital heart disease (CHD) undergoing cardiac surgery and cardiopulmonary bypass (CPB). The present study aimed to investigate whether S100B blood levels in the perioperative period differed in infants complicated or not by cyanotic CHD (CHDc) and correlated with oxygenation status (PaO2). Methods: We conducted a case-control study of 48 CHD infants without pre-existing neurological disorders undergoing surgical repair and CPB. 24 infants were CHDc and 24 were CHD controls. Blood samples for S100B assessment were collected at six monitoring time-points: before the surgical procedure (T0), after sternotomy but before CPB (T1), at the end of the cross-clamp CPB phase (T2), at the end of CPB (T3), at the end of the surgical procedure (T4), at 24 h postsurgery (T5). Results: In the CHDc group, S100B multiples of median (MoM) were significantly higher (p .05, for all) were found at T2, T3, T5. Linear regression analysis showed a positive correlation between S100B MoM at T3 and PaO2 (R = 0.84; p

PURPOSE The aim of this study was to evaluate the impact of percutaneous pulmonary valve implantation (PPVI) and surgical pulmonary valve replacement (SPVR) on biventricular and pulmonary valve function using cardiac magnetic resonance. MATERIALS AND METHODS Thirty-five patients aged 20±8 years (mean±SD) underwent PPVI, whereas 16 patients aged 30±11 years underwent SPVR. Cardiac magnetic resonance examinations were performed before and after the procedures with an average follow-up interval of 10 months. Cine steady-state free precession sequences for cardiac function and phase-contrast sequences for pulmonary flow were performed. The right ventricle (RV) and left ventricle (LV) functions were evaluated using a dedicated software. RESULTS The RV end-diastolic volume index (mL/m) decreased significantly after PPVI and SPVR, from 74 to 64 (P=0.030) and from 137 to 83 (P=0.001), respectively. The RV ejection fraction increased significantly after SPVR, from 47% to 53% (P=0.038). The LV end-diastolic volume index increased significantly after PPVI, from 66 to 76 mL/m (P

Perinatal asphyxia and its complication, hypoxic-ischemic encephalopathy, are still among the major causes of perinatal mortality and morbidity. Despite accurate standard postnatal monitoring procedures, the post-insult period is crucial because at a time when radiologic pictures are still silent, brain damage may already be at a subclinical stage. Against this background, the measurement of quantitative parameters, such as constituents of nervous tissue, that are able to detect subclinical lesions at a stage when routine brain monitoring procedures are still silent, could be particularly useful. Therefore, in the present review we report the potentials and limitations of biomarkers in predicting outcome in neonates complicated by perinatal asphyxia.

It has been shown that functional recovery of patients with acute congestive heart failure (ACHF) after treatment with conventional drugs (CD) is mediated by suppression of inflammation in peripheral blood mononuclear cells. Here, we analyzed gene expression profiles of monocytes from symptomatic ACHF patients (NYHA Class III-IV) before and after pharmacological treatment with CD. The treatment was associated with selective down-regulation of "TNFR signaling" and pro-inflammatory mediators CCL5, MIP-1α receptor, CD14, ITGAM, and significant up-regulation of "TNFR signaling" as evidenced by increase in anti-inflammatory factors including NF-kBIA, TNFAIP3 and SHP-1. In monocyte TNF-alpha-stimulated there is a down-regulation of the phosphatase SHP-1 which induces a significant activation of TAK-1/IKK/NF-kB signaling. These findings suggest that the therapeutic impact of CD treatment in symptomatic ACHF includes negative regulation of the NF-kB signaling in monocytes and the improvement of the SHP-1 activity.

