Publications by authors named "Jon A Kobashigawa"

192 Publications

Long-term outcomes after heart transplantation using ex vivo allograft perfusion in standard risk donors: A single-center experience.

Clin Transplant 2022 Jan 14:e14591. Epub 2022 Jan 14.

Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Introduction: The Organ Care System (OCS) is an ex vivo perfusion platform for donor heart preservation. Short/mid-term post-transplant outcomes after its use are comparable to standard cold storage (CS). We evaluated long-term outcomes following its use.

Methods: Between 2011 and 2013, 38 patients from a single center were randomized as a part of the PROCEED II trial to receive allografts preserved with CS (n = 19) or OCS (n = 19). Endpoints included 8-year survival, survival free from graft-related deaths, freedom from cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), and rejections.

Results: Eight-year survival was 57.9% in the OCS group and 73.7% in the CS group (p = .24). Freedom from CAV was 89.5% in the OCS group and 67.8% in the CS group (p = .13). Freedom from NF-MACE was 89.5% in the OCS group and 67.5% in the CS group (p = .14). Eight-year survival free from graft-related death was equivalent between the two groups (84.2% vs. 84.2%, p = .93). No differences in rejection episodes were observed (all p > .5).

Conclusions: In select patients receiving OCS preserved allografts, late post-transplant survival trended lower than those transplanted with an allograft preserved with CS. This is based on a small single-center series, and larger numbers are needed to confirm these findings.
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http://dx.doi.org/10.1111/ctr.14591DOI Listing
January 2022

Heterogeneity of liver fibrosis in patients with congestive hepatopathy: A biopsy and explant comparison series.

Ann Diagn Pathol 2022 Feb 13;56:151876. Epub 2021 Dec 13.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.

Purpose: Patients with end-stage heart failure and concomitant irreversible liver injury may be candidates for combined heart liver transplant (CHLT). Determining appropriate candidates for CHLT is essential given organ scarcity. Transjugular liver biopsy (TJLB) is used to evaluate the severity of parenchymal liver injury in transplant candidates. In patients with congestive hepatopathy (CH), the fibrosis pattern may be heterogenous.

Methods: We reviewed all CHLT cases between 2007 and 2017, as well as lone-heart transplant cases with post-mortem autopsy. Pre-transplant TJLB was compared to explant to assess the performance of biopsy fibrosis staging.

Results: 12 patients were included. Median age at time of transplant was 58 and the cohort was predominantly male (75%). Seven (64%) TJLB were predominantly stage 4 fibrosis and 4 (36%) were stage 1. Advanced fibrosis was the dominant pattern in 7 (70%) explants and 5 (50%) explants had heterogenous fibrosis. In 50% of CH cases, there was discordance between the TJLB and explant. In the autopsy cases, the TJLB and autopsy findings differed.

Conclusions: In this series of matched TJLB and explanted livers, we found variable performance of TJLB in predicting the predominant fibrosis stage present in the liver.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151876DOI Listing
February 2022

Post-transplantation outcomes of sensitized patients receiving durable mechanical circulatory support.

J Heart Lung Transplant 2021 Nov 18. Epub 2021 Nov 18.

Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background: Sensitization, defined as the presence of circulating antibodies, presents challenges, particularly in patients undergoing heart transplantation (HTx) bridged with durable mechanical circulatory support (MCS). We aimed to investigate the post-transplantation outcomes of sensitized MCS patients.

Methods: Among 889 consecutively enrolled heart transplant (HTx) recipients between 2010 and 2018, 86 (9.7%) sensitized MCS patients (Group A) were compared with sensitized non-MCS patients (Group B, n = 189), non-sensitized MCS patients (Group C, n = 162), and non-sensitized non-MCS patients (Group D, n = 452) regarding post-HTx outcomes, including the incidence of primary graft dysfunction (PGD), 1-year survival, and 1-year freedom from antibody-mediated rejection (AMR).

Results: Sensitized MCS patients (Group A) showed comparable rates of PGD, 1-year survival, and 1-year freedom from AMR with Groups C and D. However, Group A showed significantly higher rates of 1-year freedom from AMR (95.3% vs 85.7%, p = 0.02) and an earlier decline in panel-reactive antibody (PRA) levels (p < 0.01) than sensitized non-MCS patients (Group B). Desensitization therapy effectively reduced the levels of PRA in both Groups A and B. When Group A was further divided according to the presence of preformed donor-specific antibodies (DSA), patients with preformed DSA showed significantly lower rates of 1-year freedom from AMR than those without (84.2% vs 98.5%, p = 0.01).

Conclusions: Sensitized MCS patients showed significantly lower rates of AMR and an earlier decline in PRA levels following HTx than sensitized non-MCS patients. Removal of MCS at the time of transplantation might underlie these observations.
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http://dx.doi.org/10.1016/j.healun.2021.11.010DOI Listing
November 2021

Proceedings from the metrics forum in heart transplantation for performance monitoring.

