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Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a homozygous GAA triplet repeat expansion in the frataxin gene. Cardiac involvement, usually manifesting as hypertrophic cardiomyopathy, can range from asymptomatic cases to severe cardiomyopathy with progressive deterioration of the left ventricular ejection fraction and chronic heart failure. The management of cardiac involvement is directed to prevent disease progression and cardiovascular complications. However, direct-disease therapies are not currently available for FRDA. The present review aims to describe the current state of knowledge regarding cardiovascular involvement of FRDA, focusing on clinical-instrumental features and management of cardiac manifestation.

We describe the case of a 15-year-old female patient with Peutz-Jeghers syndrome who presented with vomiting and abdominal pain secondary to ileoileal invagination. Initial analgesic treatment was not effective, and subsequent tramadol infusion resulted in clinical manifestations compatible with Kounis and Takotsubo syndromes. However, the patient had an excellent recovery. (Level of Difficulty: Advanced.), Central Illustration

Congenital heart disease (CHD) and cardiomyopathies represent the two most important causes of paediatric heart failure (HF) in developed countries. We made a review of the literature on pathophysiology and clinical presentation of paediatric HF in children with CHD. Two main pathophysiologic models can be identified: the 'over-circulation failure', characterised by signs and symptoms of congestion or hypoperfusion, due respectively to volume or pressure overload, and the 'pump failure'. CONCLUSIONS: The comprehension of the HF pathophysiology in paediatric patients with CHD is of paramount importance for the optimal management and for addressing the best therapeutic choices.

Genetic investigation of early‐onset Dilatative cardiomyopathy phenotype, including molecular autopsy, is the key to appropriate recognition and management of rare etiologies and atypical presentations and to offer genetic counseling to the family.

Supraventricular tachyarrhythmia (SVT) is the most common type of arrhythmia in childhood. Management can be challenging with an associated risk of mortality. A female neonate was diagnosed with episodes of SVT, controlled antenatally with digoxin. Flecainide was commenced prophylactically at birth. Despite treatment, the infant developed a narrow complex tachycardia at 5 days of age. The electrocardiogram features were suggestive of either re-entry tachycardia or of automatic atrial tachycardia (AAT). Following several unsuccessful treatments, a wide complex tachycardia developed. A transesophageal electrophysiological study led to a diagnosis of AAT. Stable sinus rhythm was finally achieved through increasing daily administrations of flecainide up to six times a day, in association with nadolol. The shortening of intervals to this extent has never been reported before and supports the evidence of a personal, age-specific variability in pharmacokinetics of flecainide. Larger studies are needed to better define the appropriate dose and timing of administration.

The worldwide response to the current COVID-19 pandemic has been focused on how to prevent the disease and to protect the high-risk patient from a potentially lethal infection. Several consensus and guidelines articles have been published dealing with the cardiac patient with systemic hypertension, heart transplant or heart failure. Very little is known about the patients, both in the pediatric as well as in the adult age, with congenital heart disease. The peculiar physiology of the heart with a native, repaired or palliated congenital heart defect deserves a specialized care. Hereby we describe the early recommendations issued by the Italian Society of Pediatric Cardiology and Congenital Heart Disease and how the network of the congenital cardiac institutions in Italy reacted to the threat of potential wide spread of the infection among this fragile kind of patient.

To describe clinical and epidemiological characteristics of a Kawasaki syndrome cohort. In a monocentric, retrospective, observational study, between February 1982 and August 2018, we enrolled 361 children, aged 1 month to 24.4 years. Coronary artery lesions were detected in 20.2% of patients: 16% had coronary ectasia, and 4.15% had coronary aneurisms. A significant difference regarding age at disease onset (p = 0.025), fever duration (p 0.0001), CRP (p = 0.001) and day of first IVIG administration (p 0.0001) was detected among group. A significant correlation between coronary artery lesions and disease onset 6 months (p = 0.009), second IVIG dose (p 0.001) and male gender (p = 0.038) has been detected. Median long-term follow-up was 10.2 years (1-36 years). At the last available follow-up, patients without coronary involvement and coronary ectasia had normal cardiological tests, conversely, in patients with aneurisms, 8/13 showed persistent aneurisms at echocardiography, one ECG repolarization alterations, and one ST depression at the peak of effort during ergometric test.Conclusion: Children with lower age, longer fever, higher level of CRP and retard in IVIG administration are at higher risk to develop coronary artery lesions. Our long-term follow-up analysis confirms, over 36 years of observation, the benign course of Kawasaki syndrome even in coronary artery lesion patients, if timely treated. What is already known about this topic? • Stopping cardiologic assessment in no risk patients results economically advantageous, timesaving and able to reduce emotional discomfort in children and their families. • Age at disease onset, fever duration, CRP level, and day of first IVIG administration are possible risk factors for coronary artery lesions What is New? • During 36 years of observation in real life, our study shows the benign course of Kawasaki syndrome without coronary artery lesions after 6-8 weeks from the disease onset. • Age 6 months at disease onset is strongly related with coronary artery lesion development.

Aims: Children presenting with hypertrophic cardiomyopathy (HCM) in infancy are reported to have a poor prognosis, but this heterogeneous group has not been systematically characterized. This study aimed to describe the aetiology, phenotype, and outcomes of infantile HCM in a well-characterized multicentre European cohort. Methods and results: Of 301 children diagnosed with infantile HCM between 1987 and 2019 presenting to 17 European centres [male n=187 (62.1%)], underlying aetiology was non-syndromic (n=138, 45.6%), RASopathy (n=101, 33.6%), or inborn error of metabolism (IEM) (n=49, 16.3%). The most common reasons for presentation were symptoms (n=77, 29.3%), which were more prevalent in those with syndromic disease (n=62, 61.4%, P&nbsp

Genetic testing in children with hypertrophic cardiomyopathy (HCM) can modify clinical management and lifestyle counseling. However, predicting long-term outcome and response to management in individual patients remains challenging, because of the peculiar genetic heterogeneity of the disease in the pediatric age range. Children with HCM secondary to an inborn error of metabolism or malformation syndromes tend to have a worse outcome compared with those with the classic sarcomeric form. Among the latter, adverse genetic features are represented by the identification of a pathogenic variant in MYH7, often associated with severe hypertrophy, a complex genotype, or a de novo variant.

