Frailty in heart transplantation: Report from the heart workgroup of a consensus conference on frailty.

A consensus conference on frailty in solid organ transplantation took place on February 11, 2018, to discuss the latest developments in frailty, adopt a standardized approach to assessment, and generate ideas for future research. The findings and consensus of the Frailty Heart Workgroup (American Society of Transplantation's Thoracic and Critical Care Community of Practice) are presented here. Frailty is defined as a clinically recognizable state of increased vulnerability resulting from aging-associated decline in reserve and function across multiple physiologic systems such that the ability to cope with every day or acute stressors is compromised. Frailty is increasingly recognized as a distinct biologic entity that can adversely affect outcomes before and after heart transplantation. A greater proportion of patients referred for heart transplantation are older and have more complex comorbidities. However, outcomes data in the pretransplant setting, particularly for younger patients, are limited. Therefore, there is a need to develop objective frailty assessment tools for risk stratification in patients with advanced heart disease. These tools will help to determine appropriate recipient selection for advanced heart disease therapies including heart transplantation and mechanical circulatory support, improve overall outcomes, and help distinguish frailty phenotypes amenable to intervention.

Report from the American Society of Transplantation on frailty in solid organ transplantation.

A consensus conference on frailty in kidney, liver, heart, and lung transplantation sponsored by the American Society of Transplantation (AST) and endorsed by the American Society of Nephrology (ASN), the American Society of Transplant Surgeons (ASTS), and the Canadian Society of Transplantation (CST) took place on February 11, 2018 in Phoenix, Arizona. Input from the transplant community through scheduled conference calls enabled wide discussion of current concepts in frailty, exploration of best practices for frailty risk assessment of transplant candidates and for management after transplant, and development of ideas for future research. A current understanding of frailty was compiled by each of the solid organ groups and is presented in this paper. Frailty is a common entity in patients with end-stage organ disease who are awaiting organ transplantation, and affects mortality on the waitlist and in the posttransplant period. The optimal methods by which frailty should be measured in each organ group are yet to be determined, but studies are underway. Interventions to reverse frailty vary among organ groups and appear promising. This conference achieved its intent to highlight the importance of frailty in organ transplantation and to plant the seeds for further discussion and research in this field.

Does ex vivo perfusion lead to more or less intimal thickening in the first-year post-heart transplantation?

BACKGROUND: The Organ Care System (OCS), an ex vivo heart perfusion platform, represents an alternative to the current standard of cold organ storage that sustains the donor heart in a near-physiologic state. Previous reports showed that this system had significantly shortened the cold ischemic time from standard cold storage (CS). However, the effect of reduced ischemic injury against the coronary vascular bed has not been examined by intravascular ultrasound (IVUS). METHODS: Between August 2011 and February 2013, heart transplant (HTx) candidates enrolled in the PROCEED 2 trial were randomized to either CS or OCS. IVUS was performed at 4-6 weeks (baseline) and repeated 1 year after transplantation. The change in maximal intimal thickness (MIT) and other clinical outcomes were examined. RESULTS: Thirty-nine patients were randomized and underwent HTx by OCS (n=16) or CS (n=18). Of these, 18 patients (OCS: n=5, CS: n=13) with paired IVUS were examined. There were no significant differences in the change of MIT and other clinical outcomes between the groups. CONCLUSION: The incidence of cardiac allograft vasculopathy in donor hearts preserved with the OCS versus CS was similar. These results suggest that this ex vivo allograft perfusion system is a promising and valid platform for donor heart transportation.

Crossing low-level donor-specific antibodies in heart transplantation.

PURPOSE OF REVIEW: Donor-specific antibodies (DSA) detected by solid-phase single-antigen bead (SAB) immunoassays have been associated with antibody-mediated rejection (AMR), cardiac allograft vasculopathy (CAV) and decreased survival after heart transplantation. The clinical relevance of low-level DSA is equivocal. This review examines the techniques used to define low-level DSA, the limitations of these techniques and recent clinical experience crossing low-level DSA. RECENT FINDINGS: Solid-phase multiplex bead immunoassays were introduced to solid-organ transplantation over 15 years ago. These technologies have a much greater sensitivity and specificity than older cell-based immunoassays. It was hoped that this increased resolution would lead to better outcomes by avoiding donors with antigens that transplant candidates produced antibodies against. Although some transplant patients with DSA show increased risk of AMR and decreased survival, a subset of patients with DSA at the time of transplant have outcomes comparable with patients with no DSA. Recent studies have demonstrated that DSA delineated according to titration studies and C1q assays better define low-level DSA that are well tolerated to cross. Early experience with crossing low-level DSA shows promise in kidney and heart transplantation. SUMMARY: Preliminary findings from heart and kidney transplant patients show acceptable outcomes after crossing low-level DSA. The policy of crossing low-level DSA increases the donor pool for sensitized heart transplant candidates.