Am J Transplant 2021 Dec 6. Epub 2021 Dec 6.

University of Utah, Salt Lake City, Utah, USA.

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 posttransplant survival is still considered an appropriate and important measure to assess program performance. Waitlist mortality and offer acceptance rate as pretransplant 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.
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http://dx.doi.org/10.1111/ajt.16901DOI Listing
December 2021

The effects of donor-specific antibody characteristics on cardiac allograft vasculopathy.

Clin Transplant 2021 Dec 28;35(12):e14483. Epub 2021 Oct 28.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Background: Cardiac allograft vasculopathy (CAV) causes late graft dysfunction and post-transplant mortality. Currently, the effects of different donor-specific antibodies (DSA) on the severity of CAV remain unclear.

Method: We evaluated 526 adult heart transplant recipients at a single center between January 2010 and August 2015. Subjects were divided into those with DSA (n = 142) and those without DSA (n = 384, control). The DSA group was stratified into persistent DSA (n = 34), transient DSA (n = 105), 1:8 dilution DSA (n = 45), complement-binding (C1q) DSA (n = 36), Class I DSA (n = 37), and Class II DSA (n = 105). The primary outcome was the incidence of moderate-to-severe CAV (CAV 2/3) at 5-year follow-up.

Results: Subjects with persistent DSA, 1:8 dilution DSA, and C1q DSA had higher incidence of CAV 2/3 compared the control group (17.6%, 13.3%, and 16.7% vs. 3.1%, respectively; P≤ .001). The incidence of CAV 2/3 between subjects with transient DSA and the control group was similar (2.8% vs. 3.1%; P = .888). Subjects with Class II DSA also had higher incidence of CAV 2/3 (7.6% vs. 3.1%; P = .039).

Conclusion: DSA that are persistent, 1:8 dilution positive, C1q positive, and Class II are associated with more severe grades of CAV. These DSA characteristics may prognosticate disease and warrant consideration for treatment.
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http://dx.doi.org/10.1111/ctr.14483DOI Listing
December 2021

normothermic perfusion in heart transplantation: a review of the TransMedics Organ Care System.

Future Cardiol 2022 01 10;18(1):5-15. Epub 2021 Sep 10.

Cedars-Sinai Smidt Heart Institute, Los Angeles, CA 90048, USA.

Cardiac transplantation is the gold standard for treatment for select patients with end-stage heart failure, yet donor supply is limited. machine perfusion is an emerging technology capable of safely preserving organs and expanding the viable donor pool. The TransMedics Organ Care System™ is an investigational device which mimics physiologic conditions while maintaining the heart in a warm, beating state rather than cold storage. The use of Organ Care System allows increased opportunities for using organs from marginal donors, distant procurement sites, donation after cardiac death, and in recipients with complex anatomy. In the future, bioengineering technologies including use of mesenchymal stem cells, viral vector delivery of gene therapy, and alternate devices may further broaden the field of machine perfusion.
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http://dx.doi.org/10.2217/fca-2021-0030DOI Listing
January 2022

Eculizumab for antibody-mediated rejection in heart transplantation: A case-control study.

Clin Transplant 2021 Dec 23;35(12):e14454. Epub 2021 Sep 23.

Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Complement inhibition offers a novel treatment approach for antibody-mediated rejection (AMR). We examined patients with hemodynamic compromise AMR 2010-2020, comparing eight patients supplemented with eculizumab to 10 patients without; administration was at the treating physician's discretion. There were no significant differences between groups though eculizumab patients had a non-significantly higher inotrope score (208.8 mcg/kg/min vs. 2.6 mcg/kg/min; P = .22), more extracorporeal membrane oxygenation (ECMO) (62.5% vs. 20%; P = .066), and worse 1-year survival (37.5% vs. 60%; P = .63). The role of eculizumab is uncertain in AMR; multicenter collaborative studies are essential to better define its role.
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http://dx.doi.org/10.1111/ctr.14454DOI Listing
December 2021

Advanced heart failure and heart transplantation in adult congenital heart disease in the current era.

Clin Transplant 2021 Nov 12;35(11):e14451. Epub 2021 Sep 12.

Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Background: Adults with congenital heart disease (ACHD) may undergo heart transplantation (HTx) despite increased risk of poor short-term outcomes due to factors including surgical complexity and antibody sensitization. We assessed the clinical characteristics and outcomes of patients with ACHD in the current era referred for HTx at a single high-volume transplant center.

Methods: From 2010 to 2020, 37 ACHD patients were evaluated for HTx. ACHD HTx recipients were compared to non-ACHD HTx recipients matched for age, sex, listing status, and prior cardiac surgery.

Results: Of the 37 patients with ACHD, eight (21.6%) were declined for HTx. Of 29 ACHD patients listed, 19 (65.5%) underwent HTx. Compared with non-ACHD HTx controls, the ACHD HTx recipients had more treated cellular (21.1% vs. 15.8%, P = .010) and antibody-mediated (15.8% vs. 10.5%, P = .033) rejection. There was no difference in hospital readmission or allograft vasculopathy at 1 year. There was a nonsignificant higher 1-year mortality in ACHD HTx recipients (21.1% vs. 7.9%, P = .21).

