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Background. Left ventricular hypertrabeculation (LVHT) is a myocardial disorder with different clinical manifestations, from total absence of symptoms to heart failure, arrhythmias, sudden cardiac death (SCD), and thromboembolic events. It is challenging to distinguish between the benign and pathological forms of LVHT. The aim of this study was to describe the arrhythmic manifestations of LVHT in a large group of pediatric patients and to correlate them with genetic results or other clinical markers. Methods. We retrospectively enrolled 140 pediatric patients with diagnosis of LVHT followed at our Institution from 2013 to 2023. Data regarding family history, instrumental exams, cardiac magnetic resonance, genetic testing and outcomes were collected. Most of them had isolated LVHT (80.7%); in other patients, mixed phenotypes (hypertrophic or dilated cardiomyopathy or congenital heart disease) were present. Results. Arrhythmias were found in 33 children (23.6%): 13 (9.3%) supraventricular tachyarrhythmias; 14 (10%) ventricular arrhythmias (five frequent PVCs (premature ventricular contractions), eight patients with ventricular tachycardia (VT), one ventricular fibrillation (VF)); two (1.4%) sinus node disfunctions; two (1.4%) complete atrio-ventricular blocks (AVB), three (2.1%) paroxysmal complete AVB, one (0.7%) severe I degree AVB. Three patients received an ICD (implantable cardioverter defibrillator). Comparison between LVHT patients with (33 pts) and without (107 pts) arrhythmias as regards genetic testing showed a statistical significance for the presence of class 4 or 5 genetic variants and arrhythmic manifestation (p = 0.037). Conclusions. In our pediatric cohort with LVHT, good outcomes were observed, but arrhythmias were not so rare (23.6%); no SCD occurred.

Circulating CD11c+ B cells, a novel subset of activated B cells, have been linked to autoimmunity and shown to expand with age. Atherosclerosis is an age-associated disease that involves innate and adaptive immune responses to modified self-antigens. Yet, the expression of CD11c on specific B-cell subtypes and its link to atherosclerosis are poorly understood. In this study, we characterized the frequency of CD11c+ B cells in tissues in mice with aging. We observed an age-associated increase in CD11c+ B cells in the spleen and bone marrow of ApoE−/− mice, and this was associated with an increase in aortic plaque. In addition, we also utilized single-cell multi-omics profiling of 60 human subjects undergoing advanced imaging for coronary artery disease (CAD) to subtype CD11c+ B cells and determine their frequency in subjects with high and low severity of CAD. Using unsupervised clustering, we identified four distinct clusters of CD11c+ B cells, which include CD27 and IgD double negative 2 (DN2), age-associated (ABC), CD11c+ unswitched memory (USWM), and activated Naïve (aNav) B cells. We observed an increase in the frequency of both ABC B cells and DN2 B cells in patients with high CAD severity. Pathway analysis further demonstrated augmentation of autophagy, IFNg signaling, and TLR signaling in DN2 cells in high-severity CAD patients. On the other hand, an increase in the negative regulator of BCR signaling through CD72 was found in ABC cells in low-severity CAD patients. Through investigating scRNAseq of atheroma, these DN2 cells were also found to infiltrate human coronary atheroma.

Sotos syndrome is an autosomal dominant condition characterized by overgrowth with advanced bone age, macrodolicocephaly, motor developmental delays and learning difficulties, and characteristic facial features caused by heterozygous pathogenetic variants in the NSD1 gene located on chromosome 5q35. The prevalence of heart defects (HDs) in individuals with Sotos syndrome is estimated to be around 15–40%. Septal defects and patent ductus arteriosus are the most commonly diagnosed malformations, but complex defects have also been reported. The aim of our study was to analyze the prevalence of HD, the anatomic types, and the genetic characteristics of 45 patients with Sotos syndrome carrying pathogenetic variants of NSD1 or a 5q35 deletion encompassing NSD1, who were followed at Bambino Gesù Children’s Hospital in Rome. Thirty-nine of the forty-five patients (86.7%) had a mutation in NSD1, while six of the forty-five (13.3%) had a deletion. Most of the patients (62.2%, 28/45) were male, with a mean age of 14 ± 7 years (range 0.2–37 years). A total of 27/45 (60.0%) of the patients had heart defects, isolated or combined with other defects, including septal defects (12 patients), aortic anomalies (9 patients), mitral valve and/or tricuspid valve dysplasia/insufficiency (1 patient), patent ductus arteriosus (3 patients), left ventricular non-compaction/hypertrabeculated left ventricle (LV) (4 patients), aortic coarctation (1 patient), aortopulmonary window (1 patient), and pulmonary valve anomalies (3 patients). The prevalences of HD in the two subgroups (deletion versus intragenic mutation) were similar (66.7% (4/6) in the deletion group versus 58.91% (23/39) in the intragenic variant group). Our results showed a higher prevalence of HD in patients with Sotos syndrome in comparison to that described in the literature, with similar distributions of patients with mutated and deleted genes. An accurate and detailed echocardiogram should be performed in patients with Sotos syndrome at diagnosis, and a specific cardiological follow-up program is needed.