The Spitz classification for esophageal atresia with/without tracheoesophageal fistula (EA/TEF) predicts mortality. This study evaluates the contemporary relevance of the Spitz classification and investigates predictors of morbidity.EA/TEF patients born between 1995 and 2018 at two centers were retrospectively reviewed. Clinical variables including sex, prenatal diagnosis, birth weight, prematurity, major congenital heart disease (MCHD), and pre-operative mechanical ventilation (POMV) were collected. Index admission composite morbidity was considered positive if: length-of-stay90th percentile (139 days), ventilation days90th percentile (24 days), and/or gastrostomy was used for long-term feeding. Multivariable regression determined predictors of index admission mortality and composite morbidity. A composite morbidity predictive algorithm was created. ROC curves evaluated model discrimination.Of 253 patients, 13 (5.1%) experienced index admission mortality. Of the patients not suffering mortality, 74 (31.6%) experienced composite morbidity. Only MCHD predicted mortality (p = 0.001); birth weight did not (p = 0.173). There was no difference between the Spitz classification and MCHD alone in predicting mortality risk (p = 0.198); both demonstrated very good discrimination. Prenatal diagnosis, POMV, prematurity, and male sex predicted composite morbidity risk (p 0.001; p = 0.008; p = 0.009; p = 0.05). An algorithm incorporating these predictors demonstrated good discrimination (AUC = 0.784; 95% CI: 0.724, 0.844).The Spitz classification maintains contemporary relevance for mortality risk, though birth weight can be de-emphasized. A new morbidity risk algorithm is proposed for early postnatal counseling.Prognosis study.Level IV.

Background Cardiac MR (CMR) is the gold standard for right ventricular (RV) quantification. Three-dimensional echo (3DE) is a relatively new technique which may offer a rapid alternative for the examination of the right heart. The purpose of this study was to investigate the clinical significance and interchangeability of these modalities to evaluate patients with congenital heart disease (CHD) who underwent percutaneous pulmonary valve implantation (PPVI) for RV outflow tract dysfunction. Methods 36 patients who underwent PPVI were evaluated with 3DE and CMR to quantify the RV. RV volumes and ejection fraction (EF) were measured for both imaging techniques with commercially available softwares (Tomtec-Germany for 3DE and Medimatic-Netherlands for CMR data). Paired t-test, Bland-Altman analysis, and Pearson's correlation analysis were used as most appropriate to compare both measured techniques with CMR regarded as the reference standard. Results 86% of the patients (31 patients) had adequate image quality on 3DE and was included in the study. Patients underwent both 3D echo and CMR within a mean of 9 days of each other and at a mean time of 3 years after PPVI. Compared to CMR, 3D echo significantly underestimated volumes in all patients and overestimate RV ejection fraction (EF). Mean RV End-diastolic Volumes (EDV) and End-Systolic Volumes (ESV) were significantly greater when measured by CMR compared to 3D echo (EDV: 99 ml/m2 vs. 85 ml/m2; p Conclusions Statistically significant and clinically meaningful differences in volumetric measurements were observed between 3DE and CMR in the evaluation of RV volumes and function in patients with CHD after PPVI. Despite linear regression and Bland-Altman analysis showed that the two techniques are related and present some degree of agreement, 3D Echocardiography systematically underestimates volumes and overestimates EF and this would have to be considered in the clinical practice.

Background Patients surgically treated for congenital heart disease (e.g., Tetralogy of Fallot) frequently report long-term dysfunctions (i.e., pulmonary stenosis and/or incompetence) of the native right ventricle outflow tract (RVOT). The efficacy of percutaneous pulmonary valve implantation (PPVI) is recognized worldwide; however, the procedure is only feasible in RVOTs with appropriate size and functional substrate. Accordingly, a three-dimensional (3D) and dynamic assessment of the native RVOT function can be crucial to identify patients who can effectively benefit from PPVI, thus avoiding the risk of device embolization or fracture. Purpose We herein exploited an optical flow-based approach to develop a novel 3D framework for the quantitative in vivo assessment of dimension and dynamic changes of the native RVOT throughout the cardiac cycle. PPVI candidates (n=15) with previous surgery of the native RVOT were enrolled to demonstrate the additional contribution of our 3D patient-tailored analysis to the decision-making process. Methods Contrast-enhanced computed tomography (CT) was performed on a 64-slice dual-source multidetector CT system with retrospective ECG-gating. Multi-phase images of the RVOT were acquired at each 10% increment of the cardiac cycle (slice thickness = 1.5mm, increment = 1mm, pixel spacing = 0.35mm). We implemented a dedicated in-house framework, based on the optical flow tracking algorithm, to dynamically follow three anatomical cross-sections (i.e., proximal, mid and distal) of the native RVOT. The time course of area, perimeter and other relevant parameters (e.g., equivalent radius, elliptical ratio) were extracted and both areal (εA) and longitudinal strain (εlong) were computed on each the RVOT tracked cross-section. Maximum regional strain were calculated between the maximum and minimum value over the cardiac cycle. Dynamic changes in CT-derived variables were assessed using analysis of variance (p Results All the enrolled anatomies were successfully analysed, locally pinpointing the in vivo pattern of deformation within each 3D RVOT anatomy (a). Anatomical regional RVOT dimensions (p In vivo tracking of RVOT dynamic changes Conclusions The combination of patient-specific in vivo imaging and bioengineering strategies can improve our understanding of RVOT dysfunctions in congenital patients referred to PPVI. Our optical flow-based and clinically-oriented framework can support the patient selection process and the planning of the percutaneous procedure in order to enhance its efficacy and shorten the operating time while improving the patient safety. Acknowledgement/Funding IRCCS Policlinico San Donato is a clinical research hospital partially funded by the Italian Ministry of Health