Prolonged corrected QT interval in the donor heart: Is there a risk?

BACKGROUND: Assessing the QT interval in donors is important to exclude long QT syndrome as the cause of death. A donor heart with a corrected QT (QTc ) >500 milliseconds is often concerning. We sought to evaluate first year outcomes for donors with a QTc interval >500 milliseconds. METHODS: Between 2010 and 2014, we assessed 257 donor hearts for QTc interval >500 milliseconds. Post-transplant outcomes included 1-year survival, 1-year freedom from any-treated rejection, 1-year freedom from cardiac allograft vasculopathy (CAV) defined as stenosis ≥30% by angiography, and 1-year freedom from nonfatal major adverse cardiac events. RESULTS: Patients with QTc interval >500 milliseconds had a significantly lower 1-year freedom from CAV development. There were no significant differences for other outcomes. A significantly higher percentage of donors with QTc >500 milliseconds had a stroke or subarachnoid hemorrhage. Multivariate analysis found that donor QTc >500 milliseconds was associated with a 6.7-fold increased risk of developing CAV (P=.029, 95% CI 1.21-36.6) after adjusting for other known risk factors. CONCLUSION: QTc >500 milliseconds in the donor heart appears to be an independent risk factor for the development of early CAV after heart transplantation possibly due to a higher immunological risk.

Comparing Plasma Donor-derived Cell-free DNA to Gene Expression in Endomyocardial Biopsies in the Trifecta-Heart Study.

BACKGROUND: Plasma donor-derived cell-free DNA (dd-cfDNA) is used to screen for rejection in heart transplants. We launched the Trifecta-Heart study ( ClinicalTrials.gov No. NCT04707872), an investigator-initiated, prospective trial, to examine the correlations between genome-wide molecular changes in endomyocardial biopsies (EMBs) and plasma dd-cfDNA. The present report analyzes the correlation of plasma dd-cfDNA with gene expression in EMBs from 4 vanguard centers and compared these correlations with those in 604 kidney transplant biopsies in the Trifecta-Kidney study ( ClinicalTrials.gov No. NCT04239703). METHODS: We analyzed 137 consecutive dd-cfDNA-EMB pairs from 70 patients. Plasma %dd-cfDNA was measured by the Prospera test (Natera Inc), and gene expression in EMBs was assessed by Molecular Microscope Diagnostic System using machine-learning algorithms to interpret rejection and injury states. RESULTS: Top transcripts correlating with dd-cfDNA were related to genes increased in rejection such as interferon gamma-inducible genes (eg, HLA-DMA ) but also with genes induced by injury and expressed in macrophages (eg, SERPINA1 and HMOX1 ). In gene enrichment analysis, the top dd-cfDNA-correlated genes reflected inflammation and rejection pathways. Dd-cfDNA correlations with rejection genes in EMB were similar to those seen in kidney transplant biopsies, with somewhat stronger correlations for TCMR genes in hearts and ABMR genes in kidneys. However, the correlations with parenchymal injury-induced genes and macrophage genes were much stronger in hearts. CONCLUSIONS: In this first analysis of Trifecta-Heart study, dd-cfDNA correlates significantly with molecular rejection but also with injury and macrophage infiltration, reflecting the proinflammatory properties of injured cardiomyocytes. The relationship supports the utility of dd-cfDNA in clinical management of heart transplant recipients.

A novel donor-derived cell-free DNA assay for the detection of acute rejection in heart transplantation.

