Bo Pan

The global prevalence of heart failure in children continues to increase, accompanied by a growing disease burden. To advance early prevention and intervention by shifting the focus upstream in the disease process, the Cardiovascular Group of the Pediatrics Society of the Chinese Medical Association has introduced the concept of pediatric cardiac function staging applicable to all children. This framework categorizes pediatric cardiac function into three distinct stages: the stage of cardiac function sufficiency (Stage A), the stage of cardiac dysfunction (Stage B), and the stage of cardiac function failure (Stage C). Based on this staging system, the diagnostic criteria and management strategies for each stage are delineated, with the aim of establishing a comprehensive management pathway rooted in cardiac function staging. This approach seeks to further reduce the incidence and burden of pediatric heart failure, providing a theoretical foundation and practical guidance for achieving the goal of making pediatric heart failure preventable, manageable, and treatable.

Background: Pediatric heart failure (PHF) is a heterogeneous syndrome with high morbidity, but existing classification systems inadequately capture its developmental and pathophysiological complexity due to reliance on adult-centric parameters. Using machine learning, we aimed to identify clinically distinct PHF phenotypes with unique outcomes and therapeutic implications. Methods: In this multicenter retrospective study, we analyzed 2903 consecutive PHF patients (≤18 years) from 30 Chinese tertiary centers from 20 provinces (2013–2022). Unsupervised machine learning (k-means clustering with PCA) evaluated 99 clinical, biomarker, and echocardiographic variables to derive phenotypes, which were compared for mortality, hospitalization, and treatment responses. Results: Three phenotypically distinct clusters emerged. Cluster 1 (Chronic Hypertensive and Cardiorenal Profile, 30.1%) predominantly affected older children (78%) with hypertension (54.4%), renal dysfunction (creatinine 45.8 μmol/L), and ventricular tachycardia (53.8%). This cluster showed the lowest in-hospital mortality (2.5%) but frequent 7–14 day hospitalizations (35.8%) and the highest beta-blocker use (54.5%). Cluster 2 (Preterm and CHD-Associated HF, 43.4%) comprised preterm infants (71.4%) with congenital heart disease (72.2%) and preserved LVEF (67%), demonstrating the highest mortality (5.1%) and prolonged stays (>30 days: 10.6%) with predominant diuretic (40.6%) and antibiotic use (54.3%). Cluster 3 (Fulminant Myocarditis Profile, 26.5%) exhibited cardiogenic shock with severely reduced LVEF (33%) and elevated BNP (3234 pg/mL), showing bimodal outcomes (4.8% LOS < 3 days vs. 32.2% LOS 15–30 days) and the highest IVIG utilization (46.5%) with intermediate mortality (3.8%). The majority of between-group differences were statistically significant (p < 0.001). Conclusions: Machine learning identified three PHF phenotypes with distinct in-hospital risk profiles and therapeutic implications, challenging current classification systems. These findings highlight the potential for phenotype-specific management strategies and provide a rationale for future research into arrhythmia prevention in hypertensive profiles and early immunomodulation in fulminant myocarditis, while highlighting the need for specialized care pathways for preterm/CHD patients. Prospective validation is warranted to translate this framework into clinical practice.

Background: Pediatric heart failure (PHF) remains a major contributor to morbidity and mortality, yet standardized diagnostic and prognostic frameworks–particularly those leveraging left ventricular ejection fraction (LVEF)–are not well-established. This study evaluates clinical profiles, therapeutic interventions, and mortality outcomes across LVEF thresholds while identifying an optimal cutoff to refine risk stratification in PHF. Methods: This multicenter retrospective cohort study analyzed 1449 PHF patients (aged 1–18 years) across 30 tertiary centers (2013–2022). LVEF stratification employed conventional thresholds (50%, 55%) and an ROC-optimized cutoff (53%, derived via Youden index maximization). The primary outcome was in-hospital all-cause mortality. Multivariable logistic regression models, adjusted for clinical covariates, evaluated mortality predictors. The discriminative performance of LVEF thresholds was compared using area under the curve (AUC) analysis. Results: Distinct clinical profiles, etiologies, and treatments were observed across LVEF strata (50% vs. 55%; p < 0.05). A data-driven optimized LVEF threshold of 53% was identified for mortality prediction, demonstrating superior diagnostic accuracy with enhanced sensitivity and specificity across age groups. Multivariate analysis revealed LVEF ≥ 55% as protective (OR = 0.81, 95% CI: 0.68–0.96, p = 0.003), while ≥50% was non-significant (OR = 0.91, 95% CI: 0.74–1.12, p = 0.06). Elevated BNP (OR = 2.78, p < 0.001) and NT-proBNP (OR = 2.34, p < 0.001) strongly correlated with mortality risk. Age and sex showed no significant association with outcomes. Conclusion: In conclusion, an LVEF of 53% emerged as the optimal pediatric threshold for mortality prediction, outperforming conventional cutoffs of 50% and 55%. The integration of LVEF with biomarkers (BNP/NT-proBNP) provides a robust prognostic framework, underscoring the necessity for pediatric-specific LVEF criteria and multidimensional risk assessment in PHF management.