A 12-year-old male patient suffering from congenital glaucoma developed bradycardia, left ventricular failure, and hypotension after induction of anesthesia. Electrocardiography and echocardiography revealed a complete normalization of ECG and a complete spontaneous recovery in the cardiac function 72 hours from the beginning of the clinical manifestations, while cardiac Magnetic Resonance Imaging was performed, and coronary Computed Tomography scan revealed a myocardial bridge of a tract of the left anterior descendent coronary artery. Diagnosis of Kounis syndrome (KS) was made, a relatively novel, under-recognized clinical condition, defined as the manifestation of an acute coronary syndrome accompanied by mast cell activation and platelet aggregation involving interrelated and interacting inflammatory cells in the setting of allergic, hypersensitivity, anaphylactic or anaphylactoid insults. We described one of the first pediatric cases of KS related to anesthetic medications. In children, this syndrome has been only described in isolated case reports or small case series. Thus, it appears critical to report new cases of KS in children to increase the awareness of this disease in pediatric healthcare workers so as to enhance its early recognition and optimal therapeutic strategy. Furthermore, it appears of paramount importance the implementation of universal guidelines accepted by allergology and cardiology societies, in order to standardize the management of pediatric and adult patients with KS. Finally, a close collaboration between pediatric allergists and cardiologists seems fundamental for an optimal multidisciplinary patient care.

Marfan syndrome (MFS) and Loeys–Dietz syndrome type 4 (LDS4) are two hereditary connective tissue disorders. MFS displays ectopia lentis as a distinguishing, characterising feature, and thoracic aortic ectasia, aneurysm, dissection, and systemic features as manifestations overlapping with LDS4. LDS4 is characterised by the presence of hypertelorism, cleft palate and/or bifid uvula, with possible ectasia or aneurysms in other arteries. The variable age of onset of clinical manifestations makes clinical diagnosis more difficult. In this study, we report the case of a patient with Marfan syndrome diagnosed at our centre at the age of 33 on the basis of typical clinical manifestations of this syndrome. At the age of 38, the appearance of ectasia of the left common iliac artery and tortuosity of the iliac arteries suggested the presence of LDS4. Next Generation Sequencing (NGS) analysis, followed by Array-CGH, allowed the detection of a novel chromosomal deletion including the entire TGFB2 gene, confirming not only the clinical suspicion of LDS4, but also the clinical phenotype associated with the haploinsufficiency mechanism, which is, in turn, associated with the deletion of the entire gene. The same mutation was detected in the two young sons. This emblematic case confirms that we must be very careful in the differential diagnosis of these two pathologies, especially before the age of 40, and that, in young subjects suspected to be affected by MFS in particular, we must verify the diagnosis, extending genetic analysis, when necessary, to the search for chromosomal alterations. Recently, ectopia lentis has been reported in a patient with LDS4, confirming the tight overlap between the two syndromes. An accurate revision of the clinical parameters both characterising and overlapping the two pathologies is highly desirable.

Premature ventricular complexes (PVCs) are frequently documented in children. To date, few studies report long-term follow-up in pediatric cohorts presenting with frequent PVCs. The aim of this study is to assess the clinical relevance and long-term outcomes of frequent PVCs (≥ 500/24 h) in a large pediatric cohort. From 1996 to 2016, we enrolled all consecutive patients evaluated at Anna Meyer Children Hospital for frequent PVCs. Symptomatic children were excluded together with those patients with known underlying heart diseases; thus, our final cohort of study included 103 patients (male 66%; mean age 11 ± 3.4 years), with a mean follow-up of 9.5 ± 5.5 years. All patients were submitted to complete non-invasive cardiologic evaluation. The mean number of PVCs at Holter Monitoring (HM) was 11,479 ± 13,147/24 h; couplets and/or triplets were observed in 5/103 (4.8%) cases; 3 patients (2.9%) presented runs of non-sustained ventricular tachycardia (NSVT). High-burden PVCs (> 30,000/24 h) was confirmed in 11/103 (10.6%) patients. During the follow-up, only five patients (4.8%) developed clinical symptoms (3 for palpitations, 1 myocardial dysfunction due to frequent PVCs and NTSV; 1 arrhythmogenic cardiomyopathy); no deaths occurred. Basal PVCs were still present in 45/103 (43.7%) patients. Our data suggest that frequent PVCs may be addressed as a benign condition and should not preclude sport participation if not associated with cardiac malformations, heart dysfunction, or cardiomyopathy. This seems to be true also in presence of very frequent/high-burden PVCs. Otherwise, a careful follow-up is mandatory since sport eligibility should be reconsidered in case of onset of symptoms and/or ECG/echocardiographic changes.

