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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.

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.

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.

Heart transplant recipients are susceptible to a number of complications in the immediate postoperative period. Despite advances in surgical techniques, mechanical circulatory support (MCS), and immunosuppression, evidence supporting optimal management strategies of the critically ill transplant patient is lacking on many fronts. This review identifies some of these controversies with the aim of stimulating further discussion and development into these gray areas.

Animal studies have demonstrated beneficial effects of therapeutic hypothermia on myocardial function, yet exact mechanisms remain unclear. Impaired autophagy leads to heart failure and mitophagy is important for mitigating ischemia/reperfusion injury. This study aims to investigate whether the beneficial effects of therapeutic hypothermia are due to preserved autophagy and mitophagy. Under general anesthesia, the left anterior descending coronary artery of 19 female farm pigs was occluded for 90 minutes with consecutive reperfusion. 30 minutes after reperfusion, we performed pericardial irrigation with warm or cold saline for 60 minutes. Myocardial tissue analysis was performed one and four weeks after infarction. Therapeutic hypothermia induced a significant increase in autophagic flux, mitophagy, mitochondrial mass and function in the myocardium after infarction. Cell stress, apoptosis, inflammation as well as fibrosis were reduced, with significant preservation of systolic and diastolic function four weeks post infarction. We found similar biochemical changes in human samples undergoing open chest surgery under hypothermic conditions when compared to the warm. These results suggest that autophagic flux and mitophagy are important mechanisms implicated in cardiomyocyte recovery after myocardial infarction under hypothermic conditions. New therapeutic strategies targeting these pathways directly could lead to improvements in prevention of heart failure.

Donor-recipient size match is traditionally assessed by body weight. We assessed the ability of 5 size match metrics-predicted heart mass (PHM), weight, height, body mass index (BMI) and body surface area (BSA)-to predict 1-year mortality after heart transplant and to assess the effect of size match on donor heart turn down for size.The study cohort comprised 19,168 adult heart transplant recipients in the United Network for Organ Sharing registry between 2007 and 2016. Each size match metric was divided into 7 equally sized groups using the donor-recipient ratio for each metric. Single and multivariable Cox proportional hazard models for mortality 1 year after transplant were constructed.Recipients in the severely (donor-recipient PHM ratio 0.54-0.86) undersized group for PHM experienced increased mortality, with a hazard ratio of 1.34 (95% confidence interval, 1.13-1.59; p0.001). There was no increased risk of death at 1 year if donors were undersized for weight, height, BMI, or BSA. We found that 32% of heart offers turned down for donor size would be acceptable using a PHM threshold of 0.86 or greater and that 14% of offers accepted (most of which are female donor to male recipient) were below this threshold.PHM is the optimal donor-recipient size match metric for prediction of mortality after heart transplant. Many offers turned down for donor size were above the threshold for adequacy of size match by PHM identified, and thus, the use of PHM could improve donor heart utilization and post-transplant survival.

BACKGROUND We sought to better understand the patient population who receive a temporary total artificial heart (TAH) as bridge to transplant or as bridge to decision by evaluating data from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database. METHODS We examined data related to survival, adverse events, and competing outcomes from patients who received TAHs between June 2006 and April 2017 and used hazard function analysis to explore risk factors for mortality. RESULTS Data from 450 patients (87% men; mean age, 50 years) were available in the INTERMACS database. The 2 most common diagnoses were dilated cardiomyopathy (50%) and ischemic cardiomyopathy (20%). Risk factors for right heart failure were present in 82% of patients. Most patients were INTERMACS Profile 1 (43%) or 2 (37%) at implantation. There were 266 patients who eventually underwent transplantation, and 162 died. Overall 3-, 6-, and 12-month actuarial survival rates were 73%, 62%, and 53%, respectively. Risk factors for death included older age (p = 0.001), need for pre-implantation dialysis (p = 0.006), higher creatinine (p = 0.008) and lower albumin (p < 0.001) levels, and implantation at a low-volume center (≤10 TAHs; p < 0.001). Competing-outcomes analysis showed 71% of patients in high-volume centers were alive on the device or had undergone transplantation at 12 months after TAH implantation vs 57% in low-volume centers (p = 0.003). CONCLUSIONS Patients receiving TAHs have rapidly declining cardiac function and require prompt intervention. Experienced centers have better outcomes, likely related to patient selection, timing of implantation, patient care, and device management. Organized transfer of knowledge to low-volume centers could improve outcomes.

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.

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.

Background Mechanical circulatory support device (MCSD) patients with positive heparin-induced thrombocytopenia (HIT) screening pose a unique challenge, as clinicians must make rapid decisions about their anticoagulation and whether they can safely undergo cardiopulmonary bypass . We identified screening practices at our institution and other institutions nationwide that differed from American Society of Hematology (ASH) guidelines. This discovery prompted a data review to confirm the applicability of guidelines to this unique population and to highlight complications of "gestalt" screening. Methods Our study included MCSD patients with HIT testing from April 2014 to August 2020. We evaluated 510 PF4 IgG ELISA results. Results HIT was confirmed in 4.2% of patients. There was an increased prevalence of HIT in patients with nondurable (5.3%) vs durable devices (2.9%) or those in the preimplantation setting (1.3%), however this difference was not statistically significant (p = 0.26). None of the patients with a low probability 4T Score had HIT. All patients with a high probability 4T Score and PF4 immunoassay OD >2.0 had HIT. False positive results occurred in 22% of assays ordered for patients with a low probability 4T Score. Twelve patients with a low probability 4T Score and a false positive immunoassay were switched to a direct thrombin inhibitor (DTI) while awaiting confirmatory results. Two patients experienced clinically significant bleeding after conversion to a DTI. An organ was refused in one patient with false positive HIT screening. Conclusions Our findings demonstrate that an opportunity exists to improve clinical outcomes by re-emphasizing the utility of established guidelines and highlighting their safe use in the MCSD patient population.

Hypothermia is a valuable clinical tool in mitigating against the consequences of ischemia in surgery, stroke, cardiac arrest and organ preservation. Protection is afforded principally by a reduction of metabolism, manifesting as reduced rates of oxygen uptake, preservation of ATP levels, and a curtailing of ischemic calcium overload. The effects of non-ischemic hypothermic stress are relatively unknown. We sought to investigate the effects of clinically mild-to-severe hypothermia on mitochondrial morphology, oxygen consumption and protein expression in normoxic hearts and cardiac cells. Normoxic perfusion of rat hearts at 28–32 °C was associated with inhibition of mitochondrial fission, evidenced by a reduced abundance of the active phosphorylated form of the fission receptor Drp1 (pDrp1S616). Abundance of the same residue was reduced in H9c2 cells subjected to hypothermic culture (25–32 °C), in addition to a reduced abundance of the Drp1 receptor MFF. Hypothermia-treated H9c2 cardiomyocytes exhibited elongated mitochondria and depressed rates of mitochondrial-associated oxygen consumption, which persisted upon rewarming. Hypothermia also promoted a reduction in mRNA expression of the capsaicin receptor TRPV1 in H9c2 cells. When normothermic H9c2 cells were transfected with TRPV1 siRNA we observed reduced pDrp1S616 and MFF abundance, elongated mitochondria, and reduced rates of mitochondrial-associated oxygen consumption, mimicking the effects of hypothermic culture. In conclusion hypothermia promoted elongation of cardiac mitochondria via reduced pDrp1S616 abundance which was also associated with suppression of cellular oxygen consumption. Silencing of TRPV1 in H9c2 cardiomyocytes reproduced the morphological and respirometric phenotype of hypothermia. This report demonstrates a novel mechanism of cold-induced inhibition of mitochondrial fission.

