Ten years have brought profound transformation to global healthcare: a pandemic that halted the world, the emergence of CRISPR gene-editing technology, accelerated advances in artificial intelligence, and the diffusion of virtual-reality environments and 3D printing. Unsurprisingly, pediatric heart failure management has evolved accordingly. The ISHLT 2025 guideline significantly updates its 2014 predecessor with new definitions, diagnostic frameworks, and expanded therapeutic strategies focused on myocardial dysfunction in childhood.
Preserving the cautious philosophy of the 2014 document, the new guideline continues to emphasize a multidisciplinary approach and applies particular prudence to its recommendations due to the scarcity of randomized clinical trials in children. The role of congenital and pediatric cardiac surgeons remains crucial early in the disease course, especially for patients with complex congenital heart disease or those who may require mechanical circulatory support.
Conceptually, ISHLT 2025 redefines pediatric heart failure as a heterogeneous syndrome with distinct pathophysiologic mechanisms that cannot be extrapolated directly from the adult population. Clinical and functional classification continues to rely on the Ross and NYHA scales. Two major phenotypes persist, heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF), but the document incorporates an intermediate category representing mildly reduced EF. This change acknowledges unique pediatric phenotypes, particularly in congenital heart disease or restrictive cardiomyopathies, in which diastolic dysfunction may be severe despite apparently preserved systolic performance.
In the diagnostic domain, the 2025 guideline highlights a multimodal strategy that integrates traditional clinical evaluation with biomarker assessment and advanced imaging tools. Classic signs of heart failure in adults, such as dyspnea or peripheral edema, may be absent or nonspecific in children. Therefore, clinicians are encouraged to focus on age-dependent manifestations. Feeding difficulties and poor weight gain are characteristic in infants and young children, whereas adolescents more commonly present with exercise intolerance or abdominal discomfort.
Natriuretic peptides (BNP and NT-proBNP) are consolidated as monitoring biomarkers, with age- and size-adjusted cut-off values. High-sensitivity troponin assays are included as prognostic markers, particularly useful for the early detection of subclinical myocardial injury.
Technological advances have reshaped the diagnostic landscape over the past decade. Echocardiography remains the foundational imaging modality, with global longitudinal strain now recommended for early detection of subtle systolic dysfunction. Cardiac magnetic resonance (CMR) assumes a prominent role due to its superior ability to characterize myocardial tissue, quantify fibrosis, and assess therapeutic responses. Computed tomography maintains a more selective role, mainly for detailed anatomic assessment or when CMR is contraindicated due to the presence of devices.
The guideline also recognizes the emerging potential of artificial intelligence to enhance interpretation of imaging studies and clinical risk stratification, while noting that pediatric-focused applications still require prospective validation.
A major update in the ISHLT 2025 guideline is the integration of genetic and molecular insights into the diagnostic pathway. Unlike the 2014 version, which regarded genetic testing as an optional adjunct, the new guideline positions it as a central pillar of the etiologic workup in all pediatric patients with unexplained cardiomyopathy or a family history of sudden death or heart failure. Expanded gene panels or whole-exome sequencing are recommended, always accompanied by expert genetic counseling.
The clinical impact of identifying pathogenic variants in genes such as MYH7, TNNT2, or LMNA is emphasized, given their value for predicting disease progression, tailoring surveillance strategies, and guiding therapeutic decisions. This genetic approach also strengthens risk stratification among relatives and supports a precision-medicine framework that extends beyond the individual patient.
Regarding medical therapy, the 2025 update thoroughly revises the role of neurohormonal modulation, incorporating evidence from pediatric trials and cautiously extrapolated data from young adult populations. Angiotensin-converting enzyme inhibitors and beta-blockers remain the foundation of pharmacologic treatment. However, the guideline now introduces specific titration pathways that adjust dosage according to patient weight and body surface area, together with close hemodynamic surveillance during initiation and optimization phases.
The most significant pharmacologic advance is the incorporation of sacubitril/valsartan (ARNI) as a first-line option for patients with HFrEF who remain symptomatic despite optimized therapy. Supported by the PANORAMA-HF trial, ARNI use is recommended in children older than one year under specialist supervision, given its demonstrated improvements in functional capacity and biomarker profiles with an acceptable safety profile. Ivabradine is strengthened as an adjunct therapy for patients with persistently elevated heart rate despite optimized beta-blockade, with evidence demonstrating enhanced exercise tolerance and improved functional class.
Drawing upon positive results from the VICTORIA trial in adults, vericiguat (a soluble guanylate cyclase stimulator) is acknowledged as a potential therapeutic option for pediatric patients with persistent symptoms. Its incorporation remains conditional pending results from the ongoing VALOR trial focused on the pediatric population.
The document also addresses sodium–glucose cotransporter 2 inhibitors (SGLT2i), which have reshaped the heart failure therapeutic landscape in adults. Although pediatric data remain sparse, the guideline recognizes their hemodynamic and metabolic benefits, encouraging their use within trials or controlled registries.
