Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
[Preprint]. 2025 Jul 29:2025.07.29.25332346.
doi: 10.1101/2025.07.29.25332346.

Antibody-independent microvascular inflammation impacts long-term risk in heart transplantation

Shi Huang  1 , Nelson Chow  2 , Kyle Saysana  2 , Eric Farber-Eger  3 , Quinn S Wells  2   3 , David W Bearl  4 , JoAnn Lindenfeld  2 , Kelly H Schlendorf  2 , Kaushik Amancherla  2   3
Affiliations

Antibody-independent microvascular inflammation impacts long-term risk in heart transplantation

Shi Huang et al. medRxiv. .

Abstract

Background: Microvascular inflammation (MVI) following heart transplantation can occur with or without circulating anti-HLA donor-specific antibodies (DSAs). We sought to characterize the relationship between MVI, with or without accompanying DSA, and post-transplant outcomes.

Methods: We analyzed 8,305 endomyocardial biopsies (EMB) from 832 adult and pediatric HT recipients between July 1, 2013 and October 31, 2023. EMBs were graded by consensus guidelines, with MVI defined as pAMR grade ≥1. Rejection phenotypes were classified as no rejection, isolated cellular rejection (ACR), DSA-negative MVI, and DSA-positive MVI. Cox models with time-varying covariates were constructed to evaluate associations with incident CAV and mortality, adjusting for donor and recipient age.

Results: Among 832 HT recipients, 238 developed CAV and 121 died over a median follow-up of 4 years (IQR 2.3-6.4 years). Compared with individuals who never experienced biopsy-proven rejection, DSA-negative MVI was independently associated with CAV (HR, 1.47; 95% CI 1.01-2.16). DSA-positive MVI was associated with mortality (HR 1.97; 95% CI 1.07-3.64) with DSA-negative MVI demonstrating directional-concordance (HR 1.50, 95% CI 0.87-2.57), independent of CAV (HR 1.71, 95% CI 1.13-2.58). These associations remained consistent when stratified by adult and pediatric subgroups and in a six-month landmark sensitivity analysis.

Conclusions: MVI, with or without DSA, may be harmful in HT, extending recent renal findings to thoracic transplantation. Understanding the mechanistic basis for these results will be essential for identifying novel targets for therapeutic modulation and prolonging graft survival.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST Dr. Amancherla has an institutional disclosure filed for spatial RNA biomarkers of transplant rejection and allograft health. The other authors report no relevant conflicts of interest.

Figures

Figure 1.
Figure 1.. Distribution of rejection phenotypes across 8,305 endomyocardial biopsies.
ACR = acute cellular rejection; MVI = microvascular inflammation (defined here as pAMR1-h or pAMR1-i); AMR = antibody-mediated rejection (defined here are pAMR2 or pAMR3).
Figure 2.
Figure 2.. CAV-free survival and all-cause mortality following heart transplantation.
(A) Kaplan-Meier curve for CAV-free survival following transplantation in the entire cohort. Individuals were censored at last coronary assessment (e.g., angiography, pathology of explanted heart at time of re-do transplant or autopsy). (B) Kaplan-Meier curve for all-cause mortality following transplantation in the entire cohort.
Figure 2.
Figure 2.. CAV-free survival and all-cause mortality following heart transplantation.
(A) Kaplan-Meier curve for CAV-free survival following transplantation in the entire cohort. Individuals were censored at last coronary assessment (e.g., angiography, pathology of explanted heart at time of re-do transplant or autopsy). (B) Kaplan-Meier curve for all-cause mortality following transplantation in the entire cohort.
Figure 3.
Figure 3.. Association between microvascular inflammation (MVI), cardiac allograft vasculopathy (CAV), and all-cause mortality.
(A) Percentage of heart transplant (HT) recipients with varying rejection phenotypes—diagnosed on endomyocardial biopsy—who subsequently developed CAV. (B) Forest plot of hazard ratios (HRs) for incident CAV (yellow) and all-cause mortality (blue) derived from Cox proportional hazard models. In the CAV analysis, rejection phenotype and circulating DSAs were treated as time-varying covariates, while donor and recipient age were treated as fixed covariates. In the mortality analysis, CAV—the leading case of late mortality after HT—was also treated as a time-varying covariate.
Figure 3.
Figure 3.. Association between microvascular inflammation (MVI), cardiac allograft vasculopathy (CAV), and all-cause mortality.
(A) Percentage of heart transplant (HT) recipients with varying rejection phenotypes—diagnosed on endomyocardial biopsy—who subsequently developed CAV. (B) Forest plot of hazard ratios (HRs) for incident CAV (yellow) and all-cause mortality (blue) derived from Cox proportional hazard models. In the CAV analysis, rejection phenotype and circulating DSAs were treated as time-varying covariates, while donor and recipient age were treated as fixed covariates. In the mortality analysis, CAV—the leading case of late mortality after HT—was also treated as a time-varying covariate.
See this image and copyright information in PMC

References

    1. Sablik M, Sannier A, Raynaud M, Goutaudier V, Divard G, Astor BC, Weng P, Smith J, Garro R, Warady BA, et al. Microvascular Inflammation of Kidney Allografts and Clinical Outcomes. N Engl J Med. 2025;392:763–776. doi: 10.1056/NEJMoa2408835 - DOI - PubMed
    1. Mehra MR, Crespo-Leiro MG, Dipchand A, Ensminger SM, Hiemann NE, Kobashigawa JA, Madsen J, Parameshwar J, Starling RC, Uber PA. International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010. J Heart Lung Transplant. 2010;29:717–727. doi: 10.1016/j.healun.2010.05.017 - DOI - PubMed
    1. Colvin MM, Cook JL, Chang P, Francis G, Hsu DT, Kiernan MS, Kobashigawa JA, Lindenfeld J, Masri SC, Miller D, et al. Antibody-mediated rejection in cardiac transplantation: emerging knowledge in diagnosis and management: a scientific statement from the American Heart Association. Circulation. 2015;131:1608–1639. doi: 10.1161/CIR.0000000000000093 - DOI - PubMed
    1. Kobashigawa J, Zuckermann A, Zeevi A, Barten MJ, Chang PP, Colvin M, Coutance G, Dipchand A, Ensminger S, Farrero M, et al. Summary of the International Society for Heart and Lung Transplantation consensus conference on emerging understanding of antibodies and antibody-mediated rejection in heart transplantation. J Heart Lung Transplant. 2025. doi: 10.1016/j.healun.2025.02.1690 - DOI - PubMed
    1. Berry GJ, Burke MM, Andersen C, Bruneval P, Fedrigo M, Fishbein MC, Goddard M, Hammond EH, Leone O, Marboe C, et al. The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant. 2013;32:1147–1162. doi: 10.1016/j.healun.2013.08.011 - DOI - PubMed

Publication types