Introduction: Antibody-mediated rejection (AMR) continues to be a major barrier to favorable long-term outcomes and long-term survival. Sensitized pre-heart transplant (HTx) patients, those with anti-HLA antibodies, have previously demonstrated increased post-HTx rejection risk as well as increased mortality. In the current era, there is contention as to whether pre-HTx antibodies result in poor outcome after HTx. Methods: Between 2010 and 2015, 580 HTx patients were assessed for pre-HTx panel reactive antibodies (PRA). PRA levels were measured by the Luminex Single Antigen assay. Patients were divided into 5 groups of PRA levels including 0%, n=423 (Control); PRA 1-10%, n= 21; PRA 11-25%, n=24; PRA 26-50%, n=49; PRA 51-75%, n=32; and PRA >75%, n=35. Endpoints included 5-year survival, freedom from cardiac allograft vasculopathy (CAV), freedom from non-fatal major adverse cardiac events (NF-MACE), freedom from donor specific antibody (DSA) development, and freedom from LV dysfunction (LV ejection fraction ≤40%) and 1-year freedom from rejection (any treated rejection (ATR), acute cellular rejection (ACR), AMR). Results: All groups with PRA >10% had significantly lower 1-year freedom from AMR and 5-year freedom from DSA compared to the control, worsening with higher the PRA group. There was no significant difference in 5-year survival, 5-year freedom from CAV, NF-MACE, or LV dysfunction and 1-year freedom from ATR or ACR. Conclusions: Patients with increased anti-HLA antibody levels pre-HTx do not appear to have lower 5-year survival compared to patients without anti-HLA antibody levels. However, the development of 1-year AMR and 5-year DSA increased progressively with higher the PRA group. Further studies and longer follow-up are needed to better understand the effects of elevated pre-HTx PRA, immune therapies (desensitization) and post-HTx outcomes.

Introduction: Highly sensitized patients awaiting heart transplantation (HTx) are disadvantaged by a narrow donor pool due to incompatible potential donors. Desensitization therapy has been demonstrated to be effective in lowering antibodies and thereby enlarging the donor pool. By desensitization, the calculated panel reactive antibody (cPRA) has been reported to decrease and result in a shorter waitlist time. It has not been established whether desensitization before transplant can have impact after HTx outcomes. Methods: Between 2010 and 2015, we assessed 34 patients awaiting HTx who had a PRA >50% and underwent desensitization therapy. Desensitization therapy included combinations of IVIG, rituximab, plasmapheresis, and bortezomib. These patients who underwent HTx were then assessed for outcomes, which included 5-year survival, freedom from cardiac allograft vasculopathy (CAV), freedom from non-fatal major adverse cardiac events (NF-MACE), and freedom from donor specific antibody (DSA) development and 1-year freedom from rejection (any treated rejection (ATR), acute cellular rejection (ACR), antibody mediated rejection (AMR)). Patients who underwent desensitization were compared to a similar group of patients with PRA >50% who did not undergo desensitization and underwent HTx. Results: Patients who underwent desensitization compared to those who did not had significantly greater freedom from 5-year development of CAV (94.1 vs 78.8%, p=0.039). There was no significant difference in 5-year survival, 5-year freedom from NF-MACE or DSA development, and 1-year freedom from ATR, ACR, AMR. Conclusions: Desensitization in highly sensitized patients awaiting HTx appears to have long ranging effects to modulate the immune system after HTx, resulting in less development of CAV. Further investigation should be pursued to understand the mechanism of this intervention.

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 7 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 non‐fatal 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.

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.

Background Severe Acute Respiratory Syndrome caused by coronavirus 2 (SARS-CoV-2) is characterized by an overwhelming cytokine response. Various treatment strategies have been attempted. Methods and Results A 61-year-old male with heart transplantation in 2017 presented with fever, cough, and dyspnea, and confirmed positive for the SARS-CoV-2 disease (COVID-19). Laboratory tests showed significant elevations in C-reactive protein and interleukin-6 (IL-6). Echocardiogram showed LVEF 58% (with EF 57% 6 months prior). Given the lack of clear management guidelines, the patient was initially managed symptomatically. However, the patient subsequently had a rapid respiratory deterioration with worsening inflammatory markers on day 5 of admission. Tocilizumab (anti-IL-6R) was in low supply in the hospital. The patient was offered clazakizumab (anti-IL-6) for compassionate use. Patient received 25 mg intravenously x1 dose. Within 24 hours, he noted significant improvement in symptoms, oxygen requirements, radiological findings and inflammatory markers. There was a transient leukopenia which improved in 4 days. He was discharged home on day 11, with negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, development of positive serum COVID-19 IgG antibody, and he continued to do well on day 60, with no heart-related symptoms. Conclusion Clazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19. Although not yet FDA approved, it is being investigated for treatment of renal antibody-mediated rejection. Clinical trials of clazakizumab for treatment of COVID-19 are underway worldwide., Highlights • Severe Acute Respiratory Syndrome caused by coronavirus 2 (SARS-CoV-2) is characterized by an overwhelming cytokine response. • A 61-year-old male with heart transplantation in 2017 presented with fever, cough, and dyspnea, and confirmed positive for the SARS-CoV-2 disease (COVID-19). Laboratory tests showed significant elevations in C-reactive protein, interleukin-6 (IL-6), and other inflammatory markers. Echocardiogram showed normal LV function. • The patient received clazakizumab (anti-IL-6 monoclonal antibody) 25 mg as a single dose, with significant improvement in symptoms, oxygen requirements, radiological findings and inflammatory markers within 24 hours, and discharge to home on day 11. He had a negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, developed a positive serum COVID-19 IgG antibody, and was continuing to do well clinically on day 60. • Clazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19.