Introduction Sudden cardiac death is the most common cause of mortality in childhood onset hypertrophic cardiomyopathy. Identifying individuals at highest risk is therefore an essential part of clinical care but remains challenging. The 12 lead electrocardiogram (ECG) has been proposed as a useful tool for risk stratification and an ECG risk score has been proposed. However, this has not been independently validated and the ECG phenotype of childhood HCM has not been previously described. The aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. Methods Participants with an available baseline resting 12-lead ECG were identified from a large, international, multi-centre, retrospective cohort of patients aged less than 16 years fulfilling the diagnostic criteria for HCM (n=1029). Resting baseline ECG was evaluated and ECG variables were extracted. In addition, the ECG risk score based on 8 parameters (deviation in QRS axis, pathological T-wave inversion in limb or precordial leads, ST-segment depression, dominant S-wave in V4, limb-lead amplitude sum, 12-lead amplitude duration product and QTc) was calculated as previously described. The primary study endpoint was a composite outcome of major cardiac events (MACE) defined as SCD, resuscitated cardiac arrest, appropriate implantable cardioverter defibrillator therapy, or sustained ventricular tachycardia (VT) with haemodynamic compromise. The discriminatory performance of using an ECG risk score >5 to identify patients at increased risk of MACE at 5 years was determined using Harrell’s C-index. Results Of 356 patients with childhood HCM (68.9% male, mean age at presentation 10.1 ± 4.5 years), 347 (97.5%) had baseline ECG abnormalities such as: repolarization abnormalities (n=277, 77.8%), left ventricular hypertrophy (n=240. 67.6%), abnormal QRS axis (n=126, 35.4%) or QT prolongation (n=131, 36.8%). Over a median follow up of 3.9 years (IQR 2.0-7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93-2.04). No ECG variables were associated with 5-year MACE on univariable or multivariable Cox regression analysis. Of the 164 participants with an ECG score >5, 153 (93.3%) did not have a MACE within 5 years. Harrell’s C-index (the probability of correctly distinguishing between high and low risk patients using an ECG risk score threshold of >5) was 0.60 (95% CI 0.484-0.715) at 5 years. The corresponding positive and negative predictive values were 6.7% (95% CI 4.7 – 9.4%) and 96.9% (95% CI 94.2 – 98.4%). Conclusions In a large, international, multi-centre cohort of children with HCM, ECG abnormalities are common. No ECG characteristic, either in isolation or combined in the ECG risk score, was associated with 5-year MACE risk. This suggests that the role of the baseline ECG phenotype in improving risk stratification in childhood HCM is limited. Conflict of Interest None

Pediatric cardiomyopathies harbour significant phenotypic and genetic heterogeneity. Genetic testing is essential for the initial evaluation and the ongoing care of child and family, although challenges remain regarding its appropriate clinical implementation in minors. We here discuss the key role of genetic diagnosis in the clinical management of two patients.

Background Supraventricular tachycardias (SVTs) are common in the first year of life and may be life-threatening. Acute cardioversion is usually effective, with both pharmacological and non-pharmacological procedures. However, as yet no international consensus exists concerning the best drug required for a stable conversion to sinus rhythm (maintenance treatment). Our study intends to describe the experience of a single centre with maintenance drug treatment of both re-entry and automatic SVTs in the first year of life. Methods From March 1995 to April 2019, 55 patients under one year of age with SVT were observed in our Centre. The SVTs were divided into two groups: 45 re-entry and 10 automatic tachycardias. As regards maintenance therapy, in re-entry tachycardias, we chose to start with oral flecainide and in case of relapses switched to combined treatment with beta-blockers or digoxin. In automatic tachycardias we first administered a beta-blocker, later combined with flecainide or amiodarone when ineffective. Results The patients’ median follow-up time was 35 months. In re-entry tachycardias, flecainide was effective as monotherapy in 23/45 patients (51.1%) and in 20/45 patients (44.4%) in combination with nadolol, sotalol or digoxin (overall 95.5%). In automatic tachycardias, a beta-blocker alone was effective in 3/10 patients (30.0%), however, the best results were obtained when combined with flecainide: overall 9/10 (90%). Conclusions In this retrospective study on pharmacological treatment of SVTs under 1 year of age the combination of flecainide and beta-blockers was highly effective in long-term maintenance of sinus rhythm in both re-entry and automatic tachycardias.

Mucopolysaccharidosis are genetic disorders due to deficiency of lysosomal enzymes, resulting in abnormal glycosaminoglycans accumulation in several tissues. Heart involvement tends to be progressive and worsens with age. We describe the first case of mucopolysaccharidosis type I presenting with noncompaction/dilated-mixed cardiomyopathy and heart failure within neonatal period, which responded successfully to specific metabolic treatment. Cardiac function recovered after enzyme replacement therapy and hematopoietic stem cell transplantation, adding to the existing knowledge of the disease., Highlights • MPS can present with acute cardiac failure and cardiomyopathy within neonatal period. • Cardiomyopathies associated with MPS include also noncompaction phenotypes. • Heart failure due to MPS can respond successfully to specific metabolic treatment. • Consider complete metabolic tests in case of inexplicable neonatal heart failure.

Background: To develop a tool for assessing normalcy of the thoracic aorta (TA) by echocardiography, based on either a linear regression model (Z-score), or a machine learning technique, namely one-class support vector machine (OC-SVM) (Q-score). Methods: TA diameters were measured in 1112 prospectively enrolled healthy subjects, aging 5 to 89 years. Considering sex, age and body surface area we developed two calculators based on the traditional Z-score and the novel Q-score. The calculators were compared in 198 adults with TA > 40 mm, and in 466 patients affected by either Marfan syndrome or bicuspid aortic valve (BAV). Results: Q-score attained a better Area Under the Curve (0.989; 95% CI 0.984–0.993, sensitivity = 97.5%, specificity = 95.4%) than Z-score (0.955; 95% CI 0.942–0.967, sensitivity = 81.3%, specificity = 93.3%; p < 0.0001) in patients with TA > 40 mm. The prevalence of TA dilatation in Marfan and BAV patients was higher as Z-score > 2 than as Q-score < 4% (73.4% vs. 50.09%, p < 0.00001). Conclusions: Q-score is a novel tool for assessing TA normalcy based on a model requiring less assumptions about the distribution of the relevant variables. Notably, diameters do not need to depend linearly on anthropometric measurements. Additionally, Q-score can capture the joint distribution of these variables with all four diameters simultaneously, thus accounting for the overall aortic shape. This approach results in a lower rate of predicted TA abnormalcy in patients at risk of TA aneurysm. Further prognostic studies will be necessary for assessing the relative effectiveness of Q-score versus Z-score.

The Coronavirus disease 2019 (COVID-19) pandemic has thoroughly and deeply affected the provision of healthcare services worldwide. In order to limit the in-hospital infections and to redistribute the healthcare professionals, cardiac percutaneous intervention in Pediatric and Adult Congenital Heart Disease (ACHD) patients were limited to urgent or emergency ones. The aim of this article is to describe the impact of the COVID-19 pandemic on Pediatric and ACHD cath laboratory activity during the so-called 'hard lockdown' in Italy. Eleven out of 12 Italian institutions with a dedicated Invasive Cardiology Unit in Congenital Heart Disease actively participated in the survey. The interventional cardiology activity was reduced by more than 50% in 6 out of 11 centers. Adolescent and ACHD patients suffered the highest rate of reduction. There was an evident discrepancy in the management of the hard lockdown, irrespective of the number of COVID-19 positive cases registered, with a higher reduction in Southern Italy compared with the most affected regions (Lombardy, Piedmont, Veneto and Emilia Romagna). Although the pandemic was brilliantly addressed in most cases, we recognize the necessity for planning new, and hopefully homogeneous, strategies in order to be prepared for an upcoming new outbreak.