Conclusion: At a high-volume transplant center, ACHD patients undergoing HTx appear to have a marginally higher risk of rejection, but no significant increase in 1-year mortality. With careful selection and management, HTx for patients with ACHD may be feasible in the current era.
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http://dx.doi.org/10.1111/ctr.14451DOI Listing
November 2021

Diagnostic Accuracy of Cardiovascular Magnetic Resonance for Cardiac Transplant Rejection: A Meta-Analysis.

JACC Cardiovasc Imaging 2021 Dec 14;14(12):2337-2349. Epub 2021 Jul 14.

Department of Imaging, Mark Taper Imaging Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. Electronic address:

Objectives: The aim of this meta-analysis was to assess the diagnostic performance of various CMR imaging parameters for evaluating acute cardiac transplant rejection.

Background: Endomyocardial biopsy is the current gold standard for detection of acute cardiac transplant rejection. Cardiac magnetic resonance (CMR) is uniquely capable of myocardial tissue characterization and may be useful as a noninvasive alternative for the diagnosis of graft rejection.

Methods: PubMed and Web of Science were searched for relevant publications reporting on the use of CMR myocardial tissue characterization for detection of acute cardiac transplant rejection with endomyocardial biopsy as the reference standard. Pooled sensitivity, specificity, and hierarchical modeling-based summary receiver-operating characteristic curves were calculated.

Results: Of 478 papers, 10 studies comprising 564 patients were included. The sensitivity and specificity for the detection of acute cardiac transplant rejection were 84.6 (95% CI: 65.6-94.0) and 70.1 (95% CI: 54.2-82.2) for T1, 86.5 (95% CI: 72.1-94.1) and 85.9 (95% CI: 65.2-94.6) for T2, 91.3 (95% CI: 63.9-98.4) and 67.6 (95% CI: 56.1-77.4) for extracellular volume fraction (ECV), and 50.1 (95% CI: 31.2-68.9) and 60.2 (95% CI: 36.7-79.7) for late gadolinium enhancement (LGE). The areas under the hierarchical modeling-based summary receiver-operating characteristic curve were 0.84 (95% CI: 0.81-0.87) for T1, 0.92 (95% CI: 0.89-94) for T2, 0.78 (95% CI: 0.74-0.81) for ECV, and 0.56 (95% CI: 0.51-0.60) for LGE. T2 values demonstrated the highest diagnostic accuracy, followed by native T1, ECV, and LGE (all P values <0.001 for T1, ECV, and LGE vs T2).

Conclusions: T2 mapping demonstrated higher diagnostic accuracy than other CMR techniques. Native T1 and ECV provide high diagnostic use but lower diagnostic accuracy compared with T2, which was related primarily to lower specificity. LGE showed poor diagnostic performance for detection of rejection.
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http://dx.doi.org/10.1016/j.jcmg.2021.05.008DOI Listing
December 2021

Development and validation of specific post-transplant risk scores according to the circulatory support status at transplant: A UNOS cohort analysis.

J Heart Lung Transplant 2021 10 24;40(10):1235-1246. Epub 2021 Jun 24.

Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background: The clinical use of post-transplant risk scores is limited by their poor statistical performance. We hypothesized that developing specific prognostic models for each type of circulatory support at transplant may improve risk stratification.

Methods: We analyzed the UNOS database including contemporary, first, non-combined heart transplantations (2013-2018). The endpoint was death or retransplantation during the first year post-transplant. Three different circulatory support statuses at transplant were considered: no support, durable mechanical support and temporary support (inotropes, temporary mechanical support). We generated 1,000 bootstrap samples that we randomly split into derivation and test sets. In each sample, we derived an overall model and 3 specific models (1 for each type of circulatory support) using Cox regressions, and compared, in the test set, their statistical performance for each type of circulatory support.

Results: A total of 13,729 patients were included; 1,220 patients (8.9%) met the composite endpoint. Circulatory support status at transplant was associated with important differences in baseline characteristics and distinct prognosis (p = 0.01), interacted significantly with important predictive variables included in the overall model, and had a major impact on post-transplant predictive models (type of variables included and their corresponding hazard ratios). However, specific models suffered from poor discriminative performance and significantly improved risk stratification (discrimination, reclassification indices, calibration) compared to overall models in a very limited proportion of bootstrap samples (<15%). These results were consistent across several sensitivity analyzes.

Conclusion: Circulatory support status at transplant reflected different disease states that influenced predictive models. However, developing specific models for each circulatory support status did not significantly improve risk stratification.
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http://dx.doi.org/10.1016/j.healun.2021.06.010DOI Listing
October 2021

Commentary: Mechanical bridge over troubled waters.

J Thorac Cardiovasc Surg 2021 Jun 29. Epub 2021 Jun 29.

Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, Calif. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.06.046DOI Listing
June 2021

Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant.

J Heart Lung Transplant 2021 09 10;40(9):970-980. Epub 2021 Jun 10.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Background: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). The International Society for Heart and Lung Transplantation (ISHLT) subdivides PGD into 3 grades of increasing severity. Most studies have assessed risk factors for PGD without distinguishing between PGD severity grade. We sought to identify recipient, donor and surgical risk factors specifically associated with mild/moderate or severe PGD.

Methods: We identified 734 heart transplant recipients at our institution transplanted between January 1, 2012 and December 31, 2018. PGD was defined according to modified ISHLT criteria. Recipient, donor and surgical variables were analyzed by multinomial logistic regression with mild/moderate or severe PGD as the response. Variables significant in single variable modeling were subject to multivariable analysis via penalized logistic regression.

Results: PGD occurred in 24% of the cohort (n = 178) of whom 6% (n = 44) had severe PGD. One-year survival was reduced in recipients with severe PGD but not in those with mild or moderate PGD. Multivariable analysis identified 3 recipient factors: prior cardiac surgery, recipient treatment with ACEI/ARB/ARNI plus MRA, recipient treatment with amiodarone plus beta-blocker, and 3 surgical factors: longer ischemic time, more red blood cell transfusions, and more platelet transfusions, that were associated with severe PGD. We developed a clinical risk score, ABCE, which provided acceptable discrimination and calibration for severe PGD.

Conclusions: Risk factors for mild/moderate PGD were largely distinct from those for severe PGD, suggesting a differing pathophysiology involving several biological pathways. Further research into mechanisms underlying the development of PGD is urgently needed.
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http://dx.doi.org/10.1016/j.healun.2021.06.002DOI Listing
September 2021

Clinical Utility of SPECT in the Heart Transplant Population: Analysis from a Single Large-Volume Center.

Transplantation 2021 Apr 21. Epub 2021 Apr 21.

Departments of Imaging and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Smidt Heart Institute, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA Department of Cardiac Sciences, University of Calgary, Calgary AB, Canada.

Background: Survival after heart transplant has greatly improved, with median survival now over 12 years. Cardiac allograft vasculopathy (CAV), has become a major source of long-term morbidity and mortality. Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is used for CAV surveillance, but there is limited data on its prognostic utility.

Methods: We retrospectively identified patients undergoing SPECT MPI for CAV surveillance at a single, large-volume center. Images were assessed with semi-quantitative visual scoring (summed stress score [SSS] and summed rest score [SRS]) and quantitatively with total perfusion defect (TPD).

Results: We studied 503 patients (mean age 62.5, 69.3% male) at a median of 9.0 years post-transplant. During mean follow-up of 5.1 ± 2.5 years, 114 (22.6%) patients died. The diagnostic accuracy for significant CAV (ISHLT grade 2 or 3) was highest for SSS with an area under the curve (AUC) of 0.650 and stress TPD (AUC 0.648), with no significant difference between SSS and stress TPD (p=0.061). Stress TPD (adjusted hazard ratio 1.07, p=0.018) was independently associated with all-cause mortality, while SSS was not (p=0.064). The prognostic accuracy of quantitative assessment of perfusion tended to be higher compared to semi-quantitative assessment, with the highest accuracy for stress TPD (area under the receiver operating curve 0.584).

Conclusions: While SPECT MPI identified a cohort of higher risk patients, with quantitative analysis of perfusion demonstrating higher prognostic accuracy. However, the overall prognostic accuracy was modest and alternative non-invasive modalities may be more suitable for CAV surveillance.
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http://dx.doi.org/10.1097/TP.0000000000003791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528902PMC
April 2021

Heart transplant in Jehovah's Witness patients: A case-control study.

J Heart Lung Transplant 2021 07 21;40(7):575-579. Epub 2021 Mar 21.

Cedars-Sinai Medical Center, the Department of Cardiology, Smidt Heart Institute, Cedars-Sinai, Los Angeles, California. Electronic address:

Heart transplantation (HTx) improves quality of life and survival in patients with advanced heart failure. Jehovah's Witnesses (JW) patients decline blood transfusion (including red cells, plasma and platelets) and are prohibited from heart transplantation at many centers. We report our experience with 20 consecutive JW patients with advanced heart failure who declined blood products referred to our center for HTx consideration. Of these, 7 were declined for transplant due to prior sternotomy, need for multi-organ transplant, or being too well. Of 13 JW patients accepted for heart transplant listing, 8 underwent HTx at our center. Compared to non-JW controls without prior cardiac surgery matched for age and listing status, JW HTx recipients had comparable incidence of primary graft dysfunction, rejection, allograft vasculopathy, and survival and hemoglobin up to 1 year. With appropriate selection, patients who are JW and decline blood products may successfully undergo heart transplantation.
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http://dx.doi.org/10.1016/j.healun.2021.03.014DOI Listing
July 2021

Intermediate-term outcomes of heart transplantation for cardiac amyloidosis in the current era.