Background Giant cell myocarditis (GCM) has a poor prognosis without heart transplant, but post-transplant survival is unknown. Purpose To describe the post-transplant survival of patients with GCM at a large transplant center. Methods Seven patients underwent heart transplant for histologically confirmed GCM of the explanted heart. The median age was 59 years, and 43% (3 of 7) were female. All patients had cardiogenic shock, multiorgan failure, elevated troponin, and recurrent ventricular tachycardia, and some required mechanical circulatory support. All patients received rabbit antithymocyte globulin (rATG) in the perioperative period at a dose of 1.5 mg/kg daily for 1 to 5 days and 4 received intravenous immunoglobulin 1 g/kg daily for 2 days after rATG. All patients had early initiation of tacrolimus by first to third postoperative day depending on renal function, early mycophenolate, and high dose steroid. All were maintained using tacrolimus, mycophenolate, and prednisone. Results One patient had asymptomatic recurrence of GCM at 3 months, managed by up-titration of tacrolimus, and had asymptomatic 2R cellular rejection at 4 months, managed with steroid bolus. No patient had high-grade rejection. One patient died at 267 days, possibly of GCM. Six of 7 (86%) remain alive at a median of 842 days (2.3 years) post transplant. Conclusions Patients with GCM have excellent post-transplant survival with use of rATG and triple drug immunosuppressive therapy; however, some patients remain at risk for GCM recurrence after transplant, which may respond to augmented immunosuppression.

BackgroundCardiac 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 ResultsCS 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 (p < 0.0001) in HFrEF patients. CS correlates with clinically assessed New York Heart Association Class (p = 0.007). During 1-year follow-up, a high CS (≥ 1.9) in patients predicts increased cardiovascular events (43% vs. 26%, p = 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; p = 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.ConclusionCS, 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.

Temporary mechanical circulatory support (MCS) devices are generally used short term to maintain adequate organ perfusion in patients with advanced heart failure and cardiogenic shock. Unacceptably high waitlist mortality in this cohort motivated changes to heart allocation policy, which recognized the severity of illness by prioritization for temporary MCS and broader sharing in the new U.S. donor heart allocation policy. We evaluated the post-heart transplant outcomes for patients bridged with temporary MCS, a control population not bridged with MCS, and a cohort bridged with durable MCS.The heart transplant research database was queried to identify patients bridged with temporary MCS and bridged with durable MCS who went directly to heart transplant in our center. Temporary MCS included Impella, intra-aortic balloon pump, and extracorporeal membrane oxygenation. Post-transplant endpoints were assessed at 30 days, 6 months, and 1 year.From 2010 to 2017, a total of 23 patients were bridged to heart transplant with temporary MCS and 548 were transplanted without MCS bridge. Patients bridged with temporary MCS had younger age, lower body mass index, and higher frequencies of prior blood transfusion and Status 1 (1A/1B) listing at transplant compared to patients not bridged with MCS (all P .001). Despite the severity of illness in patients bridged with temporary MCS, post-transplant outcomes were indistinguishable from those in patients transplanted without MCS bridge, with no difference in 30-day, 6-month, or 1-year survival or 1-year freedom from cardiac allograft vasculopathy, nonfatal major adverse cardiac events, any-treated rejection, acute cellular rejection, or antibody-mediated rejection (P = .23-.97). Similarly, compared to 157 patients bridged with durable MCS, no differences in post-transplant outcomes were identified for the temporary MCS cohort (P = .15-.94).Temporary MCS as a bridge to transplant achieves similar post-transplant outcomes at 1 year compared to no MCS and durable MCS. These encouraging findings support recent changes in the Organ Procurement and Transplantation Network | United Network Organ Sharing (OPTN|UNOS) adult heart allocation policy.

Objectives Combined heart-kidney transplantation has successful outcomes. With an increasing number of patients with end-stage heart disease, there is a high incidence of significant renal insufficiency that may necessitate combined heart-kidney transplant. Outcomes for heart-kidney transplant recipients aged ≥65 years are not well described. Methods Between 2010 and 2015, 163 recipients ≥65 years of age were transplanted in a single centre: 12 heart-kidney and 151 isolated heart transplants. Outcomes assessed were estimated glomerular filtration rate at 1, 6 and 12 months after transplant, the need for dialysis, 1-year survival, 1-year freedom from rejection, 1-year freedom from cardiac allograft vasculopathy and 1-year freedom from non-fatal major adverse cardiac events. Results Recipient ages were 67.8 ± 1.6 and 69.0 ± 2.8 years for heart-kidney transplant and isolated heart transplant, and pretransplant estimated glomerular filtration rates were 26.6 ± 9.4 vs 55.2 ± 18.9, respectively. At 1 month (66.3 ± 31.4 vs 67.2 ± 28.0, P = 0.92), 6 months (68.1 ± 21.3 vs 60.5 ± 19.6, P = 0.20) and 12 months (58.6 ± 21.5 vs 52.4 ± 18.5, P = 0.27) post-transplant, estimated glomerular filtration rate was similar for heart-kidney transplant versus isolated heart transplant. There was a trend towards reduced 1-year freedom from temporary dialysis after heart-kidney transplant relative to isolated heart transplant (75.0% vs 90.4%, P = 0.06) without a difference in 1-year freedom from chronic dialysis (100% vs 95.2%, P = 0.46). There were no differences in 1-year survival, 1-year freedom from any treated rejection, acute cellular rejection, antibody-mediated rejection, cardiac allograft vasculopathy and non-fatal major adverse cardiac events. Conclusions For patients ≥65 years old, heart-kidney transplant can achieve outcomes on par with heart transplant alone.

Purpose Monotherapy with tacrolimus alone (TAC-A) was found to be safe and effective in the TICTAC Trial. However, in that trial, tacrolimus levels were maintained at 10-12 ng/mL over the first year which resulted in a higher serum creatinine level compared to those left in combination. We have been using TAC-A at lower doses in patients who have developed leukopenia or thrombocytopenia due to immunosuppression or a natural state. The presence of cytomegalovirus infections and other viruses excluded those patients from being administered monotherapy. It has not been established whether low dose TAC-A is safe and effective. Methods Between 2010 and 2017 we assessed 151 heart transplant patients who are maintained on monotherapy with TAC-A. Patients were maintained on a low level of TAC-A between 4-7 ng/ml. These patients were assessed for subsequent 1-year rejection, subsequent 3-year survival, 3-year freedom from non-fatal major adverse cardiac events (NF-MACE: MI, new CHF, PCI, ICD implant, stroke), cardiac allograft vasculopathy (CAV, epicardial disease with angiographic stenosis>30%), and cardiac dysfunction (LVEF ≤ 40%). Furthermore, periodic testing was done with the T-cell immune function test to assess whether these patients were adequately immunosuppressed. Results Patients who were maintained on TAC-A had comparable outcomes compared to patients left in combination immunosuppression (see table). The T-cell immune function test showed that these patients had adequate immunosuppression (average was 276 ng/mL with a range of 56-794 ng/mL and standard deviation of 137.1 ng/mL) with the therapeutic range being 200-550ng/ml. Patients had an average of 11 Tacrolimus lab tests (range: 4-46). Conclusion Low dose TAC-A appears safe and effective in select patients after heart transplantation guided by T cell immune function testing. Further studies with larger number of patients will be needed to confirm these findings.

