A complementary proteomics and cardiac magnetic resonance approach to characterize right ventricular remodeling after tetralogy of Fallot repair

Q: What are the key findings of this study?

Moderate-to-severe RV dilation in repaired tetralogy of Fallot was associated with 60 differentially abundant serum proteins (p<0.05) and higher indexed RV stroke volume (85 vs 59 ml/m2, p=0.023).

Q: What is the clinical evidence from this study?

Study design: Cross-Sectional. Population: Repaired tetralogy of Fallot with right ventricular dilation (n=14). Intervention: Moderate-to-severe right ventricular dilation (RVEDVi > 139 ml/m2, median 146 ml/m2) vs. Less right ventricular dilation (RVEDVi <= 139 ml/m2, median 114 ml/m2). Primary outcome: Indexed right ventricular stroke volume (RVSVi, ml/m2) and differentially abundant serum proteins (p=0.023).

Q: What does this research mean for the field?

Moderate-to-severe right ventricular dilation in patients with repaired tetralogy of Fallot is associated with higher indexed stroke volume and a distinct serum proteomic profile reflecting altered metabolism and oxidative stress response. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

Andrea L. Jones; Jonathan J. Edwards; Hossein Fazelinia; David B. Frank; Katie Clouthier; Chandni Patel; Lynn A. Spruce; Hua Ding; Julia Sabella; Catherine M. Avitabile; Mark Kevin Friedberg; Mark A. Fogel; Harry Ischiropoulos; Sushma Reddy; Laura Mercer‐Rosa

doi:10.1038/s41390-026-05555-7

October 22, 2026Pediatric ResearchOpen Access

A complementary proteomics and cardiac magnetic resonance approach to characterize right ventricular remodeling after tetralogy of Fallot repair

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Key result

RV dilation in repaired TOF is linked to distinct serum proteomics and ~26-ml/m² higher RVSVi.

P=0.023
n=14

Why the study?

Patients with repaired tetralogy of Fallot (TOF) can develop right ventricular (RV) dilation and failure. Characterizing the serum proteome signature associated with RV dilation in repaired TOF was sought to improve understanding of the mechanistic drivers of RV remodeling.

Does moderate-to-severe right ventricular dilation correlate with a distinct serum proteomic profile in adolescents with repaired tetralogy of Fallot?

Key Points

To characterize serum proteomic signatures linked to right ventricular dilation in adolescents with repaired tetralogy of Fallot.
Recruited 14 adolescents with repaired tetralogy of Fallot (median age 16 years; IQR 15, 18) who underwent cardiac magnetic resonance imaging and serum proteomics.
Stratified patients into Group 1 with higher indexed right ventricular end-diastolic volume (n=9; median RVEDVi 146 ml/m2) and Group 2 with lower volume (n=5; median RVEDVi 114 ml/m2).
Evaluated untargeted serum proteomics to identify differentially abundant proteins (p < 0.05, log2 fold change ≥ |1.2|) alongside functional pathway enrichment.
Group 1 demonstrated significantly higher indexed right ventricular stroke volume compared to Group 2 (85 ml/m2 vs. 59 ml/m2, p = 0.023) with similar right ventricular ejection fraction (57% vs. 54%, p = 0.74).
Identified 60 differentially abundant proteins (55 increased and 5 decreased in Group 1), including PSMA4 and PSMA5 detected solely in Group 1.
Pathway analyses showed enrichment in catabolism, nucleotide metabolism, detoxification of reactive oxygen species, and glucose and fatty acid metabolism.

Study Design

Type

Cross-Sectional (n=14)

Multicenter

No

Structured PICO

Does moderate-to-severe right ventricular dilation correlate with a distinct serum proteomic profile in adolescents with repaired tetralogy of Fallot?

P

Population

14 adolescents (median age 16 years, 50% female) with complete surgical repair of tetralogy of Fallot and no prior pulmonary valve replacement undergoing clinically indicated cardiac MRI.

E

Exposure

Untargeted serum proteomics via data-independent acquisition mass spectrometry and cardiac magnetic resonance imaging (CMR) in patients with greater than median indexed right ventricular end-diastolic volume (Group 1: n=9, median RVEDVi 146 ml/m2, IQR 139, 164).

C

Comparator

Patients with repaired TOF with indexed right ventricular end-diastolic volume equal to or less than the median (Group 2: n=5, median RVEDVi 114 ml/m2, IQR 108, 129).