Background: To evaluate the effectiveness/side-effects of osteopathic manipulation treatment (OMT) performed on the 7th post-natal day, on cerebro&ndash, splanchnic oximetry, tissue activation and hemodynamic redistribution in late preterm (LP) infants by using near infrared spectroscopy (NIRS). Methods: Observational pretest-test study consisting in a cohort of 18 LPs who received OMT on the 7th post-natal day. NIRS monitoring was performed at three different time-points: 30 min before (T0), (30 min during (T1) and 30 min after OMT (T2). We evaluated the effects of OMT on the following NIRS parameters: cerebral (c), splanchnic (s) regional oximetry (rSO2), cerebro&ndash, splanchnic fractional tissue oxygen extraction (FTOE) and hemodynamic redistribution (CSOR). Results: crSO2 and cFTOE significantly (P &lt, 0.001) improved at T0-T2, srSO2 significantly (P &lt, 0.001) decreased and sFTOE increased at T0-T1. Furthermore, srSO2 and sFTOE significantly improved at T1-T2. Finally, CSOR significantly (P &lt, 0.05) increased at T0-T2. Conclusions: The present data show that OMT enhances cerebro&ndash, splanchnic oximetry, tissue activation and hemodynamic redistribution in the absence of any adverse clinical or laboratory pattern. The results indicate the usefulness of further randomized studies in wider populations comparing the effectiveness of OMT with standard rehabilitation programs.

Severity of aortic coarctation (CoA) is currently assessed by estimating trans-coarctation pressure drops through cardiac catheterization or echocardiography. In principle, more detailed information could be obtained non-invasively based on space- and time-resolved magnetic resonance imaging (4D flow) data. Yet the limitations of this imaging technique require testing the accuracy of 4D flow-derived hemodynamic quantities against other methodologies. With the objective of assessing the feasibility and accuracy of this non-invasive method to support the clinical diagnosis of CoA, we developed an algorithm (4DF-FEPPE) to obtain relative pressure distributions from 4D flow data by solving the Poisson pressure equation. 4DF-FEPPE was tested against results from a patient-specific fluid-structure interaction (FSI) simulation, whose patient-specific boundary conditions were prescribed based on 4D flow data. Since numerical simulations provide noise-free pressure fields on fine spatial and temporal scales, our analysis allowed to assess the uncertainties related to 4D flow noise and limited resolution. 4DF-FEPPE and FSI results were compared on a series of cross-sections along the aorta. Bland-Altman analysis revealed very good agreement between the two methodologies in terms of instantaneous data at peak systole, end-diastole and time-averaged values: biases (means of differences) were +0.4 mmHg, −1.1 mmHg and +0.6 mmHg, respectively. Limits of agreement (2 SD) were ±0.978 mmHg, ±1.06 mmHg and ±1.97 mmHg, respectively. Peak-to-peak and maximum trans-coarctation pressure drops obtained with 4DF-FEPPE differed from FSI results by 0.75 mmHg and −1.34 mmHg respectively. The present study considers important validation aspects of non-invasive pressure difference estimation based on 4D flow MRI, showing the potential of this technology to be more broadly applied to the clinical practice.