Monocytes are associated with human cardiovascular disease progression. Monocytes are segregated into three major subsets: classical (cMo), intermediate (iMo), and nonclassical (nMo). Recent studies have identified heterogeneity within each of these main monocyte classes, yet the extent to which these subsets contribute to heart disease progression is not known. Peripheral blood mononuclear cells (PBMC) were obtained from 61 human subjects within the Coronary Assessment of Virginia (CAVA) Cohort. Coronary atherosclerosis severity was quantified using the Gensini Score (GS). We employed high-dimensional single-cell transcriptome and protein methods to define how human monocytes differ in subjects with low to severe coronary artery disease. We analyzed 487 immune-related genes and 49 surface proteins at the single-cell level using Antibody-Seq (Ab-Seq). We identified six subsets of myeloid cells (cMo, iMo, nMo, plasmacytoid DC, classical DC, and DC3) at the single-cell level based on surface proteins, and we associated these subsets with coronary artery disease (CAD) incidence based on Gensini score (GS) in each subject. Only frequencies of iMo were associated with high CAD (GS > 32), adj.p = 0.024. Spearman correlation analysis with GS from each subject revealed a positive correlation with iMo frequencies (r = 0.314, p = 0.014) and further showed a robust sex-dependent positive correlation in female subjects (r = 0.663, p = 0.004). cMo frequencies did not correlate with CAD severity. Key gene pathways differed in iMo among low and high CAD subjects and between males and females. Further single-cell analysis of iMo revealed three iMo subsets in human PBMC, distinguished by the expression of HLA-DR, CXCR3, and CD206. We found that the frequency of immunoregulatory iMo_HLA-DR+CXCR3+CD206+ was associated with CAD severity (adj.p = 0.006). The immunoregulatory iMo subset positively correlated with GS in both females (r = 0.660, p = 0.004) and males (r = 0.315, p = 0.037). Cell interaction analyses identified strong interactions of iMo with CD4+ effector/memory T cells and Tregs from the same subjects. This study shows the importance of iMo in CAD progression and suggests that iMo may have important functional roles in modulating CAD risk, particularly among females.

Whilst there has been significant public health benefits associated with global use of COVID-19 spike protein vaccines, potential serious adverse events following immunization have been reported. Acute myocarditis is a rare complication of COVID19 vaccines and often it is self-limiting. We describe two cases experiencing recurrent myocarditis following mRNA COVID-19 vaccine despite a prior episode with full clinical recovery. Between September 2021-September 2022 we observed two male adolescents with recurrent myocarditis related to mRNA-based-COVID19 vaccine. During the first episode both patients presented with fever and chest pain few days after their second dose of BNT162b2 mRNA Covid-19 Vaccine (Comirnaty®). The blood exams showed increased cardiac enzymes. In addition, complete viral panel was run, showing HHV7 positivity in a single case. The left ventricular ejection fraction (LVEF) was normal at echocardiogram but cardiac magnetic resonance scanning (CMR) was consistent with myocarditis. They were treated with supportive treatment with full recovery. The 6 months follow-up demonstrated good clinical conditions with normal cardiological findings. The CMR showed persistent lesions in left ventricle ‘s wall with LGE. After some months the patients presented at emergency department with fever and chest pain and increased cardiac enzymes. No decreased LVEF was observed. The CMR showed new focal areas of edema in the first case report and stable lesions in the second one. They reached full recovery with normalization of cardiac enzymes after few days. These case reports outline the need of strict follow-up in patients with CMR consistent with myocarditis after mRNA-based-COVID19 vaccine. More efforts are necessary to depict the underlying mechanisms of myocarditis after SARS-CoV2 vaccination to understand the risk of relapsing and the long-term sequelae.

BackgroundMonoallelic and biallelic TTN truncating variants (TTNtv) may be responsible for a wide spectrum of musculoskeletal and cardiac disorders with different age at onset. Although the prevalence of heterozygous TTNtv is relatively high in the general population, cardiac phenotyping (mainly cardiomyopathies, CMPs) in biallelic titinopathy has rarely been described in children.MethodsWe reviewed the medical records of pediatric patients with biallelic TTNtv and cardiac involvement. Clinical exome sequencing excluded pathogenic/likely pathogenic variants in major CMP genes.ResultsFive pediatric patients (four male) with biallelic TTNtv were included. Major arthrogryposis multiplex was observed in four patients; no patient showed intellectual disability. At a cardiac level, congenital heart defects (atrial and ventricular septal defects, n = 3) and left ventricular non-compaction (n = 1) were reported. All patients had dilated cardiomyopathy (DCM) diagnosed at birth in one patient and at the age of 10, 13, 14, and 17 years in the other four patients. Heart rhythm monitoring showed tachyarrhythmias (premature ventricular contractions, n = 2; non-sustained ventricular tachycardia, n = 2) and nocturnal first-degree atrio-ventricular block (n = 2). Cardiac magnetic resonance (CMR) imaging was performed in all patients and revealed a peculiar late gadolinium enhancement distribution in three patients. HyperCKemia was present in two patients and end-stage heart failure in four. End-organ damage requiring heart transplantation (HT) was indicated in two patients, who were operated on successfully.ConclusionBiallelic TTNtv should be considered when evaluating children with severe and early-onset DCM, particularly if skeletal and muscular abnormalities are present, e.g., arthrogryposis multiplex and congenital progressive myopathy. End-stage heart failure is common and may require HT.

Pediatric cardiomyopathies (CMs) and electrical diseases constitute a heterogeneous spectrum of disorders distinguished by structural and electrical abnormalities in the heart muscle, attributed to a genetic variant. They rank among the main causes of morbidity and mortality in the pediatric population, with an annual incidence of 1.1–1.5 per 100,000 in children under the age of 18. The most common conditions are dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Despite great enthusiasm for research in this field, studies in this population are still limited, and the management and treatment often follow adult recommendations, which have significantly more data on treatment benefits. Although adult and pediatric cardiac diseases share similar morphological and clinical manifestations, their outcomes significantly differ. This review summarizes the latest evidence on genetics, clinical characteristics, management, and updated outcomes of primary pediatric CMs and electrical diseases, including DCM, HCM, arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS), and short QT syndrome (SQTS).

