Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes

Halloran, Philip F.; Madill‐Thomsen, Katelynn S.; Aliabadi-Zuckermann, Arezu; Cadeiras, Martín; Crespo-Leiro, María G.; DePasquale, E.C.; Deng, Mario C.; Gökler, Johannes; Kim, Daniel H.; Kobashigawa, J.A.; Macdonald, Peter M.; Potena, Luciano; Shah, Keyur B.; Stehlik, Josef; Zuckermann, Andreas

doi:10.1016/j.healun.2021.08.004

Cited by 25 publications

(40 citation statements)

References 32 publications

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“…As clinicians, we often consider TCMR to be "treatable," but because it often has severe effects on the parenchyma, it adversely affects short-term survival, much more so than AMR, which appears to spare the parenchyma for prolonged periods of time. 20 A majority (85%) of TCMR biopsies have extensive parenchymal injury, which we suspect will persist even after TCMR activity has been sterilized by treatment. Moreover, because we do not actually know whether our usual treatments actually sterilize TCMR molecular activity, existing parenchymal injury at the time of diagnosis may be exacerbated by new injury induced by smoldering TCMR activity long term.…”

Section: Discussionmentioning

confidence: 91%

“…At early times, AMR biopsies did not have elevated Late-injury scores; however, AMR at late times (>3 y) often had Late-injury (101 of 340 or 30%), much more than late biopsies with no rejection (15 of 462 or 3%). NR-Minor biopsies (which have mild AMR-like molecular changes despite being considered no rejection 20 ) also showed rising Late-injury scores over time. Biopsies with NR (NR-Normal) showed no substantial increase in Late-injury scores at late times.…”

Section: Resultsmentioning

confidence: 98%

“…Molecular rejection sign-out categories have been described. 20 Each biopsy was assigned to 1 of the 8 modified sign-out categories: AMR, pAMR, TCMR, pTCMR, mixed, and No rejection (NR), which was subdivided into NR-Minor, NR-Normal, and NR-Early injury. 20…”

Section: Methodsmentioning

confidence: 99%

“…In addition, the published 5 rejection archetype model 20 was used for some analyses: NR, TCMR, AMR, Minor-injury, and Early-injury. Archetypes are automatically assigned and avoid subjectivity.…”

Section: Methodsmentioning

confidence: 99%

“…20 Each biopsy was assigned to 1 of the 8 modified sign-out categories: AMR, pAMR, TCMR, pTCMR, mixed, and No rejection (NR), which was subdivided into NR-Minor, NR-Normal, and NR-Early injury. 20 In addition, the published 5 rejection archetype model 20 was used for some analyses: NR, TCMR, AMR, Minorinjury, and Early-injury. Archetypes are automatically assigned and avoid subjectivity.…”

Section: Rejectionmentioning

confidence: 99%

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Assessing the Relationship Between Molecular Rejection and Parenchymal Injury in Heart Transplant Biopsies

et al. 2022

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Background. The INTERHEART study (ClinicalTrials.gov #NCT02670408) used genome-wide microarrays to detect rejection in endomyocardial biopsies; however, many heart transplants with no rejection have late dysfunction and impaired survival. We used the microarray measurements to develop a molecular classification of parenchymal injury. Methods. In 1320 endomyocardial biopsies from 645 patients previously studied for rejection-associated transcripts, we measured the expression of 10 injury-induced transcript sets: 5 induced by recent injury; 2 reflecting macrophage infiltration; 2 normal heart transcript sets; and immunoglobulin transcripts, which correlate with time. We used archetypal clustering to assign injury groups. Results. Injury transcript sets correlated with impaired function. Archetypal clustering based on the expression of injury transcript sets assigned each biopsy to 1 of 5 injury groups: 87 Severe-injury, 221 Late-injury, and 3 with lesser degrees of injury, 376 No-injury, 526 Mild-injury, and 110 Moderate-injury. Severe-injury had extensive loss of normal transcripts (dedifferentiation) and increase in macrophage and injury-induced transcripts. Late-injury was characterized by high immunoglobulin transcript expression. In Severe- and Late-injury, function was depressed, and short-term graft failure was increased, even in hearts with no rejection. T cell–mediated rejection almost always had parenchymal injury, and 85% had Severe- or Late-injury. In contrast, early antibody-mediated rejection (AMR) had little injury, but late AMR often had the Late-injury state. Conclusions. Characterizing heart transplants for their injury state provides new understanding of dysfunction and outcomes and demonstrates the differential impact of T cell–mediated rejection versus AMR on the parenchyma. Slow deterioration from AMR emerges as a major contributor to late dysfunction.

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Section: Discussionmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 98%