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COMBI-I: Long-Term Overall Survival With Spartalizumab Plus Dabrafenib and Trametinib in <i>BRAF</i> V600–Mutant Advanced Melanoma
The COMBI-I trial (ClinicalTrials.gov identifier: NCT02967692 ) evaluating spartalizumab plus dabrafenib and trametinib (sparta-DabTram, n = 267) versus placebo plus dabrafenib and trametinib (placebo-DabTram, n = 265) for BRAF V600–mutant unresectable or metastatic melanoma failed to reach its primary end point of progression-free survival at 24 months. This final analysis reports overall survival (OS) during at least 5 years of extended follow-up. At the end of the trial (August 21, 2024), the median duration of follow-up was 76.9 months (range, 73.7-83.3 months). The median OS was 61.5 months (95% CI, 41.6 to not evaluable) for the sparta-DabTram arm and 41.6 months (95% CI, 30.6 to 56.9) for the placebo-DabTram arm (hazard ratio, 0.760 [95% CI, 0.598 to 0.966]). The safety findings were consistent with the known safety profile for sparta-DabTram. The most common treatment-related adverse event (TRAE) was pyrexia (65.9% v 46.2%, respectively, in the two study arms). Grade ≥3 TRAEs were reported in 57.3% and 36.7% of patients in the two arms, respectively. The combination of sparta-DabTram appears to improve OS compared with dabrafenib and trametinib alone in patients with BRAF V600–mutant metastatic melanoma.
Prognostic and Predictive Effect of Age in Molecularly Defined Lower-Grade Gliomas
PURPOSE Age ≥40 years is regarded as a high-risk feature and an indication for adjuvant chemoradiotherapy for patients with lower-grade glioma in clinical practice guidelines. It is unclear whether age remains a relevant prognostic factor for contemporary definitions of lower-grade gliomas in the molecular era. METHODS The Prospective Gliomas Research (PROGRES) database contains individual patient-level data from 11 prospective clinical trials or observational registries of histologically defined lower-grade 2-3 oligodendroglioma or astrocytoma. We determined the association of age (18-39 years v ≥40 years) with progression-free survival (PFS) stratified by isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) status, using log-rank tests and Cox regression models. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] database). RESULTS We identified 1,619 and 1,292 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH -wildtype tumors were more common in patients 40 years and older (38% v 5%, odds ratio: 11.3 [95% CI, 6.5 to 19.7]). Age was associated with PFS in IDH -wildtype (5-year PFS for ≥40 v 18-39 years: 6% v 24%, hazard ratio [HR], 1.74 [95% CI, 1.21 to 2.50]) but not in IDH -mutant glioma (60% v 59%, HR, 0.89 [95% CI, 0.76 to 1.05], P interaction < .001). In IDH -wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% v 28%), EGFR amplification (41% v 15%), and chromosome +7/–10 alteration (57% v 25%). In a pooled analysis of four clinical trials, age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone for IDH -mutant glioma. CONCLUSION In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral of adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.
Occupational Radiation Safety in Electrophysiology During Pregnancy: Evaluating Uterine Radiation Doses During Catheter Ablations and Device Implantations
Response by Rogers et al to Letter Regarding, “Deep Learning-Based Continuous QT Monitoring to Identify High-Risk Prolongation Events After Class III Antiarrhythmic Initiation”
Clinical Cardiology at the Crossroads: Perspectives on the Next Era at <i>Circulation</i>
ABHD11-Mediated mtDNA Transcription Restored Mitochondrial Function to Attenuate Cardiomyocyte Ferroptosis After Myocardial Infarction
BACKGROUND: Cardiomyocytes exhibit marked susceptibility to ferroptosis after myocardial infarction (MI), rendering ferroptosis inhibition a promising therapeutic strategy to mitigate ischemic myocardial injury. Although mitochondrial dysfunction is recognized as a core driver of ferroptosis, the potential role of mitochondrial DNA transcription in regulating cardiomyocyte ferroptosis remains unexplored. METHODS: To clarify the temporal role of the various modes of cell death in MI progression, we performed time-course echocardiography in MI models treated with various cell death inhibitors. To characterize the crucial process and molecular regulator in cardiomyocyte ferroptosis, we integrated RNA sequencing and single-nucleus RNA sequencing data from murine post-MI hearts and performed functional rescue experiments using mitochondrial protective agents. To determine the role of ABHD11 (αβ-hydrolase domain-containing protein 11) in cardiomyocyte ferroptosis and cardiac repair after MI, we used loss- and gain-of-function approaches. To elucidate the underlying mechanisms, we conducted transcriptomics, nontargeted