Abstract Background Congenital heart disease (CHD) is the most common congenital anomaly at birth, affecting approximately 1% of live births. In recent decades great medical and surgical advances have significantly increased life expectancy, shifting healthcare professionals' and researchers’ interests in patients' Quality of Life (QoL). The main aims of our study were to evaluate generic and condition-specific QoL in a group of Italian children and adolescents with CHD and their parents and examine the level of agreement and directional disagreement between child/adolescent and parents reports on generic and condition-specific QoL. Methods A cross-sectional study was designed with CHD children and adolescents and their parents referred to the Cardiology Department of “Bambino Gesù” Children’s Hospital. The PedsQL scale was used, including generic (PedsQL 4.0) and cardiac-specific modules (PedsQL 3.0) were administered to patients and caregivers. A Kruskal–Wallis test was used to compare generic and cardiac module scores between patients with different ages, CHD diagnoses, and between patients who underwent surgery interventions and/or are currently taking cardiac medications. Results 498 families were enrolled in this study. On average, patients reported a good level of generic and condition-specific QoL, as well as their mothers and fathers. Children aged between 5–7 years old reported lower generic and cardiac-specific total QoL levels than children aged 8–12 years and adolescents (13–18 years). With regard to the agreement, patient-parent agreement on condition-specific QoL ranged from 25 to 75% while on generic QoL, it ranged from 19 to 76%. The highest percentage of disagreement between parents and children was found in patients aged 5–7 years old, both for condition-specific and generic QoL rates. Conclusions Our study contributed to the growing body of knowledge on QoL in CHD, emphasizing the need for these families to receive support from multidisciplinary standardized care, including psychological consultations and support.

Double-outlet left ventricle (DOLV) is an abnormal ventriculo-arterial connection characterized by the origin of both great arteries from the morphological left ventricle. The aim of our paper is to describe the morphological and imaging features of DOLV and to assess the prevalence of the associated malformations and their surgical outcomes. METHODS From 2011 to 2022, we retrospectively reviewed the electronic case records of patients diagnosed with DOLV at the Bambino Gesu Children’s Hospital. A systematic search was developed in MEDLINE, Web of Science, and EMBASE databases to identify reports assessing the morphology and outcomes of DOLV between 1975 and 2023. RESULTS: Over a median follow-up of 9.9 years (IQR 7.8–11.7 y), four cases of DOLV were identified at our institution. Two patients were diagnosed with (S,D,D) DOLV subaortic VSD and pulmonary stenosis (PS): one patient had (S,D,D) DOLV with doubly committed VSD and hypoplastic right ventricle, and another patient had (S,D,L) DOLV with subaortic VSD and PS (malposition type). Pulmonary stenosis was the most commonly associated lesion (75%). LITERATURE REVIEW: After systematic evaluation, a total of 12 reports fulfilled the eligibility criteria and were included in our analysis. PS or right ventricular outflow tract obstruction was the most commonly associated lesion (69%, 95% CI 62–76%). The most common locations of VSD were subaortic (pooled prevalence: 75%, 95% CI 68–81), subpulmonary (15%, 95% CI 10–21), and doubly committed (7%, 95% CI 4–12). The position of the great arteries showed that d-transposition of the aorta was present in 128 cases (59% 95% CI 42–74), and l-transposition was present in 77 cases (35%, 95% CI 29–43).

Abstract 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

Introduction: An elevated heart rate is associated with an increased risk of death or cardiac transplant in children with dilated cardiomyopathy (DCM). Whether heart rate is a clinical marker to address therapy, is poorly investigated in children.Aim: To investigate the relationship between heart rate reduction (HRR) and left ventricular ejection fraction (LVEF) in DCM, treated with carvedilol.Methods: This is a multi center retrospective analysis conducted on all children with DCM (aged 20% correlated with an improvement in LVEF >13%. At 3 years follow up, HRR demonstrated a significant reduction of LVESd (R2 = 0.1, p = 0.003) LVEDd (R2 = 0.07, p = 0.008) and LVEF recovery up to 15% (p < 0.0001). No deaths or heart transplant occurred during follow-up.Conclusion: This study demonstrates that HRR is safe and improvement in LVEF is related to the degree of HRR. The magnitude of LVEF improvement was enhanced by a major reduction in HR. It provides evidence that HRR could be used as a clinical marker to treat HF in children.

Background: Advances in the medical-surgical field have significantly increased the life expectancy of patients undergoing solid organ transplantation but this exposes patients to long-term complications due to chronic therapies and changes in lifestyle. It is known that children affected by pathology tend to be more sedentary and inactivity represents a further risk factor for the onset of non-communicable diseases. The aim of the present study was to compare the lifestyle of two groups of young patients: one group of healthy subjects (HG) and one group of kidney or liver transplant recipients (TG). Methods: Patients were asked to complete Physical Activity Questionnaire for Older Children (PAQ-C). Results: A total of 104 subjects were recruited (50.9% male, mean age 12.8 ± 3.16 years old). No significant differences were observed in the final score between groups when comparing subjects based on health condition (Healthy 2.69 ± 0.65 vs. Transplant Group 2.42 ± 0.88), the intensity of sports activities (Competitive 2.82 ± 0.59 vs. Not Competitive 2.53 ± 0.7) or type of transplant (Liver 2.51 ± 0.91 vs. Kidney 2.16 ± 0.75). Conclusion: The results of this study showed a worrying reality: children are engaged in low levels of physical activity regardless of their health status and in general the level of activity does not reach the recommended values even in the absence of contraindications. So, it is necessary to encourage healthy children to practice more PA and to introduce PA prescriptions for transplanted children to prevent their health from deteriorating due to sedentariness.