Restrictive cardiomyopathy (RCM) is a rare, fatal disorder that rapidly progresses in children. TNNI3 mutations represent the most common genetic cause. Although cTnI mutations are known to increase myofilament calcium sensitivity and impair diastolic function, this mechanism alone does not fully account for disease pathogenesis. Recent studies have revealed that the immune system plays an important role in cardiovascular diseases, however, its involvement in RCM remains unclear. Here, we generated a classic cTnIR193H mouse model using CRISPR/Cas9. Cardiac RNA-seq analysis indicated marked activation of innate immune pathways. moreover, biotin-mediated proximity labeling combined with quantitative mass spectrometry identified differential interactors of the cTnIR193H mutant, with Irgm1 emerging as the most significantly altered immune-related protein. Notably, the cTnIR193H mutation enhances binding to Irgm1 without affecting its expression, thereby indirectly inhibiting its normal function. This aberrant interaction activates the cGAS-STING pathway and elicits a type I interferon response in the hearts of RCM mice. Furthermore, treatment with the STING inhibitor C176 partially restored diastolic function and significantly alleviated cardiac fibrosis. Taken together, this study reveals for the first time that immune mechanisms play a crucial role in RCM pathogenesis and provides a potential therapeutic target for RCM treatment from an immunological perspective.

Cardiac remodeling in response to disease or tissue damage severely impairs heart function. Therefore, the description of the molecular mechanisms responsible is essential for the development of effective therapies. Trbp (Tarbp2) is a multifunctional RNA-binding protein that is essential during heart development, but its role in the adult heart and cardiac remodeling remains unknown. We generated inducible conditional knockout mice to delete Trbp from cardiomyocytes in young adults (Trbp-cKOs). While Trbp-cKO mice did not display a detectable phenotype, under stress conditions induced by transverse aortic constriction pressure overload, they rapidly developed severe heart failure; this was associated with maladaptive cardiac remodeling and increased interstitial fibrosis. RNA-sequencing revealed the induction of a fibrotic gene expression network and the TGF-β signaling pathway in Trbp-cKO hearts. In cultured neonatal rat ventricle cardiomyocytes (NRCMs), inhibition of Trbp resulted in an induction of the expression of both Tgfβ2 and Ltbp2; in contrast, Trbp overexpression repressed Tgfβ2 expression. Knockdown of Trbp in NRCMs that were co-cultured with neonatal rat cardiac fibroblasts (NRCFs) resulted in an increase in fibrotic gene expression. However, knockdown of Trbp in NRCMs combined with knockdown of Tgfβ2 in NRCFs using the same co-culture system failed to induce the same change in fibrotic gene expression. These data provide evidence for a critical role for Trbp in regulating cardiac fibrosis during cardiac remodeling mediated by cross-talk between cardiomyocytes and fibroblasts. The link to TGF-β signaling also highlights its importance and reveals a novel approach to intervention by targeting of Trbp.

Background: Although heart failure is a well‐known major global public health concern, the general understanding of the clinical status of pediatric heart failure (PHF) is inadequate. Therefore, this study aims to enhance the general understanding of clinical characteristics across different PHF age groups and provide references for improving PHF treatment strategies. Methods: This multicenter retrospective cohort study involved patients from 20 Chinese provinces, primarily including hospitalized patients (aged ≤18 years) diagnosed with heart failure between January 2013 and December 2022. The study subjects were categorized into 4 groups: neonatal, infant and toddler, young children, and adolescent. Results: Herein, 2903 hospitalized patients with PHF were included. Significant differences were observed across age groups in clinical characteristics, auxiliary examination results, comorbid diagnoses, and hospitalization outcomes. After adjusting for covariates, the odds of in‐hospital death were significantly lower in the infant and toddler (odds ratio [OR], 0.46 [95% CI, 0.25–0.85]), young children (OR, 0.39 [95% CI, 0.18–0.85]), and adolescent (OR, 0.34 [95% CI, 0.13–0.87]) groups compared with the neonatal group. Furthermore, the odds of cardiovascular adverse events were significantly higher in the young children (OR, 1.91 [95% CI, 1.62–2.88]) and adolescent (OR, 2.16 [95% CI, 1.15–4.06]) groups compared with the neonatal group. Additionally, regarding the odds of a bad Ross class, the adolescent group had 1.85 times higher odds (95% CI, 1.11–3.09) compared with the neonatal group, 2.36 times (95% CI, 1.67–3.35) higher odds compared with the infant and toddler group, and 1.45 times (95% CI, 1.05–2.02) higher odds compared with the young children group ( P <0.05). Conclusions: This study emphasizes the importance of age‐specific stratification in PHF management, revealing distinct clinical and prognostic differences across various developmental stages. Registration: URL: https://www.chictr.org.cn . Unique identifier: ChiCTR2300078262.