Italian Association of Hospital Cardiologists Position Paper 'Gender discrepancy: time to implement gender-based clinical management'.

It has been well assessed that women have been widely under-represented in cardiovascular clinical trials. Moreover, a significant discrepancy in pharmacological and interventional strategies has been reported. Therefore, poor outcomes and more significant mortality have been shown in many diseases. Pharmacokinetic and pharmacodynamic differences in drug metabolism have also been described so that effectiveness could be different according to sex. However, awareness about the gender gap remains too scarce. Consequently, gender-specific guidelines are lacking, and the need for a sex-specific approach has become more evident in the last few years. This paper aims to evaluate different therapeutic approaches to managing the most common women's diseases.

Cardio-Oncology in Childhood: State of the Art.

PURPOSE OF REVIEW: Cardio-oncology is an increasingly important field of cardiology that focuses on the detection, monitoring, and treatment of cardiovascular disease (CVD) occurring during and after oncological treatments. The survival rate for childhood cancer patients has dramatically increased thanks to new treatment protocols and cardiovascular (CV) sequelae represent the third most frequent cause of mortality in surviving patients. This study aims to provide a complete and updated review of all the main aspects of cardio-oncology in childhood and to highlight the critical issues. RECENT FINDINGS: The problem of CV complications in childhood cancer survivors raises the need to make an early diagnosis of cardiotoxicity by the new imaging and laboratory techniques in order to intervene promptly and to implement pharmacological strategies and lifestyle changes to reduce or even to prevent cardiac injury. Furthermore, a stratification of CV risk, also including new predisposing factors such as the presence of some genetic mutations, is of paramount importance before undertaking oncological treatments. Besides, a systematic and personalized planning of long-term follow-up is fundamental to ensure a transition from pediatric to adult hospital and to avoid missed or late diagnosis of cardiomyopathy. We reviewed the main risk factors for cardiotoxicity in children, both traditional and emerging ones: the mechanisms of toxicity of both old and new antineoplastic therapies, the techniques for detecting cardiac damage, and the current evidence regarding pharmacological cardioprotection. At the end, we focused our attention on the existing guidelines and strategies about the long-term follow-up of childhood cancer survivors.

The Influence of Genotype on the Phenotype, Clinical Course, and Risk of Adverse Events in Children with Hypertrophic Cardiomyopathy.

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.

Diagnosis and Management of Cardiovascular Involvement in Friedreich Ataxia.

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.

Supraventricular tachycardias in the first year of life: what is the best pharmacological treatment? 24 years of experience in a single centre.

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.

Long-term follow-up of coronary artery lesions in children in Kawasaki syndrome.

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.

Pathophysiology and clinical presentation of paediatric heart failure related to congenital heart disease.

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.

Combined Surgical and Endoscopic Approach for Ring-Sling Complex.

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.

Frequent Ventricular Premature Beats in Children and Adolescents: Natural History and Relationship with Sport Activity in a Long-Term Follow-Up.

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.

Kounis Syndrome: a pediatric perspective.

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.

Lifestyles and Cardiovascular Prevention in Childhood and Adolescence.

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.

Consensus Document of the Italian Association of Hospital Cardiologists (ANMCO), Italian Society of Pediatric Cardiology (SICP), and Italian Society of Gynaecologists and Obstetrics (SIGO): pregnancy and congenital heart diseases.

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.

Aortic Arch Interruption and Persistent Fifth Aortic Arch in Phace Syndrome: Prenatal Diagnosis and Postnatal Course.

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.

Clinical outcome, valve dysfunction, and progressive aortic dilation in a pediatric population with isolated bicuspid aortic valve.

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.

Borderline Ventricles: From Evaluation to Treatment.

A heart with a borderline ventricle refers to a situation where there is uncertainty about whether the left or right underdeveloped ventricle can effectively support the systemic or pulmonary circulation with appropriate filling pressures and sufficient physiological reserve. Pediatric cardiologists often deal with congenital heart diseases (CHDs) associated with various degrees of hypoplasia of the left or right ventricles. To date, no specific guidelines exist, and surgical management may be extremely variable in different centers and sometimes even in the same center at different times. Thus, the choice between the single-ventricle or biventricular approach is always controversial. The aim of this review is to better define when "small is too small and large is large enough" in order to help clinicians make the decision that could potentially affect the patient's entire life.

[Italian Society of Pediatric Cardiology (SICP) position paper on the prevention, diagnosis, treatment and follow-up of cardiotoxicity in pediatric patients with cancer]. / Position paper della Società Italiana di Cardiologia Pediatrica (SICP) su prevenzione, diagnosi, trattamento e follow-up della cardiotossicità nei pazienti oncologici pediatrici.