Purpose Hypertension after heart transplantation (HTx) is noted in a majority of HTx patients due to the side effects of calcineurin inhibitors (CNI). The use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) are effective anti-hypertensive agents and may have longer term clinical benefits. We assessed our patients on ACEI/ARBs versus others in the first year post-HTx and followed them for 5-year outcomes. Methods Between 2010 and 2015, we assessed 101 HTx patients who were on ACEI/ARBs only in the first year for more than 6 months. Those patients were then followed for 5 years. Likewise, a group of patients who were placed on non-ACEI/ARBs blood pressure medications, such as calcium channel-blockers, beta blockers, and diuretics, in the first year for more than 6 months were the control group. Outcomes included 5-year survival, 5-year freedom from non-fatal major adverse cardiac event (NF-MACE: MI, new CHF, PCI, ICD implant, stroke), freedom from cardiac allograft vasculopathy (CAV: angiographic stenosis >30%), freedom from left ventricular dysfunction (left ventricular ejection fraction ≤40%) and freedom from left ventricular hypertrophy (LVH), defined as intraventricular septum or posterior wall ≥1.3cm. Results The patients treated with ACEI/ARBs in the first year post-HTx compared to those without had significantly lower 5-year survival but a trend for greater 5-year freedom from CAV. There was no significant difference between the two study groups in 5-year freedom from NF-MACE, left ventricular dysfunction and LVH (see table). Baseline demographics between groups were similar for recipient age, % female, pre-transplant diabetes and renal dysfunction (creatinine >1.5mg/dl) (data not shown). Conclusion The use of ACEI/ARBs in the first year post-HTx is associated with lower survival but other factors may be involved. A possible lower development of CAV from ACEI/ARBs may be a benefit to be explored.

Purpose Heart-kidney transplant (HKTx) patients have acceptable outcomes post-transplant. Patients on mechanical circulatory support (MCS) devices who undergo heart transplantation have the potential of several complications such as longer cold ischemic time due the time relegated to explant these devices due to extensive scar tissue and bleeding. In addition, many of these patients receive a significant number of blood products for bleeding episodes which can cause right ventricular dysfunction of the donor heart. Time in the intensive care unit (ICU) is also potentially increased due to the various complications that may occur. This would also include takebacks to the operating room (OR) for extensive bleeding. We reviewed our database to illuminate differences in patients with and without MCS undergoing HKTx. Methods Between 2017 and 2019, we assessed 43 patients undergoing HKTx and divided them into MCS (n=7) versus non-MCS patients (n=36). Endpoints included cold ischemic time, time in the ICU, number of blood products administered, takebacks to the OR for bleeding, 30-day survival, 1-year survival, 1-year freedom from non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke), 1-year freedom from cardiac allograft vasculopathy (CAV, stenosis ≥30% by angiography), and the development of severe primary graft dysfunction (PGD). Results Heart-kidney transplant patients with MCS versus those without MCS had significantly greater packed red blood cells needed and prolonged ICU length of stay. There were no differences between the 2 groups in 1-year survival, freedom from CAV, NF-MACE, and PGD. Conclusion Heart-kidney transplant candidates on MCS do not appear to have worse 1-year outcomes. Excess bleeding and prolonged ICU stay are the only adverse complications noted. These patients on MCS should be considered for HKTx.

Purpose Patients with severe heart failure who have undergone placement of a mechanical circulatory support (MCS) device do develop renal dysfunction. This renal dysfunction is not severe enough to necessitate the use of combined heart transplantation (HTx) and kidney transplantation. However, it has not been firmly established whether kidney dysfunction does add to increased morbidity or mortality after HTx in these device patients. Methods Between 2012 and 2019, we assessed 79 patients who have undergone MCS, either with total artificial heart (n=22) or left ventricular assist device (n=53). Baseline creatinine/glomerular filtration rate (GFR) was measured and patients were divided into GFR categories which include 30-39 mL/min, 40-49 mL/min, 50-59 mL/min, and greater than or equal to 60 mL/min. All patients underwent HTx alone. The need for temporary dialysis was recorded, as well as peak creatinine in the first 3 months after HTx and serum creatinine at 1 year compared to baseline. Further outcomes include subsequent 1-year survival, freedom from cardiac allograft vasculopathy (CAV, stenosis ≥30%), and freedom from non-fatal major adverse cardiac event (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke). Results There was no significant difference in 1-year survival, CAV, and NF-MACE or the need for temporary dialysis amongst all groups. Furthermore, no patient in any group needed chronic dialysis. In the GFR 40-49 group compared to the other groups, there was a trend for higher creatinine at 1 year but the baseline was high. Conclusion Baseline lower GFRs between 30-39 and 40-49 mL/min in MCS patients do not appear to be a predictor of poorer outcomes after HTx in patients. These patients do not appear to require combined heart and kidney transplantation.

Different surgical techniques, each with its own advantages and disadvantages, have been used to reverse adverse left ventricular remodeling due to postinfarction left ventricular aneurysm. The most appropriate surgical technique depends on the location and size of the aneurysm and the scarred tissue, the patient's preoperative characteristics, and surgeon preference. This review covers the reconstructive surgical techniques for postinfarction left ventricular aneurysm.

Essentials Bleeding is a major source of morbidity during mechanical circulatory support. von Willebrand factor (VWF) multimer loss may contribute to bleeding. Different patterns of VWF multimer loss were seen with the two device types. This is the first report of total artificial heart associated VWF multimer loss.Background Bleeding remains a challenge during mechanical circulatory support and underlying mechanisms are incompletely understood. Functional von Willebrand factor (VWF) impairment because of loss of high-molecular-weight multimers (MWMs) produces acquired von Willebrand disease (VWD) after left ventricular assist device (LVAD). Little is known about VWF multimers with total artificial hearts (TAHs). Here, VWF profiles with LVADs and TAHs are compared using a VWD panel. Methods VWD evaluations for patients with LVAD or TAH (2013-14) were retrospectively analyzed and included: VWF activity (ristocetin cofactor, VWF:RCo), VWF antigen (VWF:Ag), ratio of VWF:RCo to VWF:Ag, and quantitative VWF multimeric analysis. Results Twelve patients with LVADs and 12 with TAHs underwent VWD evaluation. All had either normal (47.8%) or elevated (52.2%) VWF:RCo, normal (26.1%) or elevated (73.9%) VWF:Ag and 50.0% were disproportional (ratio ≤ 0.7). Multimeric analysis showed abnormal patterns in all patients with LVADs: seven with high MWM loss; five with highest MWM loss. With TAH, 10/12 patients had abnormal patterns: all with highest MWM loss. High MWM loss correlated with presence of LVAD and highest MWM loss with TAH. Increased low MWMs were detected in 22/24. Conclusion Using VWF multimeric analysis, abnormalities after LVAD or TAH were detected that would be missed with measurements of VWF level alone: loss of high MWM predominantly in LVAD, loss of highest MWM in TAH, and elevated levels of low MWM in both. This is the first study to describe TAH-associated highest MWM loss, which may contribute to bleeding.