Clin Transplant 2021 06 19;35(6):e14308. Epub 2021 Apr 19.

Smidt Cedars-Sinai Heart Institute, Los Angeles, CA, USA.

Background: Cardiac amyloidosis (CA) has been historically noted with poor outcomes after heart transplant (HTx). However, strict patient selection, appropriate multi-organ transplant, and aggressive post-transplant therapy can result in favorable outcomes. We present the experience in the largest single-center cohort of CA patients post-HTx in the recent era.

Methods: Between January 2010 and December 2018, 51 CA patients underwent HTx-13 light-chain amyloidosis (AL) and 38 transthyretin amyloidosis (ATTR), 49 were included. Endpoints included 3-year survival, freedom from cardiac allograft vasculopathy (CAV), and freedom from non-fatal major adverse cardiac events (NF-MACE).

Results: Overall 3-year survival was 81.6% (69.2% for AL and 86% for ATTR) and was comparable to survival for patients transplanted for non-amyloid restrictive cardiomyopathy (RCM) in the same period (89%, p = .46). Three-year freedom from CAV (84% vs. 89%, p = .98), NF-MACE (82% vs. 83%, p = .96), and any-treated rejection (95% vs. 89%, p = .54) were also comparable in both groups. No recurrence in amyloid was noted in endomyocardial biopsies. Six patients (46%) with AL amyloidosis underwent autologous stem cell transplant 1-year post-HTx, and two patients (8%) with variant ATTR-CA underwent combined heart-liver transplant due to cardiac cirrhosis.

Conclusion: In the current era, both AL and ATTR cardiac amyloidosis patients have acceptable outcomes after heart transplantation.
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http://dx.doi.org/10.1111/ctr.14308DOI Listing
June 2021

Total Artificial Heart as Bridge to Cardiac Retransplantation.

ASAIO J 2021 03;67(3):e77-e79

From the Department of Cardiology, Department of Cardiothoracic Surgery, Smidt Heart Institute at Cedars-Sinai, Los Angeles, California.

Mechanical circulatory support has been performed as a bridge to cardiac retransplantation in selected patients with graft failure. However, there is limited published experience on the use and potential benefit of the total artificial heart (TAH) as a bridge to cardiac retransplantation. We report on our institutional experience with 3 patients that received TAH as a bridge to retransplant, with 1 patient surviving post-retransplantation. This case series demonstrates the high-risk nature of this undertaking in cardiac retransplant candidates and highlights the issue of sensitization portending greater risk for poor outcomes after TAH as bridge to retransplantation.
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http://dx.doi.org/10.1097/MAT.0000000000001217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326319PMC
March 2021

The impact of depression on heart transplant outcomes: A retrospective single-center cohort study.

Clin Transplant 2021 03 5;35(3):e14204. Epub 2021 Jan 5.

Department of Cardiology, Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, CA, USA.

Background: Depression is prevalent in patients with heart failure and after heart transplant. We identified the prevalence of pre- and post-transplant depression and its association with clinical characteristics and post-transplant outcomes.

Methods: We reviewed 114 adults transplanted 1/1/2015 to 12/31/2015 and identified patients with pre- and post-transplant depression. Clinical characteristics and outcomes were compared.

Results: Of 114 patients, 35.1% had pre-transplant depression and 26.3% had post-transplant depression. Patients with post-transplant depression within the first year were significantly more likely to have acute rejection (10% vs 0%), longer intensive care unit (11.7 days vs 7.8 days) and hospital stay (31.7 days vs 16.3 days), and discharge to inpatient rehabilitation (26.7% vs 8.3%). Patients with post-transplant depression within the first year had significantly higher 5-year mortality (30% vs 9.5%, p = .009). However, after adjustment for total artificial heart/biventricular assist device, acute rejection, intensive care unit, and hospital length of stay, this relationship was no longer significant (HR 2.11; 95% CI 0.18-25.27; p = .556).

Conclusions: Depression is common among heart transplant candidates and recipients. While pre-transplant depression did not impact outcomes, patients with post-transplant depression were more likely to have had a complicated course, suggesting the need for increased vigilance regarding depression in such patients.
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http://dx.doi.org/10.1111/ctr.14204DOI Listing
March 2021

Response by Coutance et al to Letter Regarding Article, "Identification and Characterization of Trajectories of Cardiac Allograft Vasculopathy After Heart Transplantation: A Population-Based Study".

Circulation 2020 12 7;142(23):e409-e410. Epub 2020 Dec 7.

Université de Paris, Institut National de la Santé et de la Recherche Médicale, Paris Translational Research Centre for Organ Transplantation, France (G.C., M.R., A.L.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050849DOI Listing
December 2020

Impact of the United Network for organ sharing 2018 donor heart allocation system on transplant morbidity and mortality.

Clin Transplant 2021 02 15;35(2):e14181. Epub 2021 Jan 15.