In recent decades a significant scientific effort has focused on projects regarding the use of neurobiomarkers in perinatal medicine with a view to understanding the mechanisms that interfere with physiological patterns of brain development and lead to ominous effects in several human diseases. Numerous potential neurobiomarkers have been proposed for use in monitoring high-risk fetuses and newborns, including markers of oxidative stress, neuroproteins, and vasoactive agents. Nonetheless, the use of these markers in clinical practice remains a matter of debate. Recently, the calcium-binding S100B protein has been proposed as being an ideal neurobiomarker, thanks to its simple availability and easy reproducibility, to the possibility of detecting it noninvasively in biological fluids with good reproducibility, and to the possibility of a longitudinal evaluation in relation to reference curves. The present chapter contains an overview of the most significant studies on the assessment of S100B in different biological fluids as a trophic factor and/or marker of brain damage in high-risk fetuses and newborns.

Background. Pediatric open-heart surgery with cardiopulmonary bypass (CPB) still remains a risky interventional procedure at high mortality/morbidity. To date, there are no clinical, laboratory, and/or monitoring parameters providing useful information on perioperative stress. We therefore investigated whether blood concentrations of glutathione (GSH), a powerful endogenous antioxidant, changed in the perioperative period. Methods. We conducted an observational study in 35 congenital heart disease (CHD) children in whom perioperative standard laboratory and monitoring parameters and GSH blood levels were assessed at five monitoring time points. Results. GSH showed a pattern characterized by a progressive increase from pre-surgery up to 24 h after surgery, reaching its highest peak at the end of CPB. GSH measured at the end of CPB correlated with CPB duration, cross-clamping, arterial oxygen partial pressure, and with body core temperature. Conclusions. The increase in GSH levels in the perioperative period suggests a compensatory mechanism to oxidative damage during surgical procedure. Caution is needed in controlling different CPB phases, especially systemic reoxygenation in a population that is per se more prone to oxidative stress/damage. The findings may point the way to detecting the optimal temperature and oxygenation target by biomarker monitoring.

Multimodality imaging is the efficient integration of various methods of cardiovascular imaging to improve the ability to diagnose, guide therapy, or predict outcome. This approach implies both the availability of different technologies in a single unit and the presence of dedicated staff with cardiologic and radiologic background and certified competence in more than one imaging technique. Interaction with clinical practice and existence of research programmes and educational activities are pivotal for the success of this model. The aim of this paper is to describe the multimodality cardiac imaging programme recently started at San Donato Hospital.

Left ventricular ejection fraction (EF) is helpful to differentiate heart failure (HF) phenotype in clinical practice. The aim of the study was to identify simple echocardiographic predictors of post-discharge all-cause mortality in hospitalized HF patients. Patients with acute HF (75 ± 9.8 years), classified in preserved (≥ 50%) and reduced (

Background Pediatric patients with atrioventricular valve disease have limited options for prosthetic valve replacement in sizes Methods and Results A multicenter, retrospective cohort study was performed among patients who underwent atrioventricular valve replacement with Melody valve at 17 participating sites from North America and Europe, including 68 patients with either mitral (n=59) or tricuspid (n=9) replacement at a median age of 8 months (range, 3 days to 13 years). The median size at implantation was 14 mm (range, 9–24 mm). Immediately postoperatively, the valve was competent with low gradients in all patients. Fifteen patients died; 3 patients underwent transplantation. Nineteen patients required reoperation for adverse outcomes, including valve explantation (n=16), left ventricular outflow tract obstruction (n=1), permanent pacemaker implantation (n=1), and paravalvular leak repair (n=1). Twenty-five patients underwent 41 episodes of catheter-based balloon expansion, exhibiting a significant decrease in median gradient ( P Conclusions The Melody valve is a feasible option for surgical atrioventricular valve replacement in patients with hypoplastic annuli. The prosthesis shows acceptable short-term function and is amenable to catheter-based enlargement as the child grows. However, patients remain at risk for mortality and structural valve deterioration, despite adequate early valvular function. Device design and implantation techniques must be refined to reduce complications and extend durability. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02505074.