Abstract Aims Cardiomyopathies are a heterogeneous group of disorders that increase the risk for atrial fibrillation (AF). The aim of the study is to assess the prevalence of AF, anticoagulation management, and risk of stroke/transient ischaemic attack (TIA) in patients with cardiomyopathy. Methods and results Three thousand two hundred eight consecutive adult patients with cardiomyopathy (34.9% female; median age: 55.0 years) were prospectively enrolled as part of the EURObservational Research Programme Cardiomyopathy/Myocarditis Registry. At baseline, 903 (28.2%) patients had AF (29.4% dilated, 27.5% hypertrophic, 51.5% restrictive, and 14.7% arrhythmogenic right ventricular cardiomyopathy, P

BackgroundCarvedilol is recommended for chronic heart failure (HF) treatment in children. However, the ideal dosage and administration are not standardized, and data on its long-term effects are lacking. This study aimed to assess the effect of a high dosage regimen of carvedilol on cardiac outcomes in children with HF.MethodsWe conducted a retrospective cohort study including all children with HF and dilated cardiomyopathy. We analyzed medical records before starting treatment, at 1 and 3 years after reaching the maximum therapeutic dosage. All data were compared with a historical control group. Kaplan–Meier analysis and Cox proportional hazard regression have been used to evaluate the effect of high dosage carvedilol therapy. The main outcome was a composite of all-cause mortality and heart transplant.ResultsOne hundred thirty-five were included in the study and 65 treated with a high dosage of carvedilol regimen (up to 1 mg/kg/day). Heart rate reduction (mean reduction 30%, p < 0.0001) and ejection fraction improvement (32 ± 9.4 vs. 45. ± 10.1%, p < 0.0001) were statistically significant in those. Long-term survival and freedom from heart transplant were significantly improved in those treated with high dosage carvedilol therapy (p = 0.00001).ConclusionsTreatment with the high dosage of carvedilol, in addition to standard HF therapy, significantly improves ventricular function and survival in children with dilated cardiomyopathy and chronic HF.

Abstract Background Approximately 66% of children under the age of 5 in Sub-Saharan African countries do not reach their full cognitive potential, the highest percentage in the world. Because the majority of studies investigating child cognitive development have been conducted in high-income countries (HICs), there is limited knowledge regarding the determinants of child development in low- and middle-income countries (LMICs). Methods This analysis includes 401 mother-child dyads from the South Africa and Tanzania sites of the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) longitudinal birth cohort study. We investigated the effect of psychosocial and environmental determinants on child cognitive development measured by the Wechsler Preschool Primary Scales of Intelligence (WPPSI) at 5 years of age using multivariable linear regression. Results Socioeconomic status was most strongly associated with child cognitive development (WPSSI Score Difference (SD):14.27, 95% CI:1.96, 26.59). Modest associations between the organization of the home environment and its opportunities for cognitive stimulation and child cognitive development were also found (SD: 3.08, 95% CI: 0.65, 5.52 and SD: 3.18, 95% CI: 0.59, 5.76, respectively). Conclusion This study shows a stronger association with child cognitive development at 5 years of age for socioeconomic status compared to more proximal measures of psychosocial and environmental determinants. A better understanding of the role of these factors is needed to inform interventions aiming to alleviate the burden of compromised cognitive development for children in LMICs.

MIS-C is a multisystem inflammatory syndrome that is characterized by multi-organ failure and cardiac involvement. The aim of this study was to describe the long-term cardiovascular outcome in a cohort of MIS-C pediatric patients, who were admitted to two Italian Pediatric Referral Centers. Sixty-seven patients (mean age 8.7 ± 4.7 years, male 60%) were included; 65 (97%) of them showed cardiac involvement. All of the patients completed one month of the follow-up, and 47% completed 1 year of it. ECG abnormalities were present in 65% of them, arrhythmias were present in 9% of them during an acute phase and it disappeared at the point of discharge or later. Pericarditis were detected in 66% of them and disappeared after 6 months. Coronaritis was observed in 35% of the children during an acute phase, and there were no more instances at the 1-year point. An LV dysfunction was present in 65% of the patients at the beginning of the study, with them having a full recovery at the point of discharge and thereafter. Elevated values of the NTproBNP and hsTp were initially detected, which progressively decreased and normalized at the points of discharge and FU. The CMR at the point of FU, there was a presence of long-term myocardial scars in 50% of the patients that were tested. No deaths that were caused by MIS-C during the FU were recorded. Cardiac involvement in MIS-C patients is almost the rule, but the patients’ clinical course was satisfactory, and no additional events or sequelae were observed apart from there being long-term myocardial scars in 50% of the patients that underwent CMR.

