Kiran Kaur Khush, MD

All Publications

• Is Equity Being Traded for Access to Heart Transplant? JAMA Heidenreich, P. A., Lewis, E. F., Khush, K. K. 2024

  View details for DOI 10.1001/jama.2024.0812

  View details for PubMedID 38526454

• Research Opportunities and Ethical Considerations for Heart and Lung Xenotransplantation Research: A report from a National Heart, Lung, and Blood Institute workshop. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Khush, K. K., Bernat, J. L., Pierson, R. N., Silverman, H. J., Parent, B., Glazier, A. K., Adams, A. B., Fishman, J. A., Gusmano, M., Hawthorne, W. J., Homan, M. E., Hurst, D. J., Latham, S., Park, C., Maschke, K. J., Mohiuddin, M. M., Montgomery, R. A., Odim, J., Pentz, R. D., Reichart, B., Savulescu, J., Wolpe, P. R., Wong, R. P., Fenton, K. N. 2024

  Abstract

  Xenotransplantation offers the potential to meet the critical need for heart and lung transplantation presently constrained by the current human donor organ supply. Much was learned over the past decades regarding gene editing to prevent the immune activation and inflammation that cause early organ injury, and strategies for maintenance immunosuppression to promote longer-term xenograft survival. However, many scientific questions remain regarding further requirements for genetic modification of donor organs, appropriate contexts for xenotransplantation research (including non-human primates, recently deceased humans, and living human recipients), and risk of xenozoonotic disease transmission. Related ethical questions include appropriate selection of clinical trial participants, challenges with obtaining informed consent, animal rights and welfare considerations, and cost. Research involving recently deceased humans has also emerged as a potential novel way to understand how xeno-organs will impact the human body. Clinical xenotransplantation and research involving decedents also raise ethical questions, and will require consensus regarding regulatory oversight and protocol review. These considerations and the related opportunities for xenotransplantation research were discussed in a workshop sponsored by the National Heart, Lung, and Blood Institute, and are summarized in this meeting report.

  View details for DOI 10.1016/j.ajt.2024.03.015

  View details for PubMedID 38514013

• Sex-Specific Patterns of Donor-Derived Cell-Free DNA in Heart Transplant Rejection: An Analysis from the Genomic Research Alliance for Transplantation (GRAfT). The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation DeFilippis, E. M., Sweigart, B., Khush, K. K., Shah, P., Agbor-Enoh, S., Valantine, H. A., Vest, A. R. 2024

  Abstract

  INTRODUCTION: Non-invasive methods for surveillance of acute rejection are increasingly used in heart transplantation (HT), including donor-derived cell-free DNA (dd-cfDNA). As other cardiac biomarkers differ by sex, we hypothesized that there may be sex-specific differences in performance of dd-cfDNA for detection of acute rejection. The purpose of the current study was to examine patterns of dd-cfDNA seen in quiescence and acute rejection in males and female transplant recipients.METHODS: Patients enrolled in the Genomic Research Alliance for Transplantation (GRAfT) who were ≥18 years at the time of HT were included. Rejection was defined by endomyocardial biopsy with ISHLT acute cellular rejection (ACR) grade ≥2R and/or antibody-mediated rejection ≥ pAMR 1. dd-cfDNA was quantitated using shotgun sequencing. Median dd-cfDNA levels were compared between sexes during quiescence and rejection. The performance of dd-cfDNA by sex was assessed using AUROC. Allograft injury was defined as ddcfDNA ≥0.25%.RESULTS: 151 unique patients (49 female, 32%) were included in the analysis with 1119 available dd-cfDNA measurements. Baseline characteristics including demographics and comorbidities were not significantly different between sexes. During quiescence, there were no significant sex differences in median dd-cfDNA level (0.04% [IQR 0.00, 0.16] in females vs 0.03% [IQR 0.00, 0.12] in males, p = 0.22). There were no significant sex differences in median dd-cfDNA for ACR (0.33% [0.21, 0.36] in females vs 0.32% [0.21, 1.10] in males, p = 0.57). Overall, median dd-cfDNA levels were higher in AMR than ACR but did not significantly differ by sex (0.50% [IQR 0.18, 0.82] in females vs 0.63% [IQR 0.32, 1.95] in males, p = 0.51). Elevated dd-cfDNA detected ACR/AMR with an AUROC of 0.83 in females and 0.89 in males, p-value for comparison = 0.16.DISCUSSION: There were no significant sex differences in dd-cfDNA levels during quiescence and rejection. Performance characteristics were similar, suggesting that similar diagnostic thresholds can be used in men and women for rejection surveillance.

  View details for DOI 10.1016/j.healun.2024.03.001

  View details for PubMedID 38460620

• Knowledge Gaps in Heart and Lung Donation after the Circulatory Determination of Death: Report of a Workshop of the National Heart, Lung, and Blood Institute. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Bernat, J. L., Khush, K. K., Shemie, S. D., Hartwig, M. G., Reese, P. P., Ave, A. D., Brendan Parent, J. D., Glazier, A. K., Capron, A. M., Craig, M., Gofton, T., Gordon, E. J., Healey, A., Homan, M. E., Ladin, K., Messer, S., Murphy, N., Nakagawa, T. A., Parker, W. F., Pentz, R. D., Rodríguez-Arias, D., Schwartz, B., Sulmasy, D. P., Truog, R. D., Wall, A. E., Wall, S. P., Wolpe, P. R., Fenton, K. N. 2024

  Abstract

  In a workshop sponsored by the U.S. National Heart, Lung, and Blood Institute, experts identified current knowledge gaps and research opportunities in the scientific, conceptual, and ethical understanding of organ donation after the circulatory determination of death and its technologies. To minimize organ injury from warm ischemia and produce better recipient outcomes, innovative techniques to perfuse and oxygenate organs postmortem in situ, such as thoracoabdominal normothermic regional perfusion, are being implemented in several medical centers in the US and elsewhere. These technologies have improved organ outcomes but have raised ethical and legal questions. Re-establishing donor circulation postmortem can be viewed as invalidating the condition of permanent cessation of circulation on which the earlier death determination was made and clamping arch vessels to exclude brain circulation can be viewed as inducing brain death. Alternatively, TA-NRP can be viewed as localized in-situ organ perfusion, not whole-body resuscitation, that does not invalidate death determination. Further scientific, conceptual, and ethical studies, such as those identified in this workshop, can inform and help resolve controversies raised by this practice.

  View details for DOI 10.1016/j.healun.2024.02.1455

  View details for PubMedID 38432523

• Post-transplant Survival after Normothermic Regional Perfusion vs Direct Procurement and Perfusion in Donation after Circulatory Determination of Death Heart Transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Ran, G., Wall, A. E., Narang, N., Khush, K. K., Hoffman, J. R., Zhang, K. C., Parker, W. F. 2024

  Abstract

  Since 2019, the annual transplantation rate of hearts donated following circulatory death (DCD) has increased significantly in the United States. The two major heart procurement techniques following circulatory death are direct procurement and perfusion (DPP) and normothermic regional perfusion (NRP). Post-transplant survival for heart recipients has not been compared between these two techniques.This observational study uses data on adult heart transplants from donors after circulatory death from January 1, 2019, to December 31, 2021, in the Scientific Registry of Transplant Recipients. We identified comparable transplant cases across procurement types using propensity-score matching and measured the association between procurement technique and 1-year post-transplant survival using Kaplan-Meier and mixed-effect Cox proportional hazards models with random intercepts for each center.Among 318 DCD heart transplants, 216 (68%) were procured via DPP, and 102 (32%) via NRP. Among 22 transplant centers that accepted circulatory-death donors, 3 used NRP exclusively, and 5 used both procurement techniques. After propensity-score matching on recipient and donor factors, there was no significant difference in one-year post-transplant survival (93.1% for NRP vs 91.1% for DPP, p = 0.79) between procurement techniques.NRP and DPP procurements are associated with similar one-year post-transplant survival. If NRP is ethically permissible and improves outcomes for abdominal organs, it should be the preferred procurement technique for DCD hearts.The data that support the findings of this study are available from the Scientific Registry of Transplant Recipients (SRTR). Restrictions apply to the availability of these data, which were used under license for this study.

  View details for DOI 10.1016/j.healun.2024.02.1456

  View details for PubMedID 38423416

• Development and Validation of a Risk Score Predicting Death Without Transplant in Adult Heart Transplant Candidates. JAMA Zhang, K. C., Narang, N., Jasseron, C., Dorent, R., Lazenby, K. A., Belkin, M. N., Grinstein, J., Mayampurath, A., Churpek, M. M., Khush, K. K., Parker, W. F. 2024; 331 (6): 500-509

  Abstract

  The US heart allocation system prioritizes medically urgent candidates with a high risk of dying without transplant. The current therapy-based 6-status system is susceptible to manipulation and has limited rank ordering ability.To develop and validate a candidate risk score that incorporates current clinical, laboratory, and hemodynamic data.A registry-based observational study of adult heart transplant candidates (aged ≥18 years) from the US heart allocation system listed between January 1, 2019, and December 31, 2022, split by center into training (70%) and test (30%) datasets. Adult candidates were listed between January 1, 2019, and December 31, 2022.A US candidate risk score (US-CRS) model was developed by adding a predefined set of predictors to the current French Candidate Risk Score (French-CRS) model. Sensitivity analyses were performed, which included intra-aortic balloon pumps (IABP) and percutaneous ventricular assist devices (VAD) in the definition of short-term mechanical circulatory support (MCS) for the US-CRS. Performance of the US-CRS model, French-CRS model, and 6-status model in the test dataset was evaluated by time-dependent area under the receiver operating characteristic curve (AUC) for death without transplant within 6 weeks and overall survival concordance (c-index) with integrated AUC.A total of 16 905 adult heart transplant candidates were listed (mean [SD] age, 53 [13] years; 73% male; 58% White); 796 patients (4.7%) died without a transplant. The final US-CRS contained time-varying short-term MCS (ventricular assist-extracorporeal membrane oxygenation or temporary surgical VAD), the log of bilirubin, estimated glomerular filtration rate, the log of B-type natriuretic peptide, albumin, sodium, and durable left ventricular assist device. In the test dataset, the AUC for death within 6 weeks of listing for the US-CRS model was 0.79 (95% CI, 0.75-0.83), for the French-CRS model was 0.72 (95% CI, 0.67-0.76), and 6-status model was 0.68 (95% CI, 0.62-0.73). Overall c-index for the US-CRS model was 0.76 (95% CI, 0.73-0.80), for the French-CRS model was 0.69 (95% CI, 0.65-0.73), and 6-status model was 0.67 (95% CI, 0.63-0.71). Classifying IABP and percutaneous VAD as short-term MCS reduced the effect size by 54%.In this registry-based study of US heart transplant candidates, a continuous multivariable allocation score outperformed the 6-status system in rank ordering heart transplant candidates by medical urgency and may be useful for the medical urgency component of heart allocation.

  View details for DOI 10.1001/jama.2023.27029

  View details for PubMedID 38349372

• Donor Electrocardiogram Associations With Cardiac Dysfunction, Heart Transplant Use, and Survival: The Donor Heart Study. JACC. Heart failure Tapaskar, N., Wayda, B., Malinoski, D., Luikart, H., Groat, T., Nguyen, J., Belcher, J., Nieto, J., Neidlinger, N., Salehi, A., Geraghty, P. J., Nicely, B., Jendrisak, M., Pearson, T., Wood, R. P., Zhang, S., Weng, Y., Zaroff, J., Khush, K. K. 2024

  Abstract

  Potential organ donors often exhibit abnormalities on electrocardiograms (ECGs) after brain death, but the physiological and prognostic significance of such abnormalities is unknown.This study sought to characterize the prevalence of ECG abnormalities in a nationwide cohort of potential cardiac donors and their associations with cardiac dysfunction, use for heart transplantation (HT), and recipient outcomes.The Donor Heart Study enrolled 4,333 potential cardiac organ donors at 8 organ procurement organizations across the United States from 2015 to 2020. A blinded expert reviewer interpreted all ECGs, which were obtained once hemodynamic stability was achieved after brain death and were repeated 24 ± 6 hours later. ECG findings were summarized, and their associations with other cardiac diagnostic findings, use for HT, and graft survival were assessed using univariable and multivariable regression.Initial ECGs were interpretable for 4,136 potential donors. Overall, 64% of ECGs were deemed clinically abnormal, most commonly as a result of a nonspecific St-T-wave abnormality (39%), T-wave inversion (19%), and/or QTc interval >500 ms (17%). Conduction abnormalities, ectopy, pathologic Q waves, and ST-segment elevations were less common (each present in ≤5% of donors) and resolved on repeat ECGs in most cases. Only pathological Q waves were significant predictors of donor heart nonuse (adjusted OR: 0.39; 95% CI: 0.29-0.53), and none were associated with graft survival at 1 year post-HT.ECG abnormalities are common in potential heart donors but often resolve on serial testing. Pathologic Q waves are associated with a lower likelihood of use for HT, but they do not portend worse graft survival.

  View details for DOI 10.1016/j.jchf.2023.12.007

  View details for PubMedID 38244008

• The Importance of Randomized, Controlled Trials in the Care of Organ Donors. The New England journal of medicine Khush, K. K. 2023; 389 (22): 2098-2099

  View details for DOI 10.1056/NEJMe2311964

  View details for PubMedID 38048192

• Towards Allograft Longevity: Leveraging Omics Technologies to Improve Heart Transplant Outcomes. Current heart failure reports Truby, L. K., Maamari, D., Saha, A., Farr, M., Abdulrahim, J., Billia, F., Peltz, M., Khush, K. K., Wang, T. J. 2023

  Abstract

  Heart transplantation (HT) remains the optimal therapy for patients living with end-stage heart disease. Despite recent improvements in peri-transplant management, the median survival after HT has remained relatively static, and complications of HT, including infection, rejection, and allograft dysfunction, continue to impact quality of life and long-term survival.Omics technologies are becoming increasingly accessible and can identify novel biomarkers for, and reveal the underlying biology of, several disease states. While some technologies, such as gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA), are routinely used in the clinical care of HT recipients, a number of emerging platforms, including pharmacogenomics, proteomics, and metabolomics, hold great potential for identifying biomarkers to aid in the diagnosis and management of post-transplant complications. Omics-based assays can improve patient and allograft longevity by facilitating a personalized and precision approach to post-HT care. The following article is a contemporary review of the current and future opportunities to leverage omics technologies, including genomics, transcriptomics, proteomics, and metabolomics in the field of HT.

  View details for DOI 10.1007/s11897-023-00631-z

  View details for PubMedID 37966542

  View details for PubMedCentralID 7737223

• Disparities in donor heart acceptance between the USA and Europe: clinical implications. European heart journal Wayda, B., Angleitner, P., Smits, J. M., van Kins, A., Berchtold-Herz, M., De Pauw, M., Erasmus, M. E., Gummert, J., Hartyanszky, I., Knezevic, I., Laufer, G., Milicic, D., Rega, F., Schulze, P. C., van Caeneghem, O., Khush, K. K., Zuckermann, A. O. 2023

  Abstract

  Given limited evidence and lack of consensus on donor acceptance for heart transplant (HT), selection practices vary widely across HT centres in the USA. Similar variation likely exists on a broader scale-across countries and HT systems-but remains largely unexplored. This study characterized differences in heart donor populations and selection practices between the USA and Eurotransplant-a consortium of eight European countries-and their implications for system-wide outcomes.Characteristics of adult reported heart donors and their utilization (the percentage of reported donors accepted for HT) were compared between Eurotransplant (n = 8714) and the USA (n = 60 882) from 2010 to 2020. Predictors of donor acceptance were identified using multivariable logistic regression. Additional analyses estimated the impact of achieving Eurotransplant-level utilization in the USA amongst donors of matched quality, using probability of acceptance as a marker of quality.Eurotransplant reported donors were older with more cardiovascular risk factors but with higher utilization than in the USA (70% vs. 44%). Donor age, smoking history, and diabetes mellitus predicted non-acceptance in the USA and, by a lesser magnitude, in Eurotransplant; donor obesity and hypertension predicted non-acceptance in the USA only. Achieving Eurotransplant-level utilization amongst the top 30%-50% of donors (by quality) would produce an additional 506-930 US HTs annually.Eurotransplant countries exhibit more liberal donor heart acceptance practices than the USA. Adopting similar acceptance practices could help alleviate the scarcity of donor hearts and reduce waitlist morbidity in the USA.

  View details for DOI 10.1093/eurheartj/ehad684

  View details for PubMedID 37936176

• Prognostic value of intravascular ultrasound early after heart transplantation. European heart journal Arora, S., Zimmermann, F. M., Solberg, O. G., Nytrøen, K., Aaberge, L., Okada, K., Ahn, J. M., Honda, Y., Khush, K. K., Angeras, O., Karason, K., Gullestad, L., Fearon, W. F. 2023

  View details for DOI 10.1093/eurheartj/ehad648

  View details for PubMedID 37850514

• HLA sensitization is associated with an increased risk of primary graft dysfunction after heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Han, J., Rushakoff, J., Moayedi, Y., Henricksen, E., Lee, R., Helen Luikart, R. N., Shalakhti, O., Gragert, L., Benck, L., Malinoski, D., Kobashigawa, J., Teuteberg, J., Khush, K. K., Patel, J., Kransdorf, E. 2023

  Abstract

  PURPOSE: Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality following heart transplantation (HT). Human leukocyte antigen (HLA) sensitization increases the risk of rejection and adverse outcomes after HT. We sought to determine the association between pre-transplant HLA sensitization, as measured using the calculated panel reactive antibody (cPRA) value, and the risk of PGD.METHODS: Consecutive adult HT recipients (n=596) from 1/2015 to 12/2019 at two US centers were included. Severity of PGD was based on the 2014 ISHLT consensus statement. For each recipient, unacceptable HLA antigens were obtained and locus-specific cPRA (cPRA-LS) and pre-HT donor specific antibodies (DSA) were assessed.RESULTS: There were 90 (15.1%) cases of mild-moderate PGD and 37 (6.2%) cases of severe PGD. Univariable logistic modeling showed that peak cPRA-LS for all loci and HLA-A was associated with increased severity of PGD as an ordinal variable (all loci: OR 1.78, 95% CI: 1.01-1.14, p=0.025, HLA-A: OR 1.14, 95% CI: 1.03-1.26, p=0.011). Multivariable analysis showed peak cPRA-LS for HLA-A, recipient beta-blocker use, total ischemic time, donor age, prior cardiac surgery, and UNOS status 1 or 2 were associated with increased severity of PGD. Presence of DSA to HLA-B was associated with trend toward increased risk of mild to moderate PGD (OR 2.56, 95% CI: 0.99-6.63, p=0.053) but DSA to other HLA loci were not associated with PGD. Neither HLA mismatch nor T- or B-cell crossmatch was associated with PGD.CONCLUSION: Sensitization for all HLA loci and specifically HLA-A are associated with an increased severity of PGD. These factors should be included in pre-HT risk stratification in order to minimize the risk of PGD.

  View details for DOI 10.1016/j.healun.2023.09.017

  View details for PubMedID 37802261

• TEMPORARY REMOVAL: Heart Failure Epidemiology and Outcomes Statistics: A Report of the Heart Failure Society of America. Journal of cardiac failure Bozkurt, B., Ahmad, T., Alexander, K., Baker, W. L., Bosak, K., Breathett, K., Fonarow, G. C., Heidenreich, P., Ho, J. E., Hsich, E., Ibrahim, N. E., Jones, L. M., Khan, S. S., Khazanie, P., Koelling, T., Krumholz, H. M., Khush, K. K., Lee, C., Morris, A. A., Page, R. 3., Pandey, A., Piano, M., Stehlik, J., Stevenson, L., Teerlink, J., Vaduganathan, M., Ziaeian, B. 2023

  Abstract

  The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

  View details for DOI 10.1016/j.cardfail.2023.07.006

  View details for PubMedID 37797885

• Selection and Interpretation of Molecular Diagnostics in Heart Transplantation. Circulation Goldberg, J. F., Truby, L. K., Agbor-Enoh, S., Jackson, A. M., deFilippi, C. R., Khush, K. K., Shah, P. 2023; 148 (8): 679-694

  Abstract

  The number of heart transplants performed annually in the United States and worldwide continues to increase, but there has been little change in graft longevity and patient survival over the past 2 decades. The reference standard for diagnosis of acute cellular and antibody-mediated rejection includes histologic and immunofluorescence evaluation of endomyocardial biopsy samples, despite invasiveness and high interrater variability for grading histologic rejection. Circulating biomarkers and molecular diagnostics have shown substantial predictive value in rejection monitoring, and emerging data support their use in diagnosing other posttransplant complications. The use of genomic (cell-free DNA), transcriptomic (mRNA and microRNA profiling), and proteomic (protein expression quantitation) methodologies in diagnosis of these posttransplant outcomes has been evaluated with varying levels of evidence. In parallel, growing knowledge about the genetically mediated immune response leading to rejection (immunogenetics) has enhanced understanding of antibody-mediated rejection, associated graft dysfunction, and death. Antibodies to donor human leukocyte antigens and the technology available to evaluate these antibodies continues to evolve. This review aims to provide an overview of biomarker and immunologic tests used to diagnose posttransplant complications. This includes a discussion of pediatric heart transplantation and the disparate rates of rejection and death experienced by Black patients receiving a heart transplant. This review describes diagnostic modalities that are available and used after transplant and the landscape of future investigations needed to enhance patient outcomes after heart transplantation.

  View details for DOI 10.1161/CIRCULATIONAHA.123.062847

  View details for PubMedID 37603604

• Predicted Heart Mass: A Tale of 2 Ventricles. Circulation. Heart failure Ródenas-Alesina, E., Foroutan, F., Fan, C. P., Stehlik, J., Bartlett, I., Tremblay-Gravel, M., Aleksova, N., Rao, V., Miller, R. J., Khush, K. K., Ross, H. J., Moayedi, Y. 2023: e008311

  Abstract

  Total predicted heart mass (PHM) is the recommended metric to assess donor-recipient size matching in patients undergoing heart transplantation. Separately measuring right ventricular (RV) and left ventricular (LV) PHM may improve risk prediction of 1-year graft failure.Adult heart transplant recipients from the UNOS database from 2000 to 2018 were included in the study. LV and RV PHM were modeled as restricted cubic splines. The association with 1-year graft failure was determined using adjusted Cox regression. The risk reclassification of using both LV and RV PHM versus total PHM was assessed using the net reclassification index.A total of 34 976 recipients were included. We observed a U-shaped association between total PHM and 1-year graft failure, such that risk increased for hearts undersized by >15% and those oversized by more than 27%. Graft failure incrementally increased when LV PHM was undersized by more than 5% and when RV was oversized by >5%. There was 1.5-fold greater risk of graft failure for an LV undersized by >26% or an RV oversized by more than 40%. Using LV and RV PHM risk-assessment separately led to a net reclassification index=8.5% ([95% CI, 5.3%-11.7%], nonevent net reclassification index=9.1%, event net reclassification index=-0.6%).The association between donor-recipient PHM match and the risk of graft failure after heart transplantation can be further understood as risk attributable to LV undersizing and RV oversizing. Assessing LV and RV PHM separately instead of total PHM could further refine the methods used to match donors and recipients for heart transplantation, minimize the risk of 1-year graft failure, and increase the use of donor organs.

  View details for DOI 10.1161/CIRCHEARTFAILURE.120.008311

  View details for PubMedID 37602381

• Understanding and Investigating Sex-Based Differences in Heart Transplantation: A Call to Action. JACC. Heart failure DeFilippis, E. M., Nikolova, A., Holzhauser, L., Khush, K. K. 2023

  Abstract

  Women represent only about 25% of heart transplant recipients annually. Although the number of women living with advanced heart failure remains unknown, epidemiologic research suggests that more women should be receiving advanced heart failure therapies. Sex differences in risk factors, presentation, response to pharmacotherapy, and outcomes in heart failure have been well described. Yet, less is known about sex differences in heart transplant candidate selection, waitlist management, donor selection, perioperative considerations, and post-transplant management and outcomes. The purpose of this review was to summarize the existing published reports related to sex differences in heart transplantation, highlighting areas in which sex-based considerations are well described and supported by available evidence, and emphasizing topics that require further study.

  View details for DOI 10.1016/j.jchf.2023.06.030

  View details for PubMedID 37589612

• Left Ventricular Dysfunction Associated With Brain Death: Results From the Donor Heart Study. Circulation Khush, K. K., Malinoski, D., Luikart, H., Wayda, B., Groat, T., Nguyen, J., Belcher, J., Nieto, J., Neidlinger, N., Salehi, A., Geraghty, P. J., Nicely, B., Jendrisak, M., Pearson, T., Patrick Wood, R., Zhang, S., Weng, Y., Zaroff, J. 2023

  Abstract

  Left ventricular dysfunction in potential donors meeting brain death criteria often results in nonuse of donor hearts for transplantation, yet little is known about its incidence or pathophysiology. Resolving these unknowns was a primary aim of the DHS (Donor Heart Study), a multisite prospective cohort study.The DHS enrolled potential donors by neurologic determination of death (n=4333) at 8 organ procurement organizations across the United States between February 2015 and May 2020. Data included medications administered, serial diagnostic tests, and transthoracic echocardiograms (TTEs) performed: (1) within 48 hours after brain death was formally diagnosed; and (2) 24±6 hours later if left ventricular (LV) dysfunction was initially present. LV dysfunction was defined as an LV ejection fraction <50% and was considered reversible if LV ejection fraction was >50% on the second TTE. TTEs were also examined for presence of LV regional wall motion abnormalities and their reversibility. We assessed associations between LV dysfunction, donor heart acceptance for transplantation, and recipient 1-year survival.An initial TTE was interpreted for 3794 of the 4333 potential donors by neurologic determination of death. A total of 493 (13%) of these TTEs showed LV dysfunction. Among those donors with an initial TTE, LV dysfunction was associated with younger age, underweight, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and troponin levels. A second TTE was performed within 24±6 hours for a subset of donors (n=224) with initial LV dysfunction; within this subset, 130 (58%) demonstrated reversibility. Sixty percent of donor hearts with normal LV function were accepted for transplant compared with 56% of hearts with reversible LV dysfunction and 24% of hearts with nonreversible LV dysfunction. Donor LV dysfunction, whether reversible or not, was not associated with recipient 1-year survival.LV dysfunction associated with brain death occurs in many potential heart donors and is sometimes reversible. These findings can inform decisions made during donor evaluation and help guide donor heart acceptance for transplantation.

  View details for DOI 10.1161/CIRCULATIONAHA.122.063400

  View details for PubMedID 37465972

• The Time to Act Is Now: Racial Disparities After Heart Transplantation. Circulation Khush, K. K., Valantine, H. A. 2023; 148 (3): 207-209

  View details for DOI 10.1161/CIRCULATIONAHA.123.064499

  View details for PubMedID 37459406

• Association of High-Priority Exceptions with Waitlist Mortality Among Heart Transplant Candidates. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Johnson, D. Y., Ahn, D., Lazenby, K., Zeng, S., Zhang, K., Narang, N., Khush, K., Parker, W. F. 2023

  Abstract

  The US heart allocation system ranks candidates using six categorical status levels. Transplant programs can request exceptions to increase a candidate's status level if they believe their candidate has the same medical urgency as candidates who meet the standard criteria for that level. We aimed to determine if exception candidates have the same medical urgency as standard candidates.Using the Scientific Registry of Transplant Recipients, we constructed a longitudinal waitlist history dataset of adult heart-only transplant candidates listed between October 18, 2018 and December 1, 2021. We estimated the association between exceptions and waitlist mortality with a mixed-effects Cox proportional hazards model that treated status and exceptions as time-dependent covariates.Out of 12,458 candidates listed during the study period, 2,273 (18.2%) received an exception at listing and 1,957 (15.7%) received an exception after listing. After controlling for status, exception candidates had approximately half the risk of waitlist mortality as standard candidates (HR 0.55, 95% CI [0.41, 0.73], p < 0.001). Exceptions were associated with a 51% lower risk of waitlist mortality among Status 1 candidates (HR 0.49, 95% CI [0.27, 0.91], p = 0.023) and a 61% lower risk among Status 2 candidates (HR 0.39, 95% CI [0.24, 0.62], p < 0.001).Under the new heart allocation policy, exception candidates had significantly lower waitlist mortality than standard candidates, including exceptions for the highest priority statuses. These results suggest that candidates with exceptions, on average, have a lower level of medical urgency than candidates who meet standard criteria.

  View details for DOI 10.1016/j.healun.2023.05.009

  View details for PubMedID 37225029

• The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Velleca, A., Shullo, M. A., Dhital, K., Azeka, E., Colvin, M., DePasquale, E., Farrero, M., García-Guereta, L., Jamero, G., Khush, K., Lavee, J., Pouch, S., Patel, J., Michaud, C. J., Shullo, M. A., Schubert, S., Angelini, A., Carlos, L., Mirabet, S., Patel, J., Pham, M., Urschel, S., Kim, K. H., Miyamoto, S., Chih, S., Daly, K., Grossi, P., Jennings, D. L., Kim, I. C., Lim, H. S., Miller, T., Potena, L., Velleca, A., Eisen, H., Bellumkonda, L., Danziger-Isakov, L., Dobbels, F., Harkess, M., Kim, D., Lyster, H., Peled, Y., Reinhardt, Z. 2023; 42 (5): e1-e141

  View details for DOI 10.1016/j.healun.2022.10.015

  View details for PubMedID 37080658

• Rethinking Donor and Recipient Risk Matching in Europe and North America: Using Heart Transplant Predictors of Donor and Recipient Risk. Circulation. Heart failure Moayedi, Y., Rodenas-Alesina, E., Mueller, B., Fan, C. S., Cherikh, W. S., Stehlik, J., Teuteberg, J. J., Ross, H. J., Khush, K. K. 2023; 16 (5): e009994

  Abstract

  In Europe, there is greater acceptance of hearts from higher-risk donors for transplantation, whereas in North America, the donor heart discard rate is significantly higher. A Donor Utilization Score (DUS) was used to compare European and North American donor characteristics for recipients included in the International Society for Heart and Lung Transplantation registry from 2000 to 2018. DUS was further evaluated as an independent predictor for 1-year freedom from graft failure, after adjusting for recipient risk. Lastly, we assessed donor-recipient risk matching with the outcome of 1-year graft failure.DUS was applied to the International Society for Heart and Lung Transplantation cohort using meta-modeling. Posttransplant freedom from graft failure was summarized by Kaplan-Meier survival. Multivariable Cox proportional hazard regression was applied to quantify the effects of DUS and Index for Mortality Prediction After Cardiac Transplantation score on the 1-year risk of graft failure. We present 4 donor/recipient risk groups using the Kaplan-Meier method.European centers accept significantly higher-risk donor hearts compared to North America. DUS 0.45 versus 0.54, P<0.005). DUS was an independent predictor for graft failure with an inverse linear relationship when adjusted for covariates (P<0.001). The Index for Mortality Prediction After Cardiac Transplantation score, a validated tool to assess recipient risk, was also independently associated with 1-year graft failure (P<0.001). In North America, 1-year graft failure was significantly associated with donor-recipient risk matching (log-rank P<0.001). One-year graft failure was highest with pairing of high-risk recipients and donors (13.1% [95% CI, 10.7%-13.9%]) and lowest among low-risk recipients and donors (7.4% [95% CI, 6.8%-8.0%]). Matching of low-risk recipients with high-risk donors was associated with significantly less graft failure (9.0% [95% CI, 8.3%-9.7%]) than high-risk recipients with low-risk donors (11.4% [95% CI, 10.7%-12.2%]) Conclusions: European heart transplantation centers are more likely to accept higher-risk donor hearts than North American centers. Acceptance of borderline-quality donor hearts for lower-risk recipients could improve donor heart utilization without compromising recipient survival.

  View details for DOI 10.1161/CIRCHEARTFAILURE.122.009994

  View details for PubMedID 37192289

• How to Make the Transplantation Allocation System Better. JACC. Heart failure Khush, K. K., Sandhu, A. T., Parker, W. F. 2023; 11 (5): 516-519

  View details for DOI 10.1016/j.jchf.2022.11.029

  View details for PubMedID 37137658

• IMPACT OF MYOCARDIAL BRIDGING ON LONG TERM OUTCOMES AFTER HEART TRANSPLANTATION: AN INTRAVASCULAR ULTRASOUND OBSERVATION FROM AN INTERNATIONAL MULTICENTER HEART TRANSPLANT REGISTRY Saito, K., Okada, K., Sakagami, A., Angeras, O., Arora, S., Gullestad, L., Ahn, J., Park, S., Zimmermann, F., Luikart, H., Khush, K., Fearon, W., Honda, Y. ELSEVIER SCIENCE INC. 2023: 1390

  View details for Web of Science ID 000990866101402

• COMPLETE HEART BLOCK POST TRANSPLANT- A RARE CASE OF CARDIAC SARCOIDOSIS RECURRENCE Bahl, A., Yogeswaran, V., Khush, K., Teuteberg, J., Cheng, R. ELSEVIER SCIENCE INC. 2023: 2650

  View details for Web of Science ID 000990866102661

• Impact of myocardial bridging on coronary artery plaque formation and long-term mortality after heart transplantation. International journal of cardiology Tanaka, S., Okada, K., Kitahara, H., Luikart, H., Yock, P. G., Yeung, A. C., Schnittger, I., Tremmel, J. A., Fitzgerald, P. J., Khush, K. K., Fearon, W. F., Honda, Y. 2023

  Abstract

  OBJECTIVES: This study aimed to explore the impact of myocardial bridging (MB) on early development of cardiac allograft vasculopathy and long-term graft survival after heart transplantation.BACKGROUND: MB has been reported to be associated with acceleration of proximal plaque development and endothelial dysfunction in native coronary atherosclerosis. However, its clinical significance in heart transplantation remains unclear.METHODS: In 103 heart-transplant recipients, serial (baseline and 1-year post-transplant) volumetric intravascular ultrasound (IVUS) analyses were performed in the first 50 mm of the left anterior descending (LAD) artery. Standard IVUS indices were evaluated in 3 equally divided LAD segments (proximal, middle, and distal segments). MB was defined by IVUS as an echolucent muscular band lying on top of the artery. The primary endpoint was death or re-transplantation, assessed for up to 12.2 years (median follow-up: 4.7 years).RESULTS: IVUS identified MB in 62% of the study population. At baseline, MB patients had smaller intimal volume in the distal LAD than non-MB patients (p = 0.002). During the first year, vessel volume decreased diffusely irrespective of the presence of MB. Intimal growth diffusely distributed in non-MB patients, whereas MB patients demonstrated significantly augmented intimal formation in the proximal LAD. Kaplan-Meier analysis revealed significantly lower event-free survival in patients with versus without MB (log-rank p = 0.02). In multivariate analysis, the presence of MB was independently associated with late adverse events [hazard ratio 5.1 (1.6-22.2)].CONCLUSION: MB appears to relate to accelerated proximal intimal growth and reduced long-term survival in heart-transplant recipients.

