Fen Li

Objective: To explore the efficacy and safety of dapagliflozin therapy in children with heart failure with reduced ejection fraction. Methods: This was a retrospective cohort study based on electronic medical records. For the retrospective cohort study, 32 children with heart failure with reduced ejection fraction diagnosed at Shanghai Children's Medical Center and Fujian Children's Hospital from June 2021 to June 2023 and who were treated with dapagliflozin were enrolled. For pediatric patients weighing weight ≥10 kg) received dapagliflozin at a dose of 2.5 mg/d. Those weighing between 20 kg and less than 30 kg (30 > weight ≥20 kg) were prescribed dapagliflozin at 5 mg/d. For patients weighing 30 kg or more, the initial dose of dapagliflozin was 5 mg/d, which was increased to 10 mg/d after one month. 42 children treated during the same period without dapagliflozin were included as the control group. All children were treated with standard guideline-directed triple combination of ACEI/ARNI, β -blocker, and aldosterone receptor antagonist. Clinical characteristics, underlying diseases, cardiac function ratings, left ventricular ejection fraction, B-type natriuretic peptide, and blood biochemical indexes were collected. Changes in cardiac function ratings, left ventricular ejection fraction, and B-type natriuretic peptide at 24 (±2) weeks of treatment were observed; the incidence of hospitalization or death due to exacerbation of heart failure at 24 (±2) weeks of treatment was observed secondarily. Adverse medicine events such as hypoglycemia or hypotension were also observed during treatment. Results: Among the 32 children, 20 were male and 12 were female, aged (6.32 ± 4.00) years; weight (22.19 ± 12.66) kg. The underlying diseases included dilated cardiomyopathy in 25 cases, dilated cardiomyopathy combined with complete left bundle branch block in two cases, postoperative congenital heart disease in four cases, and atrial tachycardia in one case. At 24 (±2) weeks of treatment, left ventricular ejection fraction level significantly increased compared with baseline ( P < 0.001); B-type natriuretic peptide decreased ( P < 0.001); and New York Heart Association (NYHA) cardiac function ratings improved significantly ( P = 0.034). Compared with the control group, children in the dapagliflozin group showed greater improvement in left ventricular ejection fraction ( P = 0.032) and NYHA cardiac function rating ( P = 0.038), whereas no significant difference was observed in BNP levels ( P = 0.071). Three children developed urinary tract infection during the administration of the medication, and three children developed hypotension, while no other adverse reactions, such as hypoglycemia or hepatic or renal function impairment, were observed. Conclusion: Dapagliflozin was associated with improvements in left ventricular ejection fraction, BNP, and NYHA cardiac function classification in children with heart failure with reduced ejection fraction. No hospitalization or death due to the deterioration of heart failure and no serious adverse reactions were observed. The treatment was generally well tolerated, and the weight-stratified dosing strategy showed acceptable short-term safety.

BACKGROUND: A sustained dosage of VEGFA (vascular endothelial growth factor A) is crucial for angiogenesis in both homeostasis and cardiovascular diseases. Start codon CUG-initiated alternative translation is a conserved mechanism for producing mature VEGFA. Genetic surveys have identified stop-gained variants predicted to prematurely terminate CUG-initiated translation without affecting start codon ATG-initiated translation. However, the impacts of these variants on the vasculature in steady-state and disease conditions remain unknown. METHODS: Using CRISPR/Cas9 genome editing, we established the Vegfa ^Q150X/Q150 allele (Q150X), a mouse genetic model that mimics the human VEGFA stop-gained variant. The effects of this variant were tested in both adult homeostatic conditions and the acute myocardial infarction (MI) model. We analyzed and quantified cardiac vasculature structure using immunofluorescence and light-sheet imaging. Furthermore, we characterized cellular heterogeneity, cell-cell interactions, and gene regulation using single-nucleus RNA sequencing, as well as cell type-specific transcriptomics and epigenomics. RESULTS: Homozygous mice carrying the stop-gained variant were viable. VEGFA dosage was reduced to 70% in the Q150X homeostatic heart, with no significant alteration in cardiac function or vasculature. In the MI model, VEGFA dosage in Q150X was reduced to about 40% within the first week post-infarction, leading to functional deterioration in the post-MI hearts. Significant changes in cellular composition were observed 3 days post-MI. In particular, endothelial cells in Q150X diverged into a state that showed a higher level of hypoxia stress, an elevated inflammatory response, and increased extracellular matrix secretion. In addition, we observed an increase in Nppb ⁺ stressed cardiomyocytes in both 3 days post-MI and homeostasis. Finally, proinflammatory macrophages, neutrophils, and Cd8 ⁺ T cells were enriched in the ischemic zone of Q150X hearts. CONCLUSIONS: CUG-initiated translation contributes significantly to the production of mature VEGFA in ischemic hearts. VEGFA dosage is critical in determining the cellular microenvironment during ischemic injury.