lipidomics, site-specific mutagenesis, molecular docking, coimmunoprecipitation, native gel electrophoresis, proximity ligation assay, methylation-specific polymerase chain reaction, and chromatin immunoprecipitation assay. RESULTS: We found that cardiac ferroptosis peaked at day 7 after MI and was enriched in peri-infarct cardiomyocytes. Mitochondrial dysfunction was a key driver of cardiomyocyte ferroptosis after MI, and the lipid enzyme ABHD11 was identified as a potential regulator of both processes. ABHD11 expression was consistently reduced in mouse and human MI hearts, and its transcription was repressed by DNMT1 (DNA methyltransferase 1)–mediated promoter hypermethylation. Functionally, cardiac-specific overexpression of ABHD11 markedly alleviated cardiomyocyte ferroptosis and improved cardiac function after MI. Conversely, loss of ABHD11 in adult mice exacerbated pathological cardiac remodeling and heart failure. Mechanistically, independent of its canonical enzymatic activities, ABHD11 acted as a mitochondrial DNA transcription coactivator by enhancing the TEFM (mitochondrial transcription elongation factor)–POLRMT (mitochondrial RNA polymerase) interaction. This promoted mitochondrial DNA transcription, restored mitochondrial function, and reduced reactive oxygen species/PUFA-PLs (polyunsaturated fatty acid-containing glycerophospholipids)–driven lipid peroxidation and 4-hydroxynonenal generation. The reduction in 4-hydroxynonenal stabilized YY1 (Yin Yang 1), which subsequently regulated key ferroptosis-driving genes governing iron deposition, reactive oxygen species production, and polyunsaturated fatty acid lipids accumulation, further inhibiting lipid peroxidation and ferroptosis, and ultimately promoting cardiac recovery after MI. CONCLUSIONS: This study revealed that ABHD11-mediated mitochondrial DNA transcription attenuated cardiomyocyte ferroptosis after MI by orchestrating a mitochondrial-nuclear crosstalk, offering a novel therapeutic strategy for ischemic myocardial injury.
Letter by Li et al Regarding Article, “Deep Learning-Based Continuous QT Monitoring to Identify High-Risk Prolongation Events After Class III Antiarrhythmic Initiation”
Cell Type–Specific Targeting of Different Smooth Muscle Cell Populations by Intersectional Genetics
BACKGROUND: The Cre/loxP recombination system is the main tool for cell type–specific lineage tracing and gene targeting. Currently available smooth muscle cell (SMC)–specific Cre mouse lines show off-target activity outside the SMC lineage and are unable to distinguish among arterial SMCs (ASMCs), venous SMCs, and nonvascular SMCs (NVSMCs). These limitations prevent ASMC- and NVSMC-specific gene targeting, which is required to characterize the role of SMCs in different organs and diseases. METHODS: To achieve precise manipulation of ASMCs in vivo, we combined alleles for Cspg4-Dre and rox-Stop–containing Acta2-CreER ( Acta2-rox-CreER ), generating a mouse line with Cre activity exclusively in ASMCs. RNA sequencing of fluorescence-activated cell sorting–isolated ASMCs was used to reveal differences in ASMCs among multiple organs. To specifically target and characterize NVSMCs in different organs, a combination of Chrm2-Dre and Acta2-rox-CreER was used. Disease-specific transcriptional changes of pulmonary ASMCs and NVSMCs were determined in the Sugen 5416/hypoxia model of pulmonary arterial hypertension. Usefulness for functional studies was assessed by inactivation of the genes for the splicing factors RBPMS (RNA-binding protein with multiple splicing) and RBPMS2 (RNA-binding protein with multiple splicing 2) in ASMCs. RESULTS: Intersectional genetic approaches using Cspg4-Dre and Acta2-rox-CreER mouse lines specifically targeted ASMCs within various organs. A combination of Chrm2-Dre with Acta2-rox-CreER achieved specific targeting of NVSMCs. Transcriptomic profiling revealed distinct gene expression signatures in ASMCs of different organs, indicating organ-dependent transcriptional adaptation of ASMCs. Transcriptional differences among NVSMCs were found in the lung, intestine, and bladder. Activation of distinct pathways was uncovered in pulmonary ASMCs and bronchial SMCs after induction of pulmonary arterial hypertension. Inactivation of Rbpms and Rbpms2 in ASMCs increased thickness of the muscular layer in pulmonary arteries, whereas inactivation in all SMCs abolished the contractile phenotype of NVSMCs in the intestine. CONCLUSIONS: The successful generation of mouse lines specifically targeting different subtypes of SMCs enhances specificity, allowing distinction between vascular and nonvascular effects of diseased SMCs. The identification of vessel bed–specific gene signatures will pave the way for specific manipulation of SMCs in distinct diseased organs, such as the lung in pulmonary arterial hypertension.