Filamin C is a protein specifically expressed in myocytes and cardiomyocytes and is involved in several biological functions, including sarcomere contractile activity, signaling, cellular adhesion, and repair. FLNC variants are associated with different disorders ranging from striated muscle (myofibrillar distal or proximal) myopathy to cardiomyopathies (CMPs) (restrictive, hypertrophic, and dilated), or both. The outcome depends on functional consequences of the detected variants, which result either in FLNC haploinsufficiency or in an aberrant protein, the latter affecting sarcomere structure leading to protein aggregates. Cardiac manifestations of filaminopathies are most often described as adult onset CMPs and limited reports are available in children or on other cardiac spectrums (congenital heart defects—CHDs, or arrhythmias). Here we report on 13 variants in 14 children (2.8%) out of 500 pediatric patients with early-onset different cardiac features ranging from CMP to arrhythmias and CHDs. In one patient, we identified a deletion encompassing FLNC detected by microarray, which was overlooked by next generation sequencing. We established a potential genotype–phenotype correlation of the p.Ala1186Val variant in severe and early-onset restrictive cardiomyopathy (RCM) associated with a limb-girdle defect (two new patients in addition to the five reported in the literature). Moreover, in three patients (21%), we identified a relatively frequent finding of long QT syndrome (LQTS) associated with RCM (n = 2) and a hypertrabeculated left ventricle (n = 1). RCM and LQTS in children might represent a specific red flag for FLNC variants. Further studies are warranted in pediatric cohorts to delineate potential expanding phenotypes related to FLNC.

Despite the decades-old knowledge that males and people with diabetes mellitus (DM) are at increased risk for coronary artery disease (CAD), the reasons for this association are only partially understood. Among the immune cells involved, recent evidence supports a critical role of T cells as drivers and modifiers of CAD. CD4+ T cells are commonly found in atherosclerotic plaques. We aimed to understand the relationship of CAD with sex and DM by single-cell RNA (scRNA-Seq) and antibody sequencing (CITE-Seq) of CD4+ T cells. Peripheral blood mononuclear cells (PBMCs) of 61 men and women who underwent cardiac catheterization were interrogated by scRNA-Seq combined with 49 surface markers (CITE-Seq). CAD severity was quantified using Gensini scores, with scores above 30 considered CAD+ and below 6 considered CAD−. Four pairs of groups were matched for clinical and demographic parameters. To test how sex and DM changed cell proportions and gene expression, we compared matched groups of men and women, as well as diabetic and non-diabetic subjects. We analyzed 41,782 single CD4+ T cell transcriptomes for sex differences in 16 women and 45 men with and without coronary artery disease and with and without DM. We identified 16 clusters in CD4+ T cells. The proportion of cells in CD4+ effector memory cluster 8 (CD4T8, CCR2+ Em) was significantly decreased in CAD+, especially among DM+ participants. This same cluster, CD4T8, was significantly decreased in female participants, along with two other CD4+ T cell clusters. In CD4+ T cells, 31 genes showed significant and coordinated upregulation in both CAD and DM. The DM gene signature was partially additive to the CAD gene signature. We conclude that (1) CAD and DM are clearly reflected in PBMC transcriptomes, and (2) significant differences exist between women and men and (3) between subjects with DM and non-DM.

Chemokine receptor-6 (CCR6) mediates immune cell recruitment to inflammatory sites and has cell type-specific effects on diet-induced atherosclerosis in mice. Previously we showed that loss of CCR6 in B cells resulted in loss of B cell-mediated atheroprotection, although the B cell subtype mediating this effect was unknown. Perivascular adipose tissue (PVAT) harbors high numbers of B cells including atheroprotective IgM secreting B-1 cells. Production of IgM antibodies is a major mechanism whereby B-1 cells limit atherosclerosis development. Yet whether CCR6 regulates B-1 cell number and production of IgM in the PVAT is unknown. In this present study, flow cytometry experiments demonstrated that both B-1 and B-2 cells express CCR6, albeit at a higher frequency in B-2 cells in both humans and mice. Nevertheless, B-2 cell numbers in peritoneal cavity (PerC), spleen, bone marrow and PVAT were no different in ApoE−/−CCR6−/− compared to ApoE−/−CCR6+/+ mice. In contrast, the numbers of atheroprotective IgM secreting B-1 cells were significantly lower in the PVAT of ApoE−/−CCR6−/− compared to ApoE−/−CCR6+/+ mice. Surprisingly, adoptive transfer (AT) of CD43− splenic B cells into B cell-deficient μMT−/−ApoE−/− mice repopulated the PerC with B-1 and B-2 cells and reduced atherosclerosis when transferred into ApoE−/−CCR6+/+sIgM−/− mice only when those cells expressed both CCR6 and sIgM. CCR6 expression on circulating human B cells in subjects with a high level of atherosclerosis in their coronary arteries was lower only in the putative human B-1 cells. These results provide evidence that B-1 cell CCR6 expression enhances B-1 cell number and IgM secretion in PVAT to provide atheroprotection in mice and suggest potential human relevance to our murine findings.

Arrhythmogenic cardiomyopathy (ACM) is a cardiomyopathy characterized by the occurrence of a high risk of life-threatening ventricular arrhythmias and sudden cardiac death even at presentation. Diagnosis, evolution and outcomes in adults have been extensively reported, but little data in pediatric population are available. Risk stratification in this particular setting is still a matter of debate and new risk factors are needed in a model of an ever more “individualized medicine”.