In the setting of acute decompensation, the updated guideline preserves the principle of immediate hemodynamic stabilization, while refining recommendations on inotropic and vasodilator support. Milrinone and dobutamine remain the primary agents for short-term support, whereas levosimendan is introduced as a rescue option in refractory cases. Prolonged inotropic therapy without a clearly defined bridge-to-transplant or recovery strategy is discouraged due to the risk of adverse events and progressive organ injury. The document reinforces the need for invasive monitoring in high-acuity centers with serial reassessment of perfusion status and organ function.
Mechanical circulatory support represents one of the most substantially expanded areas in ISHLT 2025. A three-tier classification is adopted: bridge to transplant, bridge to recovery, and destination therapy. Indications for durable ventricular assist support must be grounded in objective criteria of severe cardiac dysfunction, persistent symptoms despite optimized therapy, and progressive end-organ impairment.
Pulsatile devices such as the Berlin Heart EXCOR continue to be the mainstay for infants and smaller children, while continuous-flow systems have become established for adolescents with favorable anatomy. The guideline offers detailed recommendations on anticoagulation, thrombosis and infection prevention, and structured transition to transplantation when appropriate.
Pediatric heart transplantation receives a substantially more detailed and structured approach in the 2025 guideline. Selection criteria are reframed through a multidimensional lens, integrating clinical, biochemical, psychosocial, and family-related factors. Beyond ventricular performance alone, decision-making must include realistic assessment of adherence potential and anticipated quality of life. Early involvement of psychosocial and nutritional support teams is encouraged, as well as a structured transition plan for adolescents progressing to adult care pathways to ensure long-term continuity. Recent data from the PHTS and ACTION registries support these recommendations, demonstrating improved post-transplant survival and reduced incidence of infection and rejection-related complications.
For patients with congenital heart disease, the guideline introduces a relevant conceptual shift. Heart failure mechanisms in this population often differ fundamentally, driven by volume overload, pulmonary hypertension, or systemic right ventricular morphology. Targeted, anatomy-specific management is advised, with coordinated decision-making between congenital cardiologists and cardiac surgeons. The document promotes early corrective or palliative interventions when ventricular dysfunction remains reversible. It also supports the development of specialized congenital heart failure programs capable of providing individualized medical, surgical, and mechanical circulatory support strategies.
Long-term follow-up gains a far more structured role in the 2025 guideline. Scheduled reassessments include clinical evaluation, echocardiography, and biomarker monitoring every 3 to 6 months depending on disease severity. The guideline highlights the potential value of telemonitoring platforms and electronic medical systems to improve adherence, detect early signs of decompensation, and streamline care coordination. Although artificial intelligence is acknowledged as an emerging tool for risk prediction and early event detection, its pediatric application is still considered investigational and requires prospective validation.
Quality of life is addressed through a comprehensive biopsychosocial perspective. The guideline recommends the use of validated quality-of-life instruments and encourages rehabilitation programs, physiotherapy, and psychological support as standard components of care. Emotional impact on both the child and family is considered a core therapeutic objective, given its influence on recovery and clinical stability. Educational reinforcement, social reintegration, and school adaptation are promoted as integral aspects of management.
The guideline concludes by outlining research priorities for the coming decade. These include assessing the efficacy of novel pharmacologic therapies in children, optimizing mechanical circulatory support strategies for small patients, and refining the characterization of pediatric HFpEF phenotypes. The ISHLT calls for strengthened international collaboration and standardized registries to better address knowledge gaps and shape public health policies. Pediatric heart failure is framed as a rapidly evolving entity in which advances in precision medicine, genetics, and artificial intelligence are expected to play a progressively more central role.
COMMENTARY:
In summary, the ISHLT 2025 document not only updates the accumulated knowledge but reshapes the foundational approach to pediatric heart failure. The shift from a primarily symptomatic strategy to a genetically informed, technology-supported, multidisciplinary paradigm represents a decisive evolution. Advances in pharmacotherapy, genetic diagnostics, mechanical circulatory support, and family-centered care establish a new standard for contemporary management.
Several relevant questions remain open. The guideline provides limited practical direction on the specific role of artificial intelligence or machine-learning tools in daily pediatric practice. It does not yet address the integration of virtual reality and 3D printing for procedural planning, nor does it clearly define the use of mechanical support as destination therapy in children. Likewise, guidance on remote monitoring remains broad and without concrete protocols. The 2025 update represents a substantial leap beyond the 2014 version, and one can only hope that future revisions arrive sooner than another decade.
REFERENCE:
Irving C, Azeka E, Adorisio R, Blume ED, Bogle C, Chubb H. The International Society for Heart and Lung Transplantation Guidelines for the Management of Pediatric Heart Failure (Update From 2014). J Heart Lung Transplant. 2025 Oct;44(10):e21-e71. doi: 10.1016/j.healun.2025.06.003.