Department of Cardiology, Smidt Heart Institute, Los Angeles, CA, USA.

Background: While the revised UNOS HTx donor allocation system aimed to minimize waitlist mortality by prioritizing more critically ill transplant candidates, there is concern for increased post-transplant morbidity and mortality. We examined the impact of the revised allocation system on waitlist and post-transplant outcomes at a high-volume transplant center.

Methods: One hundred and sixty nine adult patients underwent first-time single-organ HTx one year before (Era 1:79 patients) and after (Era 2:90 patients) implementation of the new allocation system (10/18/2018). Clinical characteristics, waitlist outcomes, and post-transplant morbidity and mortality were compared.

Results: Era 2 patients were twice as likely to be transplanted on temporary mechanical circulatory support (43% vs. 19%, p < .0001). While Era 2 waitlist time was shorter (10 vs. 43 days, p < .001), exception status requests (21.1% vs. 17.9%) and waitlist mortality (3.3% vs. 2.2%) were similar. There was no difference in primary graft dysfunction, intensive care unit or hospital length of stay, readmissions, rejection, allograft vasculopathy, or 1-year survival (91.1% vs. 93.7%).

Conclusions: In a high-volume center, the revised HTx allocation system shortened waitlist time with no significant change in waitlist mortality or observed impact on post-transplant outcomes. With careful patient selection, the revised allocation system may optimize waitlist and post-transplant outcomes.
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http://dx.doi.org/10.1111/ctr.14181DOI Listing
February 2021

Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients.

Am J Transplant 2021 07 11;21(7):2479-2488. Epub 2021 Feb 11.

Department of Cardiology, Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, California, USA.

Allosensitization represents a major barrier to heart transplantation (HTx). We assessed the efficacy and safety of complement inhibition at transplant in highly sensitized heart transplant recipients. We performed a single-center, single-arm, open-label trial (NCT02013037). Patients with panel reactive antibodies (PRA) ≥70% and pre-formed donor-specific antibodies (DSA) were eligible. In addition to standard of care, patients received nine infusions of eculizumab during the first 2 months posttransplant. The primary composite endpoint was antibody-mediated rejection (AMR) ≥pAMR2 and/or left ventricular dysfunction during the first year. Secondary endpoints included hemodynamic compromise, allograft rejection, and patient survival. Twenty patients were included. Median cPRA and mean fluorescence intensity of immunodominant DSA were 95% (90%-97%) and 6250 (5000-10 000), respectively. Retrospective B cell and T cell flow crossmatches were positive in 14 and 11 patients, respectively. The primary endpoint occurred in four patients (20%). Survival at 1 year was 90% with no deaths resulting from AMR. In a prespecified analysis comparing treated patients to matched control patients, we observed a dramatic reduction in the risk of biopsy-proven AMR in patients treated with eculizumab (HR = 0.36, 95% CI = 0.14-0.95, p = .032). Our findings support the prophylactic use of complement inhibition for heart transplantation at high immunological risk. ClinincalTrials.gov, NCT02013037.
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http://dx.doi.org/10.1111/ajt.16420DOI Listing
July 2021

Cocaine use in heart transplant donors: A call to expand the donor pool.

J Heart Lung Transplant 2020 12 24;39(12):1351-1352. Epub 2020 Sep 24.

Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

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http://dx.doi.org/10.1016/j.healun.2020.09.009DOI Listing
December 2020

Donor-specific antibodies in heart transplantation: can we afford the price or is it too steep to pay?

Curr Opin Organ Transplant 2020 12;25(6):555-562

Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Purpose Of Review: One-third of patients awaiting heart transplant are sensitized and 25-35% of heart allograft recipients develop de novo DSAs. Solid phase assays for DSA measurement have facilitated wider use of antibody monitoring and as such, our experience with DSAs is continuously evolving.

Recent Findings: DSAs continue to exhibit poor correlation with biopsy-proven rejection. Novel molecular technologies, such as cell-free DNA and the molecular microscope (MMDx, which detects rejection-associated intragraft mRNA transcripts), are emerging as more sensitive methods to capture subclinical graft injury. High-resolution typing techniques are providing insight into the differential immunogenicity of HLA classes through epitope and eplet analysis. As sensitization of the transplant population is continuing to rise, our repertoire of desensitization strategies is also expanding. However, there is an acute need of predictive algorithms to help forecast the responders and the durability of desensitization. Novel immunomodulatory therapies have allowed safely transplanting across a positive crossmatch with good short-term survival but reported greater degree of rejection and lower long-term graft survival.

Summary: Our experience of outcomes as pertaining to DSAs still originates primarily from single-center studies. Our field is confronted with the challenge to establish common practice algorithms for the monitoring and treatment of DSAs.
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http://dx.doi.org/10.1097/MOT.0000000000000818DOI Listing
December 2020

Association of vimentin antibody and other non-HLA antibodies with treated antibody mediated rejection in heart transplant recipients.