Aims The 12-lead electrocardiogram (ECG) is routinely performed in children with hypertrophic cardiomyopathy (HCM). An ECG risk score has been suggested as a useful tool for risk stratification, but this has not been independently validated. This aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. Methods and results Data from 356 childhood HCM patients with a mean age of 10.1 years (±4.5) were collected from a retrospective, multi-centre international cohort. Three hundred and forty-seven (97.5%) patients had ECG abnormalities at baseline, most commonly repolarization abnormalities (n = 277, 77.8%); left ventricular hypertrophy (n = 240, 67.7%); abnormal QRS axis (n = 126, 35.4%); or QT prolongation (n = 131, 36.8%). Over a median follow-up of 3.9 years (interquartile range 2.0–7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93–2.04). No ECG variables were associated with 5-year arrhythmic event on univariable or multivariable analysis. The ECG risk score threshold of >5 had modest discriminatory ability [C-index 0.60 (95% CI 0.484–0.715)], with corresponding negative and positive predictive values of 96.7% and 6.7% Conclusion In a large, international, multi-centre cohort of childhood HCM, ECG abnormalities were common and varied. No ECG characteristic, either in isolation or combined in the previously described ECG risk score, was associated with 5-year sudden cardiac death risk. This suggests that the role of baseline ECG phenotype in improving risk stratification in childhood HCM is limited.

Kounis Syndrome is defined as a hypersensitivity coronary disorder constituted by the association of an acute coronary syndrome with a hypersensitivity, allergic, anaphylactic or anaphylactoid reaction, in a pathophysiologic context involving mast-cells, platelets, eosinophils and various interacting inflammatory cells. Currently, Kounis Syndrome is established in the literature, as accompanied by a plethora of clinical case reports that further elucidate its aspects. To the best of our knowledge, a specific analysis regarding the pediatric data of Kounis Syndrome has never been performed. The aim of this review was to reveal all the pediatric Kounis Syndrome cases in the literature, in an attempt to define its clinical implications in children. Moreover, based on the data of this analysis, a new classification for Kounis Syndrome is proposed, focusing mainly in the presence or the absence of allergic myocardial infarction, as the central clinical feature for the stratification of the patients' clinical manifestations.

Introduction Pediatric cardiomyopathies (CMP) are disorders of the morphology and function of the heart, with a greater heterogeneity concerning etiology and clinical presentation than adult CMP. The assessment of etiology and genetic status is of paramount importance for prognosis, family screening, and therapeutic choices. Purpose To report clinical presentation, etiology, and outcome of a cohort of children diagnosed with CMP followed at tertiary care pediatric referral centre. Methods We retrospectively reviewed clinical, laboratory and imaging data of all patients referred to our cardiomyopathy centre from May 2008 to May 2019 for pediatric CMP ( Results We enrolled 110 patients (65 males, age at diagnosis 67±71 months). Hypertrophic cardiomyopathy (HCM, N=48, 44%) was most frequent, followed by dilated cardiomyopathy (DCM, N=35 32%) and left ventricular non-compaction phenotype (LVNC, N=12, 11%). Mixed phenotype (N=7, 6%) and restrictive cardiomyopathy (RCM, N=3, 3%) were less common. No cases of arrhythmogenic right ventricular cardiomyopathy (ARVC) were detected. Five genotype-positive patients presented with negative clinical phenotype. A diagnosis was confirmed in all patients; the most common was sarcomere disease (30%, N=33) followed by metabolic (28%,N=31) disease, genetic syndromes (11%, N=12), neuromuscular (7,3%, N=8) diseases, and post-myocarditis cases (4,5%,N=5). Twenty-one patients (19%) were identified as idiopathic. At referral, 4,5% of children presented with NYHA class III/IV. At 35 [14–72] months, 4 (3.7%) patients required ICD implantation, 8 (7.4%) underwent cardiac surgery, and 1 (1%) underwent heart transplant. Furthermore, 28 (26%) patients required hospitalization due to acute HF, with DCM patients being at higher risk (p Conclusions In our cohort, HCM was the most common cause of pediatric CMP followed by DCM and non-compaction. MACE were present in 41% of patients. While HCM had a less severe phenotype (characterized by a higher arrhythmic burden), DCM was characterized by a higher prevalence of HF hospitalizations. DCM, inborn errors in metabolism and genetic syndromes had the worst outcome in terms mortality and heart failure long term. Widespread availability of genetic testing provides several benefits to the clinician, confirming diagnosis in ambiguous cases and defining etiology in order to guide management and identifying relatives at risk. Figure 1 Funding Acknowledgement Type of funding source: None

Background Primary mitochondrial disorders (PMD) are rare conditions resulting in progressive multi-organ failure. Cardiovascular involvement (CVI) has been reported in paediatric patients. However, its age-related prevalence, clinical presentation and prognostic impact are unresolved. We detailed CVI in a cohort of children diagnosed with PMD over two decades at a tertiary referral centre. Results We enrolled 86 PMD patients (M/F = 30/56; mean age 6.4 ± 8.58 years). CVI was detected in 31 patients (36%), with mean age at onset of 5.7 ± 7.8 years including the pre- and neonatal phase in 14, often representing the first sign of PMD (42% of those with CVI). Heart disease resulted more common in males and in children with specific aetiologies (Barth, TMEM70 and MELAS syndromes). Hypertrophic, non-compaction and dilated cardiomyopathies were the prevalent disorders, although pulmonary arterial hypertension was also found. Adverse cardiac events (heart failure, resuscitated cardiac arrest, ICD/PM implantation, sudden death) occurred in 19% of children with CVI over a follow-up period of 5.4 ± 4.3 years. All-cause mortality was higher in patients with CVI compared to those without CVI (45.1% vs 21.8%; p Conclusion Cardiovascular involvement occurred in over one-third of children diagnosed with PMD, often at a very early age, and was associated with adverse prognosis. Final outcome of PMD-related CVI was influenced by the specific underlying aetiology, suggesting the need for tailored management of heart failure and sudden death prevention.