Mechanical CPR Device Use and Cardiac Arrest Survival in EMS Agencies
BACKGROUND: Cardiopulmonary resuscitation (CPR) by health care responders is often suboptimal during out-of-hospital cardiac arrest (OHCA). Mechanical CPR devices have been promoted as a strategy to improve CPR quality. Whether their use in routine care is associated with improved OHCA survival at emergency medical service (EMS) agencies is unclear. METHODS: Within the Cardiac Arrest Registry to Enhance Survival, we assessed agency-level rates of OHCA survival at EMS agencies with ≥2 years of OHCA data before and after their first documented use of a mechanical CPR device from 2013 to 2019 using an observational cohort study design. Temporal trends in favorable neurological survival (without severe neurological disability) and survival to discharge were first assessed in EMS agencies that did not initiate mechanical CPR device use (control agencies) using multivariable hierarchical logistic regression. Then an interrupted time series analysis evaluated whether introduction of mechanical CPR devices at EMS agencies was associated with higher OHCA survival. RESULTS: Among 51 994 patients with OHCA at 73 control agencies, there were no temporal trends in risk-adjusted rates of favorable neurological survival (annual rates ranged between 9.6% and 10.6%; P trend =0.23) or survival to discharge (annual rates ranged between 11.1% and 12.0%; P trend =0.31). At 49 EMS agencies that introduced mechanical CPR devices (14 110 OHCAs before and 17 804 OHCAs after), the mean EMS agency risk-adjusted rate of favorable neurological survival was 8.9% ± 2.2% before mechanical CPR device introduction and 8.3% ± 1.3% after, with no change in model intercept (adjusted odds ratio, 0.94 [95% CI, 0.80–1.11]; P =0.48) or slope after introduction of mechanical CPR devices (adjusted odds ratio per year, 1.03 [95% CI, 0.96–1.12]; P =0.41). Similarly, the mean EMS agency risk-adjusted rate of survival to discharge was 11.0% ± 2.2% before and 10.0% ± 1.0% after device introduction, with no significant change in model intercept or slope after device introduction. CONCLUSIONS: In a large US registry of OHCA, EMS agency rates of favorable neurological survival and survival to discharge were not higher after the initiation of mechanical CPR device use.
The Postcardiac Arrest Inflammatory Response: Mechanisms and Therapeutic Targets
Postcardiac arrest syndrome is a complex multisystem disorder that evolves after return of spontaneous circulation and remains a major determinant of morbidity and mortality following out-of-hospital cardiac arrest. Beyond anoxic brain injury and transient myocardial dysfunction, many patients develop a systemic ischemia/reperfusion response with endothelial and microvascular dysfunction, vasoplegia, and immune dysregulation—features that contribute to shock and organ failure. Hemodynamic instability is often mixed with low systemic vascular resistance despite preserved or recovering cardiac output, but management is still largely supportive and centered on achieving a target mean arterial pressure. An increasing understanding of the central role of inflammation, including gastrointestinal barrier disruption, cytokine release, complement activation, nitric oxide–cGMP signaling, and immune phenotypic heterogeneity has prompted evaluation of targeted adjunctive therapies. However, randomized trials of immunomodulators and other vasoactive strategies have yielded mixed results, reflecting biological heterogeneity and limited phenotypic stratification. This review synthesizes contemporary understanding of the inflammatory and hemodynamic mechanisms underpinning postcardiac arrest syndrome, examines current and emerging pharmacologic strategies, and highlights priorities for future investigation, including mechanistic phenotyping, prospective biobanking, and prospective trial requirements to guide more precise management strategies in postcardiac arrest care.
