Ex Vivo Perfusion Unmasks a Proteomic Signature of Primary Graft Dysfunction in Donor Hearts

Q: What are the key findings of this study?

Hearts destined for primary graft dysfunction demonstrated divergent proteomic trajectories during ex vivo perfusion, including early enrichment of senescence-associated pathways (NES=1.93, q<0.01).

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Primary graft dysfunction in human donation-after-circulatory-death (DCD) hearts (n=37). Intervention: Destined for Primary Graft Dysfunction (PGD) vs. Non-PGD hearts. Primary outcome: Circulating proteome remodeling and pathway enrichment during EVHP (at initiation) (NES=1.93, p=q<0.01).

Q: What does this research mean for the field?

Hearts destined to develop primary graft dysfunction exhibit divergent proteomic trajectories during ex vivo heart perfusion characterized by early enrichment of senescence-associated pathways followed by dynamic activation of apoptotic, catabolic, and inflammatory programs. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To identify perfusate proteomic alterations during ex vivo heart perfusion that distinguish donor hearts susceptible to primary graft dysfunction.

Selena S. Li; Bill Michaud; Asishana Avo Osho; David A. D’Alessandro; Gregory D. Lewis; Anthony Rosenzweig; S. Alireza Rabi; James Sawalla Guseh

doi:10.1016/j.jchf.2026.103298

August 1, 2026JACC Heart FailureOpen Access

Ex Vivo Perfusion Unmasks a Proteomic Signature of Primary Graft Dysfunction in Donor Hearts

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Key result

Hearts developing primary graft dysfunction show early enrichment of senescence-associated proteomic pathways during ex vivo perfusion.

NES=1.93
P q<0.01
n=37

Why the study?

Primary graft dysfunction remains the leading cause of early mortality after heart transplantation and limits broader adoption of donation-after-circulatory-death hearts, with molecular features during ex vivo heart perfusion not fully characterized.

Does ex vivo heart perfusion unmask distinct proteomic signatures in DCD donor hearts destined for primary graft dysfunction?

Key Points

To identify perfusate proteomic alterations during ex vivo heart perfusion that distinguish donor hearts susceptible to primary graft dysfunction.
Conducted high-throughput serial perfusate proteomics on a matched cohort of donor hearts with and without primary graft dysfunction (n = 20 total; n = 10 per group).
Donors were matched on clinical risk factors, including age, sex, ischemic time, cause of death, and transport distance.
Assessed hearts during ex vivo heart perfusion spanning 3 to 7 hours (mean 4.7 ± 1.0 hours) across initial and end-perfusion intervals.
Gene set enrichment analysis revealed significant enrichment of the Senescent Associated Secretory Pathway in hearts that developed graft dysfunction early during perfusion (NES 1.93, adjusted p<0.001) and at end-perfusion (NES 1.96, adjusted p<0.001).
At end-perfusion, CCL2/MCP-1 levels were significantly elevated in dysfunction grafts compared to non-dysfunction grafts (log 2 FC = 2.5, FDR = 0.006).
Hearts destined for graft dysfunction exhibited marked remodeling with 1,242 increased and 745 decreased proteins during perfusion, compared to 859 increased and 271 decreased proteins in non-dysfunction hearts.

Study Design

Type

Cohort (n=37)

Structured PICO

Does ex vivo heart perfusion unmask distinct proteomic signatures in DCD donor hearts destined for primary graft dysfunction?

P

Population

37 human donation-after-circulatory-death donor hearts supported on ex vivo heart perfusion (with a 20-heart propensity-matched cohort analyzed), mean age 33.8 years, 20% female, assessed for proteomic markers of early graft dysfunction.