The impact of congenital heart disease on brain aging has not been extensively investigated. We evaluated cerebral microbleeds and white matter hyperintensities on brain magnetic resonance imaging in adult patients with tetralogy of Fallot (ToF). Ten ToF patients (6 women, 4 men; aged 21–58 years; New York Heart Association [NYHA] class 1–2) were prospectively enrolled and underwent a T1-weighted, a T2-weighted dark fluid, and a T2*-weighted scans. Ten age- and sex-matched controls were prospectively recruited and subjected to the same acquisition protocol. Cerebral microbleeds (CMBs) were manually counted while white matter hyperintensities (WMHs) were segmented using ITK-Snap. Wilcoxon signed-rank test, Spearman correlation, and Bland-Altman statistics were used. The median (interquartile range [IQR]) age was 45.0 (30.5–49.5) years in ToF patients and 46.0 (30.5–49.8) years in controls. The median (IQR) of the number of CMBs was 6.0 (4.0–7.8) in ToF patients and 0 (0.0–0.0) in controls (p = 0.002). The WMHs burden was 2,506 (1,557–2,900) mm3 for ToF patients and 2,212 (1,860–2,586) mm3 for controls (p = 0.160). Moreover, a positive significant correlation was found between the WMHs burden and the NYHA class (ρ = 0.80, p = 0.005). Inter-operator concordance rate for the presence/ absence of CMBs was 90%; the reproducibility for the WMHs burden was 77%. In conclusion, we found more cerebral microbleeds and a higher WMHs burden in adult ToF patients than in controls. This preliminary comparison supports the hypothesis of an early brain aging in ToF patients. Larger studies are warranted.

Right ventricular outflow tract (RVOT) calcific obstruction is frequent after homograft conduit implantation to treat congenital heart disease. Stenting and percutaneous pulmonary valve implantation (PPVI) can relieve the obstruction and prolong the conduit lifespan, but require accurate pre-procedural evaluation to minimize the risk of coronary artery (CA) compression, stent fracture, conduit injury or arterial distortion. Herein, we test patient-specific finite element (FE) modeling as a tool to assess stenting feasibility and investigate clinically relevant risks associated to the percutaneous intervention. Three patients undergoing attempted PPVI due to calcific RVOT conduit failure were enrolled; the calcific RVOT, the aortic root and the proximal CA were segmented on CT scans for each patient. We numerically reproduced RVOT balloon angioplasty to test procedure feasibility and the subsequent RVOT pre-stenting expanding the stent through a balloon-in-balloon delivery system. Our FE framework predicted the occurrence of CA compression in the patient excluded from the real procedure. In the two patients undergoing RVOT stenting, numerical results were consistent with intraprocedural in-vivo fluoroscopic evidences. Furthermore, it quantified the stresses on the stent and on the relevant native structures, highlighting their marked dependence on the extent, shape and location of the calcific deposits. Stent deployment induced displacement and mechanical loading of the calcific deposits, also impacting on the adjacent anatomical structures. This novel workflow has the potential to tackle the analysis of complex RVOT clinical scenarios, pinpointing the procedure impact on the dysfunctional anatomy and elucidating potential periprocedural complications.

Preterm birth is still the most important cause of perinatal mortality and morbidity. Follow-up studies showed that the majority of neurological abnormalities during childhood are already present in the first week after birth. In this light, the knowledge of the timing of the insult and/or of the contributing factors is of utmost relevance in order to avoid adverse neurological outcome. Notwithstanding, the considerable advances in perinatal clinical care and monitoring, the early detection of cases at risk for brain damage is still a challenge because, when radiological pictures are still negative, brain damage may be already at a subclinical stage, with symptoms hidden by therapeutic strategies. Thus, it could be very relevant to measure quantitative parameters, such as neuroproteins, able to detect subclinical lesions at a stage when routine brain monitoring procedures are still silent. In the last decade, the assay of the brain-specific protein S100B in different biological fluids proved useful information on brain function and damage in the perinatal period. Therefore, the present study provides an overview of the most recent findings on S100B role as a reliable marker of brain development/damage in preterm high risk fetuses and newborns.

S100B protein has been recently proposed as a consolidated marker of brain damage and death in adult, children and newborn patients. The present study evaluates whether the longitudinal measurement of S100B at different perioperative time-points may be a useful tool to identify the occurrence of perioperative early death in congenital heart disease (CHD) newborns. We conducted a case-control study in 88 CHD infants, without pre-existing neurological disorders or other co-morbidities, of whom 22 were complicated by perioperative death in the first week from surgery. Control group was composed by 66 uncomplicated CHD infants matched for age at surgical procedure. Blood samples were drawn at five predetermined timepoints before during and after surgery. In all CHD children, S100B levels showed a pattern characterized by a significant increase in protein's concentration from hospital admission up to 24-h after procedure reaching their maximum peak (P