Familial dilated cardiomyopathy (DCM) is mostly caused by mutations in genes encoding cytoskeletal and sarcomeric proteins. In the pediatric population, DCM is the predominant type of primitive myocardial disease. A severe form of DCM is associated with mutations in the DMD gene encoding dystrophin, which are the cause of Duchenne Muscular Dystrophy (DMD). DMD-associated cardiomyopathy is still poorly understood and orphan of a specific therapy. In the last 5 years, a rise of interest in disease models using human induced pluripotent stem cells (hiPSCs) has led to more than 50 original studies on DCM models. In this review paper, we provide a comprehensive overview on the advances in DMD cardiomyopathy disease modeling and highlight the most remarkable findings obtained from cardiomyocytes differentiated from hiPSCs of DMD patients. We will also describe how hiPSCs based studies have contributed to the identification of specific myocardial disease mechanisms that may be relevant in the pathogenesis of DCM, representing novel potential therapeutic targets.

The benefits of physical activity are well established, leading to both cardiovascular and non-cardiovascular benefits, improving quality of life and reducing mortality. Despite such striking body of evidence, patients with hypertrophic cardiomyopathy are often discouraged by health professionals to practice physical activity and personalised exercise prescription is an exception rather than the rule. As a result, hypertrophic cardiomyopathy patients are on average less active and spend significantly less time at work or recreational physical activity than the general population. Exercise restriction derives from the evidence that vigorous exercise may occasionally trigger life-threatening arrhythmias and sudden cardiac death. However, while participation in competitive sports should be prudentially denied, hypertrophic cardiomyopathy patients can benefit from the positive effects of regular physical activity, aimed to reduce the risk of comorbidities and improve the quality of life. Based on this rationale, exercise should be prescribed and titrated just like a drug in hypertrophic cardiomyopathy patients, considering individual characteristics, symptoms, past medical history, objective individual response to exercise, previous training experience and stage of disease. Type, frequency, duration, and intensity should be defined on a personal basis. Yet exercise prescription in hypertrophic cardiomyopathy and its long-term effects represent major gaps in our current knowledge and require extensive research. We here review existing evidence regarding benefits and hazards of physical activity, with specific focus on viable modalities for tailored and safe exercise prescription in these patients, highlighting future developments and relevant research targets.

Heart failure is an important cause of late morbidity and mortality in children, adolescents, and young adults with congenital heart disease. Heart failure is the first cause of mortality in adult congenital heart disease population accounting for 30% to 50% of death while the incidence related to ventricular arrhythmias accounts for another 20%. Symptomatic heart failure requiring hospitalization is associated with 3% to 5% mortality during hospital stay and a 25% incidence of death within the first year after admission. Patients at highest risk for death as a result of heart failure are those with single-ventricle physiology or systemic right ventricular anatomy; however, patients with left-sided obstruction or chronic volume overloaded right ventricle are also at a higher risk than the general population. Medical therapy is scarcely effective in most cases of congenital heart disease related heart failure in children, adolescents and young adults. Lack of donors limits access to heart transplantation and results in adult congenital heart disease population are worse than those in other cardiac populations with heart failure.

Pediatric cardiomyopathies of genetic origin directly involving the heart muscle – i.e. not related to metabolic causes - are rare, yet serious diseases of the heart with an annual incidence of 1.1 to 1.5 per 100,000 children. Cardiomyopathies are a prevalent cause of heart failure and the most common cause of heart transplantation in children older than 1 year of age. Dilated and hypertrophic cardiomyopathy (HCM) have the largest prevalence, whereas restrictive cardiomyopathy and left ventricular non-compaction are very rare. The epidemiology, natural history and prognostic indicators of pediatric cardiomyopathies were poorly understood before the 1990s, and many gaps in knowledge remain to this day. Advances in cardiac imaging and genomic characterization, including genome-wide analysis, are providing fresh insights into the etiology and outcome of children with cardiomyopathy. While morphological and clinical manifestations are similar to those of adult patients, pediatric cardiomyopathies tend to have more severe outcomes and may respond less well to pharmacological treatment. The present review aims to examine familial cardiomyopathies in children, focusing particularly on the risk predictors and outcome of HCM, probably the field with the most impressive advances in recent years.

Pediatric Heart Failure (PHF) is a severe clinical condition associated with a large variety of underlying disorders. Many differences concerning etiology, clinical presentation and prognosis exist not only with HF in adults but also among different pediatric ages. In developed countries, the main conditions leading to HF are congenital heart diseases (CHD) and cardiomyopathies. In infants early surgery has led to a dramatic improvement of CHD-related HF, while prognosis of HF secondary to cardiomyopathies is more severe than in subsequent pediatric ages. In older children and adolescents residual defects and sequelae after cardiac surgery for CHD, cardiomyopathies and acquired disorders account for the majority of cases of HF. The clinical features of poor perfusion are common in HF presenting in the first days of life; a severe aortic stenosis or coarctation should always be considered. On the contrary, congestion accounts for most signs or symptoms in older children with HF. Extracardiac symptoms (gastrointestinal or respiratory) may be the first presentation in children and adolescents. The modified Ross classification is a useful tool to assess the presence and severity of HF in different pediatric ages. Due to the rarity and heterogeneity of the condition, a multi-institutional collaboration is needed in order to improve research and the level of clinical care.