Lamin A/C (LMNA) encodes for two nuclear intermediate filament proteins. Mutations in LMNA cause a highly heterogeneous group of diseases predominantly leading to muscular or cardiac disease, lipodystrophy syndromes, peripheral neuropathy, and accelerated aging disorders. Cardiac involvement includes progressive arrhythmias (brady/tachyarrhythmias, sudden cardiac death). Furthermore, cardiomyocyte damage often progresses into dilated cardiomyopathy (DCM), rarely described in the pediatric age group. Neuromuscular manifestations are even rarer in children. We report on six pediatric patients with LMNA mutations: patient 1 was operated on for aortic coarctation, non-compact left ventricle, atrial fibrillation (AF) preceding the diagnosis of DCM; patient 2 was operated on for ventricular septal defect (VSD), developed after years malignant arrhythmias preceding the progression to DCM (left ventricular non-compaction with LV dysfunction); patient 3 had ectopic atrial tachycardia as first manifestation of a DCM; patients 4 and 5 had no major arrhythmic events but only dilated ascending aorta, mildly dilated LV with mild hypertrabeculation of the lateral wall and a normally functioning but dilated left ventricle, respectively; patient 6 showed aortic coarctation, supraventricular tachycardia. Paroxysmal AF occurred in patients 1, 2, and 3 (50% of cases). Our series highlight the coexistence of congenital heart defects (CHDs) and aortic involvement with laminopathies in four of our patients: consisting of aortic coarctation (two patients), aortic root dilatation (one patient), and VSD (one patient). Aortic changes in laminopathies have been reported only once in an adult patient. This is the first report in the pediatric setting, and no associations with CHD have been previously described.

Patients with repaired Tetralogy of Fallot (rToF) typically report having preserved subjective exercise tolerance. Chronic pulmonary regurgitation (PR) with varying degrees of right ventricular (RV) dilation as assessed by cardiac magnetic resonance imaging (MRI) is prevalent in rToF and may contribute to clinical compromise. Cardiopulmonary exercise testing (CPET) provides an objective assessment of functional capacity, and the International Physical Activity Questionnaire (IPAQ) can provide additional data on physical activity (PA) achieved. Our aim was to assess the association between CPET values, IPAQ measures, and MRI parameters. All rToF patients who had both an MRI and CPET performed within one year between March 2019 and June 2021 were selected. Clinical data were extracted from electronic records (including demographic, surgical history, New York Heart Association (NYHA) functional class, QRS duration, arrhythmia, MRI parameters, and CPET data). PA level, based on the IPAQ, was assessed at the time of CPET. Eighty-four patients (22.8 ± 8.4 years) showed a reduction in exercise capacity (median peak VO2 30 mL/kg/min (range 25–33); median percent predicted peak VO2 68% (range 61–78)). Peak VO2, correlated with biventricular stroke volumes (RVSV: β = 6.11 (95%CI, 2.38 to 9.85), p = 0.002; LVSV: β = 15.69 (95% CI 10.16 to 21.21), p < 0.0001) and LVEDVi (β = 8.74 (95%CI, 0.66 to 16.83), p = 0.04) on multivariate analysis adjusted for age, gender, and PA level. Other parameters which correlated with stroke volumes included oxygen uptake efficiency slope (OUES) (RVSV: β = 6.88 (95%CI, 1.93 to 11.84), p = 0.008; LVSV: β = 17.86 (95% CI 10.31 to 25.42), p < 0.0001) and peak O2 pulse (RVSV: β = 0.03 (95%CI, 0.01 to 0.05), p = 0.007; LVSV: β = 0.08 (95% CI 0.05 to 0.11), p < 0.0001). On multivariate analysis adjusted for age and gender, PA level correlated significantly with peak VO2/kg (β = 0.02, 95% CI 0.003 to 0.04; p = 0.019). We observed a reduction in objective exercise tolerance in rToF patients. Biventricular stroke volumes and LVEDVi were associated with peak VO2 irrespective of RV size. OUES and peak O2 pulse were also associated with biventricular stroke volumes. While PA level was associated with peak VO2, the incremental value of this parameter should be the focus of future studies.

Background: Pediatric patients with cardiomyopathies are at risk of malignant arrhythmias and sudden cardiac death (SCD). An ICD may prevent SCD. The aim of this study was to evaluate ICD implantation outcomes, and to compare transvenous and subcutaneous ICDs (S-ICDs) implanted in pediatric patients with cardiomyopathies. Methods: The study is single center and retrospective, and includes pediatric patients with cardiomyopathies who required ICD implantation (2010–2021). Outcomes were recorded for appropriate/inappropriate ICD therapy and surgical complications. Transvenous ICD and S-ICD were compared. Data are presented as median values (25th–75th centiles). Results: Forty-four patients with cardiomyopathies (hypertrophic 39%, arrhythmogenic 32%, dilated 27%, and restrictive 2%) underwent transvenous (52%) and S-ICD (48%) implantation at 14 (12–17) years of age, mostly for primary prevention (73%). The follow-up period was 29 (14–60) months. Appropriate ICD therapies were delivered in 25% of patients, without defibrillation failures. Lower age at implantation and secondary prevention were significant risk factors for malignant ventricular arrhythmias that required appropriate ICD therapies. ICD-related complications were surgical complications (18%) and inappropriate shocks (7%). No significant differences in outcomes were recorded, either when comparing transvenous and S-ICD or comparing the different cardiomyopathies. Conclusions: In pediatric patients with cardiomyopathy, ICD therapy is effective, with a low rate of inappropriate shocks. Neither ICD type (transvenous and S-ICDs) nor the cardiomyopathies subgroup revealed divergent outcomes.

Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely heterogenous. These two factors play a major role in the difficulties of establishing standard diagnostic and therapeutic protocols. Isolated CMP in children is a frequent finding, mainly caused by sarcomeric gene variants with a detection rate that can reach up to 50% of analyzed cohorts. Complex multisystemic forms of pediatric CMP are even more heterogenous. Few studies in literature take into consideration this topic as the main core since it represents a rarity (systemic CMP) within a rarity (pediatric population CMP). Identifying etiology in this cohort is essential for understanding prognosis, risk stratification, eligibility to heart transplantation and/or mechanical-assisted procedures, preventing multiorgan complications, and relatives’ recurrence risk calculation. The previous points represent a cornerstone in patients’ empowerment and personalized medical care approach. The aim of this work is to propose a new approach for an algorithm in the setting of the diagnostic framework of systemic pediatric CMP. On the other hand, during the literature review, we noticed a relatively common etiologic pattern in some forms of complex/multisystem CMP. In other words, certain syndromes such as Danon, Vici, Alström, Barth, and Myhre syndrome share a common pathway of directly or indirectly defective “autophagy” process, which appears to be a possible initiating/triggering factor for CMPs. This conjoint aspect could be important for possible prognostic/therapeutic implications in this category of patients. However, multicentric studies detailed functional and experimental models are needed prior to deriving conclusions.

Background: Remote monitoring-enabled insertable cardiac monitors (ICMs) are useful tools for arrhythmias and symptom management. This study sought to evaluate the outcome of ICM implantation in a large, heterogeneous cohort of pediatric and young adult patients. Methods: Single centre, retrospective analysis of patients who underwent ICM implantation in 2010–2019. Patients were analysed according to age, symptoms, arrhythmias and underlying heart disease. Results: A total of 200 consecutive patients (58% male), aged 11.5 ± 5.8 years at ICM implantation, were included. Follow-up was 31 ± 18 months. Electrophysiologic study (EPS) was initially performed in 123 patients and was negative in 85%. Patients had no heart disease (57.5%), congenital heart defects (21%), channelopathies (14.5%), cardiomyopathies/heart tumors (8%). The commonest symptoms were syncope/presyncope (45.5%) and palpitations (12.5%). A definite diagnosis was made in 63% of patients (positive diagnosis in 25%, negative in 38%) after 8 (2–19) months of monitoring. EPS results and the presence/absence of an arrhythmia before ICM implantation had no impact on the diagnostic yield. Symptomatic patients as well as patients without structural heart disease showed higher diagnostic yield. Patients with a positive diagnosis underwent pacemaker/implantable cardioverter-defibrillator implantation (13%), pharmacological treatment (10.5%), or catheter ablation (1.5%). Conclusions: In a large cohort of 200 children and young adults, ICMs with remote monitoring showed a high diagnostic yield (63%), especially in symptomatic patients and in patients without structural heart disease.

Abstract Background Loeys-Dietz syndrome (LDS) is a rare multisystemic disorder characterized by vascular and skeletal abnormalities, with considerable intra- and interfamilial variability. Case presentation We report the case of an 8-year-old male with clinical features of two distinct genetic disorders, namely LDS, manifesting in the first months by progressive aortic root dilatation, arterial tortuosity, bifid uvula, and inguinal hernias and oculocutaneous albinism (OCA) manifesting by white hair and skin that does not tan, nystagmus, reduced iris pigment with iris translucency, and reduced retinal pigment). We identified previously reported, homozygous mutations of TYR, c.1A > G (p.Met1Val) and heterozygous, missense mutation of TGFBR1, c.1460G > A (p.Arg487Gln). Family history revealed that his mother underwent multiple surgical repairs for recurrent hemorrhage originating from the buccal artery. Molecular studies confirmed a maternally inherited low grade TGFBR1 mutation somatic mosaicism (18% in peripheral blood leukocytes, 18% in buccal cells and 10% in hair root cells). Maternal cardiac investigations revealed peculiar cardiovascular features: mild tortuosity at the aortic arch, dilatation of the proximal abdominal aorta, multiple deep left ventricular myocardial crypts, and dysplastic mitral valve. TGFBR2 germline mosaicism has been described in three fathers of children carrying TGFBR2 mutations but, to the best of our knowledge, no case of maternally inherited TGFBR1 mutation mosaicism has been reported so far. Conclusions This case report suggests that individuals with somatic mosaicism might be at risk for mild and unusual forms of LDS but germline mosaicism can lead to full blown picture of the disease in offspring.

Premature ventricular contractions (PVCs) are common and generally benign in childhood and tend to resolve spontaneously in most cases. When PVCs occur frequently, an arrhythmia-induced cardiomyopathy may be present requiring medical or catheter ablation. PVCs are only rarely the manifestation of a cardiomyopathy. The purpose of this review is to provide some tips and tricks to raise the suspicion of a cardiac disease based on the presence and characteristics of PVCs in children.

Background: Monosomy 1p36 syndrome is now considered the most common terminal deletion syndrome, with an estimated incidence of 1 in 5000. Cardiac involvement is well described in the literature mainly in terms of congenital heart defects (CHDs) and cardiomyopathies (CMPs). Few data in the literature describe the potential progressive nature of aortic dilatation (root and ascending aorta) in 1p36 deletion syndrome. SKI harboured in the deleted region might play a predisposing factor for this aspect. Methods: we reviewed the aortic aspect both in the literature and in our cohort, where major attention to the aortic abnormalities was given through dedicated echocardiographic measurements even in previously screened individuals. Results: aortic involvement in 1p36 deletion syndrome was described in the literature three times within the CHD context. We observed three additional patients from our cohort (three out of nine patients) with aortic dilatation. All patients with dilated aorta had SKI haploinsufficiency within the deleted region. Conclusions: at long-term outcome and with a growing population of this rare disease, this association (1p36 deletion and aortic dilatation) might represent a major concern especially in terms of risk stratification and the potential need for specific management (conservative pharmacologic and eventually surgical) whenever indicated. The present study suggests the need for detailed multicentric studies and indication to periodic echocardiographic screening in addition to baseline tests, especially in individuals with deletions harbouring SKI.