  View details for DOI 10.1016/j.ijcard.2023.03.014

  View details for PubMedID 36893856

• The Evolving Use of Biomarkers in Heart Transplantation: Consensus of an Expert Panel. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kobashigawa, J., Hall, S., Shah, P., Fine, B., Halloran, P., Jackson, A. M., Khush, K. K., Margulies, K. B., Sani, M. M., Patel, J. K., Patel, N., Peyster, E. 2023

  Abstract

  In heart transplantation, the use of biomarkers to detect the risk of rejection has been evolving. In this setting, it is becoming less clear as to what is the most reliable test or combination of tests to detect rejection and to assess the state of the alloimmune response. Therefore, a virtual expert panel was organized in heart and kidney transplantation to evaluate emerging diagnostics and how they may be best utilized to monitor and manage transplant patients. This manuscript covers the heart content of the conference and is a work product of the American Society of Transplantation's Thoracic and Critical Care Community of Practice. This paper reviews currently available and emerging diagnostic assays and defines the unmet needs for biomarkers in heart transplantation. Highlights of the in-depth discussions among conference participants that led to development of consensus statements are included. This conference should serve as a platform to further build consensus within the heart transplant community regarding the optimal framework to implement biomarkers into management protocols and to improve biomarker development, validation and clinical utility. Ultimately, these biomarkers and novel diagnostics should improve outcomes and optimize quality of life for our transplant patients.

  View details for DOI 10.1016/j.ajt.2023.02.025

  View details for PubMedID 36870390

• Primary Graft Dysfunction Is Associated With Development of Early Cardiac Allograft Vasculopathy, but Not Other Immune-mediated Complications, After Heart Transplantation. Transplantation Han, J., Moayedi, Y., Henricksen, E. J., Waddell, K., Valverde-Twiggs, J., Kim, D., Luikart, H., Zhang, B. M., Teuteberg, J., Khush, K. K. 2023

  Abstract

  We investigated associations between primary graft dysfunction (PGD) and development of acute cellular rejection (ACR), de novo donor-specific antibodies (DSAs), and cardiac allograft vasculopathy (CAV) after heart transplantation (HT).A total of 381 consecutive adult HT patients from January 2015 to July 2020 at a single center were retrospectively analyzed. The primary outcome was incidence of treated ACR (International Society for Heart and Lung Transplantation grade 2R or 3R) and de novo DSA (mean fluorescence intensity >500) within 1 y post-HT. Secondary outcomes included median gene expression profiling score and donor-derived cell-free DNA level within 1 y and incidence of cardiac allograft vasculopathy (CAV) within 3 y post-HT.When adjusted for death as a competing risk, the estimated cumulative incidence of ACR (PGD 0.13 versus no PGD 0.21; P = 0.28), median gene expression profiling score (30 [interquartile range, 25-32] versus 30 [interquartile range, 25-33]; P = 0.34), and median donor-derived cell-free DNA levels was similar in patients with and without PGD. After adjusting for death as a competing risk, estimated cumulative incidence of de novo DSA within 1 y post-HT in patients with PGD was similar to those without PGD (0.29 versus 0.26; P = 0.10) with a similar DSA profile based on HLA loci. There was increased incidence of CAV in patients with PGD compared with patients without PGD (52.6% versus 24.8%; P = 0.01) within the first 3 y post-HT.During the first year after HT, patients with PGD had a similar incidence of ACR and development of de novo DSA, but a higher incidence of CAV when compared with patients without PGD.

  View details for DOI 10.1097/TP.0000000000004551

  View details for PubMedID 36801852

• Preemptive treatment of de novo donor-specific antibodies in lung transplant patients reduces subsequent risk of chronic lung allograft dysfunction or death. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Keller, M., Yang, S., Ponor, L., Bon, A., Cochrane, A., Philogene, M., Bush, E., Shah, P., Mathew, J., Brown, A. W., Kong, H., Charya, A., Luikart, H., Nathan, S. D., Khush, K. K., Jang, M., Agbor-Enoh, S. 2023

  Abstract

  The development of donor-specific antibodies after lung transplantation is associated with downstream acute cellular rejection, antibody-mediated rejection (AMR), chronic lung allograft dysfunction (CLAD), or death. It is unknown whether preemptive (early) treatment of de novo donor-specific antibodies (dnDSAs), in the absence of clinical signs and symptoms of allograft dysfunction, reduces the risk of subsequent CLAD or death. We performed a multicenter, retrospective cohort study to determine if early treatment of dnDSAs in lung transplant patients reduces the risk of the composite endpoint of CLAD or death. In the cohort of 445 patients, 145 patients developed dnDSAs posttransplant. Thirty patients received early targeted treatment for dnDSAs in the absence of clinical signs and symptoms of AMR. Early treatment of dnDSAs was associated with a decreased risk of CLAD or death (hazard ratio, 0.36; 95% confidence interval, 0.17-0.76; P < .01). Deferring treatment until the development of clinical AMR was associated with an increased risk of CLAD or death (hazard ratio, 3.00; 95% confidence interval, 1.46-6.18; P < .01). This study suggests that early, preemptive treatment of donor-specific antibodies in lung transplant patients may reduce the subsequent risk of CLAD or death.

  View details for DOI 10.1016/j.ajt.2022.12.019

  View details for PubMedID 36732088

• The End of Endomyocardial Biopsy?: A Practical Guide for Noninvasive Heart Transplant Rejection Surveillance. JACC. Heart failure Holzhauser, L., DeFilippis, E. M., Nikolova, A., Byku, M., Contreras, J. P., De Marco, T., Hall, S., Khush, K. K., Vest, A. R. 2023

  Abstract

  Noninvasive heart transplant rejection surveillance using gene expression profiling (GEP) to monitor immune activation is widely used among heart transplant programs. With the new development of donor-derived cell-free DNA (dd-cfDNA) assays, more programs are transitioning to a predominantly noninvasive rejection surveillance protocol with a reduced frequency of endomyocardial biopsies. As a result, many practical questions arise that potentially delay implementation of these valuable new tools. The purpose of this review is to provide practical guidance for clinicians transitioning toward a less invasive acute rejection monitoring protocol after heart transplantation, and to answer 10 common questions about the GEP and dd-cfDNA assays. Evidence supporting GEP and dd-cfDNA testing is reviewed, as well as guidance on test interpretation and future directions.

  View details for DOI 10.1016/j.jchf.2022.11.002

  View details for PubMedID 36682960

• Donor hyperoxia is a novel risk factor for severe cardiac primary graft dysfunction. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Kransdorf, E. P., Rushakoff, J. A., Han, J., Benck, L., Malinoski, D., Emerson, D., Catarino, P., Rampolla, R., Kobashigawa, J. A., Khush, K. K., Patel, J. K. 2023

  Abstract

  BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). Donor risk factors for the development of PGD are incompletely characterized. Donor management goals (DMG) are predefined critical care endpoints used to optimize donors. We evaluated the relationship between DMGs as well as non-DMG parameters, and the development of PGD after HT.METHODS: A cohort of HT recipients from 2 transplant centers between 1/1/12 and 12/31/19 was linked to their respective donors in the United Network for Organ Sharing (UNOS) DMG Registry (n=1,079). PGD was defined according to modified ISHLT criteria. Variables were subject to univariate and multivariable multinomial modeling with development of mild/moderate or severe PGD as the outcome variable. A second multicenter cohort of 4,010 donors from the DMG Registry was used for validation.RESULTS: Mild/moderate and severe PGD occurred in 15% and 6% of the cohort. Multivariable modeling revealed 6 variables independently associated with mild/moderate and 6 associated with severe PGD, respectively. Recipient use of amiodarone plus beta-blocker, recipient mechanical circulatory support, donor age, donor fraction of inspired oxygen (FiO2), and donor creatinine increased risk whereas predicted heart mass ratio decreased risk of severe PGD. We found that donor age and FiO2 ≥ 40% were associated with an increased risk of death within 90 days post-transplant in a multicenter cohort.CONCLUSIONS: Donor hyperoxia at heart recovery is a novel risk factor for severe primary graft dysfunction and early recipient death. These results suggest that excessive oxygen supplementation should be minimized during donor management.

  View details for DOI 10.1016/j.healun.2022.12.022

  View details for PubMedID 36682894

• Utilization of COVID-19 positive donors for Heart transplantation and associated short-term outcomes. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation DeFilippis, E. M., Wayda, B., Lala, A., Givertz, M. M., Khush, K. K. 2022

  Abstract

  BACKGROUND: The safety and efficacy of using COVID-19 positive donors in heart transplantation (HT) are increasingly relevant, but not well established. The present study evaluated the characteristics and utilization of such donors and associated post-HT outcomes.METHODS: All adult (≥18 years old) potential donors and HT recipients in the United States from April 21, 2020 to March 31, 2022 were included. Donor COVID-19 status was defined by the presence (or absence) of any positive test within 21 days of organ recovery. Donor and recipient characteristics and post-HT outcomes, including a primary composite of death, graft failure, and re-transplantation, were compared by donor COVID-19 status.RESULTS: Of 967 COVID-19(+) potential donors, 19.3% (n=187) were used for HT compared to 26.7% (n=6277) of COVID-19(-) donors (p < 0.001). Transplanted COVID-19(+) vs COVID-19(-) donors were younger, but otherwise were similar. Recipients of hearts from COVID-19+ vs COVID-19(-) donors less frequently received pre-HT inotropes (24.1% vs 31.7%, p=0.023) and ventricular assist device therapy (29.7% vs 36.8%, p=0.040). There were no significant differences in any post-HT outcome by donor COVID-19 status, including the primary composite outcome at 90 days (5.4% vs 5.6%, p=0.91). Among COVID-19(+) donors, the presence of a subsequent negative test prior to transplant was not associated with posttransplant outcomes.CONCLUSIONS: Our results suggest that carefully selected COVID-19 positive donors may be used for HT with no difference in short-term post-transplant outcomes. Additional data regarding donor and recipient treatments and impact of vaccination should be collected to better inform our use of organs from COVID(+) donors.

  View details for DOI 10.1016/j.healun.2022.12.006

  View details for PubMedID 36609092

• Tumor Microenvironment Determinants of Immunotherapy Response Identified By Integrated Host & Viral Analysis of Post-Transplant Lymphoproliferative Disorders Schroers-Martin, J., Garofalo, A., Soo, J., Boegeholz, J., Alig, S. K., Sworder, B., Liu, C., Luikart, H., Gamino, G., Morales, D., Freystaetter, K., Hamilton, J., Kurtz, D. M., Hollander, S., Rosenthal, D., Dhillon, G., Raikhelkar, J., Verleden, S., Nijland, M., Agbor-Enoh, S., Andreas, M., Kfoury, A., Ross, H., Zaffiri, L., Natkunam, Y., Diehn, M., Khush, K., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022

  View details for DOI 10.1182/blood-2022-158647

  View details for Web of Science ID 000893223200073

• Contemporary Management of Cardiogenic Shock During Pregnancy. Journal of cardiac failure Tapaskar, N., Tremblay-Gravel, M., Khush, K. K. 2022

  Abstract

  Cardiogenic shock is the most extreme cardiovascular disease state in pregnancy. Peripartum cardiomyopathy is the most common etiology of cardiogenic shock towards the end of pregnancy and in the early postpartum period. Therapy for cardiogenic shock relies on appropriate phenotyping of shock etiology, severity, and ventricular predominance, which are critical in appropriate selection of medical and mechanical therapy. Mechanical circulatory support may be used as a bridge to recovery or as definitive therapy. Intra-aortic balloon pump, percutaneous left ventricular assist devices, and veno-arterial extracorporeal circulatory devices have been successfully used in pregnancy and the post-partum period. The most utilized mechanical therapy in the pregnant patient is extracorporeal membranous oxygenation circulatory support. The use of mechanical circulatory devices in peripartum cardiomyopathy has contributed to improved survival in recent years. Further efforts to identify the optimal mechanical circulatory support strategy for peripartum cardiomyopathy and cardiogenic shock in the peri-partum period are needed.

  View details for DOI 10.1016/j.cardfail.2022.09.014

  View details for PubMedID 36243342

• Clinical features and allograft failure rates of pulmonary antibody-mediated rejection categories. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Charya, A. V., Ponor, I. L., Cochrane, A., Levine, D., Philogene, M., Fu, Y. P., Jang, M. K., Kong, H., Shah, P., Bon, A. M., Krishnan, A., Mathew, J., Luikart, H., Khush, K. K., Berry, G., Marboe, C., Iacono, A., Orens, J. B., Nathan, S. D., Agbor-Enoh, S. 2022

  Abstract

  Pulmonary antibody-mediated rejection (AMR) consensus criteria categorize AMR by diagnostic certainty. This study aims to define the clinical features and associated outcomes of these recently defined AMR categories.Adjudication committees reviewed clinical data of 335 lung transplant recipients to define clinical or subclinical AMR based on the presence of allograft dysfunction, and the primary endpoints, time from transplant to allograft failure, a composite endpoint of chronic lung allograft dysfunction and/or death. Clinical AMR was subcategorized based on diagnostic certainty as definite, probable or possible AMR if 4, 3, or 2 characteristic features were present, respectively. Allograft injury was assessed via plasma donor-derived cell-free DNA (ddcfDNA). Risk of allograft failure and allograft injury was compared for AMR categories using regression models.Over the 38.5 months follow-up, 28.7% of subjects developed clinical AMR (n = 96), 18.5% developed subclinical AMR (n = 62) or 58.3% were no AMR (n = 177). Clinical AMR showed higher risk of allograft failure and ddcfDNA levels compared to subclinical or no AMR. Clinical AMR included definite/probable (n = 21) or possible AMR (n = 75). These subcategories showed similar clinical characteristics, ddcfDNA levels, and risk of allograft failure. However, definite/probable AMR showed greater measures of AMR severity, including degree of allograft dysfunction and risk of death compared to possible AMR.Clinical AMR showed greater risk of allograft failure than subclinical AMR or no AMR. Subcategorization of clinical AMR based on diagnostic certainty correlated with AMR severity and risk of death, but not with the risk of allograft failure.

  View details for DOI 10.1016/j.healun.2022.09.012

  View details for PubMedID 36319530

• Donor heart selection: Evidence-based guidelines for providers. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Copeland, H., Knezevic, I., Baran, D. A., Rao, V., Pham, M., Gustafsson, F., Pinney, S., Lima, B., Masetti, M., Ciarka, A., Rajagopalan, N., Torres, A., Hsich, E., Patel, J. K., Goldraich, L. A., Colvin, M., Segovia, J., Ross, H., Ginwalla, M., Sharif-Kashani, B., Farr, M. A., Potena, L., Kobashigawa, J., Crespo-Leiro, M. G., Altman, N., Wagner, F., Cook, J., Stosor, V., Grossi, P. A., Khush, K., Yagdi, T., Restaino, S., Tsui, S., Absi, D., Sokos, G., Zuckermann, A., Wayda, B., Felius, J., Hall, S. A. 2022

  Abstract

  The proposed donor heart selection guidelines provide evidence-based and expert-consensus recommendations for the selection of donor hearts following brain death. These recommendations were compiled by an international panel of experts based on an extensive literature review.

  View details for DOI 10.1016/j.healun.2022.08.030

  View details for PubMedID 36357275

• Early Trends in Cardiac Allograft Vasculopathy After Implementation of the 2018 Donor Heart Allocation Policy in the United States: Short Title: CAV Trend After Allocation Policy Change. American heart journal Tehrani, D. M., Kim, J. S., Hsu, J. J., Nsair, A., Khush, K. K., Fearon, W. F., Parikh, R. V. 2022

  Abstract

  STUDY OBJECTIVE: To evaluate the impact of the new donor heart allocation system implemented in the United States in October 2018 on development of early cardiac allograft vasculopathy (CAV).DESIGN: Retrospective cohort study.PARTICIPANTS: Adult (≥ 18 years) heart transplant recipients registered in the United Network for Organ Sharing database between October 18, 2015 - October 17, 2018 (old system) and October 18, 2018 - May 31, 2020 (new system).MAIN OUTCOME MEASURE: Incidence of angiographic CAV at 1 year (accelerated CAV) in the overall transplant population and among the highest acuity subgroup-Status 1A (old) and Status 1 or 2 (new). We included recipient and donor demographic, cardiovascular, and transplant factors in multivariable logistic regression models to identify predictors of accelerated CAV.RESULTS: Of 10,375 transplant recipients, 6,660 (64%) and 3,715 (36%) were listed in the old and new allocation cohorts, respectively. The incidence of accelerated CAV was 521 (8%) in the old period compared with 272 (7%) in the new period (p = 0.36). Similar incidence rates were observed in the highest acuity subgroup-363 (8%) compared with 143 (7%), respectively (p = 0.13). In adjusted analyses of the high-acuity cohort, the new allocation system was not associated with a higher likelihood of accelerated CAV (odds ratio = 0.87, 95% confidence interval: 0.70-1.08, p = 0.20).CONCLUSIONS: The new donor heart allocation system is not associated with development of accelerated angiographic CAV at 1 year, including among recipients requiring the most urgent transplants.

  View details for DOI 10.1016/j.ahj.2022.08.002

  View details for PubMedID 35970399

• Data Carve Out in the Midst of the COVID-19 Pandemic. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Mannon, R. B., Khush, K. K., Mohan, S., Vock, D. M., Knight, R., Pittman, J., Zinner, C., Orlowski, J. O. 2022

  View details for DOI 10.1111/ajt.17132

  View details for PubMedID 35767419

• Circulating microRNAs in cellular and antibody-mediated heart transplant rejection. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Shah, P., Agbor-Enoh, S., Bagchi, P., deFilippi, C. R., Mercado, A., Diao, G., Morales, D. J., Shah, K. B., Najjar, S. S., Feller, E., Hsu, S., Rodrigo, M. E., Lewsey, S. C., Jang, M. K., Marboe, C., Berry, G. J., Khush, K. K., Valantine, H. A., GRAfT Investigators 2022

  Abstract

  BACKGROUND: Noninvasive monitoring of heart allograft health is important to improve clinical outcomes. MicroRNAs (miRs) are promising biomarkers of cardiovascular disease and limited studies suggest they can be used to noninvasively diagnose acute heart transplant rejection.METHODS: The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter prospective cohort study that phenotyped heart transplant patients from 5 mid-Atlantic centers. Patients who had no history of rejection after transplant were compared to patients with acute cellular rejection (ACR) or antibody-mediated rejection (AMR). Small RNA sequencing was performed on plasma samples collected at the time of an endomyocardial biopsy. Differential miR expression was performed with adjustment for clinical covariates. Regression was used to develop miR panels with high diagnostic accuracy for ACR and AMR. These panels were then validated in independent samples from GRAfT and Stanford University. Receiver operating characteristic curves were generated and area under the curve (AUC) statistics calculated. Distinct ACR and AMR clinical scores were developed to translate miR expression data for clinical use.RESULTS: The GRAfT cohort had a median age of 52 years, with 35% females and 45% Black patients. Between GRAfT and Stanford, we included 157 heart transplant patients: 108 controls and 49 with rejection (50 ACR and 38 AMR episodes). After differential miR expression and regression analysis, we identified 12 miRs that accurately discriminate ACR and 17 miRs in AMR. Independent validation of the miR panels within GRAfT led to an ACR AUC 0.92 (95% confidence interval [CI]: 0.86-0.98) and AMR AUC 0.82 (95% CI: 0.74-0.90). The externally validated ACR AUC was 0.72 (95% CI: 0.59-0.82). We developed distinct ACR and AMR miR clinical scores (range 0-100), a score ≥ 65, identified ACR with 86% sensitivity, 76% specificity, and 98% negative predictive value, for AMR score performance was 82%, 84% and 97%, respectively.CONCLUSIONS: We identified novel miRs that had excellent performance to noninvasively diagnose acute rejection after heart transplantation. Once rigorously validated, the unique clinical ACR and AMR scores usher in an era whereby genomic biomarkers can be used to screen and diagnose the subtype of rejection. These novel biomarkers may potentially alleviate the need for an endomyocardial biopsy while facilitating the initiation of targeted therapy based on the noninvasive diagnosis of ACR or AMR.

  View details for DOI 10.1016/j.healun.2022.06.019

  View details for PubMedID 35872109

• Indications, Complications, and Outcomes of Cardiac Surgery After Heart Transplantation: Results From the Cash Study. Frontiers in cardiovascular medicine Gökler, J., Aliabadi-Zuckermann, A. Z., Kaider, A., Ambardekar, A. V., Antretter, H., Artemiou, P., Bertolotti, A. M., Boeken, U., Brossa, V., Copeland, H., Generosa Crespo-Leiro, M., Eixeré-Esteve, A., Epailly, E., Farag, M., Hulman, M., Khush, K. K., Masetti, M., Patel, J., Ross, H. J., Rudež, I., Silvestry, S., Suarez, S. M., Vest, A., Zuckermann, A. O. 2022; 10: 879612

  Abstract

  Allograft pathologies, such as valvular, coronary artery, or aortic disease, may occur early and late after cardiac transplantation. Cardiac surgery after heart transplantation (CASH) may be an option to improve quality of life and allograft function and prolong survival. Experience with CASH, however, has been limited to single-center reports.We performed a retrospective, multicenter study of heart transplant recipients with CASH between January 1984 and December 2020. In this study, 60 high-volume cardiac transplant centers were invited to participate.Data were available from 19 centers in North America (n = 7), South America (n = 1), and Europe (n = 11), with a total of 110 patients. A median of 3 (IQR 2-8.5) operations was reported by each center; five centers included ≥ 10 patients. Indications for CASH were valvular disease (n = 62), coronary artery disease (CAD) (n = 16), constrictive pericarditis (n = 17), aortic pathology (n = 13), and myxoma (n = 2). The median age at CASH was 57.7 (47.8-63.1) years, with a median time from transplant to CASH of 4.4 (1-9.6) years. Reoperation within the first year after transplantation was performed in 24.5%. In-hospital mortality was 9.1% (n = 10). 1-year survival was 86.2% and median follow-up was 8.2 (3.8-14.6) years. The most frequent perioperative complications were acute kidney injury and bleeding revision in 18 and 9.1%, respectively.Cardiac surgery after heart transplantation has low in-hospital mortality and postoperative complications in carefully selected patients. The incidence and type of CASH vary between international centers. Risk factors for the worse outcome are higher European System for Cardiac Operative Risk Evaluation (EuroSCORE II) and postoperative renal failure.

  View details for DOI 10.3389/fcvm.2022.879612

  View details for PubMedID 35756840

  View details for PubMedCentralID PMC9218180

• Combining donor derived cell free DNA and gene expression profiling for non-invasive surveillance after heart transplantation. Clinical transplantation Henricksen, E. J., Moayedi, Y., Purewal, S., Twiggs, J. V., Waddell, K., Luikart, H., Han, J., Feng, K., Wayda, B., Lee, R., Shudo, Y., Jimenez, S., Khush, K. K., Teuteberg, J. J. 2022: e14699

  Abstract

  BACKGROUND: Donor-derived cell free DNA (dd-cfDNA) and gene expression profiling (GEP) offer non-invasive alternatives to rejection surveillance after heart transplantation, however there is little evidence on the paired use of GEP and dd-cfDNA for rejection surveillance.METHODS: A single center, retrospective analysis of adult heart transplant recipients. A GEP cohort, transplanted from January 1, 2015 through December 31, 2017 and eligible for rejection surveillance with GEP was compared to a paired testing cohort, transplanted July 1, 2018 through June 30, 2020, with surveillance from both dd-cfDNA and GEP. The primary outcomes were survival and rejection-free survival at one year post-transplant.RESULTS: In total 159 patients were included, 95 in the GEP and 64 in the paired testing group. There were no differences in baseline characteristics, except for less use of induction in the paired testing group (65.6%) compared to the GEP group (98.9%), p< 0.01. At one-year, there were no differences between the paired testing and GEP groups in survival (98.4% v. 94.7%, p = 0.23) or rejection-free survival (81.3% v. 73.7% p = 0.28).CONCLUSIONS: Compared to post-transplant rejection surveillance with GEP alone, pairing dd-cfDNA and GEP testing was associated with similar survival and rejection-free survival at one year while requiring significantly fewer biopsies. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.14699

  View details for PubMedID 35559582

• Expecting the unexpected, and prioritizing the predictable. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Wayda, B., Khush, K. K. 2022

  View details for DOI 10.1016/j.healun.2022.04.005

  View details for PubMedID 35599176

• Heart transplantation: focus on donor recovery strategies, left ventricular assist devices, and novel therapies. European heart journal Crespo-Leiro, M. G., Costanzo, M. R., Gustafsson, F., Khush, K. K., Macdonald, P. S., Potena, L., Stehlik, J., Zuckermann, A., Mehra, M. R. 2022

  Abstract

  Heart transplantation is advocated in selected patients with advanced heart failure in the absence of contraindications. Principal challenges in heart transplantation centre around an insufficient and underutilized donor organ pool, the need to individualize titration of immunosuppressive therapy, and to minimize late complications such as cardiac allograft vasculopathy, malignancy, and renal dysfunction. Advances have served to increase the organ donor pool by advocating the use of donors with underlying hepatitis C virus infection and by expanding the donor source to use hearts donated after circulatory death. New techniques to preserve the donor heart over prolonged ischaemic times, and enabling longer transport times in a safe manner, have been introduced. Mechanical circulatory support as a bridge to transplantation has allowed patients with advanced heart failure to avoid progressive deterioration in hepato-renal function while awaiting an optimal donor organ match. The management of the heart transplantation recipient remains a challenge despite advances in immunosuppression, which provide early gains in rejection avoidance but are associated with infections and late-outcome challenges. In this article, we review contemporary advances and challenges in this field to focus on donor recovery strategies, left ventricular assist devices, and immunosuppressive monitoring therapies with the potential to enhance outcomes. We also describe opportunities for future discovery to include a renewed focus on long-term survival, which continues to be an area that is under-studied and poorly characterized, non-human sources of organs for transplantation including xenotransplantation as well as chimeric transplantation, and technology competitive to human heart transplantation, such as tissue engineering.

  View details for DOI 10.1093/eurheartj/ehac204

  View details for PubMedID 35441654

• Challenges Encountered in Conducting Donor-Based Research: Lessons Learned from the Donor Heart Study. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Khush, K. K., Luikart, H., Neidlinger, N., Salehi, A., Nguyen, J., Geraghty, P. J., Belcher, J., Nicely, B., Jendrisak, M., Pearson, T., Wood, R. P., Groat, T., Wayda, B., Zaroff, J. G., Malinoski, D. 2022

  Abstract

  Solid organ transplantation continues to be constrained by a lack of suitable donor organs. Advances in donor management and evaluation are needed to address this shortage, but performance of research studies in deceased donors is fraught with challenges. Here we discuss several of the major obstacles we faced in the conduct of the Donor Heart Study-a prospective, multi-site, observational study of donor management, evaluation, and acceptance for heart transplantation. These included recruitment and engagement of participating organ procurement organizations, ambiguities related to study oversight, obtaining authorization for donor research, logistical challenges encountered during donor management, sustaining study momentum, and challenges related to study data management. By highlighting these obstacles encountered, as well as the solutions implemented, we hope to stimulate further discussion and actions that will facilitate the design and execution of future donor research studies.

  View details for DOI 10.1111/ajt.17051

  View details for PubMedID 35373509

• Temporal shift and predictive performance of machine learning for heart transplant outcomes. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Miller, R. J., Sabovcik, F., Cauwenberghs, N., Vens, C., Khush, K. K., Heidenreich, P. A., Haddad, F., Kuznetsova, T. 2022

  Abstract

  BACKGROUND: Outcome prediction following heart transplant is critical to explaining risks and benefits to patients and decision-making when considering potential organ offers. Given the large number of potential variables to be considered, this task may be most efficiently performed using machine learning (ML). We trained and tested ML and statistical algorithms to predict outcomes following cardiac transplant using the United Network of Organ Sharing (UNOS) database.METHODS: We included 59,590 adult and 8,349 pediatric patients enrolled in the UNOS database between January 1994 and December 2016 who underwent cardiac transplantation. We evaluated 3 classification and 3 survival methods. Algorithms were evaluated using shuffled 10-fold cross-validation (CV) and rolling CV. Predictive performance for 1 year and 90 days all-cause mortality was characterized using the area under the receiver-operating characteristic curve (AUC) with 95% confidence interval.RESULTS: In total, 8,394 (12.4%) patients died within 1 year of transplant. For predicting 1-year survival, using the shuffled 10-fold CV, Random Forest achieved the highest AUC (0.893; 0.889-0.897) followed by XGBoost and logistic regression. In the rolling CV, prediction performance was more modest and comparable among the models with XGBoost and Logistic regression achieving the highest AUC 0.657 (0.647-0.667) and 0.641(0.631-0.651), respectively. There was a trend toward higher prediction performance in pediatric patients.CONCLUSIONS: Our study suggests that ML and statistical models can be used to predict mortality post-transplant, but based on the results from rolling CV, the overall prediction performance will be limited by temporal shifts inpatient and donor selection.

  View details for DOI 10.1016/j.healun.2022.03.019

  View details for PubMedID 35568604

• Comparison of donor-derived cell-free DNA between single vs. double lung transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Keller, M. B., Meda, R., Fu, S., Yu, K., Jang, M. K., Charya, A., Berry, G. J., Marboe, C. C., Kong, H., Luikart, H., Ponor, I. L., Shah, P. D., Khush, K. K., Nathan, S. D., Agbor-Enoh, S. 2022

  Abstract

  Plasma donor-derived cell-free DNA (dd-cfDNA) is a sensitive biomarker for the diagnosis of acute rejection in lung transplant recipients, however, differences in dd-cfDNA levels between single and double lung transplant remains unknown. We performed an observational analysis that included 221 patients from two prospective cohort studies who had serial measurements of plasma dd-cfDNA at the time of bronchoscopy and pulmonary function testing, and compared dd-cfDNA between single and double lung transplant recipients across a range of disease states. Levels of dd-cfDNA were lower for single vs double lung transplant in stable controls (Median (IQR): 0.15% (0.07, 0.44) vs 0.46% (0.23, 0.74), p <0.01) and acute rejection (1.06% (0.75, 2.32) vs 1.78% (1.18, 5.73), p = 0.05). Doubling dd-cfDNA for single lung transplant to account for differences in lung mass eliminated this difference. The area under the receiver operating curve (AUC) for detection of acute rejection was 0.89 and 0.86 for single and double lung transplant, respectively. The optimal dd-cfDNA threshold for detection of acute rejection was 0.54% in single lung and 1.1% in double lung transplant. In conclusion, accounting for differences in dd-cfDNA in single vs double lung transplant is key for interpretation of dd-cfDNA testing in research and clinical settings.

  View details for DOI 10.1111/ajt.17039

  View details for PubMedID 35322546

• Evolving Characteristics of Heart Transplantation Donors and Recipients: JACC Focus Seminar. Journal of the American College of Cardiology DeFilippis, E. M., Khush, K. K., Farr, M. A., Fiedler, A., Kilic, A., Givertz, M. M. 2022; 79 (11): 1108-1123

  Abstract

  Although the burden of end-stage heart failure continues to increase, the number of available organs for heart transplantation (HT) remains inadequate. The HT community has been challenged to find ways to expand the number of donor hearts available. Recent advances include use of hearts from donors infected with hepatitis C virus as well as other previously underutilized donors, including those with left ventricular dysfunction, of older age, and with a history of cocaine use. Concurrently, emerging trends in HT surgery include donation after circulatory death, exvivo normothermic heart perfusion, and controlled hypothermic preservation, which may enable procurement of organs from farther distances and prevent early allograft dysfunction. Contemporary HT recipients have also evolved in light of the 2018 revision to the U.S. heart allocation policy. This focus seminar discusses recent trends in donor and recipient phenotypes and management strategies for successful HT, as well as evolving areas and future directions.

  View details for DOI 10.1016/j.jacc.2021.11.064

  View details for PubMedID 35300823

• Donor selection for multiorgan transplantation. Current opinion in organ transplantation Hsiao, S., Khush, K. K. 1800; 27 (1): 52-56

  Abstract

  PURPOSE OF REVIEW: There is limited data and guidance on donor selection for multiorgan transplantation. In this article, we review the current Organ Procurement and Transplantation Network policy on multiorgan allocation and the ideal donor criteria for each specific organ, in order to provide a framework to guide donor selection for various scenarios of multiorgan transplantation, including heart-kidney, heart-lung, heart-liver and heart-kidney-liver transplant procedures.RECENT FINDINGS: Combined heart-kidney transplantation is the most common multiorgan transplant procedure and requires the most stringent HLA matching to ensure optimal graft survival. Using the virtual crossmatch and desensitization therapies can shorten waitlist times without increasing posttransplant rejection or mortality rates. The ideal heart-lung donor tends to be younger than other multiorgan transplants, and more tolerant to HLA mismatch, but ideally requires donors with no prior history of smoking, a short period of time on mechanical ventilation, adequate oxygenation and absence of pulmonary infection. The ideal heart-liver donor is often driven by criteria specific to the donor heart. Finally, several observational studies suggest that livers are more tolerant to HLA mismatch than other organs, and offer some degree of immune protection in combined organ transplants.SUMMARY: Multiorgan transplantation is a steadily growing field. The required short ischemic time for the donor heart is often the limiting factor, as well as the scarcity of appropriate donors available within geographical confines. In general, as with single organ transplantation, younger age, size matching, few medical comorbidities and HLA compatibility confer the best posttransplant outcomes.