The success of cardiac surgery over the past 50 years has increased numbers and median age of survivors with congenital heart disease (CHD). Adults now represent two-thirds of patients with CHD; in the USA alone the number is estimated to exceed 1 million. In this population, many affected women reach reproductive age and wish to have children. While in many CHD patients pregnancy can be accomplished successfully, some special situations with complex anatomy, iatrogenic or residual pathology are associated with an increased risk of severe maternal and fetal complications. Pre-conception counselling allows women to come to truly informed choices. Risk stratification tools can also help high-risk women to eventually renounce to pregnancy and to adopt safe contraception options. Once pregnant, women identified as intermediate or high risk should receive multidisciplinary care involving a cardiologist, an obstetrician and an anesthesiologist with specific expertise in managing this peculiar medical challenge. This document is intended to provide cardiologists working in hospitals where an Obstetrics and Gynecology Department is available with a streamlined and practical tool, useful for them to select the best management strategies to deal with a woman affected by CHD who desires to plan pregnancy or is already pregnant.

Background: Kawasaki syndrome (KS) is a severe medium size vasculitis with predilection for coronary arteries, mainly affecting young children. The identification of risk factors for coronary artery lesions (CAL) is the aim of the scientific society in order to early detect patients who need a more aggressive therapy. Objectives: To report clinical data of a monocentric cohort of children with KS over a long-term follow-up. Methods: A monocentric retrospective study between Feb 1982 and Aug 2018, involving children with KS diagnosis followed at the Rheumatology and Cardiology Unit of A. Meyer Children’s Hospital. According to cardiac involvement, patients (pts) have been stratified in subject with absence of CAL (no-CAL) and presence of CAL. This latter has been divided in coronary ectasia (CE) and presence of coronary aneurism (CAn). Data analysis was conducted performing a descriptive analysis and assessing risk factors for CAL with analysis of variance (Tukey, LSD and Bonferroni test) and correlation test (Spearman rho test, Chi-square test). Each pt, regardless coronary involvement, underwent a scheduled cardiologic follow-up after 6-8 weeks (6 months, 1 year and ergometric test at 8 years old). Pts with CAL received additionally cardiac evaluations on clinical need. Pts with a follow-up of less than 1 year were excluded from follow-up analyses. Results: Data from 361 pts (219 M, 142 F, aged 1 month-24 years and 5 months) have been reported. Median age of disease onset was 2 years and 1 month; 90% of pts developed the disease At the last follow-up, in the group of no-CAL (261 pts), cardiological visit, ECG, echocardiography and ergometric test (performed 177/261 pts) were normal in all pts. At the last available follow-up, 53 pts with CE had normal cardiological visit, ECG, echocardiography and ergometric test (performed 39/53 pts). Conversely, all 13 pts with CAn showed a normal cardiological visit, whilst ECG was abnormal in 1 patient (7.69%) and echocardiography showed persistent CAn in 8 (61.53%). Ergometric test was performed in 9/13 pts showing abnormal results in one pt (11.11%). Conclusion: Our long-term follow-up in a large, even monocentric, cohort reports possible risk factor of CAL according to current literature. Our long-term follow-up assesses, in real life, the benign course of KS in children without CAL after 6-8 weeks from onset. According to recent guidelines, stopping cardiologic assessment in no risk pts results economically advantageous, timesaving and able to reduce emotional discomfort in children and their families. Disclosure of Interests: Ilaria Maccora: None declared, Giovanni Battista Calabri: None declared, Alice Brambilla: None declared, Teresa Giani: None declared, Silvia Favilli: None declared, Rolando Cimaz: None declared, Gabriele Simonini Grant/research support from: Abbvie, Speakers bureau: Abbvie

Pathology studies demonstrated that coronary fatty streaks develop early in life and that even more advanced fibrous plaques are present in a proportion of adolescents. The presence and extent of atherosclerosis in children and adolescents can be correlated with the same risk factors present in adults; as well as, childhood levels of these risk factors predict adult cardiovascular diseases. Children are born with ideal cardiovascular health but, unfortunately, most of them develop over time modifiable behavioral risk factors. Achieving sustained lifestyle changes initiated too late in adults is difficult, and pharmacologic risk factor control cannot fully restore a low-risk state. Therefore, it seems eminently reasonable to initiate healthful lifestyle training as early in life, decreasing the prevalence of cardiovascular risk factors to retard atherogenic processes and reduce the future burden of cardiovascular diseases. Many guideline recommendations encourage universal adoption of healthier lifestyles, identification of children with cardiovascular risk factors, and their treatment using targeted lifestyle modification and, rarely, pharmacotherapy. Major gains will likely accrue from public health strategies targeting incorrect diet, physical activity, and cigarette smoking. Individualized strategies, however, will initially focus on the highest risk children such as those with familial hyperlipidaemia, diabetes, hypertension, and obesity. The primary purpose of this article is to provide a broad overview on the long-term cardiovascular effects of risk factors in children and youth and to outline various lines of evidence for the efficacy of primordial and primary prevention in young people, as well as recommendations for population- and individual-level strategies and evidence-based interventions.

Background Left pulmonary artery (LPA) sling (PAS) is a vascular ring, which is frequently associated with long-segment tracheal stenosis (TS). Mortality rate in operated children is still high, especially in cases of severe tracheal hypoplasia and/or associated congenital heart defects (CHDs). We report our experience of treatment and follow-up in a pediatric cohort of patients affected by PAS with severe tracheobronchial involvement. Methods From 2005 to 2017, we enrolled 11 children diagnosed with PAS and congenital TS requiring surgical intervention. Echocardiography, computed tomography, and bronchoscopy were performed in all patients. Associated CHD were present in 5 (45%) patients. Tracheal reconstruction techniques included slide tracheoplasty (7/11; 63%), slide tracheoplasty and costal cartilage graft (2/11; 18%), and Hazekamp technique (2/11; 18%).Nine patients underwent LPA direct reimplantation and concomitant tracheoplasty; concomitant surgical repair for CHD was performed in three children. Results Over a mean follow-up of 30 months (range: 3–75 months), a late mortality of 18% was registered; no early death occurred. Good flow through LPA could be documented in all patients. Ten children required operative bronchoscopies (mean: 16/patients) aimed at stent positioning/removal, treatment of granulomas, and tracheobronchial dilatation. Conclusions Severe tracheobronchial stenosis and associated CHD were the main determinants for hospitalization time, intensive assistance, and repeated endoscopic procedures.Patients affected by PAS/TS complex require a careful management at high-specialized centers providing multidisciplinary team.Respiratory endoscopy may play a central role both in preoperatory assessment and in postoperative management of patients showing severe tracheobronchial involvement.

