Noninvasive biomarkers for prediction and diagnosis of heart transplantation rejection

Khachatoorian, Yeraz; Khachadourian, Vahe; Chang, En‐Ting; Sernas, Erick R.; Reed, Elaine F.; Deng, Mario C.; Piening, Brian D.; Pereira, Alexandre C.; Keating, Brendan J.; Cadeiras, Martín

doi:10.1016/j.trre.2020.100590

Cited by 14 publications

(9 citation statements)

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“…It commonly remains clinically silent because of the denervation of the transplanted heart and tends to be diagnosed at an advanced stage of the disease. Presentations of CAV include myocardial infarction, congestive heart failure, arrhythmia, and/or sudden cardiac death (53)(54)(55)(56)(57)(58)(59). Because of the serious sequelae of CAV, extensive investigation has focused on risk factors, prediction, and prevention.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the pathogenesis is not fully understood, and the management of CAV continues to pose a challenge. However, both immune and non-immune factors in the donor and recipient have been identified as related to the development of CAV ( 53 – 59 ). In addition, several biomarkers in blood and tissue are found to correlate with the presence of CAV, and that may be able to predict CAV ( 53 , 54 , 59 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, both immune and non-immune factors in the donor and recipient have been identified as related to the development of CAV ( 53 – 59 ). In addition, several biomarkers in blood and tissue are found to correlate with the presence of CAV, and that may be able to predict CAV ( 53 , 54 , 59 ). Recent evidence suggests that novel imaging techniques have high sensitivity and specificity for detection of CAV, such as intravascular ultrasound (IVUS), optical coherence tomography (OCT) and coronary computed tomography angiography (CCTA) ( 55 – 58 ), but these are not yet routinely used.…”

Section: Discussionmentioning

confidence: 99%

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Clinicopathological correlations in heart transplantation recipients complicated by death or re-transplantation

McDonald

Mihalj²,

Zhao³

et al. 2022

Front. Cardiovasc. Med.

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PurposeThis study aimed to identify and correlate pathological findings with clinical outcomes in patients after orthotopic heart transplantation (OHT) who either died or underwent a re-transplantation.Methodology and study designSingle-center retrospective analysis of primary OHT patients who died or were re-transplanted between October 2012 and July 2021. Clinical data were matched with corresponding pathological findings from endomyocardial biopsies on antibody-mediated rejection, cellular rejection, and cardiac allograft vasculopathy. Re-assessment of available tissue samples was performed to investigate acute myocardial injury (AMI) as a distinct phenomenon. These were correlated with clinical outcomes, which included severe primary graft dysfunction. Patients were grouped according to the presence of AMI and compared.ResultsWe identified 47 patients with truncated outcomes after the first OHT. The median age was 59 years, 36 patients (76%) were male, 25 patients (53%) had a prior history of cardiac operation, and 21 patients (45%) were supported with a durable assist device before OHT. Of those, AMI was identified in 22 (47%) patients (AMI group), and 25 patients had no AMI (non-AMI group). Groups were comparable in baseline and perioperative data. Histopathological observations in AMI group included a non-significant higher incidence of antibody-mediated rejection Grade 1 or higher (pAMR ≥ 1) (32% vs. 12%, P = 0.154), and non-significant lower incidence of severe acute cellular rejection (ACR ≥ 2R) (32% vs. 40%, P = 0.762). Clinical observations in the AMI group found a significantly higher occurrence of severe primary graft dysfunction (68% vs. 20%, P = 0.001) and a highly significant shorter duration from transplantation to death or re-transplantation (42 days [IQR 26, 120] vs. 1,133 days [711–1,664], P < 0.0001). Those patients had a significantly higher occurrence of cardiac-related deaths (64% vs. 24%, P = 0.020). No difference was observed in other outcomes.ConclusionIn heart transplant recipients with a truncated postoperative course leading to either death or re-transplantation, AMI in endomyocardial biopsies was a common pathological phenomenon, which correlated with the clinical occurrence of severe primary graft dysfunction. Those patients had significantly shorter survival times and higher cardiac-related deaths. The presence of AMI suggests a truncated course after OHT.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Clinicopathological correlations in heart transplantation recipients complicated by death or re-transplantation

McDonald

Mihalj²,

Zhao³

et al. 2022

Front. Cardiovasc. Med.