  View details for DOI 10.1097/MOT.0000000000000940

  View details for PubMedID 34939964

• Microcirculatory Resistance Predicts Allograft Rejection and Cardiac Events After Heart Transplantation. Journal of the American College of Cardiology Ahn, J., Zimmermann, F. M., Gullestad, L., Angeras, O., Karason, K., Russell, K., Lunde, K., Okada, K., Luikart, H., Khush, K. K., Honda, Y., Pijls, N. H., Lee, S. E., Kim, J., Park, S., Solberg, O., Fearon, W. F. 2021; 78 (24): 2425-2435

  Abstract

  BACKGROUND: Single-center data suggest that the index of microcirculatory resistance (IMR) measured early after heart transplantation predicts subsequent acute rejection.OBJECTIVES: The goal of this study was to validate whether IMR measured early after transplantation can predict subsequent acute rejection and long-term outcome in a large multicenter cohort.METHODS: From 5 international cohorts, 237 patients who underwent IMR measurement early after transplantation were enrolled. The primary outcome was acute allograft rejection (AAR) within 1 year after transplantation. A key secondary outcome was major adverse cardiac events (MACE) (the composite of death, re-transplantation, myocardial infarction, stroke, graft dysfunction, and readmission) at 10 years.RESULTS: IMR was measured at a median of 7weeks (interquartile range: 3-10weeks) post-transplantation. At 1 year, the incidence of AAR was 14.4%. IMR was associated proportionally with the risk of AAR (per increase of 1-U IMR; adjusted hazard ratio [aHR]: 1.04; 95% confidence interval [CI]: 1.02-1.06; p < 0.001). The incidence of AAR in patients with an IMR≥18 was 23.8%, whereas the incidence of AAR in those with an IMR<18 was 6.3% (aHR: 3.93; 95%CI: 1.77-8.73; P=0.001). At 10 years, MACE occurred in 86 (36.3%) patients. IMR was significantly associated with the risk of MACE (per increase of 1-U IMR; aHR: 1.02; 95%CI: 1.01-1.04; P=0.005).CONCLUSIONS: IMR measured early after heart transplantation is associated with subsequent AAR at 1 year and clinical events at 10 years. Early IMR measurement after transplantation identifies patients at higher risk and may guide personalized posttransplantation management.

  View details for DOI 10.1016/j.jacc.2021.10.009

  View details for PubMedID 34886963

• Proceedings from the metrics forum in heart transplantation for performance monitoring. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kobashigawa, J., Hall, S., Farr, M., Blumberg, E., Michael Borkon, A., Colvin, M., Copeland, H., Eisen, H., Johnson, M., Jorde, U., Khush, K., Kirklin, J. K., Patel, J., Pinney, S., Saadaeijahromi, H., Schold, J. D., Stehlik, J., Consensus Conference Participants 2021

  Abstract

  Regulatory oversight for heart transplant programs is currently under review by the United Network for Organ Sharing (UNOS). There is concern whether 1-year patient and graft survival truly represent heart transplant center performance. Thus, a forum was organized by the Thoracic and Critical Care Community of Practice (TCC COP) of the American Society of Transplantation (AST) for the heart transplant community to voice their opinions on matters involving program performance monitoring by UNOS. A TCC COP work group was formed to review outcome metrics for adult heart transplantation and culminated in a virtual community forum (72 participants representing 61 heart transplant programs) on November 12-13, 2020. One-year post-transplant survival is still considered an appropriate and important measure to assess program performance. Waitlist mortality and offer acceptance rate as pre-transplant metrics could also be useful measures of program performance, recognizing that outside factors may influence these metrics. In depth discussion of these metrics and other issues including auditing thresholds, innovations to reduce risk-averse behavior and personally designed program scorecards are included in this meeting proceedings.

  View details for DOI 10.1111/ajt.16901

  View details for PubMedID 34866328

• Optimal Patient Selection for Simultaneous Heart-Kidney Transplant: A Modified Cost-Effectiveness Analysis Wayda, B., Cheng, X. S., Goldhaber-Fiebert, J. D., Khush, K. K. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000752020005412

• Optimal patient selection for simultaneous heart-kidney transplant: a modified cost-effectiveness analysis. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Wayda, B., Cheng, X. S., Goldhaber-Fiebert, J. D., Khush, K. K. 2021

  Abstract

  Increasing rates of simultaneous heart-kidney (SHK) transplant in the United States exacerbate the overall shortage of deceased donor kidneys (DDK). Current allocation policy does not impose constraints on SHK eligibility, and how best to do so remains unknown. We apply a decision analytic model to evaluate options for heart transplant (HT) candidates with comorbid kidney dysfunction. We compare SHK with a "Safety Net" strategy, in which DDK transplant is performed six months after HT, only if native kidneys do not recover. We identify patient subsets for whom SHK using a DDK is efficient, considering the quality-adjusted life year (QALY) gains from DDKs instead allocated for kidney transplant-only. For an average-aged candidate with 50% probability of kidney recovery after HT-only, SHK produces 0.64 more QALYs than Safety Net at a cost of 0.58 more kidneys used. SHK is inefficient in this scenario, producing fewer QALYs per DDK used (1.1) than a DDK allocated for KT-only (2.2). SHK is preferred to Safety Net only for candidates with a lower probability of native kidney recovery (24 - 38%, varying by recipient age). This finding favors implementation of a Safety Net provision and should inform the establishment of objective criteria for SHK transplant eligibility.

  View details for DOI 10.1111/ajt.16888

  View details for PubMedID 34741786

• Prognostic value of comprehensive intracoronary physiology assessment early after heart transplantation. European heart journal Ahn, J., Zimmermann, F. M., Arora, S., Solberg, O., Angeras, O., Rolid, K., Rafique, M., Aaberge, L., Karason, K., Okada, K., Luikart, H., Khush, K. K., Honda, Y., Pijls, N. H., Lee, S. E., Kim, J., Park, S., Gullestad, L., Fearon, W. F. 2021

  Abstract

  AIMS: We evaluated the long-term prognostic value of invasively assessing coronary physiology after heart transplantation in a large multicentre registry.METHODS AND RESULTS: Comprehensive intracoronary physiology assessment measuring fractional flow reserve (FFR), the index of microcirculatory resistance (IMR), and coronary flow reserve (CFR) was performed in 254 patients at baseline (a median of 7.2weeks) and in 240 patients at 1year after transplantation (199 patients had both baseline and 1-year measurement). Patients were classified into those with normal physiology, reduced FFR (FFR≤0.80), and microvascular dysfunction (either IMR≥25 or CFR≤2.0 with FFR>0.80). The primary outcome was the composite of death or re-transplantation at 10years. At baseline, 5.5% had reduced FFR; 36.6% had microvascular dysfunction. Baseline reduced FFR [adjusted hazard ratio (aHR) 2.33, 95% confidence interval (CI) 0.88-6.15; P=0.088] and microvascular dysfunction (aHR 0.88, 95% CI 0.44-1.79; P=0.73) were not predictors of death and re-transplantation at 10years. At 1year, 5.0% had reduced FFR; 23.8% had microvascular dysfunction. One-year reduced FFR (aHR 2.98, 95% CI 1.13-7.87; P=0.028) and microvascular dysfunction (aHR 2.33, 95% CI 1.19-4.59; P=0.015) were associated with significantly increased risk of death or re-transplantation at 10years. Invasive measures of coronary physiology improved the prognostic performance of clinical variables (chi2 improvement: 7.41, P=0.006). However, intravascular ultrasound-derived changes in maximal intimal thickness were not predictive of outcomes.CONCLUSION: Abnormal coronary physiology 1year after heart transplantation was common and was a significant predictor of death or re-transplantation at 10years.

  View details for DOI 10.1093/eurheartj/ehab568

  View details for PubMedID 34665224

• Risk of Renal Dysfunction Following Heart Transplantation in Patients Bridged with a Left Ventricular Assist Device. ASAIO journal (American Society for Artificial Internal Organs : 1992) Tibrewala, A., Khush, K. K., Cherikh, W. S., Foutz, J., Stehlik, J., Rich, J. D. 2021

  Abstract

  Acute renal failure (ARF) and chronic kidney disease (CKD) are associated with short- and long-term morbidity and mortality following heart transplantation (HT). We investigated the incidence and risk factors for developing ARF requiring hemodialysis (HD) and CKD following HT specifically in patients with a left ventricular assist device (LVAD). We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry for heart transplant patients between January 2000 and June 2015. We compared patients bridged with durable continuous-flow LVAD to those without LVAD support. Primary outcomes were ARF requiring HD before discharge following HT and CKD (defined as creatinine >2.5 mg/dl, permanent dialysis, or renal transplant) within 3 years. There were 18,738 patients, with 4,535 (24%) bridged with LVAD support. Left ventricular assist device patients had higher incidence of ARF requiring HD and CKD at 1 year, but no significant difference in CKD at 3 years compared to non-LVAD patients. Among LVAD patients, body mass index (BMI) (odds ratio [OR] = 1.79, p < 0.001), baseline estimated glomerular filtration rate (eGFR) (OR = 0.43, p < 0.001), and ischemic time (OR = 1.28, p = 0.014) were significantly associated with ARF requiring HD. Similarly, BMI (hazard ratio [HR] = 1.49, p < 0.001), baseline eGFR (HR = 0.41, p < 0.001), pre-HT diabetes mellitus (DM) (HR = 1.37, p = 0.011), and post-HT dialysis before discharge (HR = 3.93, p < 0.001) were significantly associated with CKD. Left ventricular assist device patients have a higher incidence of ARF requiring HD and CKD at 1 year after HT compared with non-LVAD patients, but incidence of CKD is similar by 3 years. Baseline renal function, BMI, ischemic time, and DM can help identify LVAD patients at risk of ARF requiring HD or CKD following HT.

  View details for DOI 10.1097/MAT.0000000000001558

  View details for PubMedID 34419984

• Impact of diabetes mellitus on clinical outcomes after heart transplantation. Clinical transplantation Feng, K. Y., Henricksen, E. J., Wayda, B., Moayedi, Y., Lee, R., Han, J., Multani, A., Yang, W., Purewal, S., Puing, A. G., Basina, M., Teuteberg, J. J., Khush, K. K. 2021

  Abstract

  PURPOSE: Diabetes mellitus (DM) is common among recipients of heart transplantation (HTx) but its impact on clinical outcomes is unclear. We evaluated the associations between pretransplant DM and posttransplant DM (PTDM) and outcomes among adults receiving HTx at a single center.METHODS: We performed a retrospective study (range 01/2008 - 07/2018), n = 244. The primary outcome was survival; secondary outcomes included acute rejection, cardiac allograft vasculopathy, infection requiring hospitalization, macrovascular events, and dialysis initiation post-transplant. Comparisons were performed using Kaplan-Meier and multivariable Cox regression analyses.RESULTS: Pretransplant DM was present in 75 (30.7%) patients and was associated with a higher risk for infection requiring hospitalization (p<0.05), but not with survival or other outcomes. Among the 144 patients without pretransplant DM surviving to one year, 29 (20.1%) were diagnosed with PTDM at the 1-year follow-up. After multivariable adjustment, PTDM diagnosis at 1-year remained associated with worse subsequent survival (hazard ratio 2.72, 95% confidence interval 1.03-7.16). Predictors of PTDM at 1-year included cytomegalovirus seropositivity and higher prednisone dose (>5mg/day) at 1-year follow-up.CONCLUSIONS: Compared to HTx recipients without baseline DM, those with baseline DM have a higher risk for infections requiring hospitalization, and those who develop DM after HTx have worse survival. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.14460

  View details for PubMedID 34390599

• REGIONAL DIFFERENCES IN PRIMARY GRAFT DYSFUNCTION IN HEART TRANSPLANTATION: A REPORT FROM THE INTERNATIONAL CONSORTIUM ON PRIMARY GRAFT DYSFUNCTION Guzman-Bofarull, J., Han, J., Moayedi, Y., Foroutan, F., Truby, L., Angleitner, P., Sabatino, M., Baughan, E., Zafar, H., Felius, J., van Zyl, J., Law, D., Chih, S., Devore, A., Miller, R., Khush, K., Hall, S., Ross, H., Potena, L., Zuckermann, A., Farr, M., Farrero, M. WILEY. 2021: 203

  View details for Web of Science ID 000689725500534

• Cost-effectiveness of Dapagliflozin for Treatment of Patients With Heart Failure With Reduced Ejection Fraction. JAMA cardiology Parizo, J. T., Goldhaber-Fiebert, J. D., Salomon, J. A., Khush, K. K., Spertus, J. A., Heidenreich, P. A., Sandhu, A. T. 2021

  Abstract

  Importance: In the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, dapagliflozin was shown to reduce cardiovascular mortality and hospitalizations due to heart failure while improving patient-reported health status. However, the cost-effectiveness of adding dapagliflozin therapy to standard of care (SOC) is unknown.Objective: To estimate the cost-effectiveness of dapagliflozin therapy among patients with chronic heart failure with reduced ejection fraction (HFrEF).Design, Setting, and Participants: This Markov cohort cost-effectiveness model used estimates of therapy effectiveness, transition probabilities, and utilities from the DAPA-HF trial and other published literature. Costs were derived from published sources. Patients with HFrEF included subgroups based on diabetes status and health status impairment due to heart failure. We compiled parameters from the literature including DAPA-HF, on which our model is based, and many other sources from December 2019 to February 27, 2021. We performed our analysis in February 2021.Exposures: Dapagliflozin or SOC.Main Outcomes and Measures: Hospitalizations for heart failure, life-years, quality-adjusted life-years (QALYs), costs, and the cost per QALY gained (incremental cost-effectiveness ratio).Results: In the model, dapagliflozin therapy yielded a mean of 0.78 additional life-years and 0.46 additional QALYs compared with SOC at an incremental cost of $38 212, resulting in a cost per QALY gained of $83 650. The cost per QALY was similar for patients with or without diabetes and for patients with mild or moderate impairment of health status due to heart failure. The cost-effectiveness was most sensitive to estimates of the effect on mortality and duration of therapy effectiveness. If the cost of dapagliflozin decreased from $474 to $270 (43% decline), the cost per QALY gained would drop below $50 000.Conclusions and Relevance: These findings suggest that dapagliflozin provides intermediate value compared with SOC, based on American College of Cardiology/American Heart Association benchmarks. Additional data regarding the magnitude of mortality reduction would improve the precision of cost-effectiveness estimates.

  View details for DOI 10.1001/jamacardio.2021.1437

  View details for PubMedID 34037681

• COST-EFFECTIVENESS AND SYSTEM-WIDE IMPACT OF USING HEPATITIS C-VIREMIC DONORS FOR HEART TRANSPLANT Wayda, B., Sandhu, A., Parizo, J., Teuteberg, J., Khush, K. ELSEVIER SCIENCE INC. 2021: 3417

  View details for Web of Science ID 000647487503438

• STATIN ADHERENCE AFTER HEART TRANSPLANTATION: AN OUTCOMES ANALYSIS Li, K., Kalwani, N., Sandhu, A., Khush, K., Fearon, W. ELSEVIER SCIENCE INC. 2021: 569

  View details for Web of Science ID 000647487500568

• Waitlist and post-transplant outcomes for eisenmenger syndrome: A comparison of transplant strategies. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Kearney, K., Lau, E. M., Darley, D., Romfh, A., Bart, N., Kotlyar, E., Hayes, D. J., Khush, K., Keogh, A. 2021

  Abstract

  BACKGROUND: End-stage Eisenmenger syndrome (ES) due to unrepaired atrial septal defect (ASD) or ventricular septal defect (VSD) is an indication for lung transplantation (LTx) or heart-lung transplantation (HLTx). Limited evidence exists as to the optimal transplant strategy for this unique population.AIM: To describe waitlist characteristics and post-transplant outcomes in patients with ES-ASD or ES-VSD.METHODS: Using the ISHLT Registry, data were extracted for all ES-ASD or ES-VSD patients who underwent transplantation between 1987 and 2018. Additional data were sought for patients listed for LTx or HLTx in the OPTN Registry during the same period. Early era was defined as 1987-2004, and current era was defined as 2005-2018.RESULTS: In the current era, patients with ES-ASD or ES-VSD represented a lessening proportion of all LTx and HLTx. Compared to LTx for other indications, the odds of transplantation were significantly less for both ES-ASD 0.18 [0.07-0.50] and ES-VSD 0.03 [0.004-0.22]. In the early era, an equivalent survival was observed for ES-ASD who underwent HLTx versus LTx (p=0.47), and superior survival for ES-VSD (p=0.015). In contrast, ES-ASD patients who underwent LTx from the current era displayed better survival compared with HLTx, 10-year survival 52% vs 30% p=0.036. Similar survival were observed for ES-VSD for both transplant strategies (p=0.68).CONCLUSION: LTx shows superior survival outcomes in the current era for ES ASD patients, and equivalent outcomes for ES-VSD. In the current era, ES-ASD or ES-VSD patients were less likely to be transplanted than other candidates for LTx.

  View details for DOI 10.1016/j.healun.2021.04.005

  View details for PubMedID 34112578

• Incidence and impact of primary graft dysfunction in adult heart transplant recipients: A systematic review and meta-analysis. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Buchan, T. A., Moayedi, Y., Truby, L. K., Guyatt, G., Posada, J. D., Ross, H. J., Khush, K. K., Alba, A. C., Foroutan, F. 2021

  Abstract

  PURPOSE: Primary graft dysfunction (PGD) is a leading cause of early mortality after heart transplant (HTx). To identify PGD incidence and impact on mortality, and to elucidate risk factors for PGD, we systematically reviewed studies using the ISHLT 2014 Consensus Report definition and reporting the incidence of PGD in adult HTx recipients.METHODS: We conducted a systematic search in January 2020 including studies reporting the incidence of PGD in adult HTx recipients. We used a random effects model to pool the incidence of PGD among HTx recipients and, for each PGD severity, the mortality rate among those who developed PGD. For prognostic factors evaluated in ≥2 studies, we used random effects meta-analyses to pool the adjusted odds ratios for development of PGD. The GRADE framework informed our certainty in the evidence.RESULTS: Of 148 publications identified, 36 observational studies proved eligible. With moderate certainty, we observed pooled incidences of 3.5%, 6.6%, 7.7%, and 1.6% and 1-year mortality rates of 15%, 21%, 41%, and 35% for mild, moderate, severe and isolated right ventricular-PGD, respectively. Donor factors (female sex, and undersized), recipient factors (creatinine, and pre-HTx use of amiodarone, and temporary or durable mechanical support), and prolonged ischemic time proved associated with PGD post-HTx.CONCLUSION: Our review suggests that the incidence of PGD may be low but its risk of mortality high, increasing with PGD severity. Prognostic factors, including undersized donor, recipient use of amiodarone pre-HTx and recipient creatinine may guide future studies in exploring donor and/or recipient selection and risk mitigation strategies.

  View details for DOI 10.1016/j.healun.2021.03.015

  View details for PubMedID 33947602

• Use of donor-derived-cell-free DNA as a marker of early allograft injury in primary graft dysfunction (PGD) to predict the risk of chronic lung allograft dysfunction (CLAD). The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Keller, M., Bush, E., Diamond, J. M., Shah, P., Matthew, J., Brown, A. W., Sun, J., Timofte, I., Kong, H., Tunc, I., Luikart, H., Iacono, A., Nathan, S. D., Khush, K. K., Orens, J., Jang, M., Agbor-Enoh, S. 2021

  Abstract

  BACKGROUND: Primary graft dysfunction (PGD) is a risk factor for chronic lung allograft dysfunction (CLAD). However, the association between PGD and degree of allograft injury remains poorly defined. In this study, we leverage a novel biomarker for allograft injury, percentage donor-derived cell-free DNA (%ddcfDNA), to study the association between PGD, degree of allograft injury, and the development of CLAD.METHODS: This prospective cohort study recruited 99 lung transplant recipients and collected plasma samples on days 1, 3, and 7 for %ddcfDNA measurements. Clinical data on day 3 was used to adjudicate for PGD. %ddcfDNA levels were compared between PGD grades. In PGD patients, %ddcfDNA was compared between those who developed CLAD and those who did not.RESULTS: On posttransplant day 3, %ddcfDNA was higher in PGD than in non-PGD patients (median [IQR]: 12.2% [8.2, 22.0] vs 8.5% [5.6, 13.2] p = 0.01). %ddcfDNA correlated with the severity grade of PGD (r = 0.24, p = 0.02). Within the PGD group, higher levels of %ddcfDNA correlated with increased risk of developing CLAD (log OR(SE) 1.38 (0.53), p = 0.009). PGD patients who developed CLAD showed 2-times higher %ddcfDNA levels than patients who did not develop CLAD (median [IQR]: 22.4% [11.8, 27.6] vs 9.9% [6.7, 14.9], p = 0.007).CONCLUSION: PGD patients demonstrated increased early posttransplant allograft injury, as measured by %ddcfDNA, in comparison to non-PGD patients, and these high %ddcfDNA levels were associated with subsequent development of CLAD. This study suggests that %ddcfDNA identifies PGD patients at greater risk of CLAD than PGD alone.

  View details for DOI 10.1016/j.healun.2021.02.008

  View details for PubMedID 33814284

• Clinical utility of donor-derived cell-free DNA testing in cardiac transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Khush, K. K. 2021

  Abstract

  Surveillance of allograft health after transplantation has traditionally relied on biopsy procedures that enable pathologic assessment for acute rejection. Noninvasive methods to assess for graft injury have been developed and tested over the past decade, and now offer a convenient way to reduce reliance on invasive testing and improve patient satisfaction. Emerging evidence suggests that detection of allograft injury via donor-derived cell-free DNA (dd-cfDNA) may, in fact, have better sensitivity compared to traditional biopsy-based strategies. This state-of-the-art review describes the development, testing, and current use of dd-cfDNA assays for acute rejection monitoring after heart transplantation, and discusses innovative ways that such assays can be used for personalized patient management.

  View details for DOI 10.1016/j.healun.2021.01.1564

  View details for PubMedID 33610430

• Consensus Conference on Heart-Kidney Transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kobashigawa, J., Dadhania, D. M., Farr, M., Tang, W. H., Bhimaraj, A., Czer, L., Hall, S., Haririan, A., Formica, R. N., Patel, J., Skorka, R., Fedson, S., Srinivas, T., Testani, J., Yabu, J. M., Cheng, X. S., Consensus Conference Participants 2021

  Abstract

  Simultaneous heart-kidney transplant (sHK) has enabled the successful transplantation of patients with end-stage heart disease and concomitant kidney disease, with non-inferior outcomes to heart transplant (HT) alone. The decision for sHK is challenged by difficulties in differentiating those patients with a significant component of reversible kidney injury due to cardiorenal syndrome who may recover kidney function after HT, from those with intrinsic advanced kidney disease who would benefit most from sHK. A consensus conference on sHK took place on June 1, 2019 in Boston, Massachusetts. The conference represented a collaborative effort by experts in cardiothoracic and kidney transplantation from centers across the United States to explore the development of guidelines for the interdisciplinary criteria for kidney transplantation in the sHK candidate, to evaluate the current allocation of kidneys to follow the heart for sHK, and to recommend standardized care for the management of sHK recipients. The conference served as a forum to unify criteria between the different specialties and to forge a pathway for patients who may need dual organ transplantation. Due to the continuing shortage of available donor organs, ethical problems related to multi-organ transplantation were also debated. The findings and consensus statements are presented.

  View details for DOI 10.1111/ajt.16512

  View details for PubMedID 33527725

• New Onset Diabetes Mellitus After Adult Heart Transplantation and the Risk of Renal Dysfunction or Mortality. Transplantation Vest, A. R., Cherikh, W. S., Noreen, S. M., Stehlik, J., Khush, K. K. 2021

  Abstract

  BACKGROUND: Diabetes mellitus (DM) may occur either pre-heart transplant (HT) or as new onset DM post-HT. We sought to define the contemporary incidence of post-HT DM, evaluate risk factors for post-HT DM, and assess the impact of post-HT DM on major outcomes.METHODS: The cohort included International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Transplant Registry adult primary HT-alone recipients, transplanted January 1995-June 2017, who survived to 1 year post-HT. DM status was characterized as (1) No DM pre- or post-HT; (2) Pre-HT DM; or (3) Post-HT DM (onset within 5 years of HT). Cox proportional hazards models were constructed to identify risk factors for post-HT DM onset, as well as risk factors for post-HT severe renal dysfunction and death/retransplantation.RESULTS: Of 26 263 eligible subjects, 57% had no DM pre- or post-HT, 22% had pre-HT DM; 21% had new onset post-HT DM. Risk factors for the development of post-HT DM included use of tacrolimus or steroids at 1-year post-HT, as well as with higher recipient age, female sex, ischemic cardiomyopathy, higher body mass index (BMI), pre-HT dialysis, and pre-HT steroid use. Post-HT DM within 5 years was associated with increased subsequent severe renal dysfunction (hazard ratio, HR, 1.89; 95% CI 1.77, 2.01) and death/retransplantation (HR 1.38; 95% CI 1.32, 1.45), compared to patients without post-HT DM.CONCLUSIONS: Post-HT DM is common, occurring in 21% of recipients within 5 years of HT. Post-HT DM is associated with increased risk of severe renal dysfunction and death or retransplantation.

  View details for DOI 10.1097/TP.0000000000003647

  View details for PubMedID 33496556

• Donor and Recipient Size Matching in Heart Transplantation with Predicted Heart and Lean Body Mass. Seminars in thoracic and cardiovascular surgery Miller, R. J., Hedman, K. n., Amsallem, M. n., Tulu, Z. n., Kent, W. n., Fatehi, A. n., Clarke, B. n., Heidenreich, P. n., Hiesinger, W. n., Khush, K. K., Teuteberg, J. n., Haddad, F. n. 2021

  Abstract

  Donor and recipient size matching during heart transplant can be assessed using weight or predicted heart mass (PHM) ratios. We developed sex-specific allomteric equations for PHM and predicted lean body mass (PLBM) using the United Kingdom Biobank (UKB) and evaluated their predictive value in the United Network of Organ Sharing (UNOS) database. Donor and recipient size matching was based on weight, PHM and PLBM ratios. PHM was calculated using the Multi-ethnic Study of Atherosclerosis and UKB equations. PLBM was calculated using the UKB and National Health and Nutrition Examination Survey (NHANES) equations. Relative prognostic utility was compared using multivariable Cox analysis, adjusted for predictors of one-year survival in the Scientific Registry of Transplant Recipients (SRTR) model. Of 53,648 adult patients in the UNOS database between 1996 and 2016, 6528 (12.2%) died within the first year. In multivariable analysis, undersized matches by any metric were associated with increased one-year mortality (all p<0.01). Oversized matches were at increased risk using PHM or PLBM (all p<0.01), but not weight ratio. There were significant differences in classification of size matching by weight or PHM in sex-mismatched donor-recipient pairs. A significant interaction was observed between pulmonary hypertension and donor undersizing (hazard ratio 1.15, p=0.026) suggesting increased risk of undersizing in pulmonary hypertension. Donor and recipient size matching with simplified PHM and PLBM offered an advantage over total body weight and may be more important for sex-mismatched donor-recipient pairs. Donor undersizing is associated with worse outcomes in patients with pulmonary hypertension.

  View details for DOI 10.1053/j.semtcvs.2021.01.001

  View details for PubMedID 33444763

• Impact of using higher-risk donor hearts for candidates with pre-transplant mechanical circulatory support. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Han, J., Moayedi, Y., Yang, W., Henricksen, E. J., Lee, R., Purewal, S., Chang, E., Duclos, S., Lyapin, A., Feng, K., Hiesinger, W., Teuteberg, J. J., Khush, K. K. 2021

  Abstract

  We evaluated post-heart transplant (HTx) outcomes after use of higher-risk donor hearts for candidates supported with pre-HTx mechanical circulatory support (MCS).In this retrospective analysis of the national United Network for Organ Sharing registry, a total of 9,915 adult candidates on MCS underwent HTx from January 1, 2010 to March 31, 2019. Multi-organ, re-transplant, and congenital heart disease patients were excluded. Higher-risk donor organs met at least one of the following criteria: left ventricular ejection fraction <50%, donor to recipient predicted heart mass ratio <0.86, donor age >55 years, or ischemic time >4 hours. Primary outcome was 1 year post-transplant survival.Among HTx recipients, 3688 (37.2%) received higher-risk donor hearts. Candidates supported with pre-HTx extracorporeal membrane oxygenation or biventricular assist device (n = 374, 3.8%) who received higher-risk donor hearts had comparable 1 year survival (HR: 1.14, 95% CI: [0.67-1.93], p = 0.64) to recipients of standard-risk donor hearts, when adjusted for recipient age and sex. In candidates supported with intra-aortic balloon pump (n = 1391, 14.6%), transplantation of higher-risk donor hearts did not adversely affect 1 year survival (HR: 0.80, 95% CI: [0.52-1.22], p = 0.30). Patients on durable left ventricular assist devices (LVAD) who received higher-risk donor hearts had comparable 1 year survival to continued LVAD support on the waitlist, but mortality was increased compared to those who received standard-risk donor hearts (HR: 1.37, 95% CI: [1.11-1.70], p = 0.004).Patients requiring pre-HTx temporary MCS who received higher-risk donor hearts had comparable 1 year post-transplant survival to those who received standard-risk donor hearts. Stable patients on durable LVADs may benefit from waiting for standard-risk donor hearts.

  View details for DOI 10.1016/j.healun.2021.09.016

  View details for PubMedID 34815161

• Cytomegalovirus Donor Seropositivity Negatively Affects Survival After Heart Transplantation. Transplantation Heim, C., Müller, P. P., Tandler, R., Cherikh, W. S., Toll, A. E., Stehlik, J., Weyand, M., Khush, K. K., Ensminger, S. M. 2021

  Abstract

  Prior studies have shown that cytomegalovirus(CMV) infection is a risk factor for the development of cardiac allograft vasculopathy(CAV) and is associated with reduced long-term survival after heart transplantation. The aim of this ISHLT Transplant Registry study was to compare post-transplant survival in different CMV donor:recipient serologic combinations.We performed a retrospective cohort study, using the ISHLT Thoracic Transplant Registry, on 15,885 adult primary heart transplant recipients with known CMV serologic status between 7/2004 and 6/2014. Post-transplant survival and risk of developing CAV were compared across 4 groups: CMV-seronegative recipients(R-) receiving CMV-positive grafts(D+), intermediate-risk patients(D+R+ and D-R+), and low-risk patients(D-R-).Baseline characteristics (donor/recipient age, BMI, recipient serum creatinine, blood group, donor cause of death, recipient diagnosis and ischemic time) were mostly balanced between the groups. Kaplan Meier survival analyses over a follow up of 10 years revealed significantly worse survival for both D+ groups as compared to the CMV low risk group (D+R+:56.61% (95%CI 53.94,59.41) vs. D-R-:63.09% (59.74,66.64) p<.01 and D+R-:57.69% (56.03,59.39) vs. D-R-; p<.001), whereas recipient seropositivity alone was not associated with reduced survival (D-R+ vs. D-R- p=.178). The risk of developing CAV after HTx was not significantly increased in D+ as compared to D- groups.In a large contemporary cohort, CMV status at the time of heart transplantation was not associated with CAV development. However, there was a significant association between donor CMV seropositivity and reduced short- and long-term survival after heart transplantation. Approaches to mitigate the impact of CMV on post-transplant survival are needed.Supplemental Visual Abstract; http://links.lww.com/TP/C292.

  View details for DOI 10.1097/TP.0000000000003961

  View details for PubMedID 34560698

• New Approaches to Donor Selection and Preparation in Heart Transplantation. Current treatment options in cardiovascular medicine Tong, C. K., Khush, K. K. 2021; 23 (5): 28

  Abstract

  Purpose of review: With increasing survival of patients with stage D heart failure, the demand for heart transplantation has increased. The supply of donor hearts remains relatively limited. Strategies have been investigated and new technologies have been developed to expand the current donor pool. These new approaches will be discussed herein.Recent findings: Donor hearts are often considered "marginal" due to risk factors such as older age, size mismatch with the intended recipient, prolonged ischemic time, presence of left ventricular hypertrophy, and hepatitis B/C infection. We reviewed recent data regarding the use of donor hearts with these risk factors and suggest ways to safely liberalize current donor heart acceptance criteria. New technologies such as temperature-controlled transport systems and ex vivo cardiac perfusion methods have also demonstrated promising short-term and intermediate outcomes as compared with routine cold storage, by promoting heart preservation and enabling heart procurement from remote sites with shorter cold ischemic time. Recent use of hearts from donation after circulatory death donors has demonstrated comparable outcomes to conventional donation after brain death, which can further expand the current donor pool.Summary: Careful selection of "marginal" donor hearts, use of ex vivo cardiac perfusion, and acceptance of hearts after circulatory death may expand our current cardiac donor pool with comparable outcomes to conventional donor selection and preparation methods.

  View details for DOI 10.1007/s11936-021-00906-5

  View details for PubMedID 33776401

• Donor-derived, cell-free DNA levels by next-generation targeted sequencing are elevated in allograft rejection after lung transplantation. ERJ open research Khush, K. K., De Vlaminck, I., Luikart, H., Ross, D. J., Nicolls, M. R. 2021; 7 (1)

  Abstract

  Surveillance after lung transplantation is critical to the detection of acute cellular rejection (ACR) and prevention of chronic lung allograft dysfunction (CLAD). Therefore, we measured donor-derived cell-free DNA (dd-cfDNA) implementing a clinical-grade, next-generation targeted sequencing assay in 107 plasma samples from 38 unique lung transplantation recipients with diagnostic cohorts classified as: (1) biopsy-confirmed or treated ACR, (2) antibody-mediated rejection (AMR), (3) obstructive CLAD, (4) allograft infection (INFXN) and (5) Stable healthy allografts (STABLE). Our principal findings are as follows: (1) dd-cfDNA level was elevated in ACR (median 0.91%; interquartile range (IQR): 0.39-2.07%), CLAD (2.06%; IQR: 0.57-3.67%) and an aggregated cohort of rejection encompassing allograft injury (1.06%; IQR: 0.38-2.51%), compared with the STABLE cohort (0.38%; IQR: 0.23-0.87%) (p=0.02); (2) dd-cfDNA level with AMR was elevated (1.34%; IQR: 0.34-2.40%) compared to STABLE, although it did not reach statistical significance (p=0.07) due to limitations in sample size; (3) there was no difference in dd-cfDNA for allograft INFXN (0.39%; IQR: 0.18-0.67%) versus STABLE, which may relate to differences in "tissue injury" with the spectrum of bronchial colonisation versus invasive infection; (4) there was no difference for dd-cfDNA in unilateral versus bilateral lung transplantation; (5) "optimal threshold" for dd-cfDNA for aggregated rejection events representing allograft injury was determined as 0.85%, with sensitivity=55.6%, specificity=75.8%, positive predictive value (PPV)=43.3% and negative predictive value (NPV)=83.6%. Measurement of plasma dd-cfDNA may be a clinically useful tool for the assessment of lung allograft health and surveillance for "tissue injury" with a spectrum of rejection.