Background We report clinical experience with combined heart and kidney transplantation (HKTx) over a 23-year time period. Methods From June 1992 to August 2015, we performed 83 combined HKTx procedures at our institution. We compared the more recent cohort of 53 HKTx recipients (group 2, March 2009 to August 2015) with the initial 30 previously reported HKTx recipients (group 1, June 1992 to February 2009). Pre-operative patient characteristics, peri-operative factors, and post-operative outcomes including survival were examined. Results The baseline characteristics of the two groups were similar, except for a lower incidence of ethanol use and higher pre-operative left-ventricular ejection fraction, cardiac output, and cardiac index in group 2 when compared with group 1 (P = .007, .046, .037, respectively). The pump time was longer in group 2 compared with group 1 (153.30 ± 38.68 vs 129.60 ± 37.60 minutes; P = .007), whereas the graft ischemic time was not significantly different between the groups, with a trend to a longer graft ischemic time in group 2 versus group 1 (195.17 ± 45.06 vs 178.07 ± 52.77 minutes; P = .056, respectively). The lengths of intensive care unit (ICU) and hospital stay were similar between the groups (P = .083 and .39, respectively). In addition, pre-operative and post-operative creatinine levels at peak, discharge, 1 year, and 5 years and the number of people on post-operative dialysis were similar between the groups (P = .37, .75, .54, .87, .56, and P = .139, respectively). Overall survival was not significantly different between groups 2 and 1 for the first 5 years after transplant, with a trend toward higher survival in group 2 (P = .054). Conclusions The most recent cohort of combined heart and kidney transplant recipients had similar ICU and hospital lengths of stay and post-operative creatinine levels at peak, discharge, and 1 and 5 years and a similar number of patients on post-operative dialysis when compared with the initial cohort. Overall survival was not significantly different between the later and earlier groups, with a trend toward higher overall survival at 5 years in the more recent cohort of patients. In selected patients with co-existing heart and kidney failure, combined heart and kidney transplantation is safe to perform and has excellent outcomes.

Thromboembolic (TE) events and hemorrhagic complications continue to remain as frequent adverse events and causes of death after mechanical circulatory support device (MCSD) implantation. To counterbalance this postimplant multifactorial hypercoagulable state, antithrombotic therapy given postimplant must be individually tailored to keep patient adequately anticoagulated yet normocoagulable. Prior studies describing different anticoagulation protocols do not define normocoagulability for patients on MCSDs. We evaluated the role of thromboelastography platelet mapping (TEG PM) in defining "normocoagulability" for MCS patients on anticoagulant (warfarin) and antiplatelet agents. Ninety-eight MCSD patients who underwent TEG PM assay at our institution from 2012 to 2014 were included for retrospective analysis. Eleven (11.2%) subjects developed at least one TE event during the study period. Of the 13 TE events, 8 occurred in patients with total artificial heart (TAH). TEG parameters closest to the event or when patient was clinically adequately anticoagulated and corresponding international normalized ratio (INR) were measured. Thromboelastography coagulation index (CI) appears to be the single most statistically significant parameter that can be used to designate a patient as normocoagulable. Based on our results, patients with HeartMate II (HM II) and Heart Ware (HW) devices should be maintained at a CI value of less than or equal to 1.5 whereas patients with TAH devices should be maintained at a CI less than or equal to 1.2. The CI should be correlated with the degree of Vitamin K-dependent coagulation factor inhibition that is achieved using device-specific goal INR ranges. A recent modification, TEG PM assesses the effects of antiplatelet drug. Maximal amplitude arachidonic acid (MA-AA) < 50 and maximal amplitude adenosine diphosphate (MA-ADP) < 50 are desired for normocoagulable state.

Purpose Mycophenolate mofetil (MMF) is an anti-proliferative agent that is used in heart transplantation (HTx). The multicenter randomized trial of mycophenolate published in Transplantation in 1998 demonstrated that MMF had a survival benefit. The average dose of MMF was 2.8 g/day. It is not clear whether lower doses of MMF also have benefit in terms of control of rejection as well as other outcomes. Methods Between 2010 and 2018, we assessed 240 HTx patients and divided them into categories of MMF dosing in the first year after HTx. The average daily dose of MMF was obtained for all patients in the first year, with an average of 10 MMF dose levels obtained over the first year. Patients were divided into groups based on receiving an average daily dose of 2000 mg/day. Endpoints included 1-year survival, 1-year freedom from cardiac allograft vasculopathy (CAV), 1-year freedom from non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, percutaneous coronary intervention/angioplasty, new congestive heart failure, pacemaker/implantable cardioverter-defibrillator placement, and stroke), and 1-year freedom from rejection (any treated rejection (ATR), acute cellular rejection (ACR), antibody mediated rejection (AMR)). Results Patients treated with 2000 mg MMF/day had a trend toward decreased freedom from ATR. There was no difference in outcome between all groups in terms of 1-year survival, freedom from CAV, freedom from NF-MACE, and freedom from ACR and AMR. Conclusion The average daily dose of MMF in the first year after HTx does not appear to have an impact on outcome. Longer follow-up will be necessary to assess whether MMF dosing correlates to long-term complications such as CAV. Larger number of patients will be needed to confirm these findings.

Purpose In the past, Hepatitis B donors have been declined in patients who have not been vaccinated by the Hepatitis B vaccine. There is concern that these donors would transmit Hepatitis B to the recipient if they are not vaccinated. There is treatment available for these Hepatitis B infections, however, it has not been established as to its efficacy in patients on immunosuppression. In addition, hepatitis viruses have been reported to affect the endothelium of vital organs. Hepatitis B may injure the endothelium of the coronary vascular tree and could potentially result in a greater development of cardiac allograft vasculopathy (CAV) after heart transplantation. Therefore, we sought to assess this possibility by examining our patients who received Hepatitis B donors. Methods Between 2010 and 2016 we assessed 24 heart transplant patients who received a Hepatitis B donor. All of the recipients had received a Hepatitis B vaccine prior to transplantation. Endpoints include 3-year survival, 3-year freedom from CAV, 3-year freedom from non-fatal major adverse cardiac events (NF-MACE), and freedom from first year rejection, including any treated rejection (ATR), acute cellular rejection (ACR), and antibody-mediated rejection (AMR). These study patients were compared with 600 patients without Hepatitis B donors in a contemporaneous era. Results 3-year survival, freedom from NF-MACE, and freedom from first year rejection were similar between the Hepatitis B and control groups. There is numerically a lower incidence of freedom from CAV in the Hepatitis B group compared to the control, but this was not statistically significant. Conclusion Hepatitis B donors appear to have acceptable outcome compared to non-Hepatitis B donors after heart transplantation. Larger numbers of Hepatitis B donors will be needed to assess risk for increased CAV development.