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“…So-called 'liquid biopsies' have seen increased use for monitoring of OHT rejection [12,13]. The two major technologies involved include gene expression profiling (GEP) of peripheral leukocytes, marketed as AlloMap (CareDx Inc., Brisbane, CA) [14]; and donor-derived cell-free DNA (dd-cf-DNA) detection, marketed as AlloSure (CareDx Inc., Brisbane, CA) [15].…”

Section: Biomarker Testing For Acute Rejectionmentioning

confidence: 99%

Noninvasive methods to reduce cardiac complications postheart transplant

Zhou

Wolfson

Vaidya

2021

Current Opinion in Organ Transplantation

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Purpose of reviewLong-term success of heart transplantation is limited by allograft rejection and cardiac allograft vasculopathy (CAV). Classic management has relied on frequent invasive testing to screen for early features of rejection and CAV to allow for early treatment. In this review, we discuss new developments in the screening and prevention of allograft rejection and CAV. Recent findingsNewer noninvasive screening techniques show excellent sensitivity and specificity for the detection of clinically significant rejection. New biomarkers and treatment targets continue to be identified and await further studies regarding their utility in preventing allograft vasculopathy. SummaryNoninvasive imaging and biomarker testing continue to show promise as alternatives to invasive testing for allograft rejection. Continued validation of their effectiveness may lead to new surveillance protocols with reduced frequency of invasive testing. Furthermore, these noninvasive methods will allow for more personalized strategies to reduce the complications of long-term immunosuppression whereas continuing the decline in the overall rate of allograft rejection.

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“…Despite continued efforts to develop noninvasive imaging tools, 8 there are limited modalities to detect acute allograft rejection before myocytes are damaged. In this regard, previous hypothesis-generating studies evaluated the clinical relevance of the index of microcirculatory resistance (IMR), a readily measurable and reliable index to define microcirculatory dysfunction, in patients after heart transplantation.…”

mentioning

confidence: 99%

Coronary Microcirculatory Dysfunction and Acute Cellular Rejection After Heart Transplantation

Lee

Choi

et al. 2021

Circulation

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Background: Acute cellular rejection is a major determinant of mortality and re-transplantation after heart transplantation. We sought to evaluate prognostic implications of coronary microcirculatory dysfunction assessed by index of microcirculatory resistance (IMR) for risk of acute cellular rejection after heart transplantation. Methods: The current study prospectively enrolled 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiologic assessment 1 month after transplantation. IMR is microcirculatory resistance under maximal hyperemia. By measuring hyperemic mean transit time using 3 injections (4 mL each) of room-temperature saline under maximal hyperemia, IMR was calculated as hyperemic distal coronary pressure × hyperemic mean transit time. The primary endpoint was biopsy-proven acute cellular rejection of grade ≥2R during 2 years of follow-up after transplantation and was compared using multivariable Cox proportional hazard regression according to IMR. The incremental prognostic value of IMR, in addition to the model with clinical factors, was evaluated by comparison of c-index, net reclassification index (NRI), and integrated discrimination index (IDI). Results: Mean age of recipients was 51.2±13.1 years (81.2% male), and cumulative incidence of acute cellular rejection was 19.0% at 2 years. Patients with acute cellular rejection had significantly higher IMR values at 1 month than those without acute cellular rejection (23.1±8.6 vs. 16.8±11.1, P=0.002). IMR was significantly associated with the risk of acute cellular rejection (per 5-unit increase: adjusted HR 1.18, 95% CI 1.04-1.34, P=0.011) and the optimal cut-off value of IMR to predict acute cellular rejection was 15. Patients with IMR≥15 showed significantly higher risk of acute cellular rejection than those with IMR<15 (34.4% vs. 3.8%, adjusted HR 15.3, 95% CI 3.6-65.7, P<0.001). Addition of IMR to clinical variables showed significantly higher discriminant and reclassification ability for risk of acute cellular rejection (C-index 0.87 vs. 0.74, P<0.001; NRI 1.05, P<0.001, IDI 0.20, P<0.001). Conclusions: Coronary microcirculatory dysfunction assessed by IMR measured early after heart transplantation showed significant association with the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02798731

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Noninvasive biomarkers for prediction and diagnosis of heart transplantation rejection

Cited by 14 publications

References 148 publications

Clinicopathological correlations in heart transplantation recipients complicated by death or re-transplantation

Clinicopathological correlations in heart transplantation recipients complicated by death or re-transplantation

Noninvasive methods to reduce cardiac complications postheart transplant

Coronary Microcirculatory Dysfunction and Acute Cellular Rejection After Heart Transplantation

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