Hum Immunol 2020 Dec 9;81(12):671-674. Epub 2020 Oct 9.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

Non-human leukocyte antigen (HLA) antibodies have been implicated in heart transplantation rejection. However, targets of non-HLA antibodies remain elusive. Here, we utilized a panel of multiplex beads-based assay to determine the specificity of non-HLA antibodies following heart transplantation. We utilized a selected cohort of recipients who did not have HLA donor specific antibodies, but were diagnosed with antibody mediated rejection and treated for antibody mediated rejection. We found the presence of vimentin antibody was associated with treated antibody mediated rejection. Our results suggest that, in heart transplant recipients who are suspected of AMR but in the absence of HLA donor specific antibodies, non-HLA antibodies should be examined.
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http://dx.doi.org/10.1016/j.humimm.2020.09.003DOI Listing
December 2020

Commentary: The anticlimax of the left ventricular assist devices-associated antibodies.

J Thorac Cardiovasc Surg 2022 01 11;163(1):136-137. Epub 2020 Jul 11.

Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, Calif. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.06.090DOI Listing
January 2022

The Impact of a High-risk Psychosocial Assessment on Outcomes After Durable Mechanical Circulatory Support.

ASAIO J 2021 04;67(4):436-442

From the Department of Cardiology, Smidt Heart Institute, Cedars-Sinai, Los Angeles, CA.

Patient adherence is vital to the success of durable mechanical circulatory support (MCS), and the pre-MCS assessment of adherence by the multidisciplinary advanced heart failure team is a critical component of the evaluation. We assessed the impact of a high-risk psychosocial assessment before durable MCS implantations on post-MCS outcomes. Between January 2010 and April 2018, 319 patients underwent durable MCS at our center. We excluded those who died or were transplanted before discharge. The remaining 203 patients were grouped by pre-MCS psychosocial assessment: high-risk (26; 12.8%) versus acceptable risk (177; 87.2%). We compared clinical characteristics, nonadherence, and outcomes between groups. High-risk patients were younger (48 vs. 56; p = 0.006) and more often on extracorporeal membrane oxygenation at durable MCS placement (26.9% vs. 9.0%; p = 0.007). These patients had a higher incidence of post-MCS nonadherence including missed clinic appointments, incorrect medication administration, and use of alcohol and illicit drugs. After a mean follow-up of 15.3 months, 100% of high-risk patients had unplanned hospitalizations compared with 76.8% of acceptable-risk patients. Per year, high-risk patients had a median of 2.9 hospitalizations per year vs. 1.2 hospitalizations per year in acceptable-risk patients. While not significant, there were more driveline infections over the follow-up period in high-risk patients (27% vs. 14.7%), deaths (27% vs. 18%), and fewer heart transplants (53.8% vs. 63.8%).The pre-MCS psychosocial assessment is associated with post-MCS evidence of nonadherence and unplanned hospitalizations. Attention to pre-MCS assessment of psychosocial risk factors is essential to optimize durable MCS outcomes.
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http://dx.doi.org/10.1097/MAT.0000000000001229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100754PMC
April 2021

cBIN1 Score (CS) Identifies Ambulatory HFrEF Patients and Predicts Cardiovascular Events.

Front Physiol 2020 25;11:503. Epub 2020 May 25.

Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, United States.

Background: Cardiac Bridging Integrator 1 (cBIN1) is a membrane deformation protein that generates calcium microdomains at cardiomyocyte t-tubules, whose transcription is reduced in heart failure, and is released into blood. cBIN1 score (CS), an inverse index of plasma cBIN1, measures cellular myocardial remodeling. In patients with heart failure with preserved ejection fraction (HFpEF), CS diagnoses ambulatory heart failure and prognosticates hospitalization. The performance of CS has not been tested in patients with heart failure with reduced ejection fraction (HFrEF).

Methods And Results: CS was determined from plasma of patients recruited in a prospective study. Two comparative cohorts consisted of 158 ambulatory HFrEF patients (left ventricular ejection fraction (LVEF) ≤ 40%, 57 ± 10 years, 80% men) and 115 age and sex matched volunteers with no known history of HF. N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations were also analyzed for comparison. CS follows a normal distribution with a median of 0 in the controls, which increases to a median of 1.9 ( < 0.0001) in HFrEF patients. CS correlates with clinically assessed New York Heart Association Class ( = 0.007). During 1-year follow-up, a high CS (≥ 1.9) in patients predicts increased cardiovascular events (43% vs. 26%, = 0.01, hazard ratio 1.9). Compared to a model with demographics, clinical risk factors, and NT-proBNP, adding CS to the model improved the overall continuous net reclassification improvement (NRI 0.64; 95% CI 0.18-1.10; = 0.006). Although performance for diagnosis and prognosis was similar to CS, NT-proBNP did not prognosticate between patients whose NT-proBNP values were > 400 pg/ml.