Purpose Combined heart and kidney transplantation have a protective effect on the cardiac graft. Little is known about the factors that impact renal graft function post-transplant. We set out to assess the impact of donor, recipient and transplant characteristics on post-transplant renal graft function. Methods We evaluated combined heart-kidney transplant recipients at a single center from March 2012 to December 2017. Recipients with primary cardiac graft dysfunction were excluded. The primary outcome was delayed renal graft function (DRGF) as defined by need for dialysis within the first week of transplantation. The secondary outcome was any dialysis requirement within the first year. A univariate logistic regression model was used to assess the association between the donor, recipient and transplant factors with the primary and secondary outcomes. Results We identified 66 combined heart-kidney transplant recipients for analysis. Elevated recipient creatinine prior to transplant was associated with DRGF (OR 1.80, 95% 1.25-2.59, p = 0.002). Other evaluated donor and recipient factors were otherwise not associated with acute renal dysfunction (Table 1). Elevated pre-transplant creatinine (OR 1.73, 95% 1.21-2.50, p = 0.003) and redo transplantation (OR 5.70, 95% 1.05-30.87, p = 0.043) were associated with needing dialysis within the first year after transplant (Table 2). Conclusion In our single center experience of combined heart and kidney transplantation, recipient creatinine prior to transplant was the biggest predictor of primary renal graft failure. In addition, redo heart transplantation increases risk of dialysis within the first year.

Purpose It is suggested that non-HLA antibodies can cause antibody mediated rejection (AMR) in heart transplant patients. The aim of this study is to characterize non-HLA antibodies in heart transplant patients with treated AMR. Methods This study included 13 heart transplant recipients who were treated with biopsy-proven AMR, but did not have HLA donor specific antibodies. The presence of non-HLA antibodies at time of diagnosis was assessed by a single antigen beads-based assay which can detect 32 antibodies simultaneously. 18 recipients who did not have rejection, were also tested as the control group. Results One or more non-HLA antibodies were detected in 12 out of the 13 heart recipients with treated AMR. Of note, 9 of 13 patients developed vimentin antibodies, which was significantly more frequent than the control group (p Conclusion The presence of vimentin antibodies is associated with AMR. In the absence of HLA donor specific antibodies, detection of non-HLA antibodies is recommended for patients who are suspected of AMR.

Background Cardiac amyloidosis, typically from abnormal deposition of AL or ATTR amyloid protein, can result in heart failure requiring transplantation (HTx). The role of mechanical circulatory support (MCS) is not well-established. The purpose of this study was to present our experience with MCS in patients with cardiac amyloidosis. Methods Consecutive patients with cardiac amyloidosis who received MCS at Cedars-Sinai Medical Center between 2010 and 2018 were reviewed. Clinical characteristics and outcomes were compared to a control group of MCS patients without amyloid matched 2:1 for age and INTERMACS Profile. Results 11 amyloid patients underwent durable MCS, two with paracorporeal biventricular assist devices and 9 with total artificial hearts. No patients received isolated left ventricular assist device support. By 1 year, 9 (82%) of patients in the MCS-Amyloid group had been transplanted and 2 (18%) had died. In the MCS-No Amyloid group, by 1 year, 8 (36%) of patients had been transplanted, 10 (46%) had died, and 4 (18%) were still living with MCS. Conclusions Over a 9-year period, patients with amyloid cardiomyopathy who required MCS at our institution all received durable biventricular MCS. For carefully selected patients, this approach is feasible with acceptable outcomes as bridge to transplantation.

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

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

Background Combined heart and kidney transplantation ( HKT x) is performed in patients with severe heart failure and advanced renal insufficiency. We analyzed the long‐term survival after HKT x, the influence of age and dialysis status, the rates of cardiac rejection, and the influence of sensitization. Methods and Results From June 1992 to December 2016, we performed 100 HKT x procedures. We compared older (≥60 years, n=53) with younger (50%, and compared these survival rates with those from the United Network for Organ Sharing database. There was no difference in 15‐year survival between the 2 age groups (35±12.4% and 49±17.3%, ≥60 versus P =0.45). There was no difference in 15‐year survival between the dialysis and nondialysis groups (44±13.4% and 37±15.2%, P =0.95). Actuarial freedom from any cardiac rejection ( acute cellular rejection >0 or antibody‐mediated rejection >0) was 92±2.8% and 84±3.8%, acute cellular rejection (≥2R/3A) 98±1.5% and 94±2.5%, and antibody‐mediated rejection (≥1) 96±2.1% and 93±2.6% at 30 days and 1 year after HKT x. There was no difference in the 5‐year survival among recipients by sensitization status with panel‐reactive antibody levels 50% (82±5.9%, 83±10.8%, and 92±8.0%; P =0.55). There was no difference in 15‐year survival after HKT x between the United Network for Organ Sharing database and our center (38±3.2% and 40±10.1%, respectively; P =0.45). Conclusions HKT x is safe to perform in patients 60 years and older or younger than 60 years and with or without dialysis dependence, with excellent outcomes. The degree of panel‐reactive antibody sensitization did not appear to affect survival after HKT x.

Importance Transverse tubule remodeling is a hallmark of heart failure. Cardiac bridging integrator 1 (cBIN1) is a circulating membrane scaffolding protein that is essential for transverse tubule health, and its plasma level declines with disease. Objective To determine if a cBIN1-derived score can serve as a diagnostic biomarker of heart failure with preserved ejection fraction (HFpEF). Design, Setting, and Participants In this cohort study, the cBIN1 score (CS) was determined from enzyme-linked immunoabsorbent assay-measured plasma cBIN1 concentrations from study participants in an ambulatory heart failure clinic at Cedars-Sinai Medical Center. Consecutive patients with a confirmed diagnosis of heart failure with preserved ejection fraction (HFpEF; defined by a left ventricular ejection fraction ≥50%) were recruited from July 2014 to November 2015 and compared with age-matched and sex-matched healthy volunteers with no known cardiovascular diagnoses and participants with risk factors for heart failure but no known HFpEF. Baseline characteristics and 1-year longitudinal clinical information were obtained through electronic medical records. Data analysis occurred from November 2016 to November 2017. Main Outcomes and Measures The analysis examined the ability of the CS and N-terminal pro-B-type natriuretic peptide (NT-proBNP) results to differentiate among patients with HFpEF, healthy control participants, and control participants with risk factors for heart failure. We further explored the association of the CS with future cardiovascular hospitalizations. Results A total of 52 consecutive patients with a confirmed diagnosis of HFpEF were enrolled (mean [SD] age, 57 [15] years; 33 [63%] male). The CS values are significantly higher in the patients with HFpEF (median [interquartile range (IQR)], 1.85 [1.51-2.28]) than in the 2 control cohorts (healthy control participants: median [IQR], -0.03 [-0.48 to 0.41]; control participants with risk factors only: median [IQR], -0.08 [-0.75 to 0.42]; P

Purpose Hemodynamic compromise rejection (HCR) is seen Methods Between 2010-15, among 589 heart transplants, we identified 15 HTx pts (2.5%) who developed HCR. At the time of presentation of HCR, results of EMB were reviewed. Outcomes of these pts included subsequent 1-year survival, freedom from cardiac allograft vasculopathy (CAV, as defined by stenosis ≥30% by angiography), freedom from non-fatal major adverse cardiac event (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, defibrillator/pacemaker implant, stroke), and freedom from subsequent recurrence of rejection episodes, including any treated rejection (ATR), acute cellular rejection (ACR), and antibody-mediated rejection (AMR). The HCR group was compared to a case-controlled group with similar age, sex, time from transplant (n=39). Results HCR did not consistently show rejection with 64% revealing neither ACR nor AMR on biopsy slides. 27% showed ACR, 9% showed AMR and the remainder showed no rejection. In the HCR group, subsequent 1-year survival and freedom from NF-MACE was significantly compromised compared to the control group. Subsequent 1-year freedom from CAV and recurrent rejections were not significantly different. (table) Conclusion In a majority of HCR cases, EMB findings reveal no rejection which may be due to an atypical immune process. In the current era, outcomes from HCR continue to be compromised which suggest the need for a more aggressive approach to immunosuppression and management.