Perinatal asphyxia (PA) still constitutes a common complication involving a large number of infants with or without congenital heart diseases (CHD). PA affects 0.2-0.6% of full-term neonates, 20% of which suffer mortal hypoxic-ischemic encephalopathy, and among survivors 25% exhibit permanent consequences at neuropsychological level. Each year, about one third of 1000 live births underwent to surgical intervention in early infancy and/or are at risk for ominous outcome. Advances in brain monitoring, in anesthetic and cardiothoracic surgical techniques, including selective or total body cooling, cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest, have essentially reduced mortality expanding the possibility to address functional neurologic and cardiac outcomes in long-term survivors. However, open-heart surgery constitutes a time-frame of planned ischemia-reperfusion injury, which is a price to pay in the treatment or palliation of CHD. Infants who underwent heart surgery and non-CHD infants complicated by PA share similarities in their neurodevelopmental profile and a common form of brain damage due to hypoxic-ischemic injury. The purpose of the present review was to evaluate different mechanisms implicated in brain injury following CPB and PA and how it is possible to monitor such injury by means of available biomarkers (S100B protein, Activin A, Adrenomedullin).

Cardiovascular diseases are the main cause of mortality and morbidity in the world. Hypertension, ischemia/reperfusion, diabetes and anti-cancer drugs contribute to heart failure through oxidative and nitrosative stresses which cause cardiomyocytes nuclear and mitochondrial DNA damage, denaturation of intracellular proteins, lipid peroxidation and inflammation. Oxidative or nitrosative stress-mediated injury lead to cardiomyocytes apoptosis or necrosis. The reactive oxygen (ROS) and nitrogen species (RNS) concentration is dependent on their production and on the expression and activity of anti-oxidant enzymes. Polyphenols are a large group of natural compounds ubiquitously expressed in plants, and epidemiological studies have shown associations between a diet rich in polyphenols and the prevention of various ROS-mediated human diseases. Polyphenols reduce cardiomyocytes damage, necrosis, apoptosis, infarct size and improve cardiac function by decreasing oxidative stress-induced production of ROS or RNS. These effects are achieved by the ability of polyphenols to modulate the expression and activity of anti-oxidant enzymes and several signaling pathways involved in cells survival. This report reviews current knowledge on the potential anti-oxidative effects of polyphenols to control the cardiotoxicity induced by ROS and RNS stress.

Aims Paediatric patients with mitral valve (MV) disease have limited options for prosthetic MV replacement. Based on long experience with the stented bovine jugular vein graft (Melody valve) in the right ventricular outflow tract, we aimed to test the use of the Melody valve as a surgical implant in the mitral position in a small group of infants with congenital mitral disease. Methods and results Eight patients, aged from 3 months to 6.2 years, with congenital MV dysplasia underwent Melody valve implantation in the mitral position between March 2014 and October 2015. Once sutured to the MV annulus, the Melody valve was expanded through a balloon catheter to achieve the best diameter (12-20 mm). Two patients needed ECMO assistance after traditional MV repair and a Melody valve was successfully implanted as possible bail-out. However, neither of them recovered from multi-organ failure and both died, in spite of the well-functioning Melody prosthesis. During follow-up, only one patient underwent catheter-based balloon expansion of the valve. Conclusions The medium-term results of this procedure are encouraging. The Melody valve opens up the opportunity to carry out MV replacement in more children at an earlier time point, and it has potential to revolutionise the treatment of MV disease.

Background Hypoxia is a common feature of many congenital heart defects (CHDs) and significantly contributes to their pathophysiology. Thus, understanding the mechanism underlying cell response to hypoxia is vital for the development of novel therapeutic strategies. Certainly, the hypoxia inducible factor (HIF) has been extensively investigated and it is now recognized as the master regulator of cell defense machinery counteracting hypoxic stress. Along this line, we recently discovered and reported a novel mechanism of HIF activation, which is mediated by sialidase NEU3. Thus, aim of this study was to test whether NEU3 played any role in the cardiac cell response to chronic hypoxia in congenital cyanotic patients. Methods Right atrial appendage biopsies were obtained from pediatric patients with cyanotic/non-cyanotic CHDs and processed to obtain mRNA and proteins. Real-Time PCR and Western Blot were performed to analyze HIF-1α and its downstream targets expression, NEU3 expression, and the NEU3 mediated effects on the EGFR signaling cascade. Results Cyanotic patients showed increased levels of HIF-1α, NEU3, EGFR and their downstream targets, as compared to acyanotic controls. The same patients were also characterized by increased phosphorylation of the EGFR signaling cascade proteins. Moreover, we found that HIF-1α expression levels positively correlated with those recorded for NEU3 in both cyanotic and control patients. Conclusions Sialidase NEU3 plays a central role in activating cell response to chronic hypoxia inducing the up-regulation of HIF-1α, and this represent a possible novel tool to treat several CHD pathologies.