Background: Transcatheter closure of perimembranous ventricular septal defects in children is a highly effective procedure, but it can result in tricuspid regurgitation (TR). The associated risk factors and long‐term outcomes of TR following the procedure are not well understood. METHODS AND RESULTS: This retrospective study included 1343 pediatric patients (age, 4.41±2.56 years) who underwent successful transcatheter perimembranous ventricular septal defect closure between 2002 and 2022, with a median follow‐up of 78 (range, 12–244) months. TR was evaluated using echocardiography, and multivariate logistic regression was performed to identify independent risk factors of postprocedural TR. Postprocedural TR occurred in 12.1% of patients, including 143 new‐onset cases and 20 with progressed preexisting TR. The majority of cases (86.5%) were mild, while 20 were moderate, and 2 were severe requiring surgical intervention. Most TR cases (84%) developed within 24 hours after the procedure. A higher right disc diameter‐to‐body weight ratio was identified as an independent risk factor of TR (odds ratio, 2.816 [95% CI, 1.315–6.032]). During follow‐up, 71.8% of TR cases improved or resolved, though moderate TR persisted in 7 cases, and 1 progressed to severe TR requiring surgery 2 years after the procedure. Conclusions: TR following perimembranous ventricular septal defect closure is common but typically mild and often resolves over time. A larger right disc diameter relative to body weight significantly increases the risk of TR, emphasizing the importance of careful device sizing, particularly in lighter patients. Long‐term follow‐up is crucial to detect potential late progression of TR.

Viral myocarditis (MC) is caused by Coxsackie virus B3 (CVB3)-induced cardiomyocyte apoptosis and inflammation, and changes in miRNA and lncRNA are linked to cardiac remodeling. The long non-coding RNA XIST (XIST) has been identified as a regulator in various pathological processes in heart diseases, but its role in CVB3-induced MC is not well understood. This research aimed to evaluate the impact that XIST has on CVB3-induced MC as well as the mechanism behind this effect. XIST expression in CVB3-exposed H9c2 cells (H9c2 cells) was evaluated by qRT-PCR. In CVB3-exposed H9c2 cells, reactive oxygen species production, inflammatory mediators, and apoptosis were experimentally observed. An investigation into and confirmation of the existence of an interaction involving XIST, miR-140-3p, and RIPK1 were carried out. The findings showed that CVB3 induced upregulation of XIST in H9c2 cells. However, XIST knockdown reduced oxidative stress, inflammation, and apoptosis of CVB3-exposed H9c2 cells. XIST was specifically bound to miR-140-3p, and there was mutual negative regulation between the two. Moreover, XIST downregulated RIPK1, which was mediated by miR-140-3p. The study suggests that downregulating XIST can alleviate inflammatory injury in CVB3-exposed H9c2 cells through the miR-140-3p/RIPK1 axis. These findings provide novel insights into the underlying mechanisms of MC.

This study investigated the efficacy of ivabradine monotherapy in pediatric patients with focal atrial tachycardia (FAT). We prospectively enrolled 12 pediatric patients (7.5 ± 4.5 years; six girls) with FAT who were resistant to conventional antiarrhythmics and received ivabradine as monotherapy. Patients were classified as having tachycardia-induced cardiomyopathy (TIC) if they had a left ventricular ejection fraction (LVEF) of < 50% and a left ventricular end-diastolic dimension (LVDD) z-score of > 2 due to tachycardia. Oral ivabradine was initiated at 0.1 mg/kg every 12 h, increased to 0.2 mg/kg every 12 h if no restoration of stable sinus rhythm was observed after two doses, and discontinued after 48 h if neither rhythm nor heart rate control was observed. Of these patients, six (50%) had incessant atrial tachycardia, and 6 had frequent short episodes of FAT. Six patients were diagnosed with TIC, and their mean LVEF and mean LVDD z-score were 36.2 ± 8.7% (range, 27–48%) and 4.2 ± 1.7 (range, 2.2–7.3), respectively. Finally, six patients achieved either rhythm (n = 3) or heart rate control (n = 3) within 48 h of ivabradine monotherapy. One patient achieved rhythm/heart rate control with ivabradine at a dose of 0.1 mg/kg every 12 h, while the others achieved rhythm/heart rate control at a dose of 0.2 mg/kg every 12 h. Five patients received ivabradine monotherapy for chronic therapy, one (20%) of whom had FAT breakthrough 1 month after discharge, and metoprolol was added. Neither FAT recurrence nor adverse effect (with or without beta-blocker) was observed during a median follow-up of 5 months. Conclusion: Ivabradine is well-tolerated and may provide early heart rate control in pediatric FAT and can be considered early, especially in the presence of left ventricular dysfunction. Further investigations are deserved to confirm the optimal dose and long-term efficacy in this population. What is Known: •  Focal atrial tachycardia (FAT) is the most common arrhythmia associated with tachycardia-induced cardiomyopathy (TIC) in children, and the efficacy of conventional antiarrhythmic medications in the treatment of FAT is poor. •  Ivabradine is currently the only selective hyperpolarization-activated cyclic nucleotide-gated (HCN) inhibitor, which can effectively low HR without negative effect on blood pressure or inotropy. What is New: • Ivabradine (0.1–0.2 mg/kg every 12 h) can effectively suppress focal atrial tachycardia in 50% of pediatric patients. •  Ivabradine provides early control of heart rate and hemodynamic stabilization in children with severe left ventricular dysfunction due to atrial tachycardia within 48 h.