Purpose Approximately 30% of patients (pts) awaiting heart transplantation (HT) develop anti-HLA antibodies (Abs) due to sensitizing events. Highly sensitized pts have peak Panel Reactive Antibody (PRA) levels≥80%. We assessed the efficacy of desensitization therapy (DTx) on these pts awaiting HT. Methods Between 2010-19, we assessed 78 pts awaiting HT with peak PRA≥80% (mean peak PRA 91.6%, range 80-100%). These pts received DTx with intravenous immunoglobulin (IVIG) alone (n=18), rituximab-based therapy (n=5), plasma exchange (PE) alone (n=15), bortezomib-based therapy (BTZ)(n=30), and finally combination therapy with rituximab/BTZ (n=-10). Peak PRAs (mean fluorescent intensity, MFI) were obtained before and after treatment. All pts received ATG induction and IVIG with eculizumab given to pts crossing high level donor-specific Ab (DSA). 3-year outcomes including survival, freedom from cardiac allograft vasculopathy (CAV, stenosis ≥30%), freedom from non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, new onset heart failure, percutaneous coronary intervention, cardioverter defibrillator/pacemaker implant, stroke), and 1-year freedom from rejection [acute cellular rejection (ACR), Ab-mediated rejection (AMR)] were obtained. A group of non-sensitized pts without pre-HT anti-HLA Abs was used as control. Results With each DTx, peak PRA was reduced (table). Post-HT, there was lower freedom from 1-year AMR in the highly sensitized pt groups compared to the control group. 3-year survival, freedom from CAV and NF-MACE were similar among all groups. 26 highly sensitized pts received eculizumab perioperatively for crossing high level DSA. Conclusion Although there is variability in how highly sensitized pts respond, pre-HT DTx appears beneficial and enables pts to undergo successful HT. Further studies and longer follow-up are needed to identify the optimal therapy for each highly sensitized individual.

Purpose Patients more than 50 years of age routinely undergo screening colonoscopies. These patients can develop severe end-stage heart disease and may require heart transplantation. Many of these patients present in cardiogenic shock and it is unclear whether the use of colonoscopy is safe and efficacious in the screening of these patients for candidacy for heart transplantation. In our single-center program, we preform colonoscopies routinely on older patients at risk for colon cancer (family history, previous polyps or adenomas, stools heme positive) awaiting heart transplantation. We now report our experience of performing colonoscopes in these patients who are in cardiogenic shock, defined as patients who are on intravenous inotropic or left ventricular assist device (LVAD) support to maintain acceptable cardiac hemodynamics. Methods Between 2014 and 2019, we evaluated 300 heart transplant candidates who developed cardiogenic shock, defined as the need for IV inotropes or LVAD support. 30 of these patients underwent colonoscopy while on IV inotropes (n=27) and LVAD (n=3). All patients had compensated hemodynamics and anticoagulation was held prior to the procedure. Results Of the 30 patients with inotropic/LVAD support who underwent colonoscopy, the average age was 61.5 years and 87% were male. The specific inotrope(s) administered are listed in the table. The following findings at colonoscopy were found: 0 adenomas and 13 benign malignancies. There was no metastatic disease demonstrated. There were no complications arising from this colonoscopy except for bleeding due to biopsies that required hemoclips but no blood transfusions. Inotropic/LVAD support was continued through these procedures. Conclusion Colonoscopies for evaluation of heart transplant candidates who are in cardiogenic shock are acceptable, but caution should be taken in terms of risk for bleeding. Colonoscopies in cardiogenic shock should be limited to patients who are at risk for colon cancer.

Purpose Chronic kidney disease after heart transplantation is not uncommon due to the nephrotoxicity of calcineurin inhibitors (CNIs). It is well established that kidney dysfunction does impact post-transplant survival. What is not known is whether early or later development of kidney dysfunction has greater impact on outcomes. Methods Between 2010 and 2017, we assessed 130 heart transplant patients and followed their course over the first 5 years. Patients were categorized as having kidney dysfunction detected with creatinine > 1.5 mg/dL at 1-year, 3-years, and 5-years after heart transplant. These patients were subsequently followed for 5 years to assess for subsequent 5-year survival, subsequent 5-year freedom from non-fatal major adverse cardiac events (NF-MACE: MI, new CHF, PCI, ICD implant, stroke), subsequent 5-year freedom from cardiac allograft vasculopathy (CAV, as defined by stenosis ≥30%), and 5-year freedom from left ventricular dysfunction (LVEF ≤ 40%). Results Patients who developed kidney dysfunction at 1-year post-heart transplant appear to have similar subsequent 5-year survival compared to those with kidney dysfunction at 3 and 5 years after heart transplant. However, significantly more patients with kidney dysfunction at 1-year required subsequent kidney dialysis. (See table) Conclusion Early development of kidney dysfunction appears to lead to more patients needing kidney dialysis compared to those patients that develop kidney dysfunction later post-heart transplant. Renal sparing protocols or CNI minimization should be aggressively approached in these early patients to prevent worsening of kidney dysfunction.

Purpose Cyclosporine (CsA) became available in the US in 1983 and improved clinical outcomes. Another calcineurin inhibitor, tacrolimus (TAC), became available in the 1990s and demonstrated benefit in further reducing rejection. In most heart transplant (HTx) programs, TAC is currently the drug of choice for immunosuppression. However, a switch to CsA does occur due to adverse effects from TAC. It is not well-established that this switch to CSA results in subsequent non-inferior outcomes. Therefore, we reviewed our single center experience to assess for real world potential outcomes. Methods Between 2010 and 2017, we identified 58 HTx patients who were administered CsA in place of TAC mostly due to neurologic adverse effects from TAC. For comparison, a TAC group was matched based on age, sex, baseline renal function and time from transplant. The average time of this switch occurred at 6.6 ± 1.1 months post-transplant. Outcomes included subsequent 1-year freedom from any treated rejection (ATR), acute cellular rejection (ACR), and antibody-mediated rejection (AMR) and 3-year subsequent survival, freedom from cardiac allograft vasculopathy (CAV, as defined by stenosis ≥30% by angiography), and freedom non-fatal major adverse cardiac event (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke). Results The CsA/MMF group compared to the TAC/MMF group had significantly lower subsequent 3-year survival and worse renal function at 1-year (after the switch to CsA). There was similar subsequent 3-year freedom from CAV and NF-MACE and 1-year rejections between the two groups. (see table) Conclusion In the current era in a large, single center study there are indications that a switch to CsA from TAC may be inferior in heart transplant recipients. Further investigation with larger numbers is needed to confirm these findings.