Aim.We investigated the predictors of tissue Doppler left ventricular (LV) longitudinal indexes in a healthy Italian pediatric population and established normative data and regression equations for the calculation ofzscores.Methods and Results.A total of 369 healthy subjects aged 1–17 years (age of 6.4 ± 1.1 years, 49.1% female) underwent echocardiography. LV peak longitudinal velocity at systole (s'), early diastole (e'), and late diastole (a') was determined by tissue Doppler. The ratio of peak early diastolic LV filling velocity toe'was calculated. Age was the only independent determinant ofs'(β=0.491,p<0.0001) and the strongest determinant ofe'(β=0.334,p<0.0001) andE/e'(β=-0.369,p<0.0001). Heart rate was the main determinant ofa'(β=0.265,p<0.0001). Male gender showed no effects except for a weak association with laterals', suggesting no need of gender-specific reference ranges. Age-specific reference ranges, regression equations, and scatterplots for the calculation ofzscores were determined for each index.Conclusion.In a pediatric Italian population, age was the strongest determinant of LV longitudinal dynamics. The availability of age-specific normality data for the calculation ofzscores may allow for correctly detecting LV dysfunction in pediatric pathological populations.

The aim of this study was to explore the medium-term clinical outcome and the risk of progression of aortic valve disease and aortic dilation in pediatric patients with isolated bicuspid aortic valve (BAV). 179 pediatric patients with isolated BAV were prospectively followed from January 1995 to December 2010. Patients with severe valve dysfunction at baseline were excluded. Clinical outcome included cardiac death, infective endocarditis, aortic complications, cardiac surgery and percutaneous valvuloplasty. Echocardiographic endpoints were: progression of aortic stenosis (AS) or regurgitation (AR) and progressive aortic enlargement at different levels of the aortic root, evaluated as z-score. The median age at diagnosis was 7.8 [2.7-12.0] years. After a median followup of 5.4 [2.3-9.2] years, all patients were alive. The clinical endpoint occurred in 4 (2.2 %) patients (0.41 events per 100 patient-years). A progression of AS and AR was observed in 9 (5.0 %) and 29 (16.2 %) patients, respectively. The z-scores at the end of follow-up were not significantly different from baseline at the annulus, Valsalva sinuses and sinotubular junction, whereas a slight increase was observed at the level of the ascending aorta (1.9 vs 1.5, p = 0.046). Significant progressive aortic dilation occurred in a minority of patients (10.6, 5.6, 9.5, and 19.0 % respectively). The clinical outcome in pediatric patients with isolated BAV is favourable and the progression of aortic valve dysfunction and aortic dilation is relatively slow. These findings may be taken into account to better guide risk assessment and clinical follow-up in these patients.

AIMS The clinical features of the adult population with congenital heart disease (CHD) are still not well characterized, particularly in the subset with more severe lesions. We report the data collected in the National Association of Hospital Cardiologists Toscana grown-up CHD (GUCH) registry over its first 8-month enrolment period. METHODS The Registry included consecutive patients aged more than 16 years with a documented diagnosis of CHD, enrolled in seven different Tuscan hospitals using a web-based electronic form. Severe CHD was defined as cyanotic CHD, or acyanotic lesion with significant haemodynamic impact requiring surgical and/or percutaneous correction. RESULTS Between November 2009 and June 2010 a total of 1641 patients (mean age 41.8 ± 19.3 years, 52.2% women) were enrolled. Atrial septal defect was the most common lesion, accounting for more than one-third of cases. Atrial and ventricular septal defects together accounted for about half of all CHDs. Nearly one-third of patients had New York Heart Association (NYHA) class 2 or more. A history of recurrent arrhythmias was reported in 15% of cases, and 12% of patients were on oral anticoagulants at the time of enrolment. The prevalence of pulmonary hypertension was 6%, and the prevalence of Eisenmenger syndrome was 1.2%. Severe CHD was present in 42% of patients. Younger age, higher NYHA class, male sex, and the need for oral anticoagulants were the only independent predictors of severe CHD. CONCLUSION Information about the clinical characteristics and the CHD type distribution of a sample of Tuscan GUCH population was provided. Severe CHD accounts for about 40% of all CHDs in this population. CHD severity is associated with younger age, male gender, worse NYHA class, and need for oral anticoagulation.

Controversial data exist about the long-term results of aortic coarctation (AC) repair. This study explored the prevalence and predictors of left ventricular (LV) hypertrophy, late hypertension, and hypertensive response to exercise in 48 subjects (age, 15.1 ± 9.7 years) currently followed in the authors' tertiary care hospital after successful AC repair. Data on medical history, clinical examination, rest and exercise echocardiography, and ambulatory blood pressure monitoring were collected. The time from AC repair to follow-up evaluation was 12.9 ± 9.2 years. The prevalence of LV hypertrophy ranged from 23 to 38 %, based on the criteria used to identify LV hypertrophy, and that of concentric geometry was 17 %. One sixth of the patients without residual hypertension experienced late-onset hypertension. One fourth of those who remained normotensive without medication showed a hypertensive response to exercise. Age at AC repair was the strongest independent predictor of LV hypertrophy, defined using indexation either for body surface area (odds ratio [OR], 1.03; p = 0.0090) or for height(2.7) (OR 1.02; p = 0.029), and it was the only predictor of late hypertension (OR 1.06; p = 0.0023) and hypertensive response to exercise (OR 1.09; p = 0.029). The risk of LV hypertrophy was 25 % for repair at the age of 3.4 years but rose to 50 and 75 % for repair at the ages of 5.9 and 8.4 years, respectively. Similar increases were found for the risk of late-onset hypertension and hypertensive response to exercise. A considerable risk of LV hypertrophy, late hypertension, and hypertensive response to exercise exists after successful AC repair. Older age at intervention is the most important predictor of these complications.