Subcutaneous Defibrillator Implantation With or Without Defibrillation Test: The Primary Results of the Randomized PRAETORIAN-DFT Trial
BACKGROUND: To improve survival of patients at risk of sudden cardiac death, subcutaneous implantable cardioverter defibrillators (S-ICDs) require optimal implant positioning for effective shocks. Defibrillation (DF) testing is recommended but carries serious risks. The PRAETORIAN score predicts defibrillation outcomes on the basis of chest X-ray. The PRAETORIAN-DFT (Prospective Randomized Comparative Trial of Subcutaneous Implantable Cardioverter Defibrillator Implantation With and Without Defibrillation Testing) trial evaluated whether omission of DF testing guided by the PRAETORIAN score is noninferior for first-shock efficacy. METHODS: In this multinational trial, S-ICD patients from 37 centers were randomized to DF testing or no DF testing. In the No-DF testing group, the PRAETORIAN score was evaluated before discharge. The primary end point was failed first shock for spontaneous ventricular arrhythmias, as a surrogate for defibrillation success, tested for noninferiority with a 3% absolute risk margin. Secondary end points included mortality, potential DF testing–related complications, and S-ICD revisions. RESULTS: The included 965 patients (No-DF testing, n=483; DF testing, n=482) were followed for a median of 41 months. Failed first shock for spontaneous ventricular arrhythmia occurred in 1.7% of the No-DF testing group versus 2.3% of the DF testing group (–0.6% [95% CI, –2.6 to 1.4], P <0.001). There were no significant differences in all-cause mortality (hazard ratio [HR], 0.9 [95% CI, 0.6–1.4]) or arrhythmic death (HR, 0.4 [95% CI, 0.04–3.4]). Potential DF testing–related complications occurred in 1.7% in the DF testing group. Postoperative S-ICD revisions due to inadequate positioning were identical between groups (n=2 each). CONCLUSIONS: PRAETORIAN score–guided omission of DF testing after S-ICD implantation did not increase the risk of failed first shocks for spontaneous ventricular arrhythmias and reduced procedural risk without increasing S-ICD revisions. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03495297.
Letter by Hu et al Regarding Article, “Cell-Specific Inducible Human APOL1 Risk Variant Expression in Mice Causes Hypertension and Renal Damage”
Perioperative Anemia and Patient Blood Management in Cardiac Surgery: A Scientific Statement From the American Heart Association
Perioperative anemia and red blood cell transfusions are important risk factors for morbidity and mortality in cardiac surgery. Preoperative anemia is common, with up to 50% of patients presenting for cardiac surgery affected. Iron deficiency—the most common and potentially modifiable cause of preoperative anemia—is a major driver of blood transfusions in the cardiac surgical setting, adversely affecting both patient outcomes and resource utilization. Perioperative blood management, a patient-centered approach to blood conservation during cardiac surgery, is a multidisciplinary collaborative effort among anesthesiologists, surgeons, perfusionists, intensivists, and transfusion laboratory teams. Strategies aim to reduce blood loss and transfusions and improve patient outcomes. There has been a recent increase in research related to anemia, iron deficiency, and patient blood management in cardiac surgery. This scientific statement highlights the latest evidence on preoperative anemia assessment and intraoperative blood conservation; discusses considerations for specific patient populations regarding anemia prevalence, treatment, and outcomes; and reviews key challenges and knowledge gaps, with the goal of minimizing the impact of preoperative anemia, intraoperative blood loss, and hemodilution on cardiac surgery outcomes.