E

Exposure

Destined for Primary Graft Dysfunction (PGD) requiring post-operative mechanical circulatory support within 7 days

C

Comparator

Non-PGD controls (destined for favorable outcomes without early severe dysfunction)

O

Outcome

Circulating proteomic profiles (protein abundance and pathway enrichment) measured at EVHP initiation (0-2 hours) and termination (3-6 hours)surrogate

Main Result

Effect estimate: NES=1.93

p-value: p=q<0.01

Limitations

Modest cohort size (n=10 per group) limits statistical power.
One baseline sample was obtained at less than 1 hour of perfusion, which may not have allowed enough rewarming time.
Findings require validation in larger cohorts and with complementary tissue-based approaches.
Analysis was restricted to donor-derived proteomics prior to implantation and does not account for recipient immune responses.
Modest cohort size (n=10 per group)
One baseline sample obtained at less than 1 hour of perfusion which may not have allowed enough rewarming time
Requires validation in larger cohorts
Analysis restricted to donor-derived proteomics, independent of recipient immune responses

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Implication

Ex vivo heart perfusion serves as a physiologic stress test that can unmask early molecular signatures of graft vulnerability, particularly senescence and apoptotic pathways, in donor hearts destined for primary graft dysfunction.

Abstract

Background: Primary graft dysfunction (PGD) remains the leading cause of early mortality after heart transplantation and limits broader adoption of donation-after-circulatory-death (DCD) hearts. Ex vivo heart perfusion (EVHP) provides a human platform to characterize molecular features associated with graft performance. Objective: This study examines the circulating proteome during EVHP to determine potential markers or modulators of PGD in DCD hearts. Methods: We prospectively studied 37 human DCD hearts supported on EVHP. Perfusate was sampled at initiation (0–2 hours) and termination (3–6 hours) and profiled using a high-throughput proteomic platform (SomaScan 11K). Ten PGD cases were propensity-matched to 10 non-PGD controls. Differential protein abundance and pathway enrichment analyses were performed. Results: At EVHP initiation, PGD hearts demonstrated enrichment of senescence-associated pathways (NES=1.93, q<0.01). By EVHP termination, proteomic profiles more clearly separated PGD from non-PGD hearts. PGD hearts exhibited broader proteomic remodeling, with 1,242 increased proteins (742 unique, q<0.05) and 745 decreased proteins (619 unique, q<0.05). Protein abundance was more dynamically associated with perfusion time in PGD hearts (33 proteins; median |ρ|=0.78, q<0.05) compared with non-PGD hearts (3 proteins; median |ρ|=0.83, q<0.05). Pathway analysis revealed enrichment of apoptotic (NES=1.75, q<0.05) and catabolic programs (NES=1.42, q<0.05), with concurrent activation of inflammatory pathways (NES = 1.68, q < 0.05) in hearts destined to have PGD. Conclusion: PGD is defined less by baseline differences than by divergent proteomic trajectories during EVHP. Early enrichment of senescence-associated pathways is followed by coordinated activation of apoptotic and catabolic programs. These findings position EVHP as a physiologic window for identifying molecular signatures of graft dysfunction and suggest an opportunity for targeted intervention in DCD donor hearts.

Discussion

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Cite This Study

Li et al. (2026) conducted a cohort in Primary graft dysfunction in human donation-after-circulatory-death (DCD) hearts (n=37). Destined for Primary Graft Dysfunction (PGD) vs. Non-PGD hearts was evaluated on Circulating proteome remodeling and pathway enrichment during EVHP (at initiation) (NES=1.93, p=q<0.01). Hearts destined for primary graft dysfunction demonstrated divergent proteomic trajectories during ex vivo perfusion, including early enrichment of senescence-associated pathways (NES=1.93, q<0.01).

synapsesocial.com/papers/6ad115f600741cc3fba7dbc9 https://doi.org/10.1016/j.jchf.2026.103298

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Ex Vivo Perfusion Unmasks a Proteomic Signature of Primary Graft Dysfunction in Donor Hearts

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Ex Vivo Perfusion Unmasks a Proteomic Signature of Primary Graft Dysfunction in Donor Hearts

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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