Anomalous left coronary artery from pulmonary artery (ALCAPA) is a rare congenital anomaly in which left coronary artery arises from the pulmonary artery resulting in progressive myocardial ischemia and dysfunction of the left ventricle. We report a case of ALCAPA with severe cardiac and respiratory failure and huge heart dilation compressing the left main bronchus and preventing from an effective ventilation. Emergency bronchial stenting allowed to improve left lung atelectasis, reduce pulmonary hypertension, resume anterograde left coronary artery perfusion and stabilize cardiovascular conditions to undertake a successful surgical correction.

Importance Predictors of lethal arrhythmic events (LAEs) after a pediatric diagnosis of hypertrophic cardiomyopathy (HCM) are unresolved. Existing algorithms for risk stratification are limited to patients older than 16 years because of a lack of data on younger individuals. Objective To describe the long-term outcome of pediatric-onset HCM and identify age-specific arrhythmic risk factors. Design, Setting, and Participants This study assessed patients with pediatric-onset hypertrophic cardiomyopathy diagnosed from 1974 to 2016 in 2 national referral centers for cardiomyopathies in Florence, Italy. Patients with metabolic and syndromic disease were excluded. Exposures Patients were assessed at 1-year intervals, or more often, if their clinical condition required. Main Outcomes and Measures Lethal arrhythmic events (LAEs) and death related to heart failure. Results Of 1644 patients with HCM, 100 (6.1%) were 1 to 16 years old at diagnosis (median [interquartile range], 12.2 [7.3-14.1] years). Of these, 63 (63.0%) were boys. Forty-two of the 100 patients (42.0%) were symptomatic (defined as an New York Heart Association classification higher than 1 or a Ross score greater than 2). The yield of sarcomere gene testing was 55 of 70 patients (79%). During a median of 9.2 years during which a mean of 1229 patients were treated per year, 24 of 100 patients (24.0%) experienced cardiac events (1.9% per year), including 19 LAEs and 5 heart failure–related events (3 deaths and 2 heart transplants). Lethal arrhythmic events occurred at a mean (SD) age of 23.1 (11.5) years. Two survivors of LAEs with symptoms of heart failure experienced recurrent cardiac arrest despite an implantable cardioverter defibrillator. Risk of LAE was associated with symptoms at onset (hazard ratio [HR], 8.2; 95% CI, 1.5-68.4; P = .02) and Troponin I or Troponin T gene mutations (HR, 4.1; 95% CI, 0.9-36.5; P = .06). Adult HCM risk predictors performed poorly in this population. Data analysis occurred from December 2016 to October 2017. Conclusions and Relevance Pediatric-onset HCM is rare and associated with adverse outcomes driven mainly by arrhythmic events. Risk extends well beyond adolescence, which calls for unchanged clinical surveillance into adulthood. In this study, predictors of adverse outcomes differ from those of adult populations with HCM. In secondary prevention, the implantable cardioverter defibrillator did not confer absolute protection in the presence of limiting symptoms of heart failure.

Controversies in the therapy of congenital complete heart block are reviewed in terms of the timing of pacemaker implantation, the type and complications of pacing and its role in the presence of myocardial dysfunction. Drug treatment may be useful in selected cases in the presence of pleural effusions, ascites and hydrops of the fetus, but have no effect on complete heart block. Administration of fluorinated steroids in anti-Ro antibody-positive mothers with the aim of preventing complete heart block has given controversial results. Because of the variety of the clinical presentations, especially in regard to pacing therapy, it is mandatory to refer patients with congenital complete heart block to specialized centers with adequate resources and experienced personnel.

PHACE is a rare congenital neurocutaneous syndrome where posterior fossa malformations, hemangiomas, cerebrovascular anomalies, aortic arch anomalies, cardiac defects, and eye abnormalities are variably associated. We describe the prenatal detection and the postnatal course of a child with PHACE syndrome with a unique type of aortic arch anomaly consisting of proximal interruption of the aortic arch and persistence of the fifth aortic arch. The fifth aortic arch represented in this case a vital systemic-to-systemic connection between the ascending aorta and the transverse portion of the aortic arch allowing adequate forward flow through the aortic arch without surgical treatment.

We describe a rare case of right aortic arch (RAA) and nonconfluent pulmonary arteries. RAA and a right-sided arterial duct (AD) were identified on the prenatal scan, but a second left-sided AD and disconnection of the left pulmonary artery were missed. The missed diagnosis in fetal life adversely affected postnatal management. We suggest that fetuses with a prenatal diagnosis of RAA and right-sided AD be delivered in tertiary care centres to rule out an association with bilateral AD and nonconfluent pulmonary arteries after birth. Prompt postnatal diagnosis will enable preservation of flow in the disconnected pulmonary artery through prostaglandin E1 infusion until surgical reconstruction.

Pulmonary arterial hypertension (PAH) is a common finding in patients with congenital heart disease (CHD), and has relevant prognostic implications. The recent introduction of advanced therapies (AT) considerably improved the clinical outcome of these patients, but real-world data are still lacking. We aimed at reporting the results of a long-term follow-up of CHD patients with PAH undergoing AT, followed at a tertiary Center during the two last decades. The study population included a total of 34 patients with an established diagnosis of CHD-related PAH. In addition to conventional treatment, 97% of patients started AT during the follow-up. Over a median follow-up of 9 [3-31] years, 11 (32.4%) patients died: 7 of them were affected by Eisenmenger syndrome and the majority of patients were in NYHA class ≥3 at the time of death. Among the 23 patients who were alive at the last follow-up, the majority were in NYHA class I-II. Oxygen saturation and 6-min walking distance improved in all subjects within the first 6 months after starting of AT. One patient with ventricular septum defect and high pulmonary resistances was successfully treated with AT to lower resistances and underwent defect closure. A good clinical outcome was also observed in the subset (n = 8) with Down syndrome. The results of this real-world experience suggest that, despite a relatively high mortality rate mostly related to late commencement of AT, the clinical outcome of subjects with CHD-related PAH undergoing AT are characterized by a good quality of life and clinical improvement in most patients.