Background:S100B is a well-established biomarker of central nervous system (CNS) development and damage in the perinatal period. Because the fetal CNS induces an overproduction of S100B measurable in the maternal bloodstream we evaluated S100B protein in healthy pregnancies in order to provide a reference curve of the protein in the second and third trimesters and to provide information on CNS development when standard monitoring procedures could be silent or unavailable.Methods:Between July 2012 and December 2014 we conducted a prospective study in 1213 healthy pregnancies delivering healthy newborns. Maternal blood samples were collected for standard monitoring procedures and S100B assessment. S100B correlations with selected outcomes (gestational age at sampling, gender of fetus, gestational age and weight at birth, delivery mode) were calculated using multiple forward stepwise regression analysis.Results:S100B concentrations in the second and third trimesters of pregnancy were found to be gestational age-, gender- and delivery mode-dependent (pConclusions:The present findings offering a S100B protein reference curve in maternal blood suggest that non-invasive fetal CNS monitoring is becoming feasible and open the way to further research in neuro-biomarker assessment in the maternal bloodstream.

Adipose tissue dysfunction represents a hallmark of diabetic patients and is a consequence of the altered homeostasis of this tissue. Mesenchymal stem cells (MSCs) and their differentiation into adipocytes contribute significantly in maintaining the mass and function of adult adipose tissue. The aim of this study was to evaluate the differentiation of MSCs from patients suffering type 2 diabetes (dASC) and how such process results in hyperplasia or rather a stop of adipocyte turnover resulting in hypertrophy of mature adipocytes. Our results showed that gene profile of all adipogenic markers is not expressed in diabetic cells after differentiation indicating that diabetic cells fail to differentiate into adipocytes. Interestingly, delta like 1, peroxisome proliferator-activated receptor alpha, and interleukin 1β were upregulated whereas Sirtuin 1 and insulin receptor substrate 1 gene expression were found downregulated in dASC compared to cells obtained from healthy subjects. Taken together our data indicate that dASC lose their ability to differentiate into mature and functional adipocytes. In conclusion, our in vitro study is the first to suggest that diabetic patients might develop obesity through a hypertrophy of existing mature adipocytes due to failure turnover of adipose tissue. Impact statement In the present manuscript, we evaluated the differentiative potential of mesenchymal stem cells (MSCs) in adipocytes obtained from healthy and diabetic patients. This finding could be of great potential interest for the field of obesity in order to exploit such results to further understand the pathophysiological processes underlying metabolic syndrome. In particular, inflammation in diabetic patients causes a dysfunction in MSCs differentiation and a decrease in adipocytes turnover leading to insulin resistance.

Bicuspid aortic valve (BAV) is the most common adult congenital heart defect and is found in 0.5% to 2.0% of the general population. The term “BAV” refers to a heterogeneous group of disorders characterized by diverse aortic valve malformations with associated aortopathy, congenital heart defects, and genetic syndromes. Even after decades of investigation, the genetic determinants of BAV and its complications remain largely undefined. Just as BAV phenotypes are highly variable, the genetic etiologies of BAV are equally diverse and vary from complex inheritance in families to sporadic cases without any evidence of inheritance. In this paper, the authors discuss current concepts in BAV genetics and propose a roadmap for unraveling unanswered questions about BAV through the integrated analysis of genetic and clinical data.

