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.

Recommendations for cardiovascular magnetic resonance and computed tomography in congenital heart disease: a consensus paper from the CMR/CCT working group of the Italian Society of Pediatric Cardiology (SICP) and the Italian College of Cardiac Radiology endorsed by the Italian Society of Medical and Interventional Radiology (SIRM) Part I.

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

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.

[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.

Comparative analysis of left ventricle function and deformation imaging in short and long axis plane in cardiac magnetic resonance imaging.

Background: Advancements in cardiac imaging have revolutionized our understanding of ventricular contraction. While ejection fraction (EF) is still the gold standard parameter to assess left ventricle (LV) function, strain imaging (SI) has provided valuable insights into ventricular mechanics. The lack of an integrative method including SI parameters in a single, validated formula may limit its use. Our aim was to compare different methods for evaluating global circumferential strain (GCS) and their relationship with global longitudinal strain (GLS) and EF in CMR and how the different evaluations fit in the theoretical relationship between EF and global strain. Methods: Retrospective monocenter study. Inclusion of every patient who underwent a CMR during a 15 months period with various clinical indication (congenital heart defect, myocarditis, cardiomyopathy). A minimum of three LV long-axis planes and a stack of short-axis slices covering the LV using classical steady-state free precession cine sequences. A single assessment of GLS on long axis (LAX) slices and a double assessment of GCS and EF with both short axis (SAX) and LAX slices were made by a single experienced CMR investigator. Results: GCS-SAX and GCS-LAX were correlated (r = 0.77, P < 0.001) without being interchangeable with a high reproducibility for GCS, GLS and EF. EF calculated from LAX images showed an overestimation compared to EF derived from SAX images of 7%. The correlation between calculated EF and theoretical EF derived from SI was high (r = 0.88 with EF-SAX, 0.95 with EF-LAX). Data conclusion: This study highlights the need to integrate strain imaging techniques into clinical by incorporating strain parameters into EF calculations, because it gives a deeper understanding of cardiac mechanics.

Recommendations for cardiovascular magnetic resonance and computed tomography in congenital heart disease: a consensus paper from the CMR/CCT Working Group of the Italian Society of Pediatric Cardiology and the Italian College of Cardiac Radiology endorsed by the Italian Society of Medical and Interventional Radiology (Part II).

Cardiovascular magnetic resonance (CMR) and computed tomography (CCT) are advanced imaging modalities that recently revolutionized the conventional diagnostic approach to congenital heart diseases (CHD), supporting echocardiography and often replacing cardiac catheterization. This is the second of two complementary documents, endorsed by experts from the Working Group of the Italian Society of Pediatric Cardiology and the Italian College of Cardiac Radiology of the Italian Society of Medical and Interventional Radiology, aimed at giving updated indications on the appropriate use of CMR and CCT in different clinical CHD settings, in both pediatrics and adults. In this article, support is also given to radiologists, pediatricians, cardiologists, and cardiac surgeons for indications and appropriateness criteria for CMR and CCT in the most referred CHD, following the proposed new criteria presented and discussed in the first document. This second document also examines the impact of devices and prostheses for CMR and CCT in CHD and additionally presents some indications for CMR and CCT exams when sedation or narcosis is needed.

Aortic Dilatation in Pediatric Patients with Bicuspid Aortic Valve: How the Choice of Nomograms May Change Prevalence.

BACKGROUND: Aortic dilation (AoD) is commonly reported in patients with bicuspid aortic valve (BAV) and has been related to flow abnormalities and genetic predisposition. AoD-related complications are reported to be extremely rare in children. Conversely, an overestimate of AoD related to body size may lead to excess diagnoses and negatively impact quality of life and an active lifestyle. In the present study, we compared the diagnosis performance of the newly introduced Q-score (based on a machine-learning algorithm) versus the traditional Z-score in a large consecutive pediatric cohort with BAV. MATERIALS AND METHODS: Prevalence and progression of AoD were evaluated in 281 pediatric patients ages > 5 and < 18 years at first observation, 249 of whom had isolated BAV and 32 had BAV associated with aortic coarctation (CoA-BAV). An additional group of 24 pediatric patients with isolated CoA was considered. Measurements were made at the level of the aortic annulus, Valsalva sinuses, sinotubular aorta, and proximal ascending aorta. Both Z-scores using traditional nomograms and the new Q-score were calculated at baseline and at followup (mean 4.5 years). RESULTS: A dilation of the proximal ascending aorta was suggested by traditional nomograms (Z-score > 2) in 31.2% of patients with isolated BAV and 18.5% with CoA-BAV at baseline and in 40.7% and 33.3%, respectively, at followup. No significant dilation was found in patients with isolated CoA. Using the new Q-score calculator, ascending aorta dilation was detected in 15.4% of patients with BAV and 18.5% with CoA-BAV at baseline and in 15.8% and 3.7%, respectively, at followup. AoD was significantly related to the presence and degree of aortic stenosis (AS) but not to aortic regurgitation (AR). No AoD-related complications occurred during the followup. CONCLUSIONS: Our data confirm the presence of ascending aorta dilation in a consistent subgroup of pediatric patients with isolated BAV, with progression during followup, while AoD was less common when CoA was associated with BAV. A positive correlation was found with the prevalence and degree of AS, but not with AR. Finally, the nomograms used may significantly influence the prevalence of AoD, especially in children, with a possible overestimation by traditional nomograms. This concept requires prospective validation in long-term followup.

Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort.

BACKGROUND: Cardiac involvement is reported in a significant proportion of patients with classical organic acidurias (OAs), contributing to disability and premature death. Different cardiac phenotypes have been described, among which dilated cardiomyopathy (DCM) is predominant. Despite recent progress in diagnosis and treatment, the natural history of patients with OAs remains unresolved, specifically with regard to the impact of cardiac complications. We therefore performed a retrospective study to address this issue at our Referral Center for Pediatric Inherited Errors of Metabolism. METHODS: Sixty patients with OAs (propionic (PA), methylmalonic (MMA) and isovaleric acidemias and maple syrup urine disease) diagnosed from 2000 to 2022 were systematically assessed at baseline and at follow-up. RESULTS: Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients) and/or acquired long QT syndrome (3/23 patients). The presence of DCM was associated with the worst prognosis. The rate of occurrence of major adverse cardiac events (MACEs) at 5 years was 55% in PA with cardiomyopathy; 35% in MMA with cardiomyopathy; and 23% in MMA without cardiomyopathy. Liver transplantation was performed in seven patients (12%), all with PA or MMA, due to worsening cardiac impairment, and led to the stabilization of metabolic status and cardiac function. CONCLUSIONS: Cardiac involvement was documented in about one third of children diagnosed with classical OAs, confined to PA and MMA, and was often associated with poor outcome in over 50%. Etiological diagnosis of OAs is essential in guiding management and risk stratification.

Genetic Testing and Counselling in Hypertrophic Cardiomyopathy: Frequently Asked Questions.

Genetic counselling and genetic testing in hypertrophic cardiomyopathy (HCM) represent an integral part of the diagnostic algorithm to confirm the diagnosis, distinguish it from phenocopies, and suggest tailored therapeutic intervention strategies. Additionally, they enable cascade genetic testing in the family. With the implementation of Next Generation Sequencing technologies (NGS), the interpretation of genetic data has become more complex. In this regard, cardiologists play a central role, aiding geneticists to correctly evaluate the pathogenicity of the identified genetic alterations. In the ideal setting, geneticists and cardiologists must work side by side to diagnose HCM as well as convey the correct information to patients in response to their many questions and concerns. After a brief overview of the role of genetics in the diagnosis of HCM, we present and discuss the frequently asked questions by HCM patients throughout our 20-year genetic counselling experience. Appropriate communication between the team and the families is key to the goal of delivering the full potential of genetic testing to our patients.

Focus on Paediatric Restrictive Cardiomyopathy: Frequently Asked Questions.

Restrictive cardiomyopathy (RCM) is characterized by restrictive ventricular pathophysiology determined by increased myocardial stiffness. While suspicion of RCM is initially raised by clinical evaluation and supported by electrocardiographic and echocardiographic findings, invasive hemodynamic evaluation is often required for diagnosis and management of patients during follow-up. RCM is commonly associated with a poor prognosis and a high incidence of heart failure, and PH is reported in paediatric patients with RCM. Currently, only a few therapies are available for specific RCM aetiologies. Early referral to centres for advanced heart failure treatment is often necessary. The aim of this review is to address questions frequently asked when facing paediatric patients with RCM, including issues related to aetiologies, clinical presentation, diagnostic process and prognosis.

Overcoming Underpowering in the Outcome Analysis of Repaired-Tetralogy of Fallot: A Multicenter Database from the CMR/CT Working Group of the Italian Pediatric Cardiology Society (SICPed).

Background: Managing repaired tetralogy of Fallot (TOF) patients is still challenging despite the fact that published studies identified prognostic clinical or imaging data with rather good negative predictive accuracy but weak positive predictive accuracy. Heterogeneity of the initial anatomy, the surgical approach, and the complexity of the mechanism leading to dilation and ventricular dysfunction explain the challenge of predicting the adverse event in this population. Therefore, risk stratification and management of this population remain poorly standardized. Design: The CMR/CT WG of the Italian Pediatric Cardiology Society set up a multicenter observational clinical database of repaired TOF evaluations. This registry will enroll patients retrospectively and prospectively assessed by CMR for clinical indication in many congenital heart diseases (CHD) Italian centers. Data collection in a dedicated platform will include surgical history, clinical data, imaging data, and adverse cardiac events at 6 years of follow-up. Summary: The multicenter repaired TOF clinical database will collect data on patients evaluated by CMR in many CHD centers in Italy. The registry has been set up to allow future research studies in this population to improve clinical/surgical management and risk stratification of this population.

Magnetic Resonance Imaging Correlates of Left Bundle Branch Disease in Patients With Nonischemic Cardiomyopathy.