Purpose Unfractionated heparin exposure in patients undergoing mechanical circulatory support device (MCSD) implantation increases the risk for developing heparin-induced-thrombocytopenia (HIT). The false positive rate of HIT in this population using current standard testing is unknown. Postoperative and device related thrombocytopenia complicate the HIT diagnosis. Methods A retrospective analysis of patients undergoing MCSD pre-implantation assessment or implantation of MCSD (October 2014 - August 2020) was performed. The primary objective was to assess the incidence of HIT with positive PF4 IgG ELISA (PF4) and serotonin release (SRA) assays. False positive HIT was defined as PF4 ≥0.4 optical density (OD) and negative SRA. Argatroban usage was also assessed. Results 366 patients with 512 tests were analyzed. PF4 tests were performed in 128 patients (158 tests) undergoing pre-implantation assessment, 136 patients (185 tests) with non-durable devices (primarily Impella®), and 102 (169 tests) patients with durable devices (72 ventricular assist devices, 30 total artificial hearts). 25% (92/366) of patients had positive PF4 ≥0.4 OD and had subsequent SRA performed (92 patients, 122 tests). True positive HIT was documented in 13% (12/92) of PF4 positive patients consisting of 1 pre-implantation, 9 non-durable MCSD, and 2 durable MCSD patients. The mean PF4 for true positive HIT was 2.2±0.7 OD. False positive HIT was documented in 15% (19/128) of pre-implantation patients (mean PF4 0.9±0.6 OD), 14% (19/136) of non-durable MCSD patients (mean PF4 0.8±0.5 OD), and 41% (42/102) of durable MCSD patients (mean PF4 1.1±0.6 OD). Argatroban was administered in 40% (37/92) of patients with a positive PF4 and 67% (25/37) of patients with a negative SRA. Conclusion Without clinical suspicion of HIT, preoperative PF4 testing is not recommended. Patients with non-durable MCSD devices are at the highest risk of developing HIT (7%). Although a PF4 ≥0.4 OD is considered a positive screening test for HIT, a higher threshold should be considered for MCSD patients. To our knowledge, this is the first in depth assessment of the incidence of HIT in patients undergoing pre-implantation evaluation for both non-durable and durable MCS devices.

Purpose Heart-liver transplant (HLvTx) has been demonstrated to show an immune protective effect with the transplanted liver protecting the heart. There are several reports suggesting less rejection in the HLvTx group. It has not been established whether this benefit is present in the current era. Methods Between 2007 and 2017, we assessed 13 HLvTx patients compared to heart alone patients (HATx, n=758). Patients were assessed for freedom from 1-year rejection [acute cellular rejection (ACR) and antibody-mediated rejection (AMR)] and donor-specific antibodies (DSA). Other endpoints included 5-year survival and freedom from cardiac allograft vasculopathy (CAV, stenosis ≥30% by angiography) and non-fatal major adverse cardiac event (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke). Results HLvTx compared to HATx showed similar freedom from 1-year rejection (ACR, AMR) and DSA. 5-year survival, freedom from CAV and NF-MACE were also similar between the two groups (see table). Conclusion In the current era, HLvTx does not appear to provide immune protection in either rejection or CAV. A larger number of heart-liver transplant patients will be needed to confirm these findings.

Purpose Donor selection in heart transplant is not standardized. Many donor hearts (DH) are declined due to quality issues such as older age, low left ventricular ejection fraction, left ventricular hypertrophy, diastolic dysfunction, underlying coronary artery disease. Yet, DH declined at one center are subsequently accepted at another center. It is not well known whether DHs declined due to quality and accepted by another program have acceptable post-transplant outcomes. Methods Between 2017 and 2019, we assessed 532 DHs that were allocated to a single center at Cedars-Sinai (CS). We declined 218 offers due to poor quality. We had follow-up with organ procurement organizations and found that 45 of these DHs that we turned down for poor quality were accepted by another program and transplanted. 1-year post-transplant survival of these patients were compared to those patients whose donor was accepted and transplanted at CS (n=314). Results The 45 declined DHs had the following issues: abnormal cardiac studies (n=12), donor cardiac history (n=6), other medical history including cirrhosis or infectious processes (n=6), possible cardiac cause of death (n=3), older age (n=14), estimated prolonged ischemic time (n=1), and other reasons (n=3). Compared to those patients transplanted at CS, there was no difference in 1-year patient or graft survival. The declined donor patients compared to CS patients had similar age and gender but had a longer cold ischemic time and less patients listed as high urgency status (status 1-3) at transplant. (see table). Conclusion DHs declined for quality may be accepted at another program with good post-transplant survival. Contrary to belief, these DHs were mostly not transplanted into high urgency waitlist patients. Donor declines due to quality should be reviewed as they could lead to more lives saved.

Purpose To date, there are no studies evaluating the effects of prophylactic antibiotic regimens in patients receiving temporary Impella® mechanical circulatory support (MCS). The purpose of this study was to compare the incidence of surgical-related infections within 30 days of temporary MCS implantation in patients receiving narrow versus broad spectrum peri-operative antibiotics. Methods 89 Patients receiving Impella® 5, 5.5, and CP devices in a surgical setting at Cedars-Sinai Medical Center from January 2017 to August 2020 were included for analysis which was IRB approved. This study period includes devices implanted before and after the implementation of MCS Antibiotic Selection for Surgical Prophylaxis Guideline. This protocol recommends cefazolin or ceftriaxone for pre-op surgical prophylaxis, with gentamicin for additional gram-negative coverage and vancomycin for beta-lactam allergy. 34/89 (38.2%) patients were identified as Stewardship (protocol adherence), while 27/89 (30.3%) were identified as Conventional (protocol non-adherence) another 28/89 (31.5%) patients were identified as Pre-existing (admitted with prior antimicrobial). The primary endpoint was the incidence of surgical site infections (SSI) and surgical-related bacteremia (SRB) within 30-day post-implant period. The secondary endpoint was protocol adherence. Results 72%, 26% and 2% of patients were bridged to heart transplant, durable MCS or no device, at 30 days respectively. There were no cases of SSI within 30 days post-operatively in any group, except for one case of SRB with Streptococcus mitis bacteremia in the Conventional group. Patients were screened for Methicillin-resistant Staphylococcus aureus (MRSA) colonization before incision in 72.2% of cases (mean, 2.6 days prior to device implantation). Reasons for non-adherence included incorrect duration of post-operative antibiotic(s) (44.4%), no pre-operative antibiotic given prior to incision (25.9%), and incorrect pre-operative antibiotic(s) given (22.2%). Conclusion The absence of SSI and SRB among Stewardship group supports narrow spectrum pre-op antibiotic prophylaxis over broad-spectrum agents for Impella® non-durable MCS.