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Because the half-life of the transplanted heart is approximately 14 years, re-transplantation may be necessary. Patients requiring redo heart transplant (HTx) may also have developed chronic kidney disease due to calcineurin inhibitor nephrotoxicity or progression of pre-existing renal dysfunction. Therefore, combined kidney transplant may be indicated. We evaluated outcomes following redo HTx with combined kidney transplant. A prospective institutional registry identified 1075 HTx cases between 1/1/2010 and 9/1/2020. Twenty-two patients undergoing redo HTx with kidney transplantation were compared to 55 patients undergoing redo HTx alone. Post-transplant outcomes included 1-year survival, 1-year freedom from cardiac allograft vasculopathy (CAV: stenosis ≥30% by angiography), non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke), any treated rejection (ATR), acute cellular rejection (ACR), and antibody-mediated rejection (AMR). Delayed graft function of the transplanted kidney was also evaluated and compared to 16540 patients identified from the national United Network for Organ Sharing database who underwent isolated kidney transplant between 2015 and 2020. Patients undergoing redo HTx with combined kidney transplant had higher incidence of post-operative dialysis and longer hospital length of stay. One-year outcomes were similar compared to patients undergoing redo HTx alone (Table). Delayed graft function of the transplanted kidney occurred in 12 patients (54.5%) after redo HTx with combined kidney transplant and 7112 patients (43.0%) after isolated kidney transplant (p=0.274). Redo HTx with combined kidney transplant has acceptable one-year outcomes. Significant renal disease in patients requiring redo HTx should not be a contraindication to re-transplantation. [ABSTRACT FROM AUTHOR]

Bortezomib, a proteasome inhibitor, offers effective desensitization in heart transplant candidates.. We reviewed our center's experience using bortezomib as desensitization therapy for highly sensitized patients to assess pre- and post-transplant outcomes. We assessed 43 HTx candidates 2010-2021 who were highly sensitized with cPRA greater than 50%, underwent bortezomib desensitization, and were subsequently transplanted. Enrolled patients received a course of up to four doses of bortezomib (1.3 mg/m2) over 2 weeks in conjunction with plasmapheresis. The efficacy of bortezomib was assessed by comparing the pre- vs post-desensitization therapy in cPRA, panel reactive antibodies to HLA Class I