Response by Poudel and Susztak to Letter Regarding Article, “Cell-Specific Inducible Human APOL1 Risk Variant Expression in Mice Causes Hypertension and Renal Damage”
Heart Failure Occurring in the Perinatal Period: A Scientific Statement From the American Heart Association
Heart failure in the perinatal period remains ambiguous in definition and management despite its recognition as a unique disease state. The true incidence and prevalence of heart failure or left ventricular systolic dysfunction during pregnancy and the postpartum period are unknown, although a prevalence as high as 1% to 2% has been reported in the general adult US population. Assessment of heart failure can be challenging in the pregnant or postpartum state, during which symptoms affecting physical function (eg, dyspnea, exercise intolerance, fatigue, and lower-extremity edema) are prevalent because of physiological changes. Delays in the recognition and diagnosis of heart failure during the perinatal period contribute to adverse maternal outcomes, highlighting the need for evidence-based definitions and thresholds, improved diagnostic criteria to aid disease recognition, and effective screening tools. This scientific statement focuses on heart failure with reduced and mildly reduced ejection fraction in the context of pregnancy and the postpartum period, caused by various forms of cardiomyopathy. It addresses challenges related to recognizing heart failure in obstetric patients, outlines established treatment standards, and underscores potential areas for research. To improve the management of preexisting and de novo heart failure in obstetric patients, standardization of disease definitions, specific therapeutic options, implementation of effective screening tools, and interventions to improve maternal health equity are imperative. Future directions include prioritizing the inclusion of pregnant and postpartum individuals in heart failure studies, implementing interventions that facilitate early disease detection, and ensuring the timely initiation of appropriate therapies with the goal of reducing adverse outcomes associated with perinatal heart failure.
Mechanosensitive Endothelial METTL7A Regulates Internal m <sup>7</sup> G mRNA Methylation and Protects Against Atherosclerosis
BACKGROUND: Internal N7-methylguanosine (m 7 G) is a recently identified chemical modification of mammalian mRNA. Although the epitranscriptome plays a key role in regulating RNA metabolism and cellular function, the specific contribution of internal m 7 G to cardiovascular disease remains unknown. Atherosclerosis preferentially develops at sites of disturbed blood flow, which promotes endothelial activation; however, whether internal m 7 G regulates endothelial mechanotransduction and atherogenesis remains unclear. METHODS: We integrated epitranscriptomic profiling, human tissues, genetically modified mice, and targeted nanomedicine approaches to investigate the role of METTL7A (methyltransferase-like protein 7A), a putative internal m 7 G methyltransferase, in endothelial mechanobiology and atherosclerosis. Vascular endothelial cells were subjected to atheroprotective and atheroprone flow waveforms in vitro and in vivo. METTL7A function was assessed using RNA sequencing, liquid chromatography–tandem mass spectrometry, crosslinking immunoprecipitation sequencing, RNA stability assays, and a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated–inspired RNA targeting system. METTL7A expression was examined in human coronary arteries with and without atherosclerosis. Atherosclerosis studies were conducted using global and endothelial-specific Mettl7a1 knockout mice. Endothelial METTL7A expression was restored using polymer-based nanoparticles delivering CDH5 promoter–driven METTL7A plasmids or VCAM-1 (vascular cell adhesion molecule-1)–targeted lipid nanoparticles delivering N1-methylpseudouridine–modified METTL7A mRNA. RESULTS: Atheroprotective unidirectional flow significantly induced METTL7A expression, which promoted internal m 7 G methylation of endothelial transcripts without affecting cap-associated m 7 G. METTL7A preferentially bound AG-enriched motifs in protein-coding mRNAs and increased internal m 7 G methylation and stability of KLF4 and NFKBIA transcripts, thereby supporting vascular homeostasis. Endothelial METTL7A expression was significantly reduced by disturbed blood flow and in human atherosclerotic lesions. Global or endothelial-specific loss of Mettl7a1 exacerbated atherosclerosis in mice independent of serum lipid levels. Endothelial restoration of METTL7A through nanoparticle delivery of either a METTL7A plasmid or N1-methylpseudouridine–modified METTL7A mRNA markedly attenuated atherosclerotic lesion formation in Mettl7a1 − / − and ApoE − / − mice. CONCLUSIONS: METTL7A is a mechanosensitive internal m 7 G methyltransferase that maintains endothelial homeostasis by stabilizing the anti-inflammatory transcripts KLF4 (Krüppel-like factor 4) and NFKBIA. Loss of METTL7A disrupts endothelial function and accelerates atherogenesis. Endothelial restoration of METTL7A through complementary targeted nanoparticle platforms significantly reduces atherosclerotic burden. These findings uncover a novel epitranscriptomic mechanism governing vascular health and position METTL7A as a promising therapeutic target for atherosclerotic cardiovascular disease.