The survival of pediatric cancer patients has significantly increased thanks to the improvement of oncological treatments. Therefore, it is of utmost importance to manage short- and long-term cardiovascular complications. In pediatric cardio-oncology, there are no recognized guidelines as in adults. Several recommendations and many indications have been derived from the data obtained in the adult cancer population, resulting in greater discrepancies in the clinical management of patients. The aim of this position paper of the Italian Society of Pediatric Cardiology (SICP) is to collect the main evidence regarding the diagnosis, prevention, treatment and follow-up of cardiotoxicity in children, to provide useful indications for clinical practice, and to promote a network between pediatric centers.

Hereditary Thoracic Aortic Diseases.

Advances in both imaging techniques and genetics have led to the recognition of a wide variety of aortic anomalies that can be grouped under the term 'hereditary thoracic aortic diseases'. The present review aims to summarize this very heterogeneous population's clinical, genetic, and imaging characteristics and to discuss the implications of the diagnosis for clinical counselling (on sports activity or pregnancy), medical therapies and surgical management.

Impact of pregnancy on the natural history of women with hypertrophic cardiomyopathy.

AIMS: Whether pregnancy is a modifier of the long-term course and outcome of women with hypertrophic cardiomyopathy (HCM) is unknown. We assessed the association of pregnancy with long-term outcomes in HCM women. METHODS AND RESULTS: Retrospective evaluation of women with HCM from 1970 to 2021. Only women with pregnancy-related information (pregnancy present or absent) and a follow-up period lasting ≥1 year were included. The peri-partum period was defined as -1 to 6 months after delivery. The primary endpoint was a composite for major adverse cardiovascular events [MACE: cardiovascular death, sudden cardiac death, appropriate defibrillator shock and heart failure (HF) progression]. Overall, 379 (58%) women were included. There were 432 pregnancies in 242 (63%) patients. In 29 (7.6%) cases, pregnancies (n = 39) occurred after HCM diagnosis. Among these, three carrying likely pathogenic sarcomeric variants suffered MACEs in the peri-partum period. At 10 ± 9 years of follow-up, age at diagnosis [hazard ratio (HR) 1.034, 95% confidence interval (CI) 1.018-1.050, P < 0.001] and New York Heart Association (NYHA) class (II vs. I: HR 1.944, 95% CI 0.896-4.218; III vs. I: HR 5.291, 95% CI 2.392-11.705, P < 0.001) were associated with MACE. Conversely, pregnancy was associated with reduced risk (HR 0.605; 95% CI 0.380-0.963, P = 0.034). Among women with pregnancy, multiple occurrences did not modify risk. CONCLUSIONS: Pregnancy is not a modifier of long-term outcome in women with HCM and mostly occurs before a cardiac diagnosis. Most patients tolerate pregnancy well and do not show a survival disadvantage compared to women without. Pregnancy should not be discouraged, except in the presence of severe HF symptoms or high-risk features.

Hypertrophic cardiomyopathy (HCM) is the most common genetic disorder of the myocardium and is characterized by important gender-related differences: women are typically 5 years older than men at diagnosis, over half are diagnosed >50 years of age and consistently show greater propensity than men for heart failure (HF)-related complications and adverse outcome. Whether pregnancy is a modifier of the long-term course and outcome of women with HCM is unknown. In this study, pregnancy was not a modifier of long-term outcome in women with HCM. In particular: At 10 ± 7 years, most patients tolerated pregnancy well and did not show a survival disadvantage compared to women without pregnancies. Only baseline heart failure symptoms and age were associated with adverse outcome.Pregnancy should not be discouraged, except in the presence of severe HF symptoms or high-risk features. Nevertheless, cardio-obstetric counselling and close supervision are key in all instances, particularly in the peri-partum period.

[Gender discrepancy: time to implement gender-based clinical management]. / Position paper ANMCO: Differenze di genere nell'approccio farmacologico cardiovascolare.

It is well established that gender strongly influences cardiovascular risk factors, playing a crucial role in cardiovascular prevention, clinical pathways, diagnostic approach and treatment. Beyond the sex, which is a biological factor, gender entails a socio-cultural condition that impacts access and quality of care due to structural and institutional barriers. However, despite its great importance, this issue has not been adequately covered. Indeed sex and gender differences scarcely impact the clinical approach, creating a lot of disparities in care and outcomes of patients. Therefore, it becomes essential to increase the awareness of the importance of sex and gender influences on cardiovascular diseases. Moreover, new strategies for reducing disparities should be developed. Importantly, these differences should be taken into account in guideline recommendations. In this regard, it is crucial to include a greater number of women in clinical trials, since they are currently underrepresented. Furthermore, more women should be involved as member of international boards in order to develop recommendations and guidelines with more attention to this important topic.The aim of this ANMCO position paper is to shed light on gender differences concerning many cardiovascular drugs in order to encourage a more personalized therapeutic approach.