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

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 1.00-2.16; P-value = 0.047). 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.