BACKGROUND: Endomyocardial biopsy (EMB), the reference surveillance test for acute rejection (AR) in heart transplant (HTx) recipients, is invasive, costly, and shows significant interobserver variability. Recent studies indicate that donor-derived cell-free DNA (dd-cfDNA), obtained non-invasively from blood, is associated with AR and could reduce the frequency of EMB surveillance. The aim of this study was to examine the performance characteristics of a novel test for detecting AR in adult HTx recipients. METHODS: Plasma samples with contemporaneous EMBs were obtained from HTx recipients. A clinically available SNP-based massively multiplexed-PCR dd-cfDNA assay was used to measure dd-cfDNA fraction. dd-cfDNA fractions were compared with EMB-defined rejection status and test performance was assessed by constructing ROC curves and calculating accuracy measures. RESULTS: A total of 811 samples from 223 patients with dd-cfDNA testing and contemporaneous EMB were eligible for the study. dd-cfDNA fraction was significantly higher in AR (median 0.58%, IQR, 0.13%-1.68%) compared to non-AR (median 0.04%, IQR, 0.01%-0.11%, pc < 0.001). ROC analysis produced an area under the curve (AUC-ROC) of 0.86 (95% CI, 0.77-0.96). Defining samples with dd-cfDNA fraction ≥0.15% as AR yielded 78.5% sensitivity (95% CI, 60.7%-96.3%) and 76.9% specificity (95% CI, 71.1%-82.7%). Positive and negative predictive values were 25.1% (95% CI, 18.8%-31.5%) and 97.3% (95% CI, 95.1%-99.5%) respectively, calculated using the cohort AR prevalence of 9.0% (95% CI, 5.3%-12.8%) with adjustment for repeat samples. CONCLUSIONS: This novel dd-cfDNA test detects AR in HTx recipients with good accuracy and holds promise as a noninvasive test for AR in HTx recipients.

Clinical Validation of a Plasma Donor-derived Cell-free DNA Assay to Detect Allograft Rejection and Injury in Lung Transplant.

Background: Lung transplant patients are vulnerable to various forms of allograft injury, whether from acute rejection (AR) (encompassing acute cellular rejection [ACR] and antibody-mediated rejection [AMR]), chronic lung allograft dysfunction (CLAD), or infection (INFXN). Previous research indicates that donor-derived cell-free DNA (dd-cfDNA) is a promising noninvasive biomarker for the detection of AR and allograft injury. Our aim was to validate a clinical plasma dd-cfDNA assay for detection of AR and other allograft injury and to confirm and expand on dd-cfDNA and allograft injury associations observed in previous studies. Methods: We measured dd-cfDNA fraction using a novel single-nucleotide polymorphism-based assay in prospectively collected plasma samples paired with clinical-pathologic diagnoses. dd-cfDNA fraction was compared across clinical-pathologic cohorts: stable, ACR, AMR, isolated lymphocytic bronchiolitis, CLAD/neutrophilic-responsive allograft dysfunction (NRAD), and INFXN. Performance characteristics were calculated for AR and combined allograft injury (AR + CLAD/NRAD + INFXN) versus the stable cohort. Results: The study included 195 samples from 103 patients. Median dd-cfDNA fraction was significantly higher for ACR (1.43%, interquartile range [IQR]: 0.67%-2.32%, P = 5 × 10-6), AMR (2.50%, IQR: 2.06%-3.79%, P = 2 × 10-5), INFXN (0.74%, IQR: 0.46%-1.38%, P = 0.02), and CLAD/NRAD (1.60%, IQR: 0.57%-2.60%, P = 1.4 × 10-4) versus the stable cohort. Area under the receiver operator characteristic curve for AR versus stable was 0.91 (95% confidence interval [CI]: 0.83-0.98). Using a ≥1% dd-cfDNA fraction threshold, sensitivity for AR was 89.1% (95% CI: 76.2%-100.0%), specificity 82.9% (95% CI: 73.3%-92.4%), positive predictive value, 51.9% (95% CI: 37.5%-66.3%), and negative predictive value, 97.3% (95% CI: 94.3%-100%). For combined allograft injury area under the receiver operator characteristic curve was 0.76 (95% CI: 0.66-0.85), sensitivity 59.9% (95% CI: 46.0%-73.9%), specificity 83.9% (95% CI: 74.1%-93.7%), positive predictive value, 43.6% (95% CI: 27.6%-59.6%), and negative predictive value, 91.0% (95% CI: 87.9%-94.0%). Conclusions: These results indicate that our dd-cfDNA assay detects AR and other allograft injury. dd-cfDNA monitoring, accompanied by standard clinical assessments, represents a valuable precision tool to support lung transplant health and is appropriate for further assessment in a prospective randomized-controlled study.