Graphical A prepubertal LV VO mouse model was first established. VO has an important influence on LV maturation and development, especially in cardiac conduction, suggesting the requirement of an early correction of AR in pediatric patients.

Aims The management of heart failure (HF) in young children is challenging. The present study aimed to clarify the effect of left univentricular epicardial pacing on dilated cardiomyopathy with left bundle branch block (LBBB) in children. Methods and results A total of five cases (30.86 ± 16.39 months, three female) of children weighing 5.8–15 kg with dilated cardiomyopathy and LBBB were included in this study. LBBB in one child occurred after device closure of peri-membranous ventricular septal defects, and the remaining four were idiopathically discovered early after birth. Before implantation, all children suffered from refractory HF and cardiac dilatation; the left ventricular ejection fraction was 33.48 ± 5.84% with Ross Heart Failure Classification III–IV. Electrical and mechanical dyssynchrony were observed in all children with QRS duration >140 ms and prolonged septal-to-left posterior wall motion delay. Left univentricular epicardial pacing was successfully implanted via left axillary minithoracotomy in the five children. Sensed atrioventricular delays (83 ± 15 ms) were optimized by velocity time integral of aortic blood flow before discharge. During the follow-up period (10.8 ± 2.68 months), the dilated failing heart was reversed significantly in terms of decreased left ventricular dimension (55.62 ± 3.46 vs. 38.94 ± 3.69 mm, P = 0.005), while the left ventricular ejection fraction improved to 60.18 ± 8.78% (P = 0.006). Conclusions In young children with low body weight, if HF is caused by or related to LBBB, left ventricular epicardial pacing still has an excellent effect.

Engineered cartilage derived from mesenchymal stromal cells (MSCs) always fails to maintain the cartilaginous phenotype in the subcutaneous environment due to the ossification tendency. Vascular invasion is a prerequisite for endochondral ossification during the development of long bone. As an oral antitumor medicine, Inlyta (axitinib) possesses pronounced antiangiogenic activity, owing to the inactivation of the vascular endothelial growth factor (VEGF) signaling pathway. In this study, axitinib‐loaded poly(ε‐caprolactone) (PCL)/collagen nanofibrous membranes are fabricated by electrospinning for the first time. Rabbit‐derived MSCs‐engineered cartilage is encapsulated in the axitinib‐loaded nanofibrous membrane and subcutaneously implanted into nude mice. The sustained and localized release of axitinib successfully inhibits vascular invasion, stabilizes cartilaginous phenotype, and helps cartilage maturation. RNA sequence further reveals that axitinib creates an avascular, hypoxic, and low immune response niche. Timp1 is remarkably upregulated in this niche, which probably plays a functional role in inhibiting the activity of matrix metalloproteinases and stabilizing the engineered cartilage. This study provides a novel strategy for stable subcutaneous chondrogenesis of mesenchymal stromal cells, which is also suitable for other medical applications, such as arthritis treatment, local treatment of tumors, and regeneration of other avascular tissues (cornea and tendon).

Background: Current right ventricular (RV) volume overload (VO) is established in adult mice. There are no neonatal mouse VO models and how VO affects postnatal RV development is largely unknown. Methods and Results: Neonatal VO was induced by the fistula between abdominal aorta and inferior vena cava on postnatal day 7 and confirmed by abdominal ultrasound, echocardiography, and hematoxylin and eosin staining. The RNA‐sequencing results showed that the top 5 most enriched gene ontology terms in normal RV development were energy derivation by oxidation of organic compounds, generation of precursor metabolites and energy, cellular respiration, striated muscle tissue development, and muscle organ development. Under the influence of VO, the top 5 most enriched gene ontology terms were angiogenesis, regulation of cytoskeleton organization, regulation of vasculature development, regulation of mitotic cell cycle, and regulation of the actin filament‐based process. The top 3 enriched signaling pathways for the normal RV development were PPAR signaling pathway, citrate cycle (Tricarboxylic acid cycle), and fatty acid degradation. VO changed the signaling pathways to focal adhesion, the PI3K‐Akt signaling pathway, and pathways in cancer. The RNA sequencing results were confirmed by the examination of the markers of metabolic and cardiac muscle maturation and the markers of cell cycle and angiogenesis. Conclusions: A neonatal mouse VO model was successfully established, and the main processes of postnatal RV development were metabolic and cardiac muscle maturation, and VO changed that to angiogenesis and cell cycle regulation.