  View details for DOI 10.1183/23120541.00462-2020

  View details for PubMedID 33532456

• Cardiopulmonary Exercise Testing With Echocardiography to Assess Recovery in Patients With Ventricular Assist Devices. ASAIO journal (American Society for Artificial Internal Organs : 1992) Christle, J. W., Moneghetti, K. J., Duclos, S., Mueller, S., Moayedi, Y., Khush, K. K., Haddad, F., Hiesinger, W., Myers, J., Ashley, E. A., Teuteberg, J. J., Wheeler, M. T., Banerjee, D. 2021; 67 (10): 1134-1138

  Abstract

  The left ventricular assist device (LVAD) is an established treatment for select patients with end-stage heart failure. Some patients recovered and are considered for explantation. Assessing recovery involves exercise testing and echo ramping on full and minimal LVAD support. Combined cardiopulmonary exercise testing with simultaneous echo ramping (CPET-R) has not been well studied. Patients were included if they had CPET within the previous 6 months, were clinically stable, and had an INR >2.0 on the day of examination. Patients had CPET-R on two occasions within 14 days: (a) with LVAD at therapeutic speed and (b) with LVAD at the lowest speed possible. Six patients were between 29 and 75 years (two female). One patient did not complete a turn-down test due to evidence of ischemia on initial CPET-R subsequently confirmed as a significant coronary artery stenosis on angiography. There were no significant differences in CPET or echo metrics between LVAD speeds. Two patients were explanted due to presumed LV recovery and remained event free for 30 and 47 months, respectively. Serial CPET-R seems safe and feasible for the evaluation of LV and global function and may result in improved clinical decision making for LVAD explantation.

  View details for DOI 10.1097/MAT.0000000000001383

  View details for PubMedID 34570726

• Cost-effectiveness and system-wide impact of using Hepatitis C-viremic donors for heart transplant. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Wayda, B., Sandhu, A. T., Parizo, J., Teuteberg, J. J., Khush, K. K. 2021

  Abstract

  The advent of direct-acting antiviral therapy for Hepatitis C (HCV) has made using HCV-viremic donors a viable strategy to address the donor shortage in heart transplantation. We employed a large-scale simulation to evaluate the impact and cost-effectiveness of using HCV-viremic donors for heart transplant.We simulated detailed histories from time of listing until death for the real-world cohort of all adults listed for heart transplant in the United States from July 2014 to June 2019 (n = 19,346). This population was imputed using historical data and captures "real-world" heterogeneity in geographic and clinical characteristics. We estimated the impact of an intervention in which all candidates accept HCV+ potential donors (n = 472) on transplant volume, waitlist outcomes, and lifetime costs and quality-adjusted life years (QALYs).The intervention produced 232 more transplants, 132 fewer delistings due to deterioration, and 50 fewer waitlist deaths within this 5-year cohort and reduced wait times by 3% to 11% (varying by priority status). The intervention was cost-effective, adding an average of 0.08 QALYs per patient at a cost of $124 million ($81,892 per QALY). DAA therapy and HCV care combined account for 11% this cost, with the remainder due to higher costs of transplant procedures and routine post-transplant care. The impact on transplant volume varied by blood type and region and was correlated with donor-to-candidate ratio (ρ = 0.71).Transplanting HCV+ donor hearts is likely to be cost-effective and improve waitlist outcomes, particularly in regions and subgroups experiencing high donor scarcity.

  View details for DOI 10.1016/j.healun.2021.09.002

  View details for PubMedID 34635381

• Evaluation of variation in insurance payor mix among heart transplant centers. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Parizo, J. T., Desai, M., Rodriguez, F., Sandhu, A. T., Khush, K. K. 2020

  View details for DOI 10.1016/j.healun.2020.09.017

  View details for PubMedID 33229249

• DD-CFDNA AS A RISK FACTOR FOR INITIATING DE-NOVO DONOR SPECIFIC ANTIBODIES IN HEART TRANSPLANTATION Depasquale, E., Kobashigawa, J., Pinney, S., Teuteberg, J., Khush, K. LIPPINCOTT WILLIAMS & WILKINS. 2020: S131–S132

  View details for Web of Science ID 000618872100177

• (ReBOOT) REmote moBile Outpatient MOnitoring in heart Transplant: A pilot study. The Canadian journal of cardiology Moayedi, Y., Hershman, S. G., Henricksen, E. J., Lee, R., Han, J., Bougouin, W., Khush, K. K., Ross, H. J., Teuteberg, J. J. 2020

  View details for DOI 10.1016/j.cjca.2020.07.005

  View details for PubMedID 32681856

• Use of direct oral anticoagulants after heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Henricksen, E. J., Tremblay-Gravel, M., Moayedi, Y., Yang, W., Lee, R., Ross, H. J., Hiesinger, W., Teuteberg, J. J., Khush, K. K. 2020

  View details for DOI 10.1016/j.healun.2019.12.007

  View details for PubMedID 32007373

• Long-term clinical outcomes with use of an angiotensin-converting enzyme inhibitor early after heart transplantation. American heart journal Arashi, H., Sato, T., Kobashigawa, J., Luikart, H., Kobayashi, Y., Okada, K., Sinha, S., Honda, Y., Yeung, A. C., Khush, K., Fearon, W. F. 2020; 222: 30–37

  Abstract

  BACKGROUND: The safety and efficacy of angiotensin converting enzyme inhibition (ACEI) after heart transplantation (HT) is unknown. This study examined long-term clinical outcomes after ACEI in HT recipients.METHODS: The ACEI after HT study was a prospective, randomized trial that tested the efficacy of ACEI with ramipril after HT. In this study, long-term clinical outcomes were assessed in 91 patients randomized to either ramipril or placebo (median, 5.8 years). The primary endpoint was a composite of death, retransplantation, hospitalization for rejection or heart failure, and coronary revascularization.RESULTS: The primary endpoint occurred in 10 of 45 patients (22.2%) in the ramipril group and in 14 of 46 patients (30.4%) in the placebo group (Hazard ratio (HR), 0.68; 95% CI, 0.29-1.51; P = .34). When the analysis was restricted to comparing patients who remained on a renin-angiotensin system inhibitor beyond 1 year with those who did not, there was a trend to improved outcomes (HR, 0.54; 95% CI, 0.22-1.28, P = .16). There was no significant difference in creatinine, blood urea nitrogen, and potassium at 3 years after randomization. The cumulative incidence of the primary endpoint was significantly higher in patients in whom the index of microcirculatory resistance increased from baseline to 1 year compared with those in whom it did not (39.1 vs 17.4%, HR: 3.36; 95% CI, 1.07-12.7; P = .037).CONCLUSION: The use of ramipril after HT safely lowers blood pressure and is associated with favorable long-term clinical outcomes. Clinical Trial Registration-URL: https://www.clinicaltrials.gov. Unique identifier: NCT01078363.

  View details for DOI 10.1016/j.ahj.2020.01.003

  View details for PubMedID 32007823

• Risk factors for early development of cardiac allograft vasculopathy by intravascular ultrasound. Clinical transplantation Moayedi, Y. n., Fan, C. P., Tremblay-Gravel, M. n., Miller, R. J., Kawana, M. n., Henricksen, E. n., Parizo, J. n., Wainwright, R. n., Fearon, W. F., Ross, H. J., Khush, K. K., Teuteberg, J. J. 2020: e14098

  Abstract

  Cardiac allograft vasculopathy (CAV) is the leading cause of late graft loss. While there are numerous post-transplant factors which may increase the risk of the development of CAV, there is a paucity of data on the impact of donor derived atherosclerosis (DA), early discontinuation of prednisone and early initiation of proliferation signal inhibitors (PSI) as assessed by intravascular ultrasound (IVUS).Retrospective single center study of all adult transplant patients (2008-2017) with serial IVUS at baseline and annually for 5 years. DA was defined as a baseline maximal intimal thickness (MIT) ≥ 0.5 mm, CAV development was defined as MIT ≥ 1 mm or an increase in MIT ≥ 0.5 mm at year 1 compared to baseline or an increase in 0.3 mm annually thereafter. Clinical risk factors for CAV were identified using multivariable hazard regression. Separate multistate models were applied to assess the association of prednisone discontinuation and PSI initiation and CAV.Of 282 patients screened, 186 patients had a 1-year angiogram. The mean age of those included in the cohort was 51±11 years, 70% were male, 58% were Caucasian and 27% were supported by a left ventricular assist device. Donor atherosclerosis was present in 40%. The cumulative incidence of CAV at 5 years is 41% in DA- vs. 59% in DA+(p=0.012). Donor age was a strong predictor of DA (p=0.016). Significant risk factors for CAV included male sex (HR= 4.141, p=0.001), non-Caucasian race (HR= 1.98, p= 0.011), BMI < 18 kg/m2 (HR=4.596, p=0.042), longer ischemic time (HR=1.374, p=0.028), older donor age (HR=1.158, p=0.009) and rejection with hemodynamic compromise within the first year (HR=2.858, p=0.043). Prednisone discontinuation within 1-year was associated with a lower risk of CAV (HR 0.58 p=0.047). Initiation of proliferation signal inhibitors (PSI) within 2 years resulted in fewer cases of CAV (HR 0.397 p<0.001).In patients with an angiogram at 1 year, those with DA were significantly more likely to develop CAV. Lower incidence of CAV by IVUS was seen in patients who discontinued prednisone in the first year or had initiation of a PSI within two years of transplantation. Knowledge of early IVUS may allow a more tailored approach to patient management.

  View details for DOI 10.1111/ctr.14098

  View details for PubMedID 32970884

• To Kidney or Not to Kidney: Applying Lessons Learned from the Simultaneous Liver-Kidney Transplant Policy to Simultaneous Heart-Kidney Transplantation. Clinical transplantation Cheng, X. S., Khush, K. K., Wiseman, A. n., Teuteberg, J. n., Tan, J. C. 2020

  Abstract

  As the medical community is increasingly offering transplantation to patients with increasing comorbidity burdens, the number of simultaneous heart-kidney (SHK) transplants is rising in the United States. How to determine eligibility for SHK transplant versus heart transplant alone is an important unknown. In this review, we situate this problem in the broader picture of organ shortage. We critically appraise available literature on outcomes in SHK versus heart transplant alone. We posit staged kidney-after-heart transplantation as a plausible alternative to SHK transplantation and review the pros and cons. Drawing lessons from the field of simultaneous liver-kidney transplant, we argue for an analogous policy for SHK transplant with standardized minimal eligibility criteria and a modified Safety Net provision. The new policy will serve as a starting point for comparing simultaneous versus staged approaches and refining the medical eligibility criteria for SHK.

  View details for DOI 10.1111/ctr.13878

  View details for PubMedID 32279361

• Recent Trends of Infectious Complications Following Heart Transplantation. Transplantation Multani, A. n., Moayedi, Y. n., Puing, A. n., Henricksen, E. n., Garvert, D. W., Gomez, C. A., Tremblay-Gravel, M. n., Bunce, P. E., Luikart, H. n., Ross, H. J., Khush, K. K., Montoya, J. G., Teuteberg, J. J. 2020

  Abstract

  Heart transplantation is a life-saving procedure that has seen improvements in transplant and patient outcomes due to advances in immunosuppression and prevention of posttransplantation infectious episodes (IEps). This study systematically evaluates IEps in the modern era of heart transplantation at Stanford University Medical Center.This is a single-center retrospective review that includes 279 consecutive adult heart transplantation recipients from January 2008 to September 2017. Baseline demographic, clinical, serological, and outcomes information were collected. Kaplan-Meier estimator was used to assess survival stratified by IEp occurrence within the first year.A total of 600 IEps occurred in 279 patients (2.15 IEps per patient) during a median follow-up period of 3 years. Overall survival was 83.3% [95% CI (76.2 to 88.4)] at 1 year posttransplantation for those with any IEp compared to 93.0% [95% CI (87.2,96.4)] in those without IEp (p=0.07). Bacterial IEps were the most common (n=375, 62.5%), followed by viral (n=180, 30.0%), fungal (n=40, 6.7%), and parasitic (n=5, 0.8%). IEps by Gram-negative bacteria (n=210) outnumbered those by Gram-positive bacteria (n=142). Compared to prior studies from our center, there was a decreased proportion of viral (including cytomegalovirus), fungal (including Aspergillus spp. and non-Aspergillus spp. molds), and Nocardia infections. There were no IEps due to Mycobacterium tuberculosis, Pneumocystis jirovecii, or Toxoplasma gondii.A significant reduction in viral, fungal, and Nocardia IEps after heart transplantation was observed, most likely due to advancements in immunosuppression and preventive strategies, including pretransplant infectious diseases screening and antimicrobial prophylaxis.

  View details for DOI 10.1097/TP.0000000000003307

  View details for PubMedID 32413012

• Impact of cytomegalovirus infection on gene expression profile in heart transplant recipients. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Kanwar, M. K., Khush, K. K., Pinney, S. n., Sherman, C. n., Hall, S. n., Teuteberg, J. n., Uriel, N. n., Kobashigawa, J. n. 2020

  Abstract

  Cytomegalovirus (CMV) infection has been implicated in the pathogenesis of allograft rejection in heart transplant (HT) recipients. The effect of a CMV infection on the gene expression profiling (GEP, AlloMap) scores in the absence of acute rejection is not known.Data from 14,985 samples collected from 2,288 adult HT recipients enrolled in Outcomes AlloMap Registry were analyzed. Patients with known CMV serology at the time of HT who had at least 1 AlloMap score reported during follow-up were included. AlloMap scores for those patients with CMV (but no ongoing rejection) were compared with those who were never infected. An exploratory analysis on the impact of CMV on available donor-derived cell-free DNA (AlloSure) was also performed.A total of 218 patients (10%) were reported to have CMV infection after transplantation. AlloMap score in those samples with CMV infection (n = 311) had a GEP score (34; range: 29-36) significantly higher than the GEP score from samples (n = 14,674) obtained in the absence of CMV infection (30; range: 26-34; p < 0.0001). Both asymptomatic viremia and CMV disease demonstrated significantly higher AlloMap scores than no CMV infection samples (median scores: 33, 35, and 30, respectively; p < 0.0001). AlloSure levels, available for 776 samples, were not significantly different (median: 0.23% in 18 samples with CMV infection vs 0.15% in 776 samples without CMV infection; p = 0.66).CMV infection in HT recipients is associated with an increase in AlloMap score, whereas AlloSure results do not appear to be impacted. This information should be considered when clinically interpreting abnormal/high AlloMap scores in HT recipients.

  View details for DOI 10.1016/j.healun.2020.11.008

  View details for PubMedID 33341360

• Impact of Deceased Donor Management on Donor Heart Use and Recipient Graft Survival. Journal of the American College of Surgeons Swanson, E. A., Adams, T. n., Patel, M. S., De La Cruz, S. n., Hutchens, M. n., Khush, K. n., Sally, M. n., Niemann, C. U., Groat, T. n., Malinoski, D. n. 2020

  Abstract

  Current risk-adjusted models used to predict donor heart utilization and cardiac graft survival from organ donors after brain death (DBDs) do not include bedside critical care data. We sought to identify novel independent predictors of heart utilization and graft survival to better understand the relationship between donor management and transplant outcomes.Prospective observational study of DBDs managed from 2008 to 2013 by 10 organ procurement organizations. Demographic data, critical care parameters, and treatments were recorded at three standardized time points during donor management. The primary outcome measures were donor heart utilization and cardiac graft survival.From 3,433 DBDs, 1,134 (33%) hearts were transplanted and 969 (85%) cardiac grafts survived after 684 (± 392) days of follow-up. After multivariable analysis, independent positive predictors of heart utilization included standard criteria donor status (OR = 3.93), male sex (OR = 1.68), ejection fraction > 50% (OR = 1.64), and PaO2:FiO2 > 300 (OR = 1.31). Independent negative predictors of heart utilization included donor age (OR = 0.94), body mass index > 30 kg/m2 (OR = 0.78), serum creatinine (OR = 0.83), and use of thyroid hormone (OR = 0.78). As for graft survival, after controlling for known recipient risk factors, thyroid hormone dose was the only independent predictor (OR = 1.04 per μg/hr).Modifiable critical care parameters and treatments predict donor heart utilization and cardiac graft survival. The discordant relationship between thyroid hormone and donor heart utilization (negative predictor) versus cardiac graft survival (positive predictor) warrants further investigation.

  View details for DOI 10.1016/j.jamcollsurg.2020.05.025

  View details for PubMedID 32562768

• Adding Insult on Injury: Immunogenic Role for Donor-derived Cell-free DNA? Transplantation Dholakia, S. n., De Vlaminck, I. n., Khush, K. K. 2020

  Abstract

  Donor derived cell-free DNA in the blood circulation is an early marker of injury in solid-organ transplantation. Here, we review recent evidence that indicates that donor derived cell-free DNA may itself be a trigger of inflammation, thereby adding insult on injury. Early un-resolving molecular allograft injury measured via changes in dd-cfDNA may be an early warning sign, and may therefore enable stratification of patients who are at risk of subsequent allograft injury. Considering dd-cfDNA as a continuous and clinically significant biomarker opens up the potential for new management strategies, therapeutics, and ways to quantify interventions by considering the immunological potential of dd-cfDNA.

  View details for DOI 10.1097/TP.0000000000003240

  View details for PubMedID 32217943

• Reply: Interpreting multiple analyses to better understand cardiac retransplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Miller, R. J., Khush, K. K., Haddad, F. 2019

  View details for DOI 10.1016/j.healun.2019.12.004

  View details for PubMedID 31928919

• Deep Sequencing of Viral Cell-Free DNA for Noninvasive Detection of Immunosuppression-Related Lymphoid Malignancies Garofalo, A., Schroers-Martin, J. G., Soo, J., Kurtz, D. M., Sworder, B., Liu, C., Pinsky, B. A., Luikart, H., Advani, R. H., Natkunam, Y., Khush, K., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-131602

  View details for Web of Science ID 000518218500906

• Impact of Myocardial Bridging on Long-Term Outcomes After Heart Transplantation: Risk Stratification With IVUS-Determined Anatomical Properties Okada, K., Nishi, T., Tanaka, S., Luikart, H., Yock, P. G., Yeung, A. C., Hibi, K., Kimura, K., Schnittger, I., Khush, K., Fearon, W., Honda, Y. ELSEVIER SCIENCE INC. 2019: B342

  View details for Web of Science ID 000487306300343

• OUTCOMES OF PATIENTS WITH INFECTION RELATED TO VENTRICULAR ASSIST DEVICE AFTER HEART TRANSPLANTATION Moayedi, Y., Multani, A., Bunce, P., Tremblay-Gravel, M., Gomez, C., Garvert, D., Duclos, S., Hiesinger, W., Ross, H., Khush, K., Montoya, J., Teuteberg, J. WILEY. 2019: 55

  View details for Web of Science ID 000491488701171

• Noninvasive detection of graft injury after heart transplant using donor-derived cell-free DNA: A prospective multicenter study AMERICAN JOURNAL OF TRANSPLANTATION Khush, K. K., Patel, J., Pinney, S., Kao, A., Alharethi, R., DePasquale, E., Ewald, G., Berman, P., Kanwar, M., Hiller, D., Yee, J. P., Woodward, R. N., Hall, S., Kobashigawa, J. 2019; 19 (10): 2889–99

  View details for DOI 10.1111/ajt.15339

  View details for Web of Science ID 000487782000026

• Survival Outcomes After Heart Transplantation: Does Recipient Sex Matter? Circulation. Heart failure Moayedi, Y., Fan, C. P., Cherikh, W. S., Stehlik, J., Teuteberg, J. J., Ross, H. J., Khush, K. K. 2019; 12 (10): e006218

  Abstract

  BACKGROUND: Currently, women represent <25% of heart transplant recipients. Reasons for this female underrepresentation have been attributed to selection and referral bias and potentially poorer outcomes in female recipients. The aim of this study was to compare long-term posttransplant survival between men and women, when matched for recipient and donor characteristics.METHODS AND RESULTS: Using the International Society for Heart and Lung Transplantation Registry, we performed descriptive analyses and estimated overall freedom from posttransplant death stratified by sex using Kaplan-Meier survival methods. Male and female recipients were matched according to the Index for Mortality Prediction After Cardiac Transplantation and Donor Risk Index score using 1:1 propensity score matching. The study cohort comprised 34198 heart transplant recipients (76.3% men, 23.7% women) between 2004 and 2014. Compared with men, women were more likely younger (51 [39-59] versus 55 [46-61] years; P<0.001) and had a different distribution of heart failure etiology (P<0.001). In general, the prevalence of comorbidities was lower in women than in men. Women were less likely to have diabetes mellitus (19.1% versus 26.2%; P<0.001), hypertension (40.7% versus 47.9%; P<0.001), peripheral vascular disease (2.4% versus 3.3%; P=0.002), tobacco use (36.5% versus 52.3%; P<0.001), and prior cardiovascular surgery (38.6% versus 50.7%; P<0.001). Women were more likely to have a history of malignancy (10.5% versus 5.3%; P<0.001), require intravenous inotropes (41.4% versus 37.2%; P<0.001), and were less likely supported by an intra-aortic balloon pump (3.3% versus 3.8%; P=0.03) or durable ventricular assist device (22% versus 31.5%; P<0.001). Transplanted male recipients had a higher Index for Mortality Prediction After Cardiac Transplantation score (5 [2-7] versus 4 [1-6]; P<0.001). When male and female heart transplant recipients were matched for recipient and donor characteristics, there was no significant survival difference (P=0.57).CONCLUSIONS: Overall survival does not differ between men and women after cardiac transplantation. Women who survive to heart transplantation appear to have lower risk features than male recipients but receive hearts from higher risk donors.

  View details for DOI 10.1161/CIRCHEARTFAILURE.119.006218

  View details for PubMedID 31597452

• Early invasive assessment of the coronary microcirculation predicts subsequent acute rejection after heart transplantation INTERNATIONAL JOURNAL OF CARDIOLOGY Okada, K., Honda, Y., Luikart, H., Yock, P. G., Fitzgerald, P. J., Yeung, A. C., Valantine, H. A., Khush, K. K., Fearon, W. F. 2019; 290: 27–32

  View details for DOI 10.1016/j.ijcard.2019.04.018

  View details for Web of Science ID 000470826500005

• Treading lightly as we step into a new era: Use of hepatitis C virus-infected organs for transplantation. The Journal of thoracic and cardiovascular surgery Moayedi, Y., Gulamhusein, A. F., Khush, K. K. 2019

  View details for DOI 10.1016/j.jtcvs.2019.05.091

  View details for PubMedID 31587888

• Outcomes of patients with infection related to a ventricular assist device after Heart Transplantation. Clinical transplantation Moayedi, Y., Multani, A., Bunce, P. E., Henricksen, E., Lee, R., Yang, W., Gomez, C. A., Garvert, D. W., Tremblay-Gravel, M., Duclos, S., Hiesinger, W., Ross, H. J., Khush, K. K., Montoya, J. G., Teuteberg, J. J. 2019: e13692

  Abstract

  BACKGROUND: Despite significant advances in durable mechanical support survival, infectious complications remain the most common adverse event after ventricular assist device (VAD) implantation and the leading cause of early death after transplantation. In this study, we aim to describe our local infectious epidemiology and review short term survival and infectious incidence rates in the post transplantation period and assess risk factors for infectious episodes after transplantation.METHODS: Retrospective single-center study of all consecutive adult heart transplant patients from 2008-2017. Survival data was estimated and summarized using the Kaplan-Meier method. We quantified and evaluated the difference in the incidence rate between patients with and without infection using a Fine-Gray model. The outcome of interest is the time to first infection diagnosis with post-transplant death as the competing event.RESULTS: Among 282 heart transplantations, 74 (26.5%) underwent LVAD implantation. Twenty-one patients (28.3%) developed an infection while supported by an LVAD. When compared to patients supported by an LVAD without a preceding infection, BMI was significantly greater (31.2 vs. 27.8 kg/m2, p=0.03). Median follow-up post transplantation was 3.01 years. Significant risk factors for the competing risk regression for infection after heart transplantation include LVAD infection (HR 1.94, [95% CI] 1.11-3.39, p=0.020) and recipient COPD (HR 2.14, [95% CI] 1.39-3.32, p=0.001) when adjusted for recipient age, gender, hypertension, diabetes mellitus and body mass index.CONCLUSIONS: Patients with LVAD-related infection had a significantly increased risk of infectious complications after heart transplantation. Further research on the avoidance of induction agents and reduced maintenance immunosuppression in this patient population is warranted This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.13692

  View details for PubMedID 31403741

• Accelerated Allograft Vasculopathy With Rituximab After Cardiac Transplantation JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Starling, R. C., Armstrong, B., Bridges, N. D., Eisen, H., Givertz, M. M., Kfoury, A. G., Kobashigawa, J., Ikle, D., Morrison, Y., Pinney, S., Stehlik, J., Tripathi, S., Sayegh, M. H., Chandraker, A., Gus, B., Keslar, K., Magyar, B., Petrich, J., Starling, R. C., Tang, W., Brooks, K., Givertz, M., Kelly, C., Klein, K., Crisalli, K., DeBronkart, S., Madsen, J., Semigran, M., Vetrano, J., DeMarco, T., Fields, S., Maguire, C., Gordon, R., Anderson, A., Regalado, J., Warzecha, A., Goldberg, L., Olt, C., Rockwell, K., Harris, A., Johnson, M., Johnston, S., Roginski, C., Ahmed, R., Cohen, I., Peace, D., Pinney, S., Yao, T., Araujo, G., Bhimaraj, A., Karanga, E., Patel, V., Chait, J., Deng, M., Fonarow, G., Shin, C., Gibbs, C., Hunt, J., Johnson, M., Worley, T., Gibbs, J., Kirk, J., Redd, W., Stehlik, J., Bryan, J., French, A., Kfoury, A. G., Konery, K., Feller, E., Lee, M., Pierson, R., Young, C., Hollifield, T., Porter, K., Schulz, M., VanBakel, A., Khush, K., Luikart, H., Son Nguyen, Pham, M., DeNofrio, D., O'Kelly, R., Garcia, L., Kobashigawa, J., Sana, S., Starks, B., Thottam, M., Yi, A., Cabuay, B., Olson, R., Tucker, L., Uppgaard, L., Eisen, H., Lai, D., Poisker, C., Dragicevic, K., Kelner, H., Luke, D., Nelson, J., Raveendran, G., Kleissas, N., Murali, S., Rayl, K., Sherry, S., Cosgrove, M., CTOT-11 Study Investigators 2019; 74 (1): 36–51

  Abstract

  The CTOT-11 (Prevention of Cardiac Allograft Vasculopathy Using Rituximab Therapy in Cardiac Transplantation [Clinical Trials in Organ Transplantation-11]) study was a randomized, placebo-controlled, multicenter, double-blinded clinical trial in nonsensitized primary heart transplant (HTX) recipients.The study sought to determine whether B cell depletion therapy would attenuate the development of cardiac allograft vasculopathy.A total of 163 HTX recipients were randomized to rituximab 1,000 mg intravenous or placebo on days 0 and 12 post-transplant. Primary outcome was change in percent atheroma volume (PAV) from baseline to 1 year measured by intravascular ultrasound. Secondary outcomes included treated episodes of acute rejection, de novo anti-HLA antibodies (including donor-specific antibodies), and phenotypic differentiation of B cells.There were no significant differences at study entry between the rituximab and placebo groups. Paired intravascular ultrasound measures were available at baseline and 1 year in 86 subjects (49 rituximab, 37 placebo). The mean ± SD change in PAV at 12 months was +6.8 ± 8.2% rituximab versus +1.9 ± 4.4% placebo (p = 0.0019). Mortality at 12 months was 3.4% rituximab versus 6.8% placebo (p = 0.47); there were no retransplants or post-transplant lymphoproliferative disorder. The rate of treated rejection was 24.7% rituximab versus 32.4% placebo (p = 0.28). Rituximab therapy effectively eliminated CD20+/CD19+ B cells followed by a gradual expansion of a CD19- cell population in the rituximab-treated group.A marked, unexpected increase in coronary artery PAV with rituximab was observed during the first year in HTX recipients. One-year mortality was not impacted; however, longer-term follow-up and mechanistic explanations are required. (Prevention of Cardiac Allograft Vasculopathy Using Rituximab [Rituxan] Therapy in Cardiac Transplantation; NCT01278745).

  View details for DOI 10.1016/j.jacc.2019.04.056

  View details for Web of Science ID 000473259200007

  View details for PubMedID 31272550

• Outcomes in patients undergoing cardiac retransplantation: A propensity matched cohort analysis of the UNOS Registry. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Miller, R. J., Clarke, B. A., Howlett, J. G., Khush, K. K., Teuteberg, J. J., Haddad, F. 2019

  Abstract

  BACKGROUND: Cardiac retransplantation accounts for approximately 3% of cardiac transplantation and is considered a risk factor for increased mortality. However, factors inherent to retransplantation including previous sternotomy, sensitization, and renal dysfunction may account for the increased mortality. We assessed whether retransplantation was associated with all-cause mortality after adjusting for such patient risk factors.METHODS: We conducted a retrospective cohort study of adult and pediatric patients enrolled in the United Network for Organ Sharing database. We identified patients undergoing cardiac retransplantation based on transplant listing diagnosis and history of previous transplant. We used propensity-score matching to identify a matched cohort undergoing initial heart transplantation.RESULTS: In total, 62,112 heart transplant recipients were identified, with a mean age 46.6 ± 19.1 years. Of these, 2,202 (3.4%) underwent late cardiac retransplantation (>1 year after initial transplant and not for acute rejection). Compared with a matched group of patients undergoing initial heart transplantation, patients undergoing late retransplantation had comparable rates of all-cause mortality at 1 year (13.6% vs 13.8%, p = 0.733). In addition, overall mortality was not significantly different after matching (unadjusted hazard ratio [HR] 1.08, p = 0.084). In contrast, patients undergoing retransplantation within 1 year of initial transplant or for acute rejection remained at increased risk of mortality post-transplant after similar matching (unadjusted HR 1.79, p < 0.001).CONCLUSIONS: After matching for comorbidities, late retransplantation in the adult population was not associated with an increase in all-cause mortality. Our findings highlight the importance of assessing indication acuity and comorbid conditions when considering retransplant candidacy.

  View details for DOI 10.1016/j.healun.2019.07.001

  View details for PubMedID 31378576

• Infectious complications after heart transplantation in patients screened with gene expression profiling JOURNAL OF HEART AND LUNG TRANSPLANTATION Moayedi, Y., Gomez, C. A., Fan, C. S., Miller, R. H., Bunce, P. E., Tremblay-Gravel, M., Foroutan, F., Manlhiot, C., Yee, J., Shullo, M. A., Khush, K. K., Ross, H. J., Montoya, J. G., Teuteberg, J. J. 2019; 38 (6): 611–18

  View details for DOI 10.1016/j.healun.2019.01.006

  View details for Web of Science ID 000468597800006

• Long-term transplant outcomes of donor hearts with left ventricular dysfunction Sibona, A., Khush, K. K., Oyoyo, U. E., Martens, T. P., Hasaniya, N. W., Razzouk, A. J., Bailey, L. L., Rabkin, D. G. MOSBY-ELSEVIER. 2019: 1865-1873

  View details for DOI 10.1016/j.jtcvs.2018.07.115

  View details for Web of Science ID 000464437100071

• Early invasive assessment of the coronary microcirculation predicts subsequent acute rejection after heart transplantation. International journal of cardiology Okada, K., Honda, Y., Luikart, H., Yock, P. G., Fitzgerald, P. J., Yeung, A. C., Valantine, H. A., Khush, K. K., Fearon, W. F. 2019

  Abstract

  BACKGROUND: Acute allograft rejection (AAR) plays an important role in patient and graft survival; therefore, more emphasis should be placed on its prediction. This study aimed to investigate baseline clinical and diagnostic variables associated with subsequent AAR during the first year post-transplant, especially focusing on early physiologic and anatomic measures.METHODS: This study enrolled 88 heart transplant patients who underwent fractional flow reserve (FFR), coronary flow reserve (CFR), the index of microcirculatory resistance (IMR) and intravascular ultrasound (IVUS) in the left anterior descending artery at baseline (within 8 weeks post-transplant). Cardiac index (CI), pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure (mPAP), right atrial pressure and left ventricular ejection fraction were also evaluated. AAR was defined as acute cellular rejection of grade ≥2R and/or pathological antibody-mediated rejection of grade ≥pAMR2.RESULTS: During the first year post-transplant, 25.0% of patients experienced AAR. Patients with AAR during the first year showed higher rates of recipient obesity, lower rates of recipient-donor sex mismatch and rATG and tacrolimus uses, higher PCWP, mPAP and IMR, and lower CFR at baseline, compared with those without. In the multivariate analysis, only baseline IMR ≥ 16.0 was independently associated with AAR during the first year, demonstrating high negative predictive value (96.7%).CONCLUSIONS: Invasively assessing microvascular resistance (baseline IMR ≥ 16.0) in the early post-transplant period was an independent determinant of subsequent acute allograft rejection during the first year post-transplant, suggesting that early assessment of IMR may enhance patient risk stratification and target medical therapies to improve patient outcome.