To determine the minimum survival time for detection of antemortem myocardial ischaemia with postmortem imaging (PMI) techniques.Nine pigs underwent ligation of the left anterior descending (LAD) (8) and/or right coronary artery (RCA) branch (4), and were killed 30 min-6 h after ligation. PMI (MRI and CT angiography) was performed 2-55 h after euthanasia. Signal intensity of myocardial segments was measured. The hearts were removed, the coronary arteries injected to mark perfused segments, and sections submitted for histology.MRI T2-weighted sequences showed the ischaemic area as hyperintense in 4/4 LAD ligations with ≥4 h of ischaemia but in 0/4 with4 h. Histological evidence of ischaemia was present in 4/4 animals after 4 h. Right ventricular ischaemic myocardium was visible on MRI T2-weighted sequences after 6 h of ischaemia in one animal. CT angiography showed the occluded coronary artery in all cases.Ischaemic lesions of the left ventricle, but not of the right, at least 4 h old can be detected as hyperintense areas on T2-weighted postmortem MRI. This technique is most sensitive in the first 24 h after death. Other sequences did not enhance detection.• Left ventricular myocardial ischaemia/infarction can be demonstrated by postmortem imaging (PMI). • Ischaemia/infarction is better detected if survival time is at least 4 h. • Right ventricular ischaemia/infarction is not reliably detected by PMI. • Computed tomography angiography can demonstrate arterial occlusion.

Congenital presentations of Langerhans cell histiocytosis (LCH) are exceedingly rare, and concurrent placental parenchymal involvement has not been definitively documented in the literature. We present 2 cases of congenital multisystem LCH with placental involvement resembling chronic villitis. Placental examination may provide the initial diagnostic evidence of LCH and may significantly influence patient management and outcome; however, the prognostic implications remain unclear. In a clinical context suspicious for congenital LCH, the observation of chronic villitis should prompt consideration of placental involvement by LCH.

AIMS Nowadays, transcatheter approaches are the treatment of choice for several congenital heart defects. However, adverse events may occur during interventional procedures. Even if the complication rate has been reduced remarkably because of learning curve and technological improvements, catastrophic events are still possible. The aim of this study was to review cardiac catheter complications that required surgical treatment during or after a percutaneous procedure. METHODS AND RESULTS We evaluated retrospectively a thirteen-year experience at our centre. We examined all transcatheter procedures involving device release or implantation needing surgical rescue. We performed 3,205 interventional catheterisation procedures with device release or implantation: ASD device closure (n=2,205), PDA device occlusion (n=355), VSD device closure (n=218), aortic coarctation or recoarctation stenting (n=199), pulmonary artery stenting (n=154) and pulmonary valve implantation (n=74). Complications that required surgical treatment occurred in 1.2% of cases. Early surgery was performed in 22 cases, while in 18 patients a surgical treatment related to late complications was performed in a mean follow-up of 17 months. There were no deaths in either group. CONCLUSIONS A spectrum of CHD can be treated today by transcatheter interventional procedures with good results and a low, but not negligible, risk of complications that require a surgical operation. The risk of developing late complications makes a long-term follow-up mandatory in such patients.

Aims Supraventricular arrhythmias are a major cause of morbidity and mortality in adult patients with congenital heart disease (CHD). Intraoperative ablation offers an alternative for patients who failed ablation procedures or are requiring concomitant surgical intervention. We present our long-term results with the surgical treatment of arrhythmias in adults with CHD (ACHD) undergoing elective cardiac surgery and the clinical predictors for arrhythmia recurrence. Methods and results Between 2002 and 2013, 80 consecutive patients with CHD, mean age of 39 years, underwent intraoperative ablation with monopolar irrigated radiofrequency during cardiac surgery procedures. Significant clinical predictors of arrhythmia recurrence were determined by univariate analysis. We performed 47 right-sided Maze procedures, and 33 Cox-Maze III procedures. In 75 survivors, the ablation was effective immediately. Over an average follow-up period of 72 months (12–155 months), arrhythmias recurred in nine (20%) patients after right-sided Maze, and in six (19%) patients after Cox-Maze III. Eleven patients were controlled with medical therapy, three underwent catheter ablation of the arrhythmia, and one required a permanent pacemaker. Preoperative arrhythmia length ≥3 years ( P ≤ 0.001), tetralogy of Fallot ( P ≤ 0.006), and preoperative atrial fibrillation ( P ≤ 0.016) were associated with recurrence arrhythmia. Conversely, NYHA class

The most commonly performed fetal cardiac intervention (FCI) is aortic balloon valvuloplasty. The primary aim of fetal aortic valvuloplasty is to modify the in utero natural history of severe aortic stenosis, characterized by left heart growth arrest, and prevent progression to hypoplastic left heart syndrome (HLHS).