Neuromuscular disorders (NMDs) are highly heterogenous from both an etiological and clinical point of view. Their signs and symptoms are often multisystemic, with frequent cardiac involvement. In fact, childhood onset forms can predispose a person to various progressive cardiac abnormalities including cardiomyopathies (CMPs), valvulopathies, atrioventricular conduction defects (AVCD), supraventricular tachycardia (SVT) and ventricular arrhythmias (VA). In this review, we selected and described five specific NMDs: Friedreich’s Ataxia (FRDA), congenital and childhood forms of Myotonic Dystrophy type 1 (DM1), Kearns Sayre Syndrome (KSS), Ryanodine receptor type 1-related myopathies (RYR1-RM) and Laminopathies. These changes are widely investigated in adults but less researched in children. We focused on these specific topics due their relative frequency and their potential unexpected cardiac manifestations in children. Moreover these conditions present different inheritance patterns and mechanisms of action. We decided not to discuss Duchenne and Becker muscular dystrophies due to extensive work regarding the cardiac aspects in children. For each described NMD, we focused on the possible cardiac manifestations such as different types of CMPs (dilated-DCM, hypertrophic-HCM, restrictive-RCM or left ventricular non compaction-LVNC), structural heart abnormalities (including valvulopathies), and progressive heart rhythm changes (AVCD, SVT, VA). We describe the current management strategies for these conditions. We underline the importance, especially for children, of a serial multidisciplinary personalized approach and the need for periodic surveillance by a dedicated heart team. This is largely due to the fact that in children, the diagnosis of certain NMDs might be overlooked and the cardiac aspect can provide signs of their presence even prior to overt neurological diagnosis.

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

Background: Global cardiovascular adaptation of normal healthy term newborns is rarely studied from a multiorgan and hematological point of view. Aims: To evaluate comprehensive neonatal cardiovascular adaptation during the first days of life with echocardiography and renal-cerebral echo color-Doppler and to correlate it with hematocrit (Ht) changes. Study design: A prospective observational study was conducted on 35 healthy term neonates with a mean ± SD gestational age and birth weight of 39.5 ± 1.1 weeks and 3,400 ± 330 g, respectively. All infants underwent serial echocardiograms at 15 ± 4 hours (day 1) and 72 ± 4 hours (day 3) of age. At the same time, cerebral and renal Doppler parameters were acquired and Ht was sampled. Results: The weight and Ht declined by 220 g (189-251) and 8.1% (6.7-9.5), respectively. Systolic and diastolic diameters of the right ventricle and diastolic left ventricle posterior wall thickness showed a reduction, while the diastolic diameter of the left ventricle showed a small increase. The Doppler cardiac evaluation showed an increase in the mitral E/A ratio and pulmonary acceleration time, a reduction of late transmitral flow peak velocity, aortic peak systolic velocity (PSV), aortic peak systolic pressure gradient, aortic velocity-time integral, aortic mean pressure gradient and pulmonary mean acceleration. We also found a reduction of cerebral resistance parameters and an increase in PSV, end-diastolic velocity, and time-averaged velocity. Other measured parameters remained unchanged. Conclusion: Systemic cardiovascular evaluation about changes in Ht is an essential approach to study newborns, especially during the first days of life when Ht shows a significant decrease. Knowledge of the laws of physics related to the effect of Ht changes on vascular parameters is another important factor in understanding the pathophysiology of neonatal disease states. Further studies are useful to help physicians make evidence-based decisions in the management of newborns in Neonatal Intensive Care Units (NICUs).

INTRODUCTION AND HYPOTHESIS:Patients with 22q11 deletion syndrome (22q11.2DS) present, in about 75% of cases, typical patterns of cardiac defects, with a particular involvement on the ventricular outflow tract and great arteries. However, in this genetic condition the dimensions of the pulmonary arteries (PAs) never were specifically evaluated. We measured both PAs diameter in patients with 22q11.2DS without cardiac defects, comparing these data to a normal control group. Moreover, we measured the PAs diameter in Tbx1 mutant mice. Finally, a cell fate mapping in Tbx1 mutants was used to study the expression of this gene in the morphogenesis of PAs. METHODS:We evaluated 58 patients with 22q11.2DS without cardiac defects. The control group consisted of 54 healthy subjects, matched for age and sex. All cases underwent a complete transthoracic echocardiography. Moreover, we crossed Tbx1+/- mice and harvested fetuses. We examined the cardiovascular phenotype of 8 wild type (WT), 37 heterozygous (Tbx1+/-) and 6 null fetuses (Tbx1-/-). Finally, we crossed Tbx1Cre/+mice with R26RmT-mG Cre reporter mice to study Tbx1 expression in the pulmonary arteries. RESULTS:The echocardiographic study showed that the mean of the LPA/RPA ratio in 22q11.2DS was smaller (0.80 ± 0.12) than in controls (0.97 ± 0.08; p < 0.0001). Mouse studies resulted in similar data as the size of LPA and RPA was not significantly different in WT embryos, but in Tbx1+/- and Tbx1-/- embryos the LPA was significantly smaller than the RPA in both mutants (P = 0.0016 and 0.0043, respectively). We found that Tbx1 is expressed near the origin of the PAs and in their adventitia. CONCLUSIONS:Children with 22q11.2DS without cardiac defects show smaller LPA compared with healthy subjects. Mouse studies suggest that this anomaly is due to haploinsufficiency of Tbx1. These data may be useful in the clinical management of children with 22q11.2DS and should guide further experimental studies as to the mechanisms underlying PAs development.