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.

HIGHLIGHTS

Microvascular inflammation (representing pAMR ≥1) following heart transplantation is associated with increased risk of CAV and all-cause mortality, with or without accompanying anti-HLA donor-specific antibodies.

Microvascular inflammation may serve as a modifiable target in post-transplant care.

Urgent mechanistic studies are needed to distinguish between pathogenic vascular injury warranting intensified surveillance and immunosuppression, and clinically-inconsequential immune activity.

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.

This study did not receive any funding.

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This study was approved by the VUMC Institutional Review Board (#200551).

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