  View details for PubMedID 30987835

• Parvovirus B19-induced severe anemia in heart transplant recipients: Case report and review of the literature CLINICAL TRANSPLANTATION Pinto, N. C., Newman, C., Gomez, C. A., Khush, K. K., Moayedi, Y., Lee, R., Teuteberg, J. J., Montoya, J. G. 2019; 33 (4)

  View details for DOI 10.1111/ctr.13498

  View details for Web of Science ID 000465099100016

• PERIARTERIAL NEOVASCULARIZATION AND ATTENUATED-SIGNAL PLAQUE PREDICT LONG-TERM MORTALITY AFTER HEART TRANSPLANTATION: RISK STRATIFICATION WITH IVUS-DETERMINED CORONARY INFLAMMATORY FINDINGS Kashiyama, K., Okada, K., Kitahara, H., Kameda, R., Hollak, M., Luikart, H., Yock, P., Yeung, A., Fitzgerald, P., Khush, K., Fearon, W., Honda, Y. ELSEVIER SCIENCE INC. 2019: 1428

  View details for Web of Science ID 000460565901440

• Non-invasive Detection of Graft Injury after Heart Transplantation Using Donor-Derived Cell-Free DNA: a Prospective Multi-Center Study. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Khush, K. K., Patel, J., Pinney, S., Kao, A., Alharethi, R., DePasquale, E., Ewald, G., Berman, P., Kanwar, M., Hiller, D., Yee, J. P., Woodward, R. N., Hall, S., Kobashigawa, J. 2019

  Abstract

  Standardized donor-derived cell-free DNA (dd-cfDNA) testing has been introduced into clinical use to monitor kidney transplant recipients for rejection. This report describes the performance of this dd-cfDNA assay to detect allograft rejection in samples from heart transplant (HT) recipients undergoingsurveillance monitoring across the UnitedStates. Venous blood was longitudinally sampled from 740 HT recipients from 26 centers, and in a single-center cohort of33 patients at high risk for antibody-mediated rejection (AMR). Plasma dd-cfDNA was quantified using targeted amplification and sequencing of a single nucleotide polymorphism panel. dd-cfDNA levels were correlated to paired events of biopsy-based diagnosis of rejection. The median dd-cfDNA was 0.07% in reference HT recipients (2164 samples) and 0.17% in samples classified as acute rejection (35, p=0.005). At a 0.2% threshold, dd-cfDNA had a 44% sensitivity to detect rejection and a 97% negative predictive value. In the cohort at risk for AMR (11 samples), dd-cfDNA levels were elevated threefold in AMR compared to patients without AMR (99 samples, p=0.004). The standardized dd-cfDNA test identified acute rejection in samples from a broad population of heart transplant recipients. The reported test performance characteristics will guide the next stage of clinical utility studies of the dd-cfDNA assay. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30835940

• Parvovirus B19-Induced Severe Anemia in Heart Transplant Recipients: Case Report and Review of the Literature. Clinical transplantation Pinto, N. C., Newman, C., Gomez, C. A., Khush, K. K., Moayedi, Y., Lee, R., Teuteberg, J. J., Montoya, J. G. 2019: e13498

  Abstract

  We report a case of a 64-year-old woman who developed transfusion-dependent anemia after cardiac transplantation, the etiology of which was unknown after initial comprehensive evaluation. At the suggestion of the Transplant Infectious Diseases consultant, microbial agents with red blood cell tropism pertinent to this patient such as Parvovirus B 19 (B19V) were investigated. The B19V viral load by PCR in peripheral blood was >100,000,000 copies/ml and after treatment with intravenous immunoglobulin (IVIG), her anemia resolved. Here, we summarize the clinical and virologic characteristics, treatment, and outcome of fifteen cases of B19V-induced anemia in heart transplant recipients. Spontaneous recovery from anemia secondary to B19V has also been reported in some heart transplant recipients, possibly due to an absence of their B19V P-antigen receptor and/or reduction of their immunosuppression. Therefore, in heart transplant patients, B19V should be suspected early as a cause of severe anemia of unknown etiology. The extent that B19V-induced anemia is underdiagnosed in heart transplant recipients is unknown. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30776137

• Association of Endothelin-1 With Accelerated Cardiac Allograft Vasculopathy and Late Mortality Following Heart Transplantation JOURNAL OF CARDIAC FAILURE Parikh, R. V., Khush, K., Pargaonkar, V. S., Luikart, H., Grimm, D., Yu, M., Okada, K., Honda, Y., Yeung, A. C., Valantine, H., Fearon, W. F. 2019; 25 (2): 97–104

  View details for DOI 10.1016/j.cardfail.2018.12.001

  View details for Web of Science ID 000460190800004

• Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation EBIOMEDICINE Agbor-Enoh, S., Wang, Y., Tunc, I., Jang, M., Davis, A., De Vlaminck, I., Luikart, H., Shah, P. D., Timofte, I., Brown, A. W., Marishta, A., Bhatti, K., Gorham, S., Fideli, U., Wylie, J., Grimm, D., Goodwin, N., Yang, Y., Patel, K., Zhu, J., Laconoad, A., Orens, J. B., Nathan, S. D., Marboe, C., Berry, G. J., Quake, S. R., Khush, K., Valantine, H. A. 2019; 40: 541-553

  View details for DOI 10.1016/j.ebiom.2018.12.029

  View details for Web of Science ID 000460696900062

• Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation. EBioMedicine Agbor-Enoh, S., Wang, Y., Tunc, I., Jang, M. K., Davis, A., De Vlaminck, I., Luikart, H., Shah, P. D., Timofte, I., Brown, A. W., Marishta, A., Bhatti, K., Gorham, S., Fideli, U., Wylie, J., Grimm, D., Goodwin, N., Yang, Y., Patel, K., Zhu, J., Iacono, A., Orens, J. B., Nathan, S. D., Marboe, C., Berry, G. J., Quake, S. R., Khush, K., Valantine, H. A. 2019

  Abstract

  BACKGROUND: Allograft failure is common in lung-transplant recipients and leads to poor outcomes including early death. No reliable clinical tools exist to identify patients at high risk for allograft failure. This study tested the use of donor-derived cell-free DNA (%ddcfDNA) as a sensitive marker of early graft injury to predict impending allograft failure.METHODS: This multicenter, prospective cohort study enrolled 106 subjects who underwent lung transplantation and monitored them after transplantation for the development of allograft failure (defined as severe chronic lung allograft dysfunction [CLAD], retransplantation, and/or death from respiratory failure). Plasma samples were collected serially in the first three months following transplantation and assayed for %ddcfDNA by shotgun sequencing. We computed the average levels of ddcfDNA over three months for each patient (avddDNA) and determined its relationship to allograft failure using Cox-regression analysis.FINDINGS: avddDNA was highly variable among subjects: median values were 3·6%, 1·6% and 0·7% for the upper, middle, and low tertiles, respectively (range 0·1%-9·9%). Compared to subjects in the low and middle tertiles, those with avddDNA in the upper tertile had a 6·6-fold higher risk of developing allograft failure (95% confidence interval 1·6-19·9, p = 0·007), lower peak FEV1 values, and more frequent %ddcfDNA elevations that were not clinically detectable.INTERPRETATION: Lung transplant patients with early unresolving allograft injury measured via %ddcfDNA are at risk of subsequent allograft injury, which is often clinically silent, and progresses to allograft failure. FUND: National Institutes of Health.

  View details for PubMedID 30692045

• Infectious complications after heart transplantation in patients screened with gene expression profiling. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Moayedi, Y., Gomez, C. A., Fan, C. P., Miller, R. J., Bunce, P. E., Tremblay-Gravel, M., Foroutan, F., Manlhiot, C., Yee, J., Shullo, M. A., Khush, K. K., Ross, H. J., Montoya, J. G., Teuteberg, J. J. 2019

  Abstract

  BACKGROUND: The risk of infection after heart transplantation is highest within the first year and represents the leading cause of early mortality. In this cohort of patients enrolled in the Outcomes AlloMap Registry (OAR), we sought to describe infection episodes (IEp) resulting in hospitalization, in the early (<1 year) and late (≥1 year) post-transplant period and determine the impact of immunosuppression on incidence of infection.METHODS: The primary aim was to assess the incidence and nature of IEp. The secondary aim was to evaluate the effect of potential risk factors, such as recipient age; sex; body mass index; panel-reactive antibodies; cytomegalovirus (CMV) primary mismatch; prednisone, tacrolimus, and sirolimus levels; and gene expression profile (GEP) score, in the development of IEp.RESULTS: The OAR comprises 1,504 patients, of whom 220 patients (14.6%) had an IEp during a median follow-up period of 382 days (interquartile range [IQR] 230 to 579 days). The cause-specific 5-year hazard ratio for any infection was 2.029 (p = 0.12). The pattern of early infection was consistent with nosocomial and opportunistic causes, whereas later infection was consistent with late-onset opportunistic and community-acquired etiologies. Sixty-two percent of the infections occurred early. In the time-dependent analysis, higher prednisone dose (log prednisone, hazard ratio [HR] 1.30, p = 0.022) was the most significant risk factor for all IEp.CONCLUSIONS: In the OAR cohort, the majority of infections occurred within 1 year after transplantation. Clinicians may consider more aggressive prednisone withdrawal in low-risk patients to reduce IEp.

  View details for PubMedID 30704838

• Gene expression profiling and racial disparities in outcomes after heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Moayedi, Y. n., Fan, C. S., Miller, R. J., Tremblay-Gravel, M. n., Posada, J. G., Manlhiot, C. n., Hiller, D. n., Yee, J. n., Woodward, R. n., McCaughan, J. A., Shullo, M. A., Hall, S. A., Pinney, S. n., Khush, K. K., Ross, H. J., Teuteberg, J. J. 2019

  Abstract

  African Americans (AAs) have lower survival rates after heart transplantation (HTx) than Caucasians. The aim of this analysis was to evaluate racial differences in gene expression and their associations with survival and the composite outcome of death, retransplant, rejection with hemodynamic compromise, and graft dysfunction in the Outcomes AlloMap Registry.Registry participants included low-risk Caucasian and AA heart transplant recipients with a baseline and at least 1 follow-up gene expression test (AlloMap(C)) within the first year after HTx. The Kaplan-Meier method with delayed entry was used to describe differences in outcomes. Multivariable Cox hazard regression was used to evaluate the associations of overall gene expression profiling score, MARCH8 and FLT3 expression, and tacrolimus levels with each outcome, and stratified Cox models were developed to quantify race-specific associations.Among 933 eligible recipients, 737 (79%) were Caucasian and 196 (21%) were AA. Compared with Caucasians, AAs were significantly younger (55 vs 59 years, p < 0.001), with higher rates of non-ischemic cardiomyopathy (68% vs 50%, p < 0.001), sensitization (>10% panel reactive antibody, 16% vs 9.1%, p = 0.009), and human leukocyte antigen mismatches (7 vs 7, p = 0.01), but less frequent primary cytomegalovirus serostatus mismatch (14.31% vs 27.3%, p < 0.001). Overall, AAs had an increased adjusted mortality risk (hazard ratio [HR] 4.13, p = 0.007). Higher tacrolimus levels were associated with decreased mortality in AAs (HR 0.62, p = 0.009). Overall gene expression profiling score was associated with increased mortality among Caucasians (HR 1.21, p = 0.048). In Caucasians, but not AAs, overexpression of MARCH8 was associated with increased mortality (HR 2.90, p = 0.001). FLT3 upregulation was associated with increased mortality (HR 2.42, p = 0.033) in AAs. There was an inverse relationship between FLT3 expression and tacrolimus levels (-0.029 and -0.176, respectively) in Caucasians and AAs.AAs have a significantly higher mortality risk after HTx than Caucasians, even in the low-risk Outcomes AlloMap Registry population. AAs and Caucasians had differential outcomes based upon the varying expression of MARCH8 and FLT3 genes following HTx.

  View details for DOI 10.1016/j.healun.2019.05.008

  View details for PubMedID 31201087

• Risk evaluation using gene expression screening to monitor for acute cellular rejection in heart transplant recipients JOURNAL OF HEART AND LUNG TRANSPLANTATION Moayedi, Y., Foroutan, F., Miller, R. H., Fan, C. S., Posada, J., Alhussein, M., Tremblay-Gravel, M., Oro, G., Luikart, H. I., Yee, J., Shullo, M. A., Khush, K. K., Ross, H. J., Teuteberg, J. J. 2019; 38 (1): 51–58

  View details for DOI 10.1016/j.healun.2018.09.004

  View details for Web of Science ID 000453912500008

• Predicted Heart Mass for Donor Organ Allocation: Getting Closer to the Target. Circulation. Heart failure Tremblay-Gravel, M. n., Khush, K. n. 2019; 12 (12): e006634

  View details for DOI 10.1161/CIRCHEARTFAILURE.119.006634

  View details for PubMedID 31805782

• Great Variability in Donor Heart Acceptance Practices across the United States. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Khush, K. K., Ball, R. L. 2019

  Abstract

  Disparities in organ acceptance practices exacerbate donor heart non-use and lead to increased waiting times and mortality for heart transplant candidates. We studied disparities in donor heart acceptance among US transplant centers and their relations to post-transplant outcomes. Candidate, potential transplant recipient match run, and deceased donor data were obtained from the United Network for Organ Sharing. We analyzed donor, candidate, and transplant center characteristics with respect to organ acceptance, offer acceptance, number of offers before acceptance (organ sequence number), and association with post-transplant mortality. A total of 693,420 donor heart offers made between April 2007 and December 2015 were included. We identified great variability in donor heart acceptance practices among US heart transplant centers. We identified donor and recipient characteristics that were strongly associated with heart organ and offer acceptance, and organ sequence number, and identified inconsistencies among centers with respect to how these characteristics influenced acceptance decisions. Finally, we identified characteristics that were highly predictive of donor heart non-use and were not associated with increased recipient mortality, which may guide future efforts aimed at increasing use of available hearts for transplantation.

  View details for DOI 10.1111/ajt.15760

  View details for PubMedID 31883229

• A novel therapy for an unusual problem: IL-1 receptor antagonist for recurrent post-transplant pericarditis. Clinical transplantation Parizo, J. T., Moayedi, Y. n., Nieman, K. n., Town, K. n., Teuteberg, J. J., Khush, K. K. 2019

  Abstract

  Heart transplant (HTx) recipients are at increased risk of pericardial disease. Idiopathic recurrent pericarditis has not been previously described following HTx. We describe a 35-year-old male who was admitted with pericarditis and moderate pericardial effusion ten months after HTx. Two weeks before his admission, his prednisone had been tapered off. A thorough infectious workup and endomyocardial biopsy was unrevealing. He was started on colchicine with the addition of tapering prednisone regimen of 40 mg daily due to unresolved pain. Over the next several years he had three recurrent episodes of pericarditis requiring re-initiation of prednisone with extensive investigations negative for rejection, autoimmune and infectious causes. Cardiac MRI confirmed pericardial inflammation. Due to his recurrent course and inability to wean off prednisone, anakinra, an IL-1 receptor antagonist, was started at 100 mg sc daily. This allowed successful discontinuation of prednisone. He is now 34 months post-transplant without recurrence on anakinra and colchicine maintenance. Due to the overlap between idiopathic recurrent pericarditis and auto-inflammatory diseases, there is growing evidence for utilizing IL-1 receptor antagonists in this condition. While pericarditis is common in the HTx population, this is the first report of successful use of an IL-1 receptor blocker for pericarditis in this population. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.13699

  View details for PubMedID 31437316

• Perceived Generational, Geographic, and Sex-Based Differences in Choosing a Career in Advanced Heart Failure. Circulation. Heart failure Moayedi, Y. n., Hershman, S. G., Ross, H. J., Khush, K. K., Teuteberg, J. J. 2019; 12 (7): e005754

  View details for DOI 10.1161/CIRCHEARTFAILURE.118.005754

  View details for PubMedID 31296097

• Safety and Efficacy of PCSK9 Inhibitors After Heart Transplantation CANADIAN JOURNAL OF CARDIOLOGY Moayedi, Y., Kozuszko, S., Knowles, J. W., Chih, S., Oro, G., Lee, R., Fearon, W. F., Ross, H. J., Teuteberg, J. J., Khush, K. K. 2019; 35 (1)

  View details for DOI 10.1016/j.cjca.2018.11.004

  View details for Web of Science ID 000454536800017

• Optimizing the Use of Heart Transplant in the United States. JAMA Sandhu, A. T., Woo, Y. J., Khush, K. K. 2019; 322 (18): 1772–74

  View details for DOI 10.1001/jama.2019.16002

  View details for PubMedID 31714972

• Safety and Efficacy of PCSK9 Inhibitors After Heart Transplantation. The Canadian journal of cardiology Moayedi, Y., Kozuszko, S., Knowles, J. W., Chih, S., Oro, G., Lee, R., Fearon, W. F., Ross, H. J., Teuteberg, J. J., Khush, K. K. 2019; 35 (1)

  Abstract

  Dyslipidemia is common in patients undergoing heart transplantation and is associated with the progression of cardiac allograft vasculopathy. Two monoclonal antibodies directed against PCSK9i-evolocumab and alirocumab-are currently available. However, their use, safety and efficacy in the post-transplant setting have not been studied. We present our experience with 6 heart transplant recipients treated with a PCSK9i. A > 70% reduction in LDL-cholesterol was observed after evolocumab therapy. PCSK9 inhibitors are a potentially lipid-lowering therapeutic option for heart transplant patients with suboptimal LDL despite maximal tolerated statin doses.

  View details for PubMedID 30595172

• Association of Endothelin-1 with Accelerated Cardiac Allograft Vasculopathy and Late Mortality Following Heart Transplantation. Journal of cardiac failure Parikh, R. V., Khush, K., Pargaonkar, V. S., Luikart, H., Grimm, D., Yu, M., Akada, K., Honda, Y., Yeung, A. C., Valantine, H., Fearon, W. F. 2018

  Abstract

  BACKGROUND: Endothelin-1 (ET-1) has been implicated in the development of post-heart transplantation (HT) cardiac allograft vasculopathy (CAV), but has not been well-studied in humans.METHODS AND RESULTS: In 90 HT patients, plasma ET-1 was measured within 8 weeks of HT (baseline) via a competitive enzyme-linked immunosorbent assay. 3D volumetric intravascular ultrasound of the left anterior descending artery was performed at baseline and at 1 year. Accelerated CAV (lumen volume loss) was defined using the 75th percentile as a cutoff. Patients were followed beyond the first year post-HT for late death or re-transplantation. A receiver operative characteristic curve demonstrated that a baseline ET-1 concentration of 1.75 pg/mL provided the best accuracy for diagnosis of accelerated CAV at 1 year [area under the curve=0.69 (0.57-0.82), p=0.007]. In multivariate logistic regression, a higher baseline ET-1 concentration was independently associated with accelerated CAV [odds ratio (OR)=2.13, 95% confidence interval (CI): 1.15-3.94; p=0.01]; this relationship persisted when ET-1 was dichotomized at 1.75 pg/mL (OR=4.88, 95% CI: 1.69-14.10; p=0.003). Eighteen deaths occurred during a median follow-up period of 3.99 (2.51-9.95) years. Treated as a continuous variable, baseline ET-1 was not associated with late mortality in multivariate Cox regression [hazard ratio (HR)=1.22, 95% CI: 0.72-2.05; p=0.44]. However, ET-1 >1.75 pg/mL conferred a significantly lower cumulative event-free survival on Kaplan-Meier analysis (p=0.047), and was independently associated with late mortality (HR=2.94, 95% CI: 1.12-7.72; p=0.02).CONCLUSIONS: Elevated ET-1 early after HT is an independent predictor of accelerated CAV and late mortality, suggesting that ET-1 has durable prognostic value in the HT arena.

  View details for PubMedID 30543947

• Current Use of Hearts From Hepatitis C Viremic Donors. Circulation. Heart failure Moayedi, Y., Fan, C. P., Gulamhusein, A. F., Manlhiot, C., Ross, H. J., Teuteberg, J. J., Khush, K. K. 2018; 11 (12): e005276

  Abstract

  BACKGROUND: Strategies to improve donor heart utilization are required in the setting of limited donor availability. One innovative strategy is to consider the use of hepatitis C viremic (HCV) nucleic acid amplification test positive donors in hepatitis C-negative recipients, given the availability of highly effective direct acting antiviral agents. We utilized United Network for Organ Sharing data to evaluate the geographic distribution, clinical characteristics, and post-transplant outcomes of HCV+ donor hearts.METHODS AND RESULTS: The United Network for Organ Sharing registry was queried for all HCV+ recovered donors and those considered for heart donation classified by sex, age group, United Network for Organ Sharing region, and cause of death from January 1, 2014, to December 31, 2017. Propensity score matching (3:1) was applied to the recipients based on the index for mortality prediction after cardiac transplantation score and donor risk index. A total of 1306 HCV+ donors were recovered from 2014 to 2017 of whom 1078 (82.5%) were 18 to 49 and predominantly from the Appalachia region (United Network for Organ Sharing regions 2, 3, and 11). A total of 64 (5%) HCV+ donor hearts were transplanted in this interval. The match-adjusted risk difference in survival was estimated to be 0.87% ( P=0.83) at 12 months.CONCLUSIONS: To meet the demands of heart transplantation, we must consider additional strategies to expand the donor pool. From 2014 to 2017, despite availability of highly effective direct acting antiviral therapy, only 5% of HCV+ donor hearts were accepted for transplantation. National efforts may be required to capitalize on this resource while we continue to carefully monitor the safety of this novel approach.

  View details for PubMedID 30562093

• Current Use of Hearts From Hepatitis C Viremic Donors A United Network for Organ Sharing Registry Analysis CIRCULATION-HEART FAILURE Moayedi, Y., Fan, C. S., Gulamhusein, A. F., Manlhiot, C., Ross, H. J., Teuteberg, J. J., Khush, K. K. 2018; 11 (12)

  View details for DOI 10.1161/CIRCHEARTFAILURE.118.005276

  View details for Web of Science ID 000453934500006

• Lymphoma Virome Dynamics Revealed By Cell-Free DNA Sequencing Schroers-Martin, J. G., Garofalo, A., Soo, J., Jin, M. C., Kurtz, D. M., Buedts, L., Duehrsen, U., Huettmann, A., Cottereau, A., Meignan, M., Casasnovas, O., Westin, J. R., Gaidano, G., Rossi, D., Roschewski, M., Wilson, W. H., Advani, R. H., Vandenberghe, P., Diehn, M., Khush, K., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-119905

  View details for Web of Science ID 000454842800062

• Usefulness of Asymmetric Dimethylarginine to Predict Outcomes After Heart Transplantation AMERICAN JOURNAL OF CARDIOLOGY Parikh, R., Khush, K., Luikart, H., Sakarovitch, C., Lee, J., Desai, M., Valantine, H., Yeung, A. C., Fearon, W. F. 2018; 122 (10): 1707–11

  Abstract

  Asymmetric dimethylarginine (ADMA) is a key mediator of vascular homeostasis and an independent predictor of the development of accelerated cardiac allograft vasculopathy after heart transplantation. However, its association with clinical outcomes in heart transplant recipients has not been described. Plasma levels of ADMA were assayed within 8 weeks following transplantation (baseline) using a competitive enzyme-linked immunosorbent assay. The primary end point was the composite of nonfatal myocardial infarction, percutaneous coronary intervention, retransplantation, or death at 5-year follow-up. Kaplan-Meier curves were generated to assess the association between baseline ADMA levels (stratified at 0.70 µM, a previously established cutoff) and cumulative event-free survival. Multivariate Cox regression was performed to adjust for other candidate predictors. In 69 heart transplant recipients at Stanford, the primary end point occurred in 11 patients (16%)-4 percutaneous coronary intervention, 1 retransplant, and 6 deaths-during 5-years follow-up. Patients with baseline ADMA ≥0.70 µM had lower cumulative 5-year event-free survival (77% vs 93%, p = 0.059). In multivariate Cox analysis, baseline ADMA was the only significant predictor of the primary end point (hazard ratio 1.33, 95% confidence interval 1.03 to 1.72 per 0.1 µM; p = 0.031). This association remained significant even after restricting the end point to death or retransplantation (hazard ratio 1.48, 95% confidence interval 1.12 to 1.97 per 0.1 µM; p = 0.006). In conclusion, elevated baseline plasma levels of ADMA independently predicted 5-year clinical outcomes after heart transplantation, suggesting that ADMA has potential prognostic value in the heart transplant arena.

  View details for PubMedID 30220417

• Impact of Myocardial Bridging on Long-Term Mortality After Heart Transplantation: Risk Stratification With Ivus-Determined Cardiac Allograft Vasculopathy Kameda, R., Okada, K., Tanaka, S., Luikart, H., Yock, P. G., Yeung, A. C., Schnittger, I., Fitzgerald, P. J., Khush, K. K., Fearon, W. F., Honda, Y. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619403405

• Current opinions in organ allocation AMERICAN JOURNAL OF TRANSPLANTATION Achille, M., Agarwal, G., Albert, M., Amarelli, C., Baran, D. A., Blosser, C., Brown, K., Bucuvalas, J., Butler, C. R., Caicedo, J. C., Caulfield, T., Cendales, L. C., Chadban, S., Cooper, M., Dalal, P., Danovitch, G., Delos Santos, R., Denu, R. A., Devuni, D., Foley, D. P., Formica, R. N., Forsythe, J., Fortin, M., Foster, B. J., Fowler, K. J., Friedewald, J., Friedman, B., Gentry, S., Gill, J. S., Gill, J., Glazier, A., Goldberg, D., Golebiewska, J. E., Gordon, E. J., Greenwald, M. A., Gross, J., Halazun, K. J., Hammel, L., Hays, R. A., Heimbach, J., Hippen, B., Hsu, E. K., Husain, S., Jadlowiec, C. C., Jevnikar, A., Jhajj, G., Johnson, M., Kamoun, M., Kapnadak, S. G., Karp, S. J., Kayler, L., Khush, K. K., Kinkhabwala, M., Kulkarni, S., Kute, V., Kwong, A. J., La Muraglia Ii, G., Lai, J. C., Lavee, J., Lentine, K., Levitsky, J., Lynch, R., Mahdavi-Mazdeh, M., Manonelles, A., Mansard, M., Mathur, A. K., McEvoy, C., McIntosh, C. M., Mohan, S., Muller, E., Mulvihill, M. S., Newell, K., Ogdon, J., Orlowski, J., Parajuli, S., Patel, J. K., Patzer, R., Peradejordi, M., Rahmel, A., Riella, L., Roll, G. R., Ruff, S. F., Samuel, U., Sawinski, D., Schaffer, R. L., Schmidt, L., Schold, J., Shaffer, A. A., Shah, R. A., Sharma, P., Shawar, S., Sholkamy, A., Snyder, J., Solez, K., Sosa, R. A., Stehlik, J., Sweet, S., Taner, T., Thomas, A. G., Treleaven, D., Webster, A. C., West, S. C., Westphal, S. G., White, D. M., Witkowski, P., Wojciechowski, D., Woodle, E., Yabu, J. M., Amer Journal Transplantation 2018; 18 (11): 2625–34

  Abstract

  Existing methods of academic publication provide limited opportunity to obtain stakeholder input on issues of broad interest. This article reports the results of an experiment to produce a collaborative, crowdsourced article examining a current controversial issue in transplant medicine (hereby referred to as the "C4 Article"). The editorial team as a whole selected the topic of organ allocation, then divided into six sections, each supported by an individual editorial team. Widely promoted by the American Journal of Transplantation, the C4 Article was open for public comment for 1 month. The nonblinded editorial teams reviewed the contributions daily and interacted with contributors in near-real time to clarify and expand on the content received. Draft summaries of each section were posted and subsequently revised as new contributions were received. One hundred ninety-four individuals viewed the manuscript, and 107 individuals contributed to the manuscript during the submission period. The article engaged the international transplant community in producing a contemporary delineation of issues of agreement and controversy related to organ allocation and identified opportunities for new policy development. This initial experience successfully demonstrated the potential of a crowdsourced academic manuscript to advance a broad-based understanding of a complex issue.

  View details for DOI 10.1111/ajt.15094

  View details for Web of Science ID 000449512400007

  View details for PubMedID 30303603

• Long-term transplant outcomes of donor hearts with left ventricular dysfunction. The Journal of thoracic and cardiovascular surgery Sibona, A., Khush, K. K., Oyoyo, U. E., Martens, T. P., Hasaniya, N. W., Razzouk, A. J., Bailey, L. L., Rabkin, D. G. 2018

  Abstract

  OBJECTIVE: Despite small single-center reports demonstrating acceptable outcomes using donor hearts with left ventricular dysfunction, 19% of potential donor hearts are currently unused exclusively because of left ventricular dysfunction. We investigated modern long-term survival of transplanted donor hearts with left ventricular dysfunction using a large, diverse cohort.METHODS: Using the United Network for Organ Sharing database, we reviewed all adult heart transplants between January 2000 and March 2016. Baseline and postoperative characteristics and Kaplan-Meier survival curves were compared. A covariates-adjusted Cox regression model was developed to estimate post-transplant mortality. To address observed variation in patient profile across donor ejection fraction, a propensity score was built using Cox predictors as covariates in a generalized multiple linear regression model. All the variables in the original Cox model were included. For each recipient, a predicted donor ejection fraction was generated and exported as a new balancing score that was used in a subsequent Cox model. Cubic spline analysis suggested that at most 3 and perhaps no ejection fraction categories were appropriate. Therefore, in 1 Cox model we added donor ejection fraction as a grouped variable (using the spline-directed categories) and in the other as a continuous variable.RESULTS: A total of 31,712 donor hearts were transplanted during the study period. A total of 742 donor hearts were excluded for no recorded left ventricular ejection fraction, and 20 donor hearts were excluded for left ventricular ejection fraction less than 20%. Donor hearts with reduced left ventricular ejection fraction were from younger donors, more commonly male donors, and donors with lower body mass index than normal donor hearts. Recipients of donor hearts with reduced left ventricular ejection fraction were more likely to be on mechanical ventilation. Kaplan-Meier curves revealed no significant differences in recipient survival up to 15years of follow-up (P=.694 log-rank test). Cox regression analysis showed that after adjustment for propensity variation, transplant year, and region, ejection fraction had no statistically significant impact on mortality when analyzed as a categoric or continuous variable. Left ventricular ejection fraction at approximately 1year after transplantation was normal for all groups.CONCLUSIONS: Carefully selected donor hearts with even markedly diminished left ventricular ejection fraction can be transplanted with long-term survival equivalent to normal donor hearts and therefore should not be excluded from consideration on the basis of depressed left ventricular ejection fraction alone. Functional recovery of even the most impaired donor hearts in this study suggests that studies of left ventricular function in the setting of brain death should be interpreted cautiously.

  View details for PubMedID 30853225

• Increasing complexity of thoracic transplantation and the rise of multiorgan transplantation around the world: Insights from the International Society for Heart and Lung Transplantation Registry. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Stehlik, J., Chambers, D. C., Zuckermann, A., Mehra, M. R., Khush, K. K. 2018; 37 (10): 1145–54

  View details for PubMedID 30293611

• Increasing complexity of thoracic transplantation and the rise of multiorgan transplantation around the world: Insights from the International Society for Heart and Lung Transplantation Registry JOURNAL OF HEART AND LUNG TRANSPLANTATION Stehlik, J., Chambers, D. C., Zuckermann, A., Mehra, M. R., Khush, K. K. 2018; 37 (10): 1145-1154

  View details for DOI 10.1016/j.healun.2018.07.016

  View details for Web of Science ID 000450568000001

• Longitudinal Changes in Kidney Function Following Heart Transplantation: Stanford Experience. Clinical transplantation Taiwo, A., Khush, K., Stedman, M. R., Zheng, Y., Tan, J. C. 2018: e13414

  Abstract

  Many heart transplant recipients experience declining kidney function following transplantation. We aimed toquantify change in kidney function in heart transplant recipients stratified by pre-transplant kidney function. 230 adult heart transplant recipients between May 1, 2008 and December 31, 2014 were evaluated for up to 5 years post-transplant (median 1 year). Using 19,398 total eGFR assessments, we evaluated trends in estimated glomerular filtration rate (eGFR) in recipients with normal/near normal (eGFR >45 mL/min/1.73m2 ) versus impaired (eGFR <45 mL/min/1.73m2 ) kidney function and the likelihood of reaching an eGFR of 20 mL/min/1.73m2 after heart transplant. Baseline characteristics were similar. Immediately following heart transplant, the impaired pre-transplant kidney function group showed a mean eGFR gain of 9.5mL/min/1.73m2 (n=193) versus a mean decline of 4.9 mL/min/1.73m2 (n=37) in the normal/near normal group. Subsequent rates of eGFR decline were 2.2 mL/min/1.73m2 /yrversus2.9 mL/min/1.73m2 /yr, respectively. The probability of reaching an eGFR of 20 mL/min/1.73m2 or less at 1, 5, and 10 years following heart transplant was 1%, 4% and 30% in the impaired group, and <1%, <1%, and 10% in the normal/near normal group. Estimates of expected recovery in kidney function and its decline over time will help inform decision making about kidney care after heart transplantation. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.13414

  View details for PubMedID 30240515

• Risk evaluation using gene expression screening to monitor for acute cellular rejection in heart transplant recipients. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Moayedi, Y., Foroutan, F., Miller, R. J., Fan, C. S., Posada, J. G., Alhussein, M., Tremblay-Gravel, M., Oro, G., Luikart, H. I., Yee, J., Shullo, M. A., Khush, K. K., Ross, H. J., Teuteberg, J. J. 2018

  Abstract

  BACKGROUND: Gene expression profiling (GEP) was developed for non-invasive surveillance of acute cellular rejection. Despite its widespread use, there has been a paucity in outcome data for patients managed with GEP outside of clinical trials.METHODS: The Outcomes AlloMap Registry (OAR) is an observational, prospective, multicenter study including patients aged ≥ 15 years and ≥ 55 days post-cardiac transplant. Primary outcome was death and a composite outcome of hemodynamically significant rejection, graft dysfunction, retransplantation, or death. Secondary outcomes included readmission rates and development of coronary allograft vasculopathy and malignancies.RESULTS: The study included 1,504 patients, who were predominantly Caucasian (69%), male (74%), and aged 54.1 ± 12.9 years. The prevalence of moderate to severe acute cellular rejection (≥2R) was 2.0% from 2 to 6 months and 2.2% after 6 months. In the OAR there was no association between higher GEP scores and coronary allograft vasculopathy (p = 0.25), cancer (p = 0.16), or non-cytomegalovirus infection (p = 0.10). Survival at 1, 2, and 5 years post-transplant was 99%, 98%, and 94%, respectively. The composite outcome occurred in 103 patients during the follow-up period. GEP scores in dual-organ recipients (heart-kidney and heart-liver) were comparable to heart-alone recipients.CONCLUSIONS: This registry comprises the largest contemporary cohort of patients undergoing GEP for surveillance. Among patients selected for GEP surveillance, survival is excellent, and rates of acute rejection, graft dysfunction, readmission, and death are low.