Conclusion: CS, which is mechanistically distinct from NT-proBNP, successfully differentiates myocardial health between patients with HFrEF and matched controls. A high CS reflects advanced NYHA stage, pathologic cardiac muscle remodeling, and predicts 1-year risk of cardiovascular events in ambulatory HFrEF patients. CS is a marker of myocardial remodeling in HFrEF patients, independent of volume status.
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http://dx.doi.org/10.3389/fphys.2020.00503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326053PMC
May 2020

Heart transplantation in the era of the SARS-CoV-2 pandemic: Is it safe and feasible?

Clin Transplant 2020 10 24;34(10):e14029. Epub 2020 Jul 24.

Cedars-Sinai Smidt Heart Institute, Los Angeles, California, USA.

As the SARS-CoV-2-pandemic continues to unfold, the number of heart transplants completed in the United States has been declining steadily. The current case series examines the immediate short-term outcomes of seven heart transplant recipients transplanted during the SARS-CoV-2 pandemic. We hope to illustrate that with proper preparation, planning, and testing, heart transplantation can be continued during a pandemic. We assessed 7 patients transplanted from March 4, 2020, to April 15, 2020. The following endpoints were noted: in-hospital survival, in-hospital freedom from rejection, in-hospital nonfatal major cardiac adverse events (NF-MACE), severe primary graft dysfunction, hospital length of stay, and ICU length of stay. There were no expirations throughout the hospital admission. In addition, there were no patients with NF-MACE or treated rejection, and 1 patient developed severe primary graft dysfunction. Average length of stay was 17.2 days with a standard deviation of 5.9 days. ICU length of stay was 7.7 days with a standard deviation of 2.3 days. Despite the decreasing trend in completed heart transplants due to SARS-CoV-2, heart transplantation appears to be feasible in the immediate short term. Further follow-up is needed, however, to assess the impact of SARS-CoV-2 on post-heart transplant outcomes months after transplantation.
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http://dx.doi.org/10.1111/ctr.14029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361065PMC
October 2020

Stem cell donor HLA typing improves CPRA in kidney allocation.

Am J Transplant 2021 01 13;21(1):138-147. Epub 2020 Jul 13.

Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana, USA.

The Organ Procurement and Transplantation Network (OPTN) Kidney Allocation System provides a priority to sensitized candidates based on the calculated panel reactive antibody (CPRA) value. The human leukocyte antigen (HLA) haplotype reference panel used for calculation of the CPRA by the United Network for Organ Sharing (UNOS), the OPTN contractor, has limitations. We derived a novel panel from the National Marrow Donor Program HLA haplotype data set and compared the accuracy of CPRA values generated with this panel (NMDP-CPRA) to those generated from the UNOS panel (UNOS-CPRA), using predicted and actual deceased donor kidney offers for a cohort of 24 282 candidates. The overall accuracy for kidney offers was similar using NMDP-CPRA and UNOS-CPRA. Accuracy was slightly higher for NMDP-CPRA than UNOS-CPRA for candidates in several highly sensitized CPRA categories, with deviations in linkage disequilibrium for Caucasians and the smaller size of the UNOS panel as contributing factors. HLA data derived from stem cell donors yields CPRA values that are comparable to those derived from deceased kidney donors while improving upon several problems with the current reference panel. Consideration should be given to using stem cell donors as the reference panel for calculation of CPRA to improve equity in kidney transplant allocation.
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http://dx.doi.org/10.1111/ajt.16156DOI Listing
January 2021

Donor organ evaluation in the era of coronavirus disease 2019: A case of nosocomial infection.

J Heart Lung Transplant 2020 06 12;39(6):611-612. Epub 2020 Apr 12.

Smidt Cedars-Sinai Heart Institute, Los Angeles, California. Electronic address:

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http://dx.doi.org/10.1016/j.healun.2020.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152866PMC
June 2020

HLA-DQ mismatches stimulate de novo donor specific antibodies in heart transplant recipients.

Hum Immunol 2020 Jul 17;81(7):330-336. Epub 2020 Apr 17.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

The development of donor specific antibody is associated with graft rejection and increased mortality in solid organ transplant recipients. The majority of de novo donor specific antibodies (dnDSA) are against HLA-DQ antigens, but it has not been investigated if this is caused by more mismatches in the HLA-DQ locus between the recipient and donor. Here we examined the impact of HLA mismatches in eight HLA loci on the development of dnDSA and on rejection in a large cohort of heart transplant recipients. We evaluated HLA mismatches at the antigen level, the eplet level using HLAMatchmaker, and the epitope level using the PIRCHE algorithm. We found that the majority of dnDSA were against HLA-DQ antigens, and the number of dnDSA per mismatch is highest for HLA-DQ compared to other HLA loci. Furthermore, mismatches of HLA-DQ at the epitope level were associated with antibody-mediated rejection. Our results suggest that HLA mismatches at the HLA-DQ locus are more immunogenic than mismatches at other HLA loci to stimulate the development of dnDSA and to cause graft rejection.
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http://dx.doi.org/10.1016/j.humimm.2020.04.003DOI Listing
July 2020
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