The pathologic correlates of intraventricular conduction delays in patients with nonischemic cardiomyopathy (NIC) have been scarcely investigated. We assessed left ventricular (LV) structural, functional, and tissue abnormalities associated with intraventricular conduction left bundle disease (LBD), including left anterior hemiblock or complete left bundle branch block, in a cohort of patients with NIC submitted to cardiovascular magnetic resonance. Twelve-lead electrocardiogram and cardiovascular magnetic resonance were performed in 196 consecutive patients with NIC. The presence and extent of myocardial fibrosis was evaluated with late gadolinium enhancement (LGE) technique. Compared with normal intraventricular conduction patients, those with LBD were older (66 vs 59 years, p = 0.001), had greater LV volumes (p = 0.035 for end-diastolic and p = 0.009 for end-systolic volume) and mass (p = 0.034), and showed lower LV ejection fraction (33% vs 40%, p = 0.008). LGE was observed more commonly in LBD than in normal intraventricular conduction patients and was more often located in the ventricular septum (p < 0.001). On multivariate analysis, septal LGE was independently associated with a higher likelihood of LBD (odds ratio 6.1, 95% confidence interval 2.9 to 12.7, p < 0.001), even after correction for LV volumes, mass, and ejection fraction. In conclusion, in NIC, the presence of LBD is associated with worse LV remodeling and dysfunction than normal intraventricular conduction. Septal fibrosis yielded a 6-fold greater likelihood of LBD, independently of the degree of LV dilatation and systolic dysfunction.

Pre-operative left atrial strain predicts post-operative atrial fibrillation in patients undergoing aortic valve replacement for aortic stenosis.

Post-operative atrial fibrillation (AF) is a common and serious complication in patients undergoing aortic valve replacement (AVR). Speckle tracking echocardiography (STE) has recently enabled the quantification of longitudinal myocardial left atrial (LA) deformation dynamics. Our aim was to investigate LA preoperative mechanical function in patients undergoing AVR for aortic stenosis using STE and determine predictors of post-operative AF. 76 patients with aortic stenosis in sinus rhythm, undergoing AVR, were prospectively enrolled. Conventional echocardiographic parameters, and peak atrial longitudinal strain (PALS) were measured in all subjects the day before surgery. PALS values were obtained by averaging all segments in the 4- and 2-chamber views (global PALS). All patients received biological valve prostheses and a standard postoperative care. Postoperative AF occurred in 15 patients (19.7 %). On univariate analysis among all clinical and echocardiographic variables, global PALS showed the highest diagnostic accuracy (HR 6.55 p < 0.0001; AUC of 0.89) with a cut-off value <16.9 %, having sensitivity and specificity of 86 and 91 %, respectively, in predicting postoperative AF. LA volume indexed and E/e' ratio had lower diagnostic accuracy (AUC 0.76 and 0.51, respectively). On multivariate analysis global PALS remains a significant predictor of postoperative AF (p < 0.0001). STE analysis of LA myocardial deformation is considered a promising tool for the evaluation of LA subclinical dysfunction in patients undergoing AVR, giving a potentially better risk stratification for the occurrence of postoperative AF.

Comparison of right versus left ventricular strain analysis as a predictor of outcome in patients with systolic heart failure referred for heart transplantation.

The aim of the present study was to explore the relation between right ventricular (RV) and left ventricular (LV) echocardiographic parameters with clinical outcome in patients with advanced heart failure referred for cardiac transplantation. Ninety-eight consecutive patients with advanced systolic heart failure, referred for cardiac transplant evaluation, were enrolled. All patients were prospectively followed for the development of new outcome events, which included hospitalization for acute heart failure, cardiovascular death, heart transplantation, intra-aortic balloon pump implantation, and ventricular assist device implantation. Conventional transthoracic echocardiography was performed in all subjects. RV longitudinal strain (RVLS) by speckle-tracking echocardiography was assessed by averaging all segments in apical 4-chamber view (global RVLS) and by averaging RV free-wall segments (free-wall RVLS). LV global longitudinal and global circumferential strains were also calculated. Of the 98 subjects at baseline, 46 had 67 new events during a mean follow-up of 1.5 ± 0.9 years. Free-wall RVLS, global RVLS, N-terminal fragment of the prohormone brain natriuretic peptide, RV fractional area change, and LV end-diastolic volume were independently predictive of combined outcomes (all p <0.0001). The overall performance for the prediction of cardiovascular events was greatest for free-wall RVLS (area under the curve free-wall RVLS: 0.87; global RVLS: 0.67; RV fractional area change: 0.60; N-terminal fragment of the prohormone brain natriuretic peptide, 0.62; global circumferential strain: 0.55; global longitudinal strain: 0.35; and LV ejection fraction: 0.26). Free-wall RVLS showed the highest adjusted hazards ratio. A graded association between the grade of RV dysfunction and the risk of cardiovascular events was only evident for free-wall RVLS and global RVLS. In conclusion, in patients referred for heart transplantation, RVLS is a stronger predictor of outcome than LV longitudinal strain and other conventional parameters, providing a stronger prognostic stratification.