  View details for PubMedID 30352779

• Transplant phenomapping: A move toward personalized immunosuppression. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Miller, R. J., Khush, K. K. 2018; 37 (8): 943–44

  View details for PubMedID 30055812

• Transplant phenomapping: A move toward personalized immunosuppression JOURNAL OF HEART AND LUNG TRANSPLANTATION Miller, R. H., Khush, K. K. 2018; 37 (8): 943-944

  View details for DOI 10.1016/j.healun.2018.05.005

  View details for Web of Science ID 000441535600002

• Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis JOURNAL OF HEART AND LUNG TRANSPLANTATION Agbor-Enoh, S., Jackson, A. M., Tunc, I., Berry, G. J., Cochrane, A., Grimm, D., Davis, A., Shah, P., Brown, A. W., Wang, Y., Timofte, I., Shah, P., Gorham, S., Wylie, J., Goodwin, N., Jang, M., Marishta, A., Bhatti, K., Fideli, U., Yang, Y., Luikart, H., Cao, Z., Pirooznia, M., Zhu, J., Marboe, C., Iacono, A., Nathan, S. D., Orens, J., Valantine, H. A., Khush, K. 2018; 37 (7): 925–32

  Abstract

  Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation.We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR+ LTRs.Compared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs -0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels.Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.

  View details for PubMedID 29500138

• Accepting hepatitis C virus-infected donor hearts for transplantation: Multistep consent, unrealized opportunity, and the Stanford experience CLINICAL TRANSPLANTATION Moayedi, Y., Gulamhusein, A. F., Ross, H. J., Teuteberg, J. J., Khush, K. K. 2018; 32 (7)

  View details for DOI 10.1111/ctr.13308

  View details for Web of Science ID 000438497900019

• Accepting hepatitis C virus infected donor hearts for transplantation: Multi-step consent, unrealized opportunity, and the Stanford experience. Clinical transplantation Moayedi, Y., Gulamhusein, A. F., Ross, H. J., Teuteberg, J. J., Khush, K. K. 2018: e13308

  Abstract

  The current mismatch between supply of and demand for donor organs has prompted transplant clinicians to consider innovative solutions to broaden the donor pool. Despite a 10% increase in the number of organ donors available from 2015 to 2016, wait times remain unacceptable for the 4,000 patients listed for heart transplantation in the United States (US). (1) Many hearts that would otherwise be acceptable go unused because the donors have hepatitis C virus (HCV). Advancements and availability of highly efficacious and safe direct acting antiviral (DAA) therapy for chronic HCV allows consideration of use of organs from viremic, nucleic acid testing (NAT) positive donors in HCV negative recipients. We describe Stanford's experience with using organs from HCV infected donors for heart transplantation and the associated ethical implications and programmatic planning required, as put forth in the recent American Society of Transplantation (AST) meeting report (May 2017).(2) This article is protected by copyright. All rights reserved.

  View details for PubMedID 29869354

• New Horizons on the 50th Anniversary of Heart Transplantation in Canada: "Where There Is Death, There Is Hope" CANADIAN JOURNAL OF CARDIOLOGY Moayedi, Y., Alhussein, M., Posada, J., Kozuszko, S., Khush, K. K., Teuteberg, J. J., Badiwala, M. V., Ross, H. J. 2018; 34 (6): 694–95

  View details for PubMedID 29703422

• Early detection of post-transplant lymphoproliferative disorder using circulating tumor DNA. Soo, J., Schroers-Martin, J., Garofalo, A., Kurtz, D., D'Emilio, N., Grimm, D. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.7572

  View details for Web of Science ID 000442916003038

• Post-transplant head and neck cancers: A prospective analysis of clinical factors for risk stratification. Soo, J., Schroers-Martin, J., Garofalo, A., Kurtz, D., D'Emilio, N., Grimm, D. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.e18051

  View details for Web of Science ID 000442916005614

• Disclosure of infectious risk to heart transplant candidates: Shared decision-making is here to stay JOURNAL OF HEART AND LUNG TRANSPLANTATION Moayedi, Y., Ross, H. J., Khush, K. K. 2018; 37 (5): 564–67

  Abstract

  The Public Health Service has defined 12 criteria of increased-risk (PHS-IR) for transmissible viral infections in potential organ donors where clinicians are required to document informed consent. Over the last decade, there has been a near tripling of PHS-IR donor organs in the United States. In light of the paucity in guidelines and consensus statements to guide clinicians on how to provide informed consent to potential recipients, using a typical case, we provide an overview including: how to effectively communicate infectious risk, whether clinicians should decline PHS-IR organs, the need to standardize disclosure practice across centers and finally how much information about the donor should be communicated to the transplant candidate. Many patients can be empowered by involving them in shared decision making to understand the minimal risk associated with the use of PHS-IR organs; an important step in improving donor utilization.

  View details for PubMedID 29395752

• The ratio of circulating regulatory cluster of differentiation 4 T cells to endothelial progenitor cells predicts clinically significant acute rejection after heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Choi, D., Chmura, S. A., Ramachandran, V., Dionis-Petersen, K. Y., Kobayashi, Y., Nishi, T., Luikart, H., Dimbil, S., Kobashigawa, J., Khush, K., Lewis, D. B., Fearon, W. F. 2018; 37 (4): 496–502

  View details for DOI 10.1016/j.healun.2017.10.012

  View details for Web of Science ID 000429915500012

• IMPACT OF ENDOTHELIN-1 ON CARDIAC ALLOGRAFT VASCULOPATHY, LATE MORTALITY AND RE-TRANSPLANTATION FOLLOWING HEART TRANSPLANTATION Parikh, R., Khush, K., Luikart, H., Grimm, D., Yu, M., Yeung, A., Valantine, H., Fearon, W. ELSEVIER SCIENCE INC. 2018: 2667

  View details for DOI 10.1016/S0735-1097(18)33208-X

  View details for Web of Science ID 000429659705117

• Throwing out the good with the bad: Declining potential donor hearts with left ventricular dysfunction JOURNAL OF HEART AND LUNG TRANSPLANTATION Moayedi, Y., Khush, K. K. 2018; 37 (3): 321–22

  View details for PubMedID 29029801

• Change in lymphocyte to neutrophil ratio predicts acute rejection after heart transplantation INTERNATIONAL JOURNAL OF CARDIOLOGY Choi, D., Kobayashi, Y., Nishi, T., Luikart, H., Dimbil, S., Kobashigawa, J., Khush, K., Fearon, W. F. 2018; 251: 58–64

  View details for DOI 10.1016/j.ijcard.2017.10.060

  View details for Web of Science ID 000416951600017

• Change in lymphocyte to neutrophil ratio predicts acute rejection after heart transplantation. International journal of cardiology Choi, D. H., Kobayashi, Y. n., Nishi, T. n., Luikart, H. n., Dimbil, S. n., Kobashigawa, J. n., Khush, K. n., Fearon, W. F. 2018; 251: 58–64

  Abstract

  Most immunosuppressive drugs provide targeted immunosuppression by selective inhibition of lymphocyte activation and proliferation. This study evaluated whether a change in the lymphocyte to neutrophil ratio (LNR) is related to acute rejection.In 74 cardiac transplant recipients peripheral blood lymphocyte and neutrophil counts were measured soon after (baseline) and three, six, and 12months after heart transplantation. The primary endpoint was the incidence of acute rejection.Significant acute rejection after heart transplantation occurred in 20 patients (27%) during a median follow-up of 49.4 [IQR 37.4-61.1] months. LNR significantly increased over time (0.1149±0.1354 at baseline, 0.2330±0.2266 at 3months, 0.2961±0.2849 at 6months, and 0.3521±0.2383 at 12months; P<0.001), especially during the first 3months in the group without acute rejection. The area under the curve of the change in LNR during the first three months (ΔLNR) for acute rejection was 0.565 (95% CI 0.420 to 0.710, P=0.380) on ROC curve analysis. The best cutoff value of Δ LNR to differentiate those with and without acute rejection was ≤0.046 by ROC curve analysis. Kaplan-Meier analysis revealed that the low ΔLNR group (≤0.046) had a significantly higher rate of acute rejection than the high ΔLNR group (>0.046) (37.5% vs. 19.0%, log-rank: P=0.0358). The low ΔLNR for the first 3months was an independent predictor of clinically significant acute rejection after adjusting for cytomegalovirus donor seropositive and recipient seronegative.The results of this study suggest that ΔLNR over the first 3months after heart transplantation is a strong and independent predictor of acute rejection after heart transplantation. ΔLNR can be used as an early biomarker for predicting of acute rejection after heart transplantation.

  View details for PubMedID 29074043

• Donor selection in the modern era ANNALS OF CARDIOTHORACIC SURGERY Khush, K. K. 2018; 7 (1): 126–34

  Abstract

  The growing disparity between the supply of donor hearts for transplantation and the demand for such organs has led to liberalization of the criteria for donor heart acceptance over the past few decades. The upper age limit and size restrictions for donor heart acceptance continue to be revised and hearts are being routinely used from donors with left ventricular dysfunction, left ventricular hypertrophy (LVH), cocaine use, multiple medical co-morbidities and after cardiopulmonary resuscitation. This article reviews recent data for use of such "expanded criteria" donor hearts and suggests ways to further increase the donor pool, including use of hearts from donors with hepatitis C and after circulatory determination of death. Donor biomarkers and risk scores may eventually aid in heart acceptance decisions, while ethical issues surrounding information sharing with transplant recipients remain a topic of great debate.

  View details for PubMedID 29492390

  View details for PubMedCentralID PMC5827134

• Long-term prognostic value of invasive and non-invasive measures early after heart transplantation. International journal of cardiology Kobayashi, Y. n., Kobayashi, Y. n., Yang, H. M., Bouajila, S. n., Luikart, H. n., Nishi, T. n., Choi, D. H., Schnittger, I. n., Valantine, H. A., Khush, K. K., Yeung, A. C., Haddad, F. n., Fearon, W. F. 2018; 260: 31–35

  Abstract

  Invasively assessed coronary microvascular resistance early after heart transplantation predicts worse long-term outcome; however, little is known about the relationship between microvascular resistance, left ventricular function and outcomes in this setting.A total of 100 cardiac transplant recipients had fractional flow reserve (FFR) and the index of microcirculatory resistance (IMR) measured in the left anterior descending artery and echocardiographic assessment of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) at 1 year after heart transplantation. The primary endpoint was the composite of death and retransplantation occurring beyond the first post-operative year.The mean FFR, IMR, LVEF, and GLS values at 1 year were 0.87 ± 0.06, 21.3 ± 17.3, 60.4 ± 5.4%, and 14.2 ± 2.4%, respectively. FFR and IMR had no significant correlation with LVEF and GLS. During a mean follow-up of 6.7 ± 4.2 years, the primary endpoint occurred in 24 patients (24.0%). By ROC curve analysis, IMR = 19.3 and GLS = 13.3% were the best cutoff values for predicting death or retransplantation. Cumulative event-free survival was significantly lower in patients with higher IMR (log-rank p = 0.02) and lower GLS (log-rank p < 0.001). Cumulative event-free survival can be further stratified by the combination of IMR and GLS (long-rank p < 0.001). By multivariable Cox proportional hazards model, higher IMR and lower GLS were independently associated with long-term death or retransplantation (elevated IMR, hazard ratio = 2.50, p = 0.04 and reduced GLS, hazard ratio = 3.79, p = 0.003, respectively).Invasively assessed IMR does not correlate with GLS at 1 year after heart transplantation. IMR and GLS determined at 1 year may be used as independent predictors of late death or retransplantation.

  View details for PubMedID 29622448

• Molecular Diagnostic Testing in Cardiac Transplantation CURRENT CARDIOLOGY REPORTS Khush, K., Zarafshar, S. 2017; 19 (11): 118

  Abstract

  Acute rejection is one of the most feared complications of cardiac transplantation. Developing non-invasive methods for detection and surveillance of acute rejection have long been a goal for post-transplant care.Here, we will review molecular diagnostic tests that are currently in use or under development to diagnose acute cellular rejection after cardiac transplantation. Gene expression, microRNA, molecular microscope, and cell-free DNA assays offer non-invasive alternatives to the endomyocardial biopsy for acute rejection surveillance.

  View details for PubMedID 29030720

• Myriad Applications of Circulating Cell-Free DNA in Precision Organ Transplant Monitoring Burnham, P., Khush, K., De Vlaminck, I. AMER THORACIC SOC. 2017: S237–S241

  Abstract

  Solid organ transplantation remains the preferred treatment for many end-stage organ diseases, but complications due to acute rejection and infection occur frequently and undermine its long-term benefits. Monitoring of the health of the allograft is therefore a critically important component of post-transplant therapy. Here, we review several emerging applications of circulating cell-free DNA (cfDNA) in the post-transplant monitoring of rejection, infection, and immunosuppression. We further discuss the cellular origins and salient biophysical properties of cfDNA. A property of cfDNA that has been prominent since its discovery in the late 1940s is its ability to yield surprises. We review recent insights into the epigenetic features of cfDNA that yet again provide novel opportunities for transplant monitoring.

  View details for PubMedID 28945480

  View details for PubMedCentralID PMC5711344

• Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Agbor-Enoh, S., Tunc, I., De Vlaminck, I., Fideli, U., Davis, A., Cuttin, K., Bhatti, K., Marishta, A., Solomon, M. A., Jackson, A., Graninger, G., Harper, B., Luikart, H., Wylie, J., Wang, X., Berry, G., Marboe, C., Khush, K., Zhu, J., Valantine, H. 2017; 36 (9): 1004–12

  Abstract

  Use of new genomic techniques in clinical settings requires that such methods are rigorous and reproducible. Previous studies have shown that quantitation of donor-derived cell-free DNA (%ddcfDNA) by unbiased shotgun sequencing is a sensitive, non-invasive marker of acute rejection after heart transplantation. The primary goal of this study was to assess the reproducibility of %ddcfDNA measurements across technical replicates, manual vs automated platforms, and rejection phenotypes in distinct patient cohorts.After developing and validating the %ddcfDNA assay, we subjected the method to a rigorous test of its reproducibility. We measured %ddcfDNA in technical replicates performed by 2 independent laboratories and verified the reproducibility of %ddcfDNA patterns of 2 rejection phenotypes: acute cellular rejection and antibody-mediated rejection in distinct patient cohorts.We observed strong concordance of technical-replicate %ddcfDNA measurements across 2 independent laboratories (slope = 1.02, R2 > 0.99, p < 10-6), as well as across manual and automated platforms (slope = 0.80, R2 = 0.92, p < 0.001). The %ddcfDNA measurements in distinct heart transplant cohorts had similar baselines and error rates. The %ddcfDNA temporal patterns associated with rejection phenotypes were similar in both patient cohorts; however, the quantity of ddcfDNA was significantly higher in samples with severe vs mild histologic rejection grade (2.73% vs 0.14%, respectively; p < 0.001).The %ddcfDNA assay is precise and reproducible across laboratories and in samples from 2 distinct types of heart transplant rejection. These findings pave the way for larger studies to assess the clinical utility of %ddcfDNA as a marker of acute rejection after heart transplantation.

  View details for PubMedID 28624139

• Quantification of transplant-derived circulating cell-free DNA in absence of a donor genotype PLOS COMPUTATIONAL BIOLOGY Sharon, E., Shi, H., Kharbanda, S., Koh, W., Martin, L. R., Khush, K. K., Valantine, H., Pritchard, J. K., De Vlaminck, I. 2017; 13 (8): e1005629

  Abstract

  Quantification of cell-free DNA (cfDNA) in circulating blood derived from a transplanted organ is a powerful approach to monitoring post-transplant injury. Genome transplant dynamics (GTD) quantifies donor-derived cfDNA (dd-cfDNA) by taking advantage of single-nucleotide polymorphisms (SNPs) distributed across the genome to discriminate donor and recipient DNA molecules. In its current implementation, GTD requires genotyping of both the transplant recipient and donor. However, in practice, donor genotype information is often unavailable. Here, we address this issue by developing an algorithm that estimates dd-cfDNA levels in the absence of a donor genotype. Our algorithm predicts heart and lung allograft rejection with an accuracy that is similar to conventional GTD. We furthermore refined the algorithm to handle closely related recipients and donors, a scenario that is common in bone marrow and kidney transplantation. We show that it is possible to estimate dd-cfDNA in bone marrow transplant patients that are unrelated or that are siblings of the donors, using a hidden Markov model (HMM) of identity-by-descent (IBD) states along the genome. Last, we demonstrate that comparing dd-cfDNA to the proportion of donor DNA in white blood cells can differentiate between relapse and the onset of graft-versus-host disease (GVHD). These methods alleviate some of the barriers to the implementation of GTD, which will further widen its clinical application.

  View details for PubMedID 28771616

• The Conundrum of Equitable Organ Allocation in Heart Transplantation: The Moving Target of Candidate Risk Score. Transplantation Potena, L., Khush, K. K. 2017

  View details for DOI 10.1097/TP.0000000000001841

  View details for PubMedID 28590947

• Report from the American society of transplantation conference on donor heart selection in adult cardiac transplantation in the U.S. American journal of transplantation Kobashigawa, J., Khush, K., Colvin, M., Acker, M., Van Bakel, A., Eisen, H., Naka, Y., Patel, J., Baran, D. A., Daun, T., Luu, M., Olymbios, M., Rogers, J., Jeevanandam, V., Esmailian, F., Pagani, F. D., Lima, B., Stehlik, J. 2017

  Abstract

  Cardiac transplantation remains the only definitive treatment for end-stage heart failure. Transplantation rates are limited by a shortage of donor hearts. This shortage is magnified because many hearts are discarded because of strict selection criteria and concern for regulatory reprimand for less-than-optimal posttransplant outcomes. There is no standardized approach to donor selection despite proposals to liberalize acceptance criteria. A donor heart selection conference was organized to facilitate discussion and generate ideas for future research. The event was attended by 66 participants from 41 centers with considerable experience in cardiac donor selection. There were state-of-the-art presentations on donor selection, with subsequent breakout sessions on standardizing the process and increasing utilization of donor hearts. Participants debated misconceptions and established agreement on donor and recipient risk factors for donor selection and identified the components necessary for a future donor risk score. Ideas for future initiatives include modification of regulatory practices to consider extended criteria donors when evaluating outcomes and prospective studies aimed at identifying the factors leading to nonacceptance of available donor hearts. With agreement on the most important donor and recipient risk factors, it is anticipated that a consistent approach to donor selection will improve rates of heart transplantation.

  View details for DOI 10.1111/ajt.14354

  View details for PubMedID 28510318

• Precision monitoring of immunotherapies in solid organ and hematopoietic stem cell transplantation ADVANCED DRUG DELIVERY REVIEWS DiLoreto, R., Khush, K., De Vlaminck, I. 2017; 114: 272–84

  Abstract

  Pharmacological immunotherapies are a key component of post-transplant therapy in solid-organ and hematopoietic stem cell transplantation. In current clinical practice, immunotherapies largely follow a one-size fits all approach, leaving a large portion of transplant recipients either over- or under-immunosuppressed, and consequently at risk of infections or immune-mediated complications. Our goal here is to review recent and rapid advances in precision and genomic medicine approaches to monitoring of post-transplant immunotherapies. We will discuss recent advances in precision measurements of pharmacological immunosuppression, measurements of the plasma and gut microbiome, strategies to monitor for allograft injury and post-transplant malignancies via circulating cell-free DNA, and comprehensive measurements of the B and T cell immune cell repertoire.

  View details for PubMedID 28625828

• Combined heart lung transplantation: an updated review of the current literature. Transplantation Pasupneti, S., Dhillon, G., Reitz, B., Khush, K. 2017

  Abstract

  Heart lung transplantation is a viable treatment option for patients with many end stage heart and lung pathologies. However, given the complex nature of the procedure, it is imperative that patients are selected appropriately and the clinician is aware of the many unique aspects in management of this population. This review seeks to describe updated organ selection policies, peri and postoperative management strategies, monitoring of graft function, and clinical outcomes for patients following combined heart-lung transplantation in the current era.

  View details for DOI 10.1097/TP.0000000000001820

  View details for PubMedID 28505026

• Personalized treatment in heart transplantation. Current opinion in organ transplantation Khush, K. K. 2017

  Abstract

  We are entering the era of personalized medicine, in which pharmacogenomics and biomarker-based assays can be used to tailor diagnostic tests and drug therapies to individual patients. This new approach to patient-specific care offers the potential to maximize the efficacy of available medical treatments while reducing the incidence of adverse side effects. Here, we present approaches to personalize the care of heart transplant recipients.Four strategies for personalized posttransplant care are described, including use of pharmacogenomic data to individualize the use of immunosuppressive drugs, immune monitoring to prevent acute rejection while reducing the long-term consequences of over immunosuppression, noninvasive surveillance for acute rejection, and targeted prophylaxis against opportunistic infections.The long-term survival of heart transplant recipients is limited by side effects of immunosuppressive drugs, including infectious complications, renal dysfunction, and malignancy. We discuss strategies to maximize the benefits of immunosuppressive and prophylactic therapies while minimizing their long-term toxicities.

  View details for DOI 10.1097/MOT.0000000000000406

  View details for PubMedID 28266942

• The ratio of circulating regulatory cluster of differentiation 4 T cells to endothelial progenitor cells predicts clinically significant acute rejection after heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Choi, D. H., Chmura, S. A., Ramachandran, V. n., Dionis-Petersen, K. Y., Kobayashi, Y. n., Nishi, T. n., Luikart, H. n., Dimbil, S. n., Kobashigawa, J. n., Khush, K. n., Lewis, D. B., Fearon, W. F. 2017

  Abstract

  The aim of this study was to determine the value of the ratio of the percentage of circulating regulatory cluster of differentiation 4 T cells (%Tregs) to the percentage of endothelial progenitor cells (%EPCs; Treg/EPC ratio) for predicting clinically significant acute rejection.Peripheral blood %Tregs and %EPCs were quantified in 91 cardiac transplant recipients using flow cytometry at a mean of 42 ± 13 days after transplant. The primary end point was clinically significant acute rejection, defined as an event that led to an acute augmentation of immunosuppression in conjunction with an International Society for Heart and Lung Transplantation grade ≥ 2R in a right ventricular endomyocardial biopsy specimen or non-cellular rejection (specimen-negative rejection) with hemodynamic compromise (decrease in left ventricular ejection fraction by > 25%).Significant rejection occurred in 27 recipients (29.7%) during a median of 49.4 months (interquartile range, 37.0-62.0 months). The mean %Tregs and %EPCs were not significantly different between those with and without an episode of significant rejection, but the mean Treg/EPC ratio was significantly lower in recipients with significant rejection (44.9 vs 106.7, p = 0.001). Receiver operating characteristic curve analysis showed an area under the curve value for significant rejection for a Treg/EPC ratio of 0.712. The best cutoff value of the Treg/EPC ratio that distinguished between those with or without significant rejection was ≤ 18 by receiver operating characteristic curve analysis. Kaplan-Meier analysis revealed that patients with a Treg/EPC ratio of ≤ 18 had a significantly higher rate of rejection than those with a Treg/EPC ratio > 18 (61.5% vs 16.9%, log-rank p < 0.0001). A low Treg/EPC ratio was an independent predictor of significant rejection.A low Treg/EPC ratio measured soon after heart transplantation is an independent predictor of acute rejection. The Treg/EPC ratio has potential as an early biomarker after heart transplantation for predicting acute rejection.

  View details for PubMedID 29198869

• Impact of Asymmetric Dimethylarginine on Coronary Physiology Early After Heart Transplantation. The American journal of cardiology Parikh, R. V., Khush, K. K., Luikart, H. n., Pargaonkar, V. S., Kobayashi, Y. n., Lee, J. H., Sinha, S. n., Cohen, G. n., Valantine, H. A., Yeung, A. C., Fearon, W. F. 2017

  Abstract

  Cardiac allograft vasculopathy is a major cause of long-term graft failure following heart transplantation. Asymmetric dimethylarginine (ADMA), a marker of endothelial dysfunction, has been mechanistically implicated in the development of cardiac allograft vasculopathy, but its impact on coronary physiology early after transplantation is unknown. Invasive indices of coronary physiology, namely, fractional flow reserve (FFR), the index of microcirculatory resistance, and coronary flow reserve, were measured with a coronary pressure wire in the left anterior descending artery within 8 weeks (baseline) and 1 year after transplant. Plasma levels of ADMA were concurrently assayed using high-performance liquid chromatography. In 46 heart transplant recipients, there was a statistically significant correlation between elevated ADMA levels and lower FFR values at baseline (r = -0.33; p = 0.024); this modest association persisted 1 year after transplant (r = -0.39; p = 0.0085). Patients with a baseline FFR <0.90 (a prognostically validated cutoff) had significantly higher baseline ADMA levels (0.63 ± 0.16 vs 0.54 ± 0.12 µM; p = 0.034). Baseline ADMA (odds ratio 1.80 per 0.1 µM; 95% confidence interval 1.07 to 3.03; p = 0.027) independently predicted a baseline FFR <0.90 after multivariable adjustment. Even after dichotomizing ADMA (≥0.60 µM, provides greatest diagnostic accuracy by receiver operating characteristic curve), this association remained significant (odds ratio 7.52, 95% confidence interval 1.74 to 32.49; p = 0.006). No significant relationship between ADMA and index of microcirculatory resistance or coronary flow reserve was detected. In conclusion, baseline ADMA was a strong independent predictor of FFR <0.90, suggesting that elevated ADMA levels are associated with abnormal epicardial function soon after heart transplantation.

  View details for PubMedID 28754566

• Coronary Endothelial Dysfunction and the Index of Microcirculatory Resistance as a Marker of Subsequent Development of Cardiac Allograft Vasculopathy. Circulation Lee, J. H., Okada, K. n., Khush, K. n., Kobayashi, Y. n., Sinha, S. n., Luikart, H. n., Valantine, H. n., Yeung, A. C., Honda, Y. n., Fearon, W. F. 2017; 135 (11): 1093–95

  View details for PubMedID 28289008

• Angiotensin-Converting Enzyme Inhibition Early After Heart Transplantation. Journal of the American College of Cardiology Fearon, W. F., Okada, K. n., Kobashigawa, J. A., Kobayashi, Y. n., Luikart, H. n., Sana, S. n., Daun, T. n., Chmura, S. A., Sinha, S. n., Cohen, G. n., Honda, Y. n., Pham, M. n., Lewis, D. B., Bernstein, D. n., Yeung, A. C., Valantine, H. A., Khush, K. n. 2017; 69 (23): 2832–41

  Abstract

  Cardiac allograft vasculopathy (CAV) remains a leading cause of mortality after heart transplantation (HT). Angiotensin-converting enzyme inhibitors (ACEIs) may retard the development of CAV but have not been well studied after HT.This study tested the safety and efficacy of the ACEI ramipril on the development of CAV early after HT.In this prospective, multicenter, randomized, double-blind, placebo-controlled trial, 96 HT recipients were randomized to undergo ramipril or placebo therapy. They underwent coronary angiography, endothelial function testing; measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR); and intravascular ultrasonography (IVUS) of the left anterior descending coronary artery, within 8 weeks of HT. At 1 year, the invasive assessment was repeated. Circulating endothelial progenitor cells (EPCs) were quantified at baseline and 1 year.Plaque volumes at 1 year were similar between the ramipril and placebo groups (162.1 ± 70.5 mm(3) vs. 177.3 ± 94.3 mm(3), respectively; p = 0.73). Patients receiving ramipril had improvement in microvascular function as shown by a significant decrease in IMR (21.4 ± 14.7 to 14.4 ± 6.3; p = 0.001) and increase in CFR (3.8 ± 1.7 to 4.8 ± 1.5; p = 0.017), from baseline to 1 year. This did not occur with IMR (17.4 ± 8.4 to 21.5 ± 20.0; p = 0.72) or CFR (4.1 ± 1.8 to 4.1 ± 2.2; p = 0.60) in the placebo-treated patients. EPCs decreased significantly at 1 year in the placebo group but not in the ramipril group.Ramipril does not slow development of epicardial plaque volume but does stabilize levels of endothelial progenitor cells and improve microvascular function, which have been associated with improved long-term survival after HT. (Angiotensin Converting Enzyme [ACE] Inhibition and Cardiac Allograft Vasculopathy; NCT01078363).

  View details for PubMedID 28595700

• ALLELIC AND EPITOPE HLA MISMATCH ANALYSIS IN LUNG TRANSPLANT Sninsky, J. J., Fear, A., Lew, D., Trachtenberg, E., De Vlaminck, I., Khush, K. K., Erlich, H. A., Woodward, R. N. ELSEVIER SCIENCE INC. 2017: 171

  View details for DOI 10.1016/j.humimm.2017.06.216

  View details for Web of Science ID 000411658700210

• Incremental Value of Deformation Imaging and Hemodynamics Following Heart Transplantation: Insights From Graft Function Profiling. JACC. Heart failure Kobayashi, Y. n., Sudini, N. L., Rhee, J. W., Aymami, M. n., Moneghetti, K. J., Bouajila, S. n., Kobayashi, Y. n., Kim, J. B., Schnittger, I. n., Teuteberg, J. J., Khush, K. K., Fearon, W. F., Haddad, F. n. 2017; 5 (12): 930–39

  Abstract

  This study investigated to define graft dysfunction and to determine its incremental association with long-term outcome after heart transplantation (HT).Although graft failure is an established cause of late mortality after HT, few studies have analyzed the prognostic value of graft dysfunction at 1- and 5-year follow-up of HT.Patients who underwent HT and completed their first annual evaluation with right heart catheterization and echocardiography at Stanford University between January 1999 and December 2011 were included in the study. Hierarchical clustering was used to identify modules to capture independent features of graft dysfunction at 1 year. The primary endpoint for analysis consisted of the composite of cardiovascular mortality, re-transplantation, or heart failure hospitalization within 5 years of HT. The study further explored whether changes in graft dysfunction between 1 and 5 years were associated with 10-year all-cause mortality.A total of 215 HT recipients were included in the study. Using hierarchical clustering, 3 functional modules were identified; among them, left ventricular global longitudinal strain (LVGLS), stroke volume index, and right atrial pressure (RAP) or pulmonary capillary wedge pressure (PCWP) captured key features of graft function. Graft dysfunction based on pre defined LVGLS in absolute value <14%, stroke volume index <35 ml/m2, RAP >10 mm Hg, or PCWP >15 mm Hg were present in 41%, 36%, and 27%, respectively. The primary endpoint at 5 years occurred in 52 patients (24%), whereas 10-year all-cause mortality occurred in 30 (27%) of 110 patients alive at 5 years. On multivariate analysis, RAP (standardized hazard ratio: 1.63), LVGLS (standardized hazard ratio: 1.39), and a history of hemodynamically compromising rejection within 1 year (hazard ratio: 2.18) were independent predictors of 5-year outcome. RAP at 5 years, as well as change in RAP from 1 to 5 years, was predictive of 10-year all-cause mortality.RAP and LVGLS at the first annual evaluation provide complementary prognostic information in predicting 5-year outcome after HT.

  View details for PubMedID 29191301

• Early Left Ventricular Dysfunction is Associated with Cardiac Allograft Vasculopathy and Late Mortality After Heart Transplantation Okada, K., Honda, Y., Luikart, H., Yock, P. G., Fitzgerald, P. J., Yeung, A. C., Valantine, H., Khush, K., Fearon, W. ELSEVIER SCIENCE INC. 2016: B331

  View details for DOI 10.1016/j.jacc.2016.09.909

  View details for Web of Science ID 000398590400337

• Attenuated-Signal Plaque Progression Predicts Long-Term Mortality After Heart Transplantation: IVUS Assessment of Cardiac Allograft Vasculopathy. Journal of the American College of Cardiology Okada, K., Fearon, W. F., Luikart, H., Kitahara, H., Otagiri, K., Tanaka, S., Kimura, T., Yock, P. G., Fitzgerald, P. J., Yeung, A. C., Valantine, H. A., Khush, K. K., Honda, Y. 2016; 68 (4): 382-392

  Abstract

  Although cardiac allograft vasculopathy (CAV) is typically characterized by diffuse coronary intimal thickening with pathological vessel remodeling, plaque instability may also play an important role in CAV. Previous studies of native coronary atherosclerosis have demonstrated associations between attenuated-signal plaque (ASP), plaque instability, and adverse clinical events.This study's aim was to characterize the association between ASP and long-term mortality post-heart transplantation.In 105 heart transplant recipients, serial (baseline and 1-year post-transplant) intravascular ultrasound was performed in the first 50 mm of the left anterior descending artery. The ASP score was calculated by grading the measured angle of attenuation from grades 0 to 4 (specifically, 0°, 1° to 90°, 91° to 180°, 181° to 270°, and >270°) at 1-mm intervals. The primary endpoint was all-cause death or retransplantation.At 1-year post-transplant, 10.5% of patients demonstrated ASP progression (newly developed or increased ASP). Patients with ASP progression had a higher incidence of acute cellular rejection during the first year (63.6% vs. 22.3%; p = 0.006) and tendency for greater intimal growth (percent intimal volume: 9.2 ± 9.3% vs. 4.4 ± 5.3%; p = 0.07) than those without. Over a median follow-up of 4.6 years, there was a significantly lower event-free survival rate in patients with ASP progression at 1-year post-transplant compared with those without. In contrast, maximum intimal thickness did not predict long-term mortality.ASP progression appears to reflect chronic inflammation related to acute cellular rejection and is an independent predictor of long-term mortality after heart transplantation. Serial assessments of plaque instability may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies.

  View details for DOI 10.1016/j.jacc.2016.05.028

  View details for PubMedID 27443435

• Assessment of Heart Transplant Waitlist Time and Pre- and Post-transplant Failure A Mixed Methods Approach EPIDEMIOLOGY Goldstein, B. A., Thomas, L., Zaroff, J. G., John Nguyen, J., Menza, R., Khush, K. K. 2016; 27 (4): 469-476

  Abstract

  Over the past two decades, there have been increasingly long waiting times for heart transplantation. We studied the relationship between heart transplant waiting time and transplant failure (removal from the waitlist, pretransplant death, or death or graft failure within 1 year) to determine the risk that conservative donor heart acceptance practices confer in terms of increasing the risk of failure among patients awaiting transplantation.We studied a cohort of 28,283 adults registered on the United Network for Organ Sharing heart transplant waiting list between 2000 and 2010. We used Kaplan-Meier methods with inverse probability censoring weights to examine the risk of transplant failure accumulated over time spent on the waiting list (pretransplant). In addition, we used transplant candidate blood type as an instrumental variable to assess the risk of transplant failure associated with increased wait time.Our results show that those who wait longer for a transplant have greater odds of transplant failure. While on the waitlist, the greatest risk of failure is during the first 60 days. Doubling the amount of time on the waiting list was associated with a 10% (1.01, 1.20) increase in the odds of failure within 1 year after transplantation.Our findings suggest a relationship between time spent on the waiting list and transplant failure, thereby supporting research aimed at defining adequate donor heart quality and acceptance standards for heart transplantation.