O

Outcome

Differentially abundant serum proteins (p < 0.05, log2 fold change >= |1.2|) and enriched functional pathways associated with CMR-defined right ventricular dilation.surrogate

Main Result

Absolute Event Rate: 85% vs 59%

p-value: p=0.023

Adolescents with repaired tetralogy of Fallot and moderate-to-severe right ventricular dilation exhibit a distinct serum proteomic signature involving metabolic and oxidative stress pathways despite preserved ejection fraction, demonstrating the potential of proteomics to characterize RV remodeling.

Limitations

Small sample size of 14 patients
No statistical correction for multiple comparisons was performed
Significant age difference between the two RV dilation phenogroups (median 15 vs. 18 years)
Inability to distinguish cause and effect or whether circulating protein concentrations are cardiac-specific
Limited depth of proteomics profiling due to use of neat serum samples without depletion of highly abundant interfering proteins
Lack of healthy control comparison group
Small sample size (n=14 feasibility study)
Correction for multiple comparisons was not performed
Patients in Group 1 were younger than Group 2 (15 vs. 18 years, p=0.014), raising the possibility that developmental or maturational differences could influence the circulating proteome independent of remodeling

Implication

Distinct proteomic signatures accompany RV dilation in repaired TOF; leaves open utility for risk stratification or intervention.

Abstract

Background Patients with repaired tetralogy of Fallot (TOF) can develop right ventricular (RV) dilation and failure. We sought to utilize an untargeted serum proteomics approach to characterize the proteome signature associated with RV dilation in repaired TOF to improve the understanding of mechanistic drivers of RV remodeling. Methods Patients with repaired TOF undergoing cardiac magnetic resonance imaging were recruited. Groups were based on indexed RV end-diastolic volume (RVEDVi). Serum proteomics identified differentially abundant proteins ( p value < 0.05), and pathway enrichment identified functional pathways. Results Fourteen TOF adolescents (median age 16 years; IQR 15, 18) were divided into Group 1 ( n = 9; median RVEDVi 146 ml/m 2 ; IQR 139, 164) and Group 2 ( n = 5; median RVEDVi 114 ml/m 2 ; IQR 104, 130). Group 1 had a higher indexed RV stroke volume (85 ml/m 2 vs. 59 ml/m 2 , p = 0.023) with a similar RV ejection fraction. Group 1 had altered regulation of genes in multiple pathways, including glucose and fatty acid metabolism and antioxidant response. Conclusion Patients with repaired TOF and moderate-severe RV dilation have a distinct serum proteomic profile despite preserved ejection fraction, which may reflect alterations in fuel sources and oxidative stress. These hypothesis-generating findings are a first step in the integration of proteomics into clinical management. Impact An untargeted serum proteomics approach to identifying altered protein profiles associated with CMR-defined RV dilation is a novel approach to characterizing right ventricular remodeling after tetralogy of Fallot repair. RV dilation after repair of tetralogy of Fallot is associated with a specific proteomic profile suggesting adaptive and maladaptive remodeling. Identification of dysregulated proteins associated with RV remodeling provides insight into the mechanisms leading to ventricular failure after tetralogy of Fallot repair. With additional data from future larger studies, serum proteomics evaluation may assist in prognostication and clinical decision making in patients after tetralogy of Fallot repair.

Discussion

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Cite This Study

Jones et al. (2026) conducted a cross-sectional in Repaired tetralogy of Fallot with right ventricular dilation (n=14). Moderate-to-severe right ventricular dilation (RVEDVi > 139 ml/m2, median 146 ml/m2) vs. Less right ventricular dilation (RVEDVi <= 139 ml/m2, median 114 ml/m2) was evaluated on Indexed right ventricular stroke volume (RVSVi, ml/m2) and differentially abundant serum proteins (p=0.023). Moderate-to-severe RV dilation in repaired tetralogy of Fallot was associated with 60 differentially abundant serum proteins (p<0.05) and higher indexed RV stroke volume (85 vs 59 ml/m2, p=0.023).

synapsesocial.com/papers/6adb36d68ac4c2b7d2630bad https://doi.org/10.1038/s41390-026-05555-7

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A complementary proteomics and cardiac magnetic resonance approach to characterize right ventricular remodeling after tetralogy of Fallot repair

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

A complementary proteomics and cardiac magnetic resonance approach to characterize right ventricular remodeling after tetralogy of Fallot repair

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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