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ObjectivesTo evaluate the clinical implications of adjunctive molecular gene expression analysis (MMDx)of biopsy specimens in heart transplant (HT)recipients with suspected rejection.IntroductionHistopathological evaluation remains the standard method for rejection diagnosis in HT. However, the wide interobserver variability combined with a relatively common incidence of “biopsy-negative” rejection has raised concerns about the likelihood of false-negative results. MMDx, which uses gene expression to detect early signs of rejection, is a promising test to further refine the assessment of HT rejection.MethodsSingle-center prospective study of 418 consecutivefor-causeendomyocardial biopsies performed between November 2022 and May 2024. Each biopsy was graded based on histology and assessed for rejection patterns using MMDx. MMDx results were deemed positive if borderline or definitive rejection was present. The impact of MMDx results on clinical management was evaluated. Primary outcomes were 1-year survival and graft dysfunction following MMDx-guided clinical management. Secondary outcomes included changes in donor-specific antibodies, MMDx gene transcripts, and donor-derived cell-free DNA (dd-cfDNA) levels.ResultsWe analyzed 418 molecular samples from 237 unique patients. Histology identified rejection in 32 cases (7.7%), while MMDx identified rejection in 95 cases (22.7%). Notably, in 79 of the 95 cases where MMDx identified rejection, histology results were negative, with the majority of these cases being antibody-mediated rejection (62.1%). Samples with rejection on MMDx were more likely to show a combined elevation of dd-cfDNA and peripheral blood gene expression profiling than those with borderline or negative MMDx results (36.7% vs 28.0% vs 10.3%; p<0.001). MMDx results led to the implementation of specific antirejection protocols or changes in immunosuppression in 20.4% of cases, and in 73.4% of cases where histology was negative and MMDx showed rejection. 1-year survival was better in the positive MMDx group where clinical management was guided by MMDx results (87.0% vs 78.6%; log rank p=0.0017).ConclusionsIn our cohort, MMDx results more frequently indicated rejection than histology, often leading to the initiation of antirejection treatment. Intervention guided by positive MMDx results was associated with improved outcomes.Graphical abstract
ObjectivesTo evaluate the clinical implications of adjunctive molecular gene expression analysis (MMDx)of biopsy specimens in heart transplant (HT)recipients with suspected rejection.IntroductionHistopathological evaluation remains the standard method for rejection diagnosis in HT. However, the wide interobserver variability combined with a relatively common incidence of “biopsy-negative” rejection has raised concerns about the likelihood of false-negative results. MMDx, which uses gene expression to detect early signs of rejection, is a promising test to further refine the assessment of HT rejection.MethodsSingle-center prospective study of 418 consecutivefor-causeendomyocardial biopsies performed between November 2022 and May 2024. Each biopsy was graded based on histology and assessed for rejection patterns using MMDx. MMDx results were deemed positive if borderline or definitive rejection was present. The impact of MMDx results on clinical management was evaluated. Primary outcomes were 1-year survival and graft dysfunction following MMDx-guided clinical management. Secondary outcomes included changes in donor-specific antibodies, MMDx gene transcripts, and donor-derived cell-free DNA (dd-cfDNA) levels.ResultsWe analyzed 418 molecular samples from 237 unique patients. Histology identified rejection in 32 cases (7.7%), while MMDx identified rejection in 95 cases (22.7%). Notably, in 79 of the 95 cases where MMDx identified rejection, histology results were negative, with the majority of these cases being antibody-mediated rejection (62.1%). Samples with rejection on MMDx were more likely to show a combined elevation of dd-cfDNA and peripheral blood gene expression profiling than those with borderline or negative MMDx results (36.7% vs 28.0% vs 10.3%; p<0.001). MMDx results led to the implementation of specific antirejection protocols or changes in immunosuppression in 20.4% of cases, and in 73.4% of cases where histology was negative and MMDx showed rejection. 1-year survival was better in the positive MMDx group where clinical management was guided by MMDx results (87.0% vs 78.6%; log rank p=0.0017).ConclusionsIn our cohort, MMDx results more frequently indicated rejection than histology, often leading to the initiation of antirejection treatment. Intervention guided by positive MMDx results was associated with improved outcomes.Graphical abstract
ObjectiveCell‐free DNA (cfDNA) is used as a biomarker after transplantation to detect graft injury, relying on the donor fraction (DF). We have established a PCR‐based approach allowing us to separately quantify absolute values of dd‐cfDNA and recipient‐derived cfDNA (rd‐cfDNA). We aimed to present typical clinical scenarios after heart transplantation (HTx) to illustrate the advantages of absolute cfDNA values over DF.MethodsWe used the cfDNA results of our cohort (509 samples of 52 patients followed during the first year after HTx) as background and determined the trajectories of cfDNA in specific clinical situations. We profiled an uncomplicated clinical course, viral and bacterial infections, acute and chronic rejection, and false‐negative and false‐positive rejections in six patients (five adults, one child).ResultsThere was a substantial discrepancy between relative (DF) and absolute cfDNA‐levels in several clinical situations. Rd‐ and dd‐cfDNA were independently elevated during episodes of rejection and infection and were better suited to depict treatment response than DF alone.ConclusionsAbsolute quantification of cfDNA may offer clinically relevant information additive to DF in various situations after HTx and could be helpful for more accurate monitoring of diagnosis and treatment of rejection.
Background: Heart transplantation (HT) remains the ultimate treatment for end-stage heart failure. An endomyocardial biopsy (EMB) is “the gold standard” diagnostic procedure used in HT rejection surveillance. The aim of this study is to provide a detailed analysis of the histopathological characteristics of the EMB and to investigate if there is a correlation between some histopathological changes, such as fibrosis, vasculitis, Quilty effect (Q.E.), myocytes damage, and the presence of episodes of acute rejection. Methods: In this retrospective study, 200 EMBs were included, coming from 65 patients transplanted in the Emergency Institute for Cardiovascular Diseases and Transplantation (ICvDT) Targu Mures between 2012 and 2024. Fibrosis, vasculitis, Q.E., myocyte damage, etc., were microscopically evaluated to see if these parameters correlate with rejection episodes. Results: The mean age was 38.18 years (SD 15.67), 25% of biopsies being recorded in the 41–50 age group. 77.14% of total acute cellular rejection (ACR) was of mild rejection, with most registered in the 11–20 age group; the cases of severe rejection being recorded in the 41–50 age group. Antibody-mediated rejection (AMR) was recorded more frequently in women with a representation of 23.4%, compared to 8.5% of men. 86.7% (39 cases) of the total number of EMBs with fibrosis score 3 and 71.4% (15 cases) of the total EMBs with fibrosis score 2 were recorded in men, compared to the 28.6% (6 cases) of fibrosis score 2 recorded in women (p = 0.013). 50.0% of all the EMB recorded in the 61–70 age group showed fibrosis score 3, compared to 34.8% of those from the 21–30 age group. The Q.E. was identified in 13% of the biopsies and, in some patients, it was observed across 3–4 successive biopsies. Mild vasculitis was associated in 34.9% of cases with ISHLT ≥ 1R and moderate vasculitis was associated in 87.5% of cases with ISHLT ≥ 1R. Conclusions: Fibrosis was detected much more frequently in men and in the 61–70 age group. In addition to the histopathological changes specific to acute rejection, there are other pathological changes, such as the Q.E., and vasculitis and myocytes damage and disarray, that seem to suggest a close connection with rejection, but extensive studies are needed to confirm this.
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