  View details for DOI 10.1097/EDE.0000000000000472

  View details for Web of Science ID 000379847600007

  View details for PubMedCentralID PMC4892941

• Single-stranded DNA library preparation uncovers the origin and diversity of ultrashort cell-free DNA in plasma SCIENTIFIC REPORTS Burnham, P., Kim, M. S., Agbor-Enoh, S., Luikart, H., Valantine, H. A., Khush, K. K., De Vlaminck, I. 2016; 6

  Abstract

  Circulating cell-free DNA (cfDNA) is emerging as a powerful monitoring tool in cancer, pregnancy and organ transplantation. Nucleosomal DNA, the predominant form of plasma cfDNA, can be adapted for sequencing via ligation of double-stranded DNA (dsDNA) adapters. dsDNA library preparations, however, are insensitive to ultrashort, degraded cfDNA. Drawing inspiration from advances in paleogenomics, we have applied a single-stranded DNA (ssDNA) library preparation method to sequencing of cfDNA in the plasma of lung transplant recipients (40 samples, six patients). We found that ssDNA library preparation yields a greater portion of sub-100 bp nuclear genomic cfDNA (p 10(-5), Mann-Whitney U Test), and an increased relative abundance of mitochondrial (10.7x, p 10(-5)) and microbial cfDNA (71.3x, p 10(-5)). The higher yield of microbial sequences from this method increases the sensitivity of cfDNA-based monitoring for infections following transplantation. We detail the fragmentation pattern of mitochondrial, nuclear genomic and microbial cfDNA over a broad fragment length range. We report the observation of donor-specific mitochondrial cfDNA in the circulation of lung transplant recipients. A ssDNA library preparation method provides a more informative window into understudied forms of cfDNA, including mitochondrial and microbial derived cfDNA and short nuclear genomic cfDNA, while retaining information provided by standard dsDNA library preparation methods.

  View details for DOI 10.1038/srep27859

  View details for Web of Science ID 000377827700001

  View details for PubMedID 27297799

  View details for PubMedCentralID PMC4906518

• Association of periarterial neovascularization with progression of cardiac allograft vasculopathy and long-term clinical outcomes in heart transplant recipients JOURNAL OF HEART AND LUNG TRANSPLANTATION Kitahara, H., Okada, K., Tanaka, S., Yang, H., Miki, K., Kobayashi, Y., Kimura, T., Luikart, H., Yock, P. G., Yeung, A. C., Fitzgerald, P. J., Khush, K. K., Fearon, W. F., Honda, Y. 2016; 35 (6): 752-759

  Abstract

  This study investigated the relationship between periarterial neovascularization, development of cardiac allograft vasculopathy (CAV), and long-term clinical outcomes after heart transplantation. Proliferation of the vasa vasorum is associated with arterial inflammation. The contribution of angiogenesis to the development of CAV has been suggested.Serial (baseline and 1-year post-transplant) intravascular ultrasound was performed in 102 heart transplant recipients. Periarterial small vessels (PSV) were defined as echolucent luminal structures <1 mm in diameter, located ≤2 mm outside of the external elastic membrane. The signal void structures were excluded when they connected to the coronary lumen (considered as side branches) or could not be followed in ≥3 contiguous frames. The number of PSV was counted at 1-mm intervals throughout the first 50 mm of the left anterior descending artery, and the PSV score was calculated as the sum of cross-sectional values. Patients with a PSV score increase of ≥ 4 between baseline and 1-year post-transplant were classified as the "proliferative" group. Maximum intimal thickness was measured for the entire analysis segment.During the first year post-transplant, the proliferative group showed a greater increase in maximum intimal thickness (0.33 ± 0.36 mm vs 0.10 ± 0.28 mm, p < 0.001) and had a higher incidence of acute cellular rejection (50.0% vs 23.9%, p = 0.025) than the non-proliferative group. On Kaplan-Meier analysis, cardiac death-free survival rate over a median of 4.7 years was significantly lower in the proliferative group than in the non-proliferative group (hazard ratio, 3.10; p = 0.036).The increase in PSV, potentially representing an angioproliferative response around the coronary arteries, was associated with early CAV progression and reduced survival after heart transplantation.

  View details for DOI 10.1016/j.healun.2016.02.002

  View details for PubMedID 27068036

• Elevated Troponin? Take Heart and Reconsider! CIRCULATION-HEART FAILURE Pasupneti, S., Khush, K. 2016; 9 (6)

  View details for DOI 10.1161/CIRCHEARTFAILURE.116.003237

  View details for Web of Science ID 000378139000014

  View details for PubMedID 27329986

  View details for PubMedCentralID PMC4918512

• Invasive Assessment of Coronary Physiology Predicts Late Mortality After Heart Transplantation CIRCULATION Yang, H., Khush, K., Luikart, H., Okada, K., Lim, H., Kobayashi, Y., Honda, Y., Yeung, A. C., Valantine, H., Fearon, W. F. 2016; 133 (20): 1945-1950

  Abstract

  -The aim of this study is to determine the prognostic value of invasively assessing coronary physiology early after heart transplantation.-Seventy-four cardiac transplant recipients had fractional flow reserve (FFR), coronary flow reserve (CFR), the index of microcirculatory resistance (IMR) and intravascular ultrasound (IVUS) performed down the left anterior descending coronary artery soon after (baseline) and 1 year after heart transplantation. The primary endpoint was the cumulative survival free of death or retransplantation at a mean follow-up of 4.5±3.5 years. The cumulative event-free survival was significantly lower in patients with an FFR<0.90 at baseline (42 vs 79%, p=0.01) or an IMR≥20 measured one year after heart transplantation (39 vs. 69%, p=0.03). Patients in whom IMR decreased or did not change from baseline to 1 year had higher event-free survival compared to those patients with an increase in IMR (66 vs. 36%, p=0.03). FFR<0.90 at baseline (hazards ratio [HR] 0.13, 95% confidence interval [CI] 0.02-0.81, p=0.03), IMR ≥20 at 1 year (HR 3.93, 95% CI 1.08-14.27, p=0.04) and rejection during the first year (HR 6.00, 95% CI 1.56-23.09, p=0.009) were independent predictors of death/retransplantation, while IVUS parameters were not.-Invasive measures of coronary physiology (FFR and IMR) determined early after heart transplantation are significant predictors of late death or retransplantation.

  View details for DOI 10.1161/CIRCULATIONAHA.115.018741

  View details for PubMedID 27143679

• HIGHER LEVELS OF ASYMMETRIC DIMETHYLARGININE ARE ASSOCIATED WITH LOWER FRACTIONAL FLOW RESERVE AFTER ORTHOTOPIC HEART TRANSPLANTATION Parikh, R., Khush, K., Luikart, H., Pargaonkar, V., Kobayashi, Y., Lee, J., Sinha, S., Cohen, G., Valantine, H., Yeung, A., Fearon, W. ELSEVIER SCIENCE INC. 2016: 1355

  View details for DOI 10.1016/S0735-1097(16)31356-0

  View details for Web of Science ID 000375188702201

• ENDOTHELIUM DEPENDENT AND INDEPENDENT VASODILATOR RESPONSES AFTER HEART TRANSPLANTATION: GEOGRAPHIC DISTRIBUTION AND ASSOCIATION WITH PROGRESSION OF CARDIAC ALLOGRAFT VASCULOPATHY Okada, K., Kimura, T., Miki, K., Yock, P., Yeung, A., Fitzgerald, P., Luikart, H., Khush, K., Honda, Y., Fearon, W. ELSEVIER SCIENCE INC. 2016: 254

  View details for DOI 10.1016/S0735-1097(16)30255-8

  View details for Web of Science ID 000375188701098

• THE IMPACT OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS ON ASYMMETRIC DIMETHYLARGININE IN ORTHOTOPIC HEART TRANSPLANTATION RECIPIENTS: A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL Parikh, R., Khush, K., Sana, S., Daun, T., Luikart, H., Pargaonkar, V., Sinha, S., Cohen, G., Valantine, H., Yeung, A., Kobashigawa, J., Fearon, W. ELSEVIER SCIENCE INC. 2016: 1356

  View details for DOI 10.1016/S0735-1097(16)31357-2

  View details for Web of Science ID 000375188702202

• ANGIOTENSIN-CONVERTING ENZYME INHIBITION EARLY AFTER CARDIAC TRANSPLANTATION: A MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND TRIAL COMPARING RAMIPRIL VERSUS PLACEBO Kobayashi, Y., Okada, K., Khush, K., Sana, S., Daun, T., Sinha, S., Cohen, G., Honda, Y., Luikart, H., Valantine, H., Yeung, A., Kobashigawa, J., Fearon, W. ELSEVIER SCIENCE INC. 2016: 1445

  View details for DOI 10.1016/S0735-1097(16)31446-2

  View details for Web of Science ID 000375188702291

• EARLY CORONARY ENDOTHELIAL DYSFUNCTION PREDICTS ACCELERATED PLAQUE PROGRESSION 1 YEAR AFTER CARDIAC TRANSPLANTATION: SERIAL VOLUMETRIC EVALUATION BY INTRAVASCULAR ULTRASOUND Lee, J., Okada, K., Khush, K., Kobayashi, Y., Sinha, S., Luikart, H., Valantine, H., Yeung, A., Honda, Y., Fearon, W. ELSEVIER SCIENCE INC. 2016: 364

  View details for DOI 10.1016/S0735-1097(16)30365-5

  View details for Web of Science ID 000375188701208

• Paradoxical Vessel Remodeling of the Proximal Segment of the Left Anterior Descending Artery Predicts Long-Term Mortality After Heart Transplantation JACC-HEART FAILURE Okada, K., Kitahara, H., Yang, H., Tanaka, S., Kobayashi, Y., Kimura, T., Luikart, H., Yock, P. G., Yeung, A. C., Valantine, H. A., Fitzgerald, P. J., Khush, K. K., Honda, Y., Fearon, W. F. 2015; 3 (12): 942-952

  Abstract

  This study investigated the association between arterial remodeling and geographic distribution of cardiac allograft vasculopathy (CAV), and outcomes after heart transplantation.CAV is characterized by a combination of coronary intimal thickening and pathological vessel remodeling, which varies at different locations in coronary arteries.In 100 transplant recipients, serial volumetric intravascular ultrasonography (IVUS) was performed at baseline and 1 year post-transplantation in the first 50 mm of the left anterior descending artery (LAD). IVUS indices were evaluated in the entire segment and 3 equally divided LAD segments. Paradoxical vessel remodeling was defined as [Δvessel volume/Δintimal volume <0].After 1 year, death or re-transplantation occurred in 20 patients over a median follow-up period of 4.7 years. Paradoxical vessel remodeling was observed in 57%, 41%, 50%, and 40% for the entire vessel, proximal, middle, and distal LAD segments, respectively. Kaplan-Meier analysis revealed a significantly lower event-free rate of survival in patients with paradoxical vessel remodeling involving the proximal LAD segment, which was not present when involving the entire LAD or mid and distal LAD segments. In multivariate analysis, paradoxical vessel remodeling of the proximal LAD segment was independently associated with death or re-transplantation (hazard ratio [HR]: 11.18; 95% confidence interval [CI]: 2.39 to 83.23; p = 0.0015).Despite the diffuse nature of CAV, paradoxical vessel remodeling of the proximal LAD segment at 1 year was the primary determinant of long-term mortality or re-transplantation. Assessment of arterial remodeling combined with coronary intimal thickening may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies.

  View details for DOI 10.1016/j.jchf.2015.07.013

  View details for Web of Science ID 000366949300002

• Design and Implementation of the International Genetics and Translational Research in Transplantation Network TRANSPLANTATION Keating, B. J., van Setten, J., Jacobson, P. A., Holmes, M. V., Verma, S. S., Chandrupatla, H. R., Nair, N., Gao, H., Li, Y. R., Chang, B., Wong, C., Phillips, R., Cole, B. S., Mukhtar, E., Zhang, W., Cao, H., Mohebnasab, M., Hou, C., Lee, T., Steel, L., Shaked, O., Garifallou, J., Miller, M. B., Karczewski, K. J., Akdere, A., Gonzalez, A., Lloyd, K. M., McGinn, D., Michaud, Z., Colasacco, A., Lek, M., Fu, Y., Pawashe, M., Guettouche, T., Himes, A., Perez, L., Guan, W., Wu, B., Schladt, D., Menon, M., Zhang, Z., Tragante, V., de Jonge, N., Otten, H. G., de Weger, R. A., van de Graaf, E. A., Baan, C. C., Manintveld, O. C., De Vlaminck, I., Piening, B. D., Strehl, C., Shaw, M., Snieder, H., Klintmalm, G. B., O'Leary, J. G., Amaral, S., Goldfarb, S., Rand, E., Rossano, J. W., Kohli, U., Heeger, P., Stahl, E., Christie, J. D., Fuentes, M. H., Levine, J. E., Aplenc, R., Schadt, E. E., Stranger, B. E., Kluin, J., Potena, L., Zuckermann, A., Khush, K., Alzahrani, A. J., Al-Muhanna, F. A., Al-Ali, A. K., Al-Ali, R., Al-Rubaish, A. M., Al-Mueilo, S., Byrne, E. M., Miller, D., Alexander, S. I., Onengut-Gumuscu, S., Rich, S. S., Suthanthiran, M., Tedesco, H., Saw, C. L., Ragoussis, J., Kfoury, A. G., Horne, B., Carlquist, J., Gerstein, M. B., Reindl-Schwaighofer, R., Oberbauer, R., Wijmenga, C., Palmer, S., Pereira, A. C., Segovia, J., Alonso-Pulpon, L. A., Comez-Bueno, M., Vilches, C., Jaramillo, N., de Borst, M. H., Naesens, M., Hao, K., MacArthur, D., Balasubramanian, S., Conlon, P. J., Lord, G. M., Ritchie, M. D., Snyder, M., Olthoff, K. M., Moore, J. H., Petersdorf, E. W., Kamoun, M., Wang, J., Monos, D. S., de Bakker, P. I., Hakonarson, H., Murphy, B., Lankree, M. B., Garcia-Pavia, P., Oetting, W. S., Birdwell, K. A., Bakker, S. J., Israni, A. K., Shaked, A., Asselbergs, F. W. 2015; 99 (11): 2401-2412

  Abstract

  Genetic association studies of transplantation outcomes have been hampered by small samples and highly complex multifactorial phenotypes, hindering investigations of the genetic architecture of a range of comorbidities which significantly impact graft and recipient life expectancy. We describe here the rationale and design of the International Genetics & Translational Research in Transplantation Network. The network comprises 22 studies to date, including 16494 transplant recipients and 11669 donors, of whom more than 5000 are of non-European ancestry, all of whom have existing genomewide genotype data sets.We describe the rich genetic and phenotypic information available in this consortium comprising heart, kidney, liver, and lung transplant cohorts.We demonstrate significant power in International Genetics & Translational Research in Transplantation Network to detect main effect association signals across regions such as the MHC region as well as genomewide for transplant outcomes that span all solid organs, such as graft survival, acute rejection, new onset of diabetes after transplantation, and for delayed graft function in kidney only.This consortium is designed and statistically powered to deliver pioneering insights into the genetic architecture of transplant-related outcomes across a range of different solid-organ transplant studies. The study design allows a spectrum of analyses to be performed including recipient-only analyses, donor-recipient HLA mismatches with focus on loss-of-function variants and nonsynonymous single nucleotide polymorphisms.

  View details for DOI 10.1097/TP.0000000000000913

  View details for Web of Science ID 000369087800037

  View details for PubMedCentralID PMC4623847

• Noninvasive monitoring of infection and rejection after lung transplantation. Proceedings of the National Academy of Sciences of the United States of America De Vlaminck, I., Martin, L., Kertesz, M., Patel, K., Kowarsky, M., Strehl, C., Cohen, G., Luikart, H., Neff, N. F., Okamoto, J., Nicolls, M. R., Cornfield, D., Weill, D., Valantine, H., Khush, K. K., Quake, S. R. 2015; 112 (43): 13336-13341

  Abstract

  The survival rate following lung transplantation is among the lowest of all solid-organ transplants, and current diagnostic tests often fail to distinguish between infection and rejection, the two primary posttransplant clinical complications. We describe a diagnostic assay that simultaneously monitors for rejection and infection in lung transplant recipients by sequencing of cell-free DNA (cfDNA) in plasma. We determined that the levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0.9). We also analyzed the nonhuman cfDNA as a hypothesis-free approach to test for infections. Cytomegalovirus is most frequently assayed clinically, and the levels of CMV-derived sequences in cfDNA are consistent with clinical results. We furthermore show that hypothesis-free monitoring for pathogens using cfDNA reveals undiagnosed cases of infection, and that certain infectious pathogens such as human herpesvirus (HHV) 6, HHV-7, and adenovirus, which are not often tested clinically, occur with high frequency in this cohort.

  View details for DOI 10.1073/pnas.1517494112

  View details for PubMedID 26460048

• Monitoring Pharmacologically Induced Immunosuppression by Immune Repertoire Sequencing to Detect Acute Allograft Rejection in Heart Transplant Patients: A Proof-of-Concept Diagnostic Accuracy Study PLOS MEDICINE Vollmers, C., De Vlaminck, I., Valantine, H. A., Penland, L., Luikart, H., Strehl, C., Cohen, G., Khush, K. K., Quake, S. R. 2015; 12 (10)

  Abstract

  It remains difficult to predict and to measure the efficacy of pharmacological immunosuppression. We hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation.In this proof-of-concept study, we implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire. We used this assay to measure the temporal response of the B cell repertoire to immunosuppression after heart transplantation. We selected a subset of 12 participants from a larger prospective cohort study (ClinicalTrials.gov NCT01985412) that is ongoing at Stanford Medical Center and for which enrollment started in March 2010. This subset of 12 participants was selected to represent post-heart-transplant events, with and without acute rejection (six participants with moderate-to-severe rejection and six without). We analyzed 130 samples from these patients, with an average follow-up period of 15 mo. Immune repertoire sequencing enables the measurement of a patient's net state of immunosuppression (correlation with tacrolimus level, r = -0.867, 95% CI -0.968 to -0.523, p = 0.0014), as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4% (95% CI 30.3% to 94.9%) and a specificity of 82.0% (95% CI 72.1% to 89.1%) (cell-free donor-derived DNA as noninvasive gold standard). To illustrate the potential of immune repertoire sequencing to monitor atypical post-transplant trajectories, we analyzed two more patients, one with chronic infections and one with amyloidosis. A larger, prospective study will be needed to validate the power of immune repertoire sequencing to predict rejection events, as this proof-of-concept study is limited to a small number of patients who were selected based on several criteria including the availability of a large number of samples and the absence or presence of rejection events.If confirmed in larger, prospective studies, the method described here has potential applications in the tailored management of post-transplant immunosuppression and, more broadly, as a method for assessing the overall activity of the immune system.

  View details for DOI 10.1371/journal.pmed.1001890

  View details for Web of Science ID 000364466600008

  View details for PubMedID 26466143

  View details for PubMedCentralID PMC4605651

• Gene expression profiling to study racial differences after heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Khush, K. K., Pham, M. X., Teuteberg, J. J., Kfoury, A. G., Deng, M. C., Kao, A., Anderson, A. S., Cotts, W. G., Ewald, G. A., Baran, D. A., Hiller, D., Yee, J., Valantine, H. A. 2015; 34 (7): 970-977

  Abstract

  The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a function of calcineurin inhibitor (CNI) levels and gene expression profile (GEP) scores.We determined the event rate of the primary outcome, comparing racial groups, stratified by time after transplant. Logistic regression was used to compute the relative risk across racial groups, and linear modeling was used to measure the dependence of CNI levels and GEP score on race.In 580 patients monitored for a median of 19 months, the incidence of the primary end point was 18.3% in African Americans, 22.2% in other non-Caucasians, and 8.5% in Caucasians (p < 0.001). There were small but significant correlations of race and tacrolimus trough levels to the GEP score. Tacrolimus levels were similar among the races. Of patients receiving tacrolimus, other non-Caucasians had higher GEP scores than the other racial groups. African American recipients demonstrated a unique decrease in expression of the FLT3 gene in response to higher tacrolimus levels.African Americans and other non-Caucasian heart transplant recipients were 2.5-times to 3-times more likely than Caucasians to experience outcome events in the Invasive Monitoring Attenuation through Gene Expression study. The increased risk of adverse outcomes may be partly due to the biology of the alloimmune response, which is less effectively inhibited at similar tacrolimus levels in minority racial groups.

  View details for DOI 10.1016/j.healun.2015.01.987

  View details for Web of Science ID 000356998800014

  View details for PubMedID 25840504

  View details for PubMedCentralID PMC4475410

• INVASIVE CORONARY PHYSIOLOGY AT ONE YEAR PREDICTS LATE MORTALITY AFTER HEART TRANSPLANTATION Yang, H., Okada, K., Cohen, G., Strehl, C., Luikart, H., Valantine, H., Honda, Y., Khush, K., Fearon, W. ELSEVIER SCIENCE INC. 2015: A1685

  View details for DOI 10.1016/S0735-1097(15)61685-0

  View details for Web of Science ID 000375328802007

• ASSOCIATION OF PERIARTERIAL NEOVASCULARIZATION WITH PROGRESSION OF CARDIAC ALLOGRAFT VASCULOPATHY AND LONG-TERM CLINICAL OUTCOMES IN HEART TRANSPLANT RECIPIENTS Kitahara, H., Okada, K., Tanaka, S., Yang, H., Kobayashi, Y., Kimura, T., Luikart, H., Yock, P., Yeung, A., Fitzgerald, P., Khush, K., Fearon, W., Honda, Y. ELSEVIER SCIENCE INC. 2015: A1710

  View details for DOI 10.1016/S0735-1097(15)61710-7

  View details for Web of Science ID 000375328802032

• IMPACT OF MYOCARDIAL BRIDGING ON CORONARY ARTERY PLAQUE FORMATION AND LONG-TERM MORTALITY AFTER HEART TRANSPLANTATION Tanaka, S., Okada, K., Kitahara, H., Kobayashi, Y., Luikart, H., Yock, P., Yeung, A., Schnittger, I., Fitzgerald, P., Khush, K., Fearon, W., Honda, Y. ELSEVIER SCIENCE INC. 2015: A1741

  View details for DOI 10.1016/S0735-1097(15)61741-7

  View details for Web of Science ID 000375328802063

• PARADOXICAL ARTERIAL REMODELING OF THE PROXIMAL SEGMENT OF THE LEFT ANTERIOR DESCENDING ARTERY PREDICTS LONG-TERM MORTALITY AFTER HEART TRANSPLANTATION Okada, K., Kitahara, H., Yang, H., Tanaka, S., Kobayashi, Y., Luikart, H., Yock, P., Yeung, A., Fitzgerald, P., Khush, K., Honda, Y., Fearon, W. ELSEVIER SCIENCE INC. 2015: A1740

  View details for DOI 10.1016/S0735-1097(15)61740-5

  View details for Web of Science ID 000375328802062

• National decline in donor heart utilization with regional variability: 1995-2010. American journal of transplantation Khush, K. K., Zaroff, J. G., Nguyen, J., Menza, R., Goldstein, B. A. 2015; 15 (3): 642-649

  Abstract

  The severe shortage of donor hearts limits the availability of transplantation for the growing population of patients with end-stage heart disease. We examined national trends in donor heart acceptance for transplant. OPTN data were analyzed for all potential adult cardiac organ donors between 1995 and 2010. Donor heart disposition was categorized as transplanted, declined for transplant or other. We studied changes in the probability of donor heart acceptance according to demographic and clinical characteristics, nationwide and by UNOS region. Of 82 053 potential donor hearts, 34% were accepted and 48% were declined (18% used for other purposes). There was a significant decrease in donor heart acceptance from 44% in 1995 to 29% in 2006, and subsequent increase to 32% in 2010. Older donor age, female sex and medical co-morbidities predicted non-acceptance. Donor age and co-morbidities increased during the study period, with a concomitant decrease in acceptance of hearts from donors with undesirable characteristics. Overall, predictors of heart non-use were similar across UNOS regions, although utilization varied between regions. Regional variation suggests a potential to improve heart acceptance rates in under-performing regions, and supports research and policy efforts aimed at establishing evidence-based criteria for donor heart evaluation and acceptance for transplantation.

  View details for DOI 10.1111/ajt.13055

  View details for PubMedID 25676093

• Reliability of transthoracic echocardiogram interpretation in potential adult heart transplant donors JOURNAL OF HEART AND LUNG TRANSPLANTATION Khush, K. K., Nguyen, J., Goldstein, B. A., McGlothlin, D. P., Zaroff, J. G. 2015; 34 (2): 266–69

  View details for PubMedID 25434522

  View details for PubMedCentralID PMC4423611

• Reliability of echocardiographic measurements of left ventricular systolic function in potential pediatric heart transplant donors. journal of heart and lung transplantation Chen, S., Selamet Tierney, E. S., Khush, K. K., Nguyen, J., Goldstein, B. A., May, L. J., Hollander, S. A., Kaufman, B. D., Rosenthal, D. N. 2015; 34 (1): 100-106

  Abstract

  Echocardiogram reports, but not images, are usually available for the evaluation of potential donor hearts. To assess the reliability of local reports of potential pediatric heart donors, we compared echocardiographic measurements of left ventricular (LV) systolic function between local hospitals and a central echocardiography laboratory.We identified all potential donors aged <18 years managed by the California Transplant Donor Network from 2009 to 2013. Echocardiograms and reports were obtained from local hospitals. All studies were reviewed in a central laboratory by an experienced pediatric cardiologist blinded to local reports. Local and central measurements of fractional shortening (FS) were compared using the Bland-Altman method (mean difference ± 2 standard deviations). LV function was categorized based on FS as normal or mild, moderately, or severely depressed.There were 70 studies from 59 donors with local and central measurements of FS. The mean difference between local and central FS was 3.9 ± 9.0. The limits of agreement ranged from -14.2 to 22. Twenty-five studies had discordant measurements of LV function, with 17 discordant by 1 category and 8 by 2 or more categories. Of 55 studies categorized as normal by local measurement, 6 were moderately to severely depressed by central review. Of 15 studies categorized as depressed by local measurement, 3 were normal by central review.Local and central measurements of LV systolic function were discordant in 36% of studies. Given such discordance, efforts to obtain and view actual echocardiographic images should be part of the standard evaluation of potential pediatric heart donors.

  View details for DOI 10.1016/j.healun.2014.08.019

  View details for PubMedID 25307622

  View details for PubMedCentralID PMC4278954

• Appropriate Intravascular Ultrasound Measurement Intervals for Assessment of Cardiac Allograft Vasculopathy after Heart Transplantation Okada, K., Kitahara, H., Otagiri, K., Tanaka, S., Kobayashi, Y., Yock, P., Yeung, A., Fitzgerald, P. J., Valantine, H. A., Khush, K. K., Fearon, W. F., Honda, Y. ELSEVIER SCIENCE INC. 2014: B105

  View details for DOI 10.1016/j.jacc.2014.07.407

  View details for Web of Science ID 000359649700355

• Attenuated-Signal Plaque and Cardiac Allograft Vasculopathy: A Serial Volumetric IVUS Study of Heart Transplant Recipients Okada, K., Kitahara, H., Otagiri, K., Tanaka, S., Kobayashi, Y., Yock, P., Yeung, A., Fitzgerald, P., Valantine, H. A., Khush, K. K., Fearon, W. F., Honda, Y. ELSEVIER SCIENCE INC. 2014: B102

  View details for DOI 10.1016/j.jacc.2014.07.398

  View details for Web of Science ID 000359649700346

• Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection SCIENCE TRANSLATIONAL MEDICINE De Vlaminck, I., Valantine, H. A., Snyder, T. M., Strehl, C., Cohen, G., Luikart, H., Neff, N. F., Okamoto, J., Bernstein, D., Weisshaar, D., Quake, S. R., Khush, K. K. 2014; 6 (241)

  Abstract

  Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation. Circulating cell-free DNA was purified from plasma and sequenced (mean depth, 1.2 giga-base pairs) to quantify the fraction of cfdDNA. Through a comparison with endomyocardial biopsy results, we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation, with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself. This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk, discomfort, and expense of an invasive biopsy.

  View details for DOI 10.1126/scitranslmed.3007803

  View details for Web of Science ID 000338711700003

• VOLUMETRIC VERSUS PLANAR INTRAVASCULAR ULTRASOUND ANALYSIS TO ASSESS SEVERITY OF CARDIAC ALLOGRAFT VASCULOPATHY Okada, K., Kitahara, H., Otagiri, K., Tanaka, S., Kobayashi, Y., Yock, P., Yeung, A., Valantine, H., Khush, K., Fearon, W., Fitzgerald, P., Honda, Y. ELSEVIER SCIENCE INC. 2014: A1765

  View details for DOI 10.1016/S0735-1097(14)61768-X

  View details for Web of Science ID 000359579102523

• Identification of Common Blood Gene Signatures for the Diagnosis of Renal and Cardiac Acute Allograft Rejection PLOS ONE Li, L., Khush, K., Hsieh, S., Ying, L., Luikart, H., Sigdel, T., Roedder, S., Yang, A., Valantine, H., Sarwal, M. M. 2013; 8 (12)

  Abstract

  To test, whether 10 genes, diagnostic of renal allograft rejection in blood, are able to diagnose and predict cardiac allograft rejection, we analyzed 250 blood samples from heart transplant recipients with and without acute rejection (AR) and with cytomegalovirus (CMV) infection by QPCR. A QPCR-based logistic regression model was built on 5 of these 10 genes (AR threshold composite score>37% = AR) and tested for AR prediction in an independent set of 109 samples, where it correctly diagnosed AR with 89% accuracy, with no misclassifications for AR ISHLT grade 1b. CMV infection did not confound the AR score. The genes correctly diagnosed AR in a blood sample within 6 months prior to biopsy diagnosis with 80% sensitivity and untreated grade 1b AR episodes had persistently elevated scores until 6 months after biopsy diagnosis. The gene score was also correlated with presence or absence of cardiac allograft vasculopathy (CAV) irrespective of rejection grade. In conclusion, there is a common transcriptional axis of immunological trafficking in peripheral blood in both renal and cardiac organ transplant rejection, across a diverse recipient age range. A common gene signature, initially identified in the setting of renal transplant rejection, can be utilized serially after cardiac transplantation, to diagnose and predict biopsy confirmed acute heart transplant rejection.

  View details for DOI 10.1371/journal.pone.0082153

  View details for Web of Science ID 000328735700038

  View details for PubMedID 24358149

  View details for PubMedCentralID PMC3864873

• Temporal response of the human virome to immunosuppression and antiviral therapy. Cell De Vlaminck, I., Khush, K. K., Strehl, C., Kohli, B., Luikart, H., Neff, N. F., Okamoto, J., Snyder, T. M., Cornfield, D. N., Nicolls, M. R., Weill, D., Bernstein, D., Valantine, H. A., Quake, S. R. 2013; 155 (5): 1178-1187

  Abstract

  There are few substantive methods to measure the health of the immune system, and the connection between immune strength and the viral component of the microbiome is poorly understood. Organ transplant recipients are treated with posttransplant therapies that combine immunosuppressive and antiviral drugs, offering a window into the effects of immune modulation on the virome. We used sequencing of cell-free DNA in plasma to investigate drug-virome interactions in a cohort of organ transplant recipients (656 samples, 96 patients) and find that antivirals and immunosuppressants strongly affect the structure of the virome in plasma. We observe marked virome compositional dynamics at the onset of the therapy and find that the total viral load increases with immunosuppression, whereas the bacterial component of the microbiome remains largely unaffected. The data provide insight into the relationship between the human virome, the state of the immune system, and the effects of pharmacological treatment and offer a potential application of the virome state to predict immunocompetence.

  View details for DOI 10.1016/j.cell.2013.10.034

  View details for PubMedID 24267896

• Pregnancy-Related Human Leukocyte Antigen Sensitization Leading to Cardiac Allograft Vasculopathy and Graft Failure in a Heart Transplant Recipient: A Case Report TRANSPLANTATION PROCEEDINGS Ginwalla, M., Pando, M. J., Khush, K. K. 2013; 45 (2): 800-802

  Abstract

  In this report, we present a heart transplant recipient who developed cross-reactive paternal and donor-specific human leukocyte antigen (HLA) class II antibodies during pregnancy, leading to accelerated cardiac allograft vasculopathy and severe allograft dysfunction 17 years after transplantation. This resulted in acute heart failure and ventricular arrhythmias requiring repeat heart transplantation.

  View details for DOI 10.1016/j.transproceed.2012.10.038

  View details for Web of Science ID 000316772500058

  View details for PubMedID 23498823

• Donor Predictors of Allograft Use and Recipient Outcomes After Heart Transplantation CIRCULATION-HEART FAILURE Khush, K. K., Menza, R., John Nguyen, J., Zaroff, J. G., Goldstein, B. A. 2013; 6 (2): 300-309

  Abstract

  Despite a national organ-donor shortage and a growing population of patients with end-stage heart disease, the acceptance rate of donor hearts for transplantation is low. We sought to identify donor predictors of allograft nonuse, and to determine whether these predictors are in fact associated with adverse recipient post-transplant outcomes.We studied a cohort of 1872 potential organ donors managed by the California Transplant Donor Network from 2001 to 2008. Forty-five percent of available allografts were accepted for heart transplantation. Donor predictors of allograft nonuse included age >50 years, female sex, death attributable to cerebrovascular accident, hypertension, diabetes mellitus, a positive troponin assay, left-ventricular dysfunction and regional wall motion abnormalities, and left-ventricular hypertrophy. For hearts that were transplanted, only donor cause of death was associated with prolonged recipient hospitalization post-transplant, and only donor diabetes mellitus was predictive of increased recipient mortality.Whereas there are many donor predictors of allograft discard in the current era, these characteristics seem to have little effect on recipient outcomes when the hearts are transplanted. Our results suggest that more liberal use of cardiac allografts with relative contraindications may be warranted.