Combined heart and kidney transplantation-Is there a protective effect against cardiac allograft vasculopathy using intravascular ultrasound?

BACKGROUND: Because cardiac and renal disease are physiologically related and often coexist, the prevalence of combined heart and kidney transplantation (HKTx) has significantly increased over the last few years. It has been suggested that combined organ allografts modulate the immune system favorably for one or both allografts resulting in successful clinical outcomes. However, whether the addition of kidney transplantation has a protective immune effect against developing cardiac allograft vasculopathy (CAV) has not been fully investigated. METHODS: From March 2010 to September 2018, 30 HKTx recipients who had baseline (4-6 weeks) and 1-year intravascular ultrasound (IVUS) were matched with 60 isolated heart transplant (HTx-alone) recipients using propensity scores. First-year changes in maximal intimal thickness (MIT), maximal intimal area (MIA), maximal percent stenosis (MPS), percent atheroma volume (PAV), and incidence of rapid plaque progression were compared between the groups. RESULTS: First-year coronary plaque progression was significantly decreased in HKTx recipients compared with HTx-alone recipients by change in the MIT (0.11 ± 0.14 mm vs 0.40 ± 0.32 mm, p < 0.001), MIA (0.52 ± 1.52 mm2 vs 1.86 ± 2.68 mm2, p = 0.002), MPS (2.10% ± 5.64 percentage points vs 7.22% ± 8.59 percentage points, p = 0.001), and PAV (1.62% ± 3.07 percentage points vs 5.90% ± 5.92 percentage points, p < 0.001). Rapid plaque progression occurred in 2 of 30 in HKTx (6.7%) and in 22 of 60 HTx alone (36.7%), p = 0.002. CONCLUSIONS: Combined heart and kidney transplantation is associated with a decrease in CAV by coronary plaque progression on IVUS. These results suggest that HKTx may have an immune modulating benefit over HTx alone.

Imaging in Heart Transplant Patients.

Heart transplantation is an accepted treatment for select patients with end-stage heart failure. Improvements to immunosuppressive therapies and patient management have increased the half-life of heart transplant patients to over 10 years. Despite this success, rejection remains the "Achilles heel" of heart transplantation. The early detection of acute rejection and cardiac allograft vasculopathy are paramount to avoiding graft loss. Unlike in kidney and liver transplantation, there are no clinically validated biomarkers for detecting heart transplant rejection. Existing methods for monitoring the cardiac allograft are invasive. The endomyocardial biopsy is the standard-of-care for monitoring for acute rejection but carries risks of complications, and histologic assessment is often subjective. Equally, intracoronary angiography remains the standard-of-care for detecting cardiac allograft vasculopathy, but it is invasive and less than ideally sensitive. Newer echocardiographic techniques, computed tomography, magnetic resonance, and positron emission tomography are less invasive than conventional biopsy and show promise in excluding rejection thereby potentially decreasing the frequency of biopsies in low-risk patients. Intravascular ultrasonography and optical coherence tomography, although still invasive, improve on the assessment of the coronary tree through increased resolution, evaluation of the microvasculature, and visualization of the vessel wall. This review outlines the invasive and noninvasive imaging modalities that are employed in the routine care of heart transplant patients and examines newer techniques that are under evaluation.

The management of antibodies in heart transplantation: An ISHLT consensus document.

Despite the successes from refined peri-operative management techniques and immunosuppressive therapies, antibodies remain a serious cause of morbidity and mortality for patients both before and after heart transplantation. Patients awaiting transplant who possess antibodies against human leukocyte antigen are disadvantaged by having to wait longer to receive an organ from a suitably matched donor. The number of pre-sensitized patients has been increasing, a trend that is likely due to the increased use of mechanical circulatory support devices. Even patients who are not pre-sensitized can go on to produce donor-specific antibodies after transplant, which are associated with worse outcomes. The difficulty in managing antibodies is uncertainty over which antibodies are of clinical relevance, which patients to treat, and which treatments are most effective and safe. There is a distinct lack of data from prospective trials. An international consensus conference was organized and attended by 103 participants from 75 centers to debate contentious issues, determine the best practices, and formulate ideas for future research on antibodies. Prominent experts presented state-of-the-art talks on antibodies, which were followed by group discussions, and then, finally, a reconvened session to establish consensus where possible. Herein we address the discussion, consensus points, and research ideas.