HFpEF at the Splice Junction: A Thin Filament Mechanism of Diastolic Dysfunction
Alternative Splicing of TPM1 Mediated by SRPK3 Drives Cardiac Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, a condition characterized by impaired diastolic function and elevated left ventricular stiffness. TPM1 (tropomyosin 1), a crucial part of the thin filament in cardiomyocytes, has multiple alternative exons. However, the impact of TPM1 alternative splicing (AS) in HFpEF remains unclear. METHODS: We examined cardiac myofiber disarray in HFpEF using transmission electron microscopy. Nanoindentation was used to detect myocardial compliance. Using genetically engineered (adenovirus-associated virus serotype 9) mouse models and human pluripotent stem cell–derived cardiomyocytes, we investigated the role of TPM1 isoforms and TPM1’s upstream SRPK3 (serine/arginine rich protein kinase 3). Subsequently, the underlying mechanisms were investigated using RNA pulldown, mass spectrometry, AS analysis, and other molecular techniques. RESULTS: We identified unique myofilament disorders in HFpEF and observed upregulation of the TPM1b isoform, which skips exon 9a through AS, in both patients with HFpEF and mouse models. Cardiomyocyte-specific overexpression of distinct TPM1 isoforms showed that TPM1b (without exon 9a) exacerbated HFpEF phenotypes in mice and human pluripotent stem cell–derived cardiomyocytes. Furthermore, we found that the splicing kinase SRPK3 mediates the AS of TPM1 exon 9a. Cardiomyocyte-specific overexpression of SRPK3 induced myofiber disarray and diastolic dysfunction, whereas SRPK3 knockdown ameliorated these pathological phenotypes. Supplementation with TPM1 containing exon 9a partially rescued the diastolic dysfunction under conditions of SRPK3 overexpression. Preventive intervention experiments demonstrated that inactivating SRPK3 can alleviate diastolic dysfunction in the HFpEF mouse model. CONCLUSIONS: AS of TPM1 exon 9a is a critical pathogenic mechanism in myofilament disorder and diastolic dysfunction in HFpEF, which is dependent on the upstream splicing kinase SRPK3. SRPK3 may represent a novel therapeutic target for HFpEF.
The Pediatric Pulmonary Hypertension International Risk Score: A Prediction Model for Outcomes Using Machine Learning
BACKGROUND: Risk prediction is fundamental to pulmonary hypertension (PH) guideline-based care, yet pediatric-specific risk prediction models remain limited, relying primarily on single predictors, expert opinion, or application of adult models to children. The authors developed and externally validated a data-driven 1-year risk prediction model for pediatric PH. METHODS: Pediatric patients with PH (n=345; World Symposium on Pulmonary Hypertension groups 1 and 3) enrolled in the Pediatric Pulmonary Hypertension Network Registry (2014–2020; 50.4% male; median age, 4.9 years [interquartile range, 1.9–10.3]) were split into training (80%) and test cohorts (20%). The Dutch National Registry for Pulmonary Hypertension in Childhood (n=155 [1993–2020]) and the Spanish Registry of Pediatric Pulmonary Hypertension (n=327 [2009–2023]) were used for external validation. From 176 variables, BorutaSHAP feature selection with random forest identified 16 predictors for a 1-year outcome of time to death, transplant, Potts shunt, or atrial septostomy, modeled using extreme gradient boosting. Performance was assessed with the area under the receiver operating characteristic curve, confusion matrices, calibration, and Kaplan-Meier event-free survival. RESULTS: The final model achieved an area under the receiver operating characteristic curve of 0.90 (0.79–0.97) and 99% (96%–99%) negative predictive value in testing, dividing participants into 3 groups with strong outcome discrimination. External validation showed an area under the receiver operating characteristic curve of 0.76 (Dutch National Registry for Pulmonary Hypertension in Childhood, 0.70–0.81) and 0.77 (Spanish Registry of Pediatric Pulmonary Hypertension, 0.73–0.82) with negative predictive values of 93% (93%–97%) and 96% (93%–97%), respectively. Kaplan-Meier analysis significantly differentiated outcomes by risk group. CONCLUSIONS: This multicenter, validated model provides good 1-year risk prediction in pediatric PH across World Symposium on Pulmonary Hypertension groups 1 and 3, providing a robust tool for clinical risk stratification to guide therapy and addressing a gap in pediatric PH care.