  View details for DOI 10.1161/CIRCHEARTFAILURE.112.000165

  View details for Web of Science ID 000331381200026

• Identification of common blood gene signatures for the diagnosis of renal and cardiac acute allograft rejection. PloS one Li, L., Khush, K., Hsieh, S., Ying, L., Luikart, H., Sigdel, T., Roedder, S., Yang, A., Valantine, H., Sarwal, M. M. 2013; 8 (12)

  Abstract

  To test, whether 10 genes, diagnostic of renal allograft rejection in blood, are able to diagnose and predict cardiac allograft rejection, we analyzed 250 blood samples from heart transplant recipients with and without acute rejection (AR) and with cytomegalovirus (CMV) infection by QPCR. A QPCR-based logistic regression model was built on 5 of these 10 genes (AR threshold composite score>37% = AR) and tested for AR prediction in an independent set of 109 samples, where it correctly diagnosed AR with 89% accuracy, with no misclassifications for AR ISHLT grade 1b. CMV infection did not confound the AR score. The genes correctly diagnosed AR in a blood sample within 6 months prior to biopsy diagnosis with 80% sensitivity and untreated grade 1b AR episodes had persistently elevated scores until 6 months after biopsy diagnosis. The gene score was also correlated with presence or absence of cardiac allograft vasculopathy (CAV) irrespective of rejection grade. In conclusion, there is a common transcriptional axis of immunological trafficking in peripheral blood in both renal and cardiac organ transplant rejection, across a diverse recipient age range. A common gene signature, initially identified in the setting of renal transplant rejection, can be utilized serially after cardiac transplantation, to diagnose and predict biopsy confirmed acute heart transplant rejection.

  View details for DOI 10.1371/journal.pone.0082153

  View details for PubMedID 24358149

• Beta-Adrenergic Receptor Polymorphisms and Cardiac Graft Function in Potential Organ Donors AMERICAN JOURNAL OF TRANSPLANTATION Khush, K. K., Pawlikowska, L., Menza, R. L., Goldstein, B. A., Hayden, V., Nguyen, J., Kim, H., Poon, A., Sapru, A., Matthay, M. A., Kwok, P. Y., Young, W. L., Baxter-Lowe, L. A., Zaroff, J. G. 2012; 12 (12): 3377-3386

  Abstract

  Prior studies have demonstrated associations between beta-adrenergic receptor (βAR) polymorphisms and left ventricular dysfunction-an important cause of allograft nonutilization for transplantation. We hypothesized that βAR polymorphisms predispose donor hearts to LV dysfunction after brain death. A total of 1043 organ donors managed from 2001-2006 were initially studied. The following βAR single nucleotide polymorphisms were genotyped: β1AR 1165C/G (Arg389Gly), β1AR 145A/G (Ser49Gly), β2AR 46G/A (Gly16Arg) and β2AR 79C/G (Gln27Glu). In multivariable regression analyses, the β2AR46 SNP was significantly associated with LV systolic dysfunction, with each minor allele additively decreasing the odds for LV ejection fraction <50%. The β1AR1165 and β2AR46 SNPs were associated with higher dopamine requirement during the donor management period: donors with the GG and AA genotypes had ORs of 2.64 (95% CI 1.52-4.57) and 2.70 (1.07-2.74) respectively for requiring >10 μg/kg/min of dopamine compared to those with the CC and GG genotypes. However, no significant associations were found between βAR SNPs and cardiac dysfunction in 364 donors managed from 2007-2008, perhaps due to changes in donor management, lack of power in this validation cohort, or the absence of a true association. βAR polymorphisms may be associated with cardiac dysfunction after brain death, but these relationships require further study in independent donor cohorts.

  View details for DOI 10.1111/j.1600-6143.2012.04266.x

  View details for Web of Science ID 000311854800022

  View details for PubMedID 22994654

  View details for PubMedCentralID PMC3513582

• The Development of De Novo Anti-hla Antibodies after Heart Transplant is Related to the Development of Rejection Depending of Their Complement Fixing Capability Farrero Torres, M., Rigal, M., Valantine, H., Smith, S. B., Khush, K. LIPPINCOTT WILLIAMS & WILKINS. 2012

  View details for Web of Science ID 000208885004042

• The 4G/4G Genotype of the PAI-1 (Serpine-1) 4G/5G Polymorphism Is Associated With Decreased Lung Allograft Utilization AMERICAN JOURNAL OF TRANSPLANTATION Sapru, A., Zaroff, J. G., Pawlikowska, L., Liu, K. D., Khush, K. K., Baxter-Lowe, L. A., Hayden, V., Menza, R. L., Convery, M., Lo, V., Poon, A., Kim, H., Young, W. L., Kukreja, J., Matthay, M. A. 2012; 12 (7): 1848-1854

  Abstract

  Widespread thrombi are found among donor lungs rejected for transplantation. The 4G/5G polymorphism in the plasminogen activator inhibitor (PAI-1) gene impacts transcription and the 4G allele is associated with increased PAI-1 levels. We hypothesized that the 4G/4G genotype would be associated with decreased lung graft utilization, potentially because of worse oxygenation in the donor. We genotyped donors managed by the California Transplant Donor Network from 2001 to 2008 for the 4G/5G polymorphism in the PAI-1 gene. Non-Hispanic donors from 2001 to 2005 defined the discovery cohort (n = 519), whereas donors from 2006 to 2008 defined the validation cohort (n = 369). We found, that the odds of successful lung utilization among Non-Hispanic white donors were lower among donors with the 4G/4G genotype compared to those without this genotype in both the discovery (OR = 0.55, 95% CI = 0.3-0.9, p = 0.02) and validation (OR = 0.5, 95% CI = 0.3-0.9, p = 0.03) cohorts. This relationship was independent of age, gender, cause of death, drug use and history of smoking. Donors with the 4G/4G genotype also had a lower PaO2/FiO2 ratio (p = 0.03) and fewer donors with the 4G/4G genotype achieved the threshold PaO2/FiO2 ratio ≥ 300 (p = 0.05). These findings suggest a role for impaired fibrinolysis resulting in worse gas exchange and decreased donor utilization.

  View details for DOI 10.1111/j.1600-6143.2012.03996.x

  View details for Web of Science ID 000305789400023

  View details for PubMedID 22390401

• Electrocardiographic Characteristics of Potential Organ Donors and Associations With Cardiac Allograft Use CIRCULATION-HEART FAILURE Khush, K. K., Menza, R., Nguyen, J., Goldstein, B. A., Zaroff, J. G., Drew, B. J. 2012; 5 (4): 475-483

  Abstract

  Current regulations require that all cardiac allograft offers for transplantation must include an interpreted 12-lead electrocardiogram (ECG). However, little is known about the expected ECG findings in potential organ donors or the clinical significance of any identified abnormalities in terms of cardiac allograft function and suitability for transplantation.A single experienced reviewer interpreted the first ECG obtained after brain stem herniation in 980 potential organ donors managed by the California Transplant Donor Network from 2002 to 2007. ECG abnormalities were summarized, and associations between specific ECG findings and cardiac allograft use for transplantation were studied. ECG abnormalities were present in 51% of all cases reviewed. The most common abnormalities included voltage criteria for left ventricular hypertrophy, prolongation of the corrected QT interval, and repolarization changes (ST/T wave abnormalities). Fifty-seven percent of potential cardiac allografts in this cohort were accepted for transplantation. Left ventricular hypertrophy on ECG was a strong predictor of allograft nonuse. No significant associations were seen among corrected QT interval prolongation, repolarization changes, and allograft use for transplantation after adjusting for donor clinical variables and echocardiographic findings.We have performed the first comprehensive study of ECG findings in potential donors for cardiac transplantation. Many of the common ECG abnormalities seen in organ donors may result from the heightened state of sympathetic activation that occurs after brain stem herniation and are not associated with allograft use for transplantation.

  View details for DOI 10.1161/CIRCHEARTFAILURE.112.968388

  View details for Web of Science ID 000313578100018

  View details for PubMedID 22615333

  View details for PubMedCentralID PMC3400714

• Relation of Improvement in Estimated Glomerular Filtration Rate With Atorvastatin to Reductions in Hospitalizations for Heart Failure (from the Treating to New Targets [TNT] Study) AMERICAN JOURNAL OF CARDIOLOGY Ho, J. E., Waters, D. D., Kean, A., Wilson, D. J., DeMicco, D. A., Breazna, A., Wun, C., Deedwania, P. C., Khush, K. K. 2012; 109 (12): 1761-1766

  Abstract

  Impaired kidney function often accompanies heart failure (HF) and is associated with a worse prognosis. This post hoc analysis of the Treating to New Targets (TNT) trial examined whether the observed decrease in HF hospitalizations with high- compared to low-dose atorvastatin could be related to improvements in kidney function. Of 10,001 TNT participants, 9,376 had estimated glomerular filtration rate (eGFR) measurements at baseline and 1 year and were included in this analysis. The association of change in year-1 eGFR and subsequent HF hospitalization was examined using Cox regression models. In total 218 participants developed subsequent HF hospitalization. Little change in eGFR occurred over 1 year in the atorvastatin 10-mg group, whereas eGFR improved in the 80-mg group by 1.48 ml/min/1.73 m(2) (95% confidence interval 1.29 to 1.67, p <0.0001). Subsequent HF was preceded by a decrease in eGFR over 1 year compared to modest improvement in those without subsequent HF (-0.09 ± 7.89 vs 0.81 ± 6.90 ml/min/1.73 m(2), p = 0.0015). After adjusting for baseline eGFR, each 5-ml/min/1.73 m(2) increase in eGFR at 1 year was associated with a lower risk of subsequent HF hospitalization (hazard ratio 0.85, 95% confidence interval 0.77 to 0.94, p = 0.002). This relation was independent of treatment effect or change in low-density lipoprotein cholesterol level at 1 year. In conclusion, treatment with high- compared to low-dose atorvastatin was associated with improvement in eGFR at 1 year, which was related to a decrease in subsequent HF hospitalization. This suggests that improvement in kidney function may be related to the beneficial effect of high-dose atorvastatin on HF hospitalization.

  View details for DOI 10.1016/j.amjcard.2012.02.019

  View details for Web of Science ID 000305729200014

  View details for PubMedID 22459310

• Influence of donor and recipient sex mismatch on heart transplant outcomes: Analysis of the International Society for Heart and Lung Transplantation Registry JOURNAL OF HEART AND LUNG TRANSPLANTATION Khush, K. K., Kubo, J. T., Desai, M. 2012; 31 (5): 459-466

  Abstract

  Prior studies have presented contradictory results after analyzing associations between donor and recipient sex on survival after heart transplantation and causes of death such as acute rejection (AR) and cardiac allograft vasculopathy (CAV). We used the International Society for Heart and Lung Transplantation (ISHLT) Registry, the largest repository of heart transplant outcomes worldwide, to comprehensively address these questions.We studied 60,584 adult recipients of heart transplants performed between 1990 and 2008. Outcomes of interest were overall survival, death-censored allograft survival, AR, and CAV, which were studied using regression models. To assess whether donor/recipient sex mismatch affected outcomes, the experience of male recipients with female vs male donors was compared with that of female recipients with female vs male donors through inclusion of an interaction term between donor and recipient sex.Significant differences were observed between male and female recipients in overall survival and death-censored allograft survival for female vs male donors. Male recipients of female allografts had a 10% increase in adjusted mortality relative to male recipients of male allografts, whereas female recipients of female allografts had a 10% decrease in adjusted mortality relative to female recipients of male allografts (p < 0.0001). Findings were similar for death-censored allograft survival. Differences in the effect of donor sex on AR or CAV between male and female recipients were not significant.Analysis of the ISHLT data set has demonstrated a strong association between donor/recipient sex mismatch and reduced survival after heart transplantation.

  View details for DOI 10.1016/j.healun.2012.02.005

  View details for Web of Science ID 000302756700005

  View details for PubMedID 22418079

  View details for PubMedCentralID PMC3322315

• Universal noninvasive detection of solid organ transplant rejection PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Snyder, T. M., Khush, K. K., Valantine, H. A., Quake, S. R. 2011; 108 (15): 6229-6234

  Abstract

  It is challenging to monitor the health of transplanted organs, particularly with respect to rejection by the host immune system. Because transplanted organs have genomes that are distinct from the recipient's genome, we used high throughput shotgun sequencing to develop a universal noninvasive approach to monitoring organ health. We analyzed cell-free DNA circulating in the blood of heart transplant recipients and observed significantly increased levels of cell-free DNA from the donor genome at times when an endomyocardial biopsy independently established the presence of acute cellular rejection in these heart transplant recipients. Our results demonstrate that cell-free DNA can be used to detect an organ-specific signature that correlates with rejection, and this measurement can be made on any combination of donor and recipient. This noninvasive test holds promise for replacing the endomyocardial biopsy in heart transplant recipients and may be applicable to other solid organ transplants.

  View details for DOI 10.1073/pnas.1013924108

  View details for Web of Science ID 000289413600060

  View details for PubMedID 21444804

  View details for PubMedCentralID PMC3076856

• Single-nucleotide polymorphisms in the beta-adrenergic receptor genes are associated with lung allograft utilization JOURNAL OF HEART AND LUNG TRANSPLANTATION Sapru, A., Pawlikowska, L., Liu, K. D., Khush, K. K., Ann-Baxter-Lowe, L., Hayden, V., Menza, R. L., Convery, M., Poon, A., Landeck, M., Zaroff, J. G., Matthay, M. A. 2011; 30 (2): 211-217

  Abstract

  Pulmonary edema and associated impaired oxygenation are a major reason for rejection of donor lung allografts offered for transplantation. Clearance of pulmonary edema can be upregulated by stimulation of β-adrenergic receptors (βARs). Single-nucleotide polymorphisms (SNPs) in βAR genes have functional effects in vitro and in vivo. We hypothesized that SNPs in βAR genes would be associated with rates of utilization of donor lung allografts offered for transplantation.Nine hundred fifty-one organ donors were genotyped for 4 amino-acid-coding SNPs in the βAR genes. Lung allograft utilization was compared among donors stratified by genotypes.Utilization of donor lung allografts was 55% vs 35% (p = 0.02) among donors with GG vs AA/AG genotypes of the Ser49Gly SNP, 39% vs 32% (p = 0.04) with GG vs AA/AG genotype of Gly16Arg SNP and 37% vs 32% (p = 0.1) with CC vs GC/GG genotype of the Arg389Gly SNP. In the combined analysis, donors carrying 0 or 1 associated genotype had a utilization rate of 33%, whereas donors carrying 2 or 3 associated genotypes had utilization rates of 44% and 58%, respectively (p = 0.008). There was a stepwise decrease in chest radiograph infiltrates and an increase in partial pressure of oxygen/fraction of inspired oxygen (PaO(2)/FIO(2)) with an increasing number of these associated genotypes.Genetic variants in the βAR genes among organ donors are associated with higher rates of lung allograft utilization. The increased utilization may be related to increased clearance of pulmonary edema and improved oxygenation in donors with favorable genotypes and suggests that βAR agonists may have a role in donor management.

  View details for DOI 10.1016/j.healun.2010.08.011

  View details for Web of Science ID 000286545200015

  View details for PubMedID 20869266

  View details for PubMedCentralID PMC3019270

• Differentially Expressed RNA from Public Microarray Data Identifies Serum Protein Biomarkers for Cross-Organ Transplant Rejection and Other Conditions PLOS COMPUTATIONAL BIOLOGY Chen, R., Sigdel, T. K., Li, L., Kambham, N., Dudley, J. T., Hsieh, S., Klassen, R. B., Chen, A., Caohuu, T., Morgan, A. A., Valantine, H. A., Khush, K. K., Sarwal, M. M., Butte, A. J. 2010; 6 (9)

  Abstract

  Serum proteins are routinely used to diagnose diseases, but are hard to find due to low sensitivity in screening the serum proteome. Public repositories of microarray data, such as the Gene Expression Omnibus (GEO), contain RNA expression profiles for more than 16,000 biological conditions, covering more than 30% of United States mortality. We hypothesized that genes coding for serum- and urine-detectable proteins, and showing differential expression of RNA in disease-damaged tissues would make ideal diagnostic protein biomarkers for those diseases. We showed that predicted protein biomarkers are significantly enriched for known diagnostic protein biomarkers in 22 diseases, with enrichment significantly higher in diseases for which at least three datasets are available. We then used this strategy to search for new biomarkers indicating acute rejection (AR) across different types of transplanted solid organs. We integrated three biopsy-based microarray studies of AR from pediatric renal, adult renal and adult cardiac transplantation and identified 45 genes upregulated in all three. From this set, we chose 10 proteins for serum ELISA assays in 39 renal transplant patients, and discovered three that were significantly higher in AR. Interestingly, all three proteins were also significantly higher during AR in the 63 cardiac transplant recipients studied. Our best marker, serum PECAM1, identified renal AR with 89% sensitivity and 75% specificity, and also showed increased expression in AR by immunohistochemistry in renal, hepatic and cardiac transplant biopsies. Our results demonstrate that integrating gene expression microarray measurements from disease samples and even publicly-available data sets can be a powerful, fast, and cost-effective strategy for the discovery of new diagnostic serum protein biomarkers.

  View details for DOI 10.1371/journal.pcbi.1000940

  View details for Web of Science ID 000282372600010

  View details for PubMedID 20885780

  View details for PubMedCentralID PMC2944782

• Effect of pulmonary hypertension on clinical outcomes in advanced heart failure: Analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) database AMERICAN HEART JOURNAL Khush, K. K., Tasissa, G., Butler, J., McGlothlin, D., De Marco, T. 2009; 157 (6): 1026-1034

  Abstract

  Pulmonary hypertension has been shown to predict hospitalizations and mortality in patients with heart failure. We aimed to define the prevalence of mixed pulmonary hypertension (MPH; mean pulmonary artery pressure > or = 25 mm Hg, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance > or = 3 Wood units), identify clinical predictors of MPH, and determine whether MPH predicts adverse outcomes in patients hospitalized with severe heart failure.This is a subgroup analysis of patients assigned to pulmonary artery catheter placement in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. Patients with and without MPH were compared with respect to baseline characteristics and clinical outcomes, including NYHA class, 6-minute walk distance, quality of life, days hospitalized, and 6-month mortality.Of the 171 patients studied, 80 (47%) had MPH. Older age was the only significant predictor of MPH. MPH patients had lower cardiac index (1.8 +/- 0.5 L/min vs 2.1 +/- 0.5 L/min, P = .001) and higher systemic vascular resistance index (3,179 +/- 1,454 vs 2,550 +/- 927 dynes x s/cm5 x m2, P < .001) compared to those without MPH. Importantly, right ventricular function was relatively preserved (median RVSWI 8.7 gm-m/m2/beat) in MPH patients. There were no significant differences in clinical outcomes between the two groups.Mixed pulmonary hypertension is common in patients hospitalized with advanced heart failure and is not associated with adverse short-term clinical outcomes over and above the poor prognosis of ADHF patients without MPH.

  View details for DOI 10.1016/j.ahj.2009.02.022

  View details for Web of Science ID 000266669500010

  View details for PubMedID 19464413

• New developments in immunosuppressive therapy for heart transplantation EXPERT OPINION ON EMERGING DRUGS Khush, K. K., Valantine, H. A. 2009; 14 (1): 1-21

  Abstract

  Heart transplantation is a well-established therapeutic option for many patients with end-stage heart disease. A major challenge in heart transplantation today is providing effective immunosuppression to prevent graft rejection while minimizing the many adverse effects of currently available therapies.To systematically review current immunosuppressive treatment strategies after heart transplantation and to review emerging drugs in various stages of development.A comprehensive literature review was performed using the online PubMed and Pharmaprojects databases.This article gives an overview of the immunosuppressive agents in current use, with a detailed review of emerging drugs with novel therapeutic targets.

  View details for DOI 10.1517/14728210902791605

  View details for Web of Science ID 000264685900001

  View details for PubMedID 19265486

• Thiazolidinediones in heart failure: Slippery when wet JOURNAL OF CARDIAC FAILURE Khush, K. K. 2008; 14 (6): 453–55

  View details for DOI 10.1016/j.cardfail.2008.04.002

  View details for Web of Science ID 000258564700002

  View details for PubMedID 18672191

• Association of African American race with elevated pulmonary artery Diastolic pressure: Data from the heart and soul study JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Kush, K. K., Shah, S. J., Ristow, B., De Marco, T., Whooley, M. A., Schiller, N. B. 2007; 20 (11): 1307-1313

  Abstract

  Whether increased severity of heart failure in African Americans is a result of differences in cardiac physiology is uncertain. The end-diastolic pulmonary regurgitation (EDPR) gradient is associated with abnormal cardiac physiology. We hypothesized that African American race is associated with an elevated EDPR gradient that may partially predispose African Americans to heart failure.The Heart and Soul Study prospectively assessed the EDPR gradient in 480 patients with coronary disease. We used multivariable linear regression to investigate the independent association of African American race with EDPR gradient.Compared with 393 non-African Americans, the 87 African Americans had similar indices of left ventricular systolic and diastolic function, left ventricular mass index, mitral regurgitation, peak tricuspid regurgitation gradient, and pulmonary velocity time integral. However, the EDPR gradient was significantly higher in African Americans (4.2 +/- 3.3 mm Hg) than in Caucasians (3.1 +/- 2.5 mm Hg) or other racial groups (3.5 +/- 2.7 mm Hg) (P = .008). In a multivariable model, African American race was a significant predictor of elevated EDPR gradient (beta coefficient 0.75, P = .03).African American race is independently associated with an elevated EDPR gradient in patients with coronary artery disease.

  View details for DOI 10.1016/j.ccho.2007.03.011

  View details for Web of Science ID 000251062300012

  View details for PubMedID 17588717

  View details for PubMedCentralID PMC2776673

• Donor cardiac troponin I levels do not predict recipient survival after cardiac transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Khush, K. K., Menza, R. L., Babcock, W. D., Zaroff, J. G. 2007; 26 (10): 1048-1053

  Abstract

  Serum levels of cardiac troponin I (cTnI) are frequently measured in the evaluation of potential heart donors. However, the utility of cTnI levels for predicting recipient outcomes remains controversial. This study was performed to determine whether donor cardiac cTnI levels exceeding 1.0 microg/liter are associated with adverse recipient outcomes.All donors managed by the California Transplant Donor Network between January 2001 and July 2002 with consent for donor evaluation and at least 1 measured cTnI level were included in the study if 1-year recipient mortality data were available. Each study subject was classified as having elevated cTnI if any level exceeded 1.0 microg/liter. Donor variables, recipient risk of 30-day and 1-year mortality, and recipient need for mechanical circulatory support were compared between the 2 groups.A total of 263 potential donors were evaluated, and 98 had elevated cTnI levels. Of these potential donors, 139 were accepted for transplantation. The cTnI levels were normal in 96 and elevated in 43. Most donors (77%) with elevated cTnI levels had levels of less than 10 microg/liter. Donor cardiopulmonary resuscitation was associated with cTnI elevations. Donors with elevated cTnI levels did not require higher doses of inotropic drugs before transplantation and had similar hemodynamic profiles compared with donors with normal cTnI levels. Although there was a trend towards longer post-transplant hospitalization in recipients of grafts from donors with elevated cTnI levels (17 days vs 15 days, p = 0.044), there was no significant difference in the recipient need for mechanical circulatory support or 30-day and 1-year mortality between the 2 groups.In this study, a modestly elevated donor cTnI was not associated with a higher risk of recipient mortality or need for post-transplant mechanical circulatory support. A potential donor heart should not be discarded solely because the troponin level is elevated.

  View details for DOI 10.1016/j.healun.2007.07.026

  View details for Web of Science ID 000250268900013

  View details for PubMedID 17919626

• Effect of high-dose atorvastatin on hospitalizations for heart failure - Subgroup analysis of the treating to new targets (TNT) study 78th Annual Scientific Session of the American-Heart-Association Khush, K. K., Waters, D. D., Bittner, V., Deedwania, P. C., Kastelein, J. J., Lewis, S. J., Wenger, N. K. LIPPINCOTT WILLIAMS & WILKINS. 2007: 576–83

  Abstract

  Statins reduce the rate of major cardiovascular events in high-risk patients, but their potential benefit as treatment for heart failure (HF) is less clear.Patients (n=10,001) with stable coronary disease were randomized to treatment with atorvastatin 80 or 10 mg/d and followed up for a median of 4.9 years. A history of HF was present in 7.8% of patients. A known ejection fraction <30% and advanced HF were exclusion criteria for the study. A predefined secondary end point of the study was hospitalization for HF. The incidence of hospitalization for HF was 2.4% in the 80-mg arm and 3.3% in the 10-mg arm (hazard ratio, 0.74; 95% confidence interval, 0.59 to 0.94; P=0.0116). The treatment effect of the higher dose was more marked in patients with a history of HF: 17.3% versus 10.6% in the 10- and 80-mg arms, respectively (hazard ratio, 0.59; 95% confidence interval, 0.4 to 0.88; P=0.009). Among patients without a history of HF, the rates of hospitalization for HF were much lower: 1.8% in the 80-mg group and 2.0% in the 10-mg group (hazard ratio, 0.87; 95% confidence interval, 0.64 to 1.16; P=0.34). Only one third of patients hospitalized for HF had evidence of preceding angina or myocardial infarction during the study period. Blood pressure was almost identical during follow-up in the treatment groups.Compared with a lower dose, intensive treatment with atorvastatin in patients with stable coronary disease significantly reduces hospitalizations for HF. In a post hoc analysis, this benefit was observed only in patients with a history of HF. The mechanism accounting for this benefit is unlikely to be due primarily to a reduction in interim coronary events or differences in blood pressure.

  View details for DOI 10.1161/CIRCULATIONAHA.106.625574

  View details for Web of Science ID 000244000800009

  View details for PubMedID 17261662

• Effects of statin therapy on the development and progression of heart failure: Mechanisms and clinical trials JOURNAL OF CARDIAC FAILURE Khush, K. K., Waters, D. D. 2006; 12 (8): 664-674

  Abstract

  Statin therapy has been shown to effectively lower low-density lipoprotein cholesterol levels and reduce cardiovascular events. Statins also appear to exert other favorable effects, including anti-inflammatory actions and improvement in endothelial function. Statin therapy may therefore yield important clinical benefits in patients with heart failure-a physiologic state characterized by systemic inflammation and endothelial dysfunction.This review summarizes basic and clinical investigations regarding the role of statin therapy in heart failure, focusing on potential mechanisms and preliminary clinical data. There is now extensive evidence suggesting that statins improve endothelial function, inhibit neurohormonal activation, restore autonomic balance, reduce inflammation, and prevent ventricular remodeling. Retrospective and small-scale prospective studies suggest that statins prevent the development of heart failure and reduce mortality in patients with established HF.Preliminary evidence supports a role for statins in improving surrogate markers and clinical outcomes in ischemic and nonischemic heart failure. Large-scale randomized clinical trials are needed to definitively address this important topic.

  View details for DOI 10.1016/j.cardfail.2006.05.003

  View details for Web of Science ID 000241534400013

  View details for PubMedID 17045188

• Nesiritide acutely increases pulmonary and systemic levels of nitric oxide in patients with pulmonary hypertension JOURNAL OF CARDIAC FAILURE Khush, K. K., De Marco, T., Vakharia, K. T., Harmon, C., Fineman, J. R., Chatterjee, K., Michaels, A. D. 2006; 12 (7): 507-513

  Abstract

  Pulmonary hypertension (PH) is characterized by decreased pulmonary vascular expression of nitric oxide (NOx), a vasodilator that increases levels of smooth muscle cyclic guanosine monophosphate (cGMP). This study investigated mechanisms by which the vasodilator B-type natriuretic peptide (BNP) affects the systemic and pulmonary vasculature in PH patients.Twenty PH patients with mean pulmonary artery (PA) pressure > 25 mm Hg were enrolled. Ten had precapillary (pulmonary capillary wedge pressure [PCWP] < or = 15 mm Hg) and 10 had postcapillary (PCWP > 15 mm Hg) PH. Right heart catheterization was performed before and 30 minutes after intravenous nesiritide infusion. NOx and cGMP levels from the PA and systemic (AO) arteries were obtained before and after nesiritide infusion. The postcapillary PH patients demonstrated significantly reduced pulmonary vascular resistance after nesiritide; there was no change in the precapillary PH cohort. NOx levels increased significantly in both AO (P < .0001) and PA (P = .0093), as did cGMP levels (P < .0001). There was a higher increase in NOx levels from the pulmonary arteries in precapillary PH patients compared to postcapillary PH patients (P = .020).In PH patients, nesiritide infusion significantly increases NOx levels, suggesting a novel mechanism for its vasodilatory effects. These responses may differ between pre- and postcapillary PH patients.

  View details for DOI 10.1016/j.cardfail.2006.05.004

  View details for Web of Science ID 000240708700003

  View details for PubMedID 16952783

• Obese patients have lower B-type and atrial natriuretic peptide levels compared with nonobese. Congestive heart failure (Greenwich, Conn.) Khush, K. K., Gerber, I. L., Mckeown, B., Marcus, G., Vessey, J., Foster, E., Chatterjee, K., Michaels, A. D. 2006; 12 (2): 85-90

  Abstract

  Obesity is a risk factor for the development of heart failure, but the causal mechanism remains unclear. Impaired production or enhanced clearance of natriuretic peptides, which regulate sodium balance and sympathetic activation, may play an important role. The authors investigated the relationship of plasma B-type natriuretic peptide and atrial natriuretic peptide levels to body mass index in 100 patients referred for left heart catheterization. Hemodynamic and echocardiographic data were obtained for all study participants. Atrial natriuretic peptide and B-type natriuretic peptide levels were compared in obese (body mass index > or = 30 kg/m2) and nonobese (body mass index < 30 kg/m2) subjects. Multivariate regression analyses were performed, adjusting for clinical and hemodynamic covariates. Obese patients had significantly lower B-type natriuretic peptide (p = 0.03) and atrial natriuretic peptide (p = 0.04) levels compared with nonobese. Multivariate analysis revealed lower B-type natriuretic peptide (p = 0.095) and atrial natriuretic peptide (p = 0.007) levels in obese patients while controlling for age, sex, left ventricular end-diastolic pressure, and left ventricular ejection fraction. Low levels of circulating natriuretic peptides are thus associated with obesity and may contribute to the development of heart failure.

  View details for PubMedID 16596042

• The history of the coronary care unit 58th Annual Meeting of the Canadian-Cardiovascular-Society Khush, K. K., Rapaport, E., Waters, D. PULSUS GROUP INC. 2005: 1041–45

  Abstract

  The first coronary care units were established in the early 1960s in an attempt to reduce mortality from acute myocardial infarction. Pioneering cardiologists recognized the threat of death due to malignant arrhythmias in the postinfarction setting, and developed techniques for successful external defibrillation. The ability to abort sudden death led to continuous monitoring of the cardiac rhythm and an organized system of cardiopulmonary resuscitation, incorporating external defibrillation with cardiac drugs and specialized equipment. Arrhythmia monitoring and cardiopulmonary resuscitation could be performed by trained nursing staff, which eliminated delays in treatment and significantly reduced mortality. These early triumphs in aborting sudden death led to the development of techniques to treat cardiogenic shock, limit infarct size and initiate prehospital coronary care, all of which laid the foundation for the current era of interventional cardiology.

  View details for Web of Science ID 000232871000009

  View details for PubMedID 16234887

• A full house: complications from an uncorrected patent ductus arteriosus. Current cardiology reports Khush, K. K., Randhawa, R., Israel, E. 2005; 7 (4): 310-313

  Abstract

  True aneurysms of the pulmonary artery are rare, and are most often due to pulmonary hypertension arising from congenital heart defects. We report the case of a 40-year-old man with an uncorrected patent ductus arteriosus who presented with pulmonary infarction and pneumonia, and subsequently died of cardiac arrest. Autopsy revealed a large pulmonary artery aneurysm, in situ pulmonary artery thrombosis complicated by pulmonary infarction, pulmonary artery dissection, and cardiac tamponade. Although each of these complications is rare in and of itself, this case demonstrates the entire spectrum of complications from a single uncorrected congenital cardiac anomaly.

  View details for PubMedID 15987630

• Age and aneurysm position predict patterns of left ventricular dysfunction after subarachnoid hemorrhage JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Khush, K., Kopelnik, A., Tung, P., Banki, N., Dae, M., Lawton, M., Smith, W., Drew, B., Foster, E., Zaroff, J. 2005; 18 (2): 168-174

  Abstract

  Cardiac injury, including left ventricular dysfunction, frequently occurs in patients with subarachnoid hemorrhage. Patterns of left ventricular dysfunction often do not follow coronary artery distributions, and may correlate with myocardial sympathetic innervation. Left ventricular dysfunction of the anterior and anteroseptal walls that spares the apex is unusual for patients with myocardial infarction and may represent a neurally mediated pattern of injury. We performed serial echocardiography on 225 patients with subarachnoid hemorrhage and classified those with regional wall-motion abnormalities as following either an apex-sparing (AS) or apex-affected (AA) pattern. Wall-motion abnormalities were found in 61 of 225 patients studied (27%). The AS pattern was found in 49% of these patients. Younger age and anterior aneurysm position were independent predictors of this AS pattern. Both patterns of wall-motion abnormalities appear to be transient, reversible phenomena. The AS pattern may represent a unique form of neurally mediated cardiac injury.

  View details for DOI 10.1016/j.echo.2004.08.045

  View details for Web of Science ID 000226972000011

  View details for PubMedID 15682055

• Lessons prom the PROVE-IT trial - Higher dose of potent statin better for high-risk patients CLEVELAND CLINIC JOURNAL OF MEDICINE Khush, K. K., Waters, D. 2004; 71 (8): 609-616

  Abstract

  The Pravastatin or Atorvastatin Evaluation and Infection Therapy trial (PROVE-IT/TIMI-22) showed that in patients with acute coronary syndromes, aggressive lipid-lowering using atorvastatin 80 mg/day provided greater protection against death or major cardiovascular events than did moderate lipid-lowering using pravastatin 40 mg/day. Lowering the low-density lipoprotein cholesterol level to approximately 62 mg/dL with atorvastatin resulted in a 16% reduction in cardiovascular end points.

  View details for Web of Science ID 000223379600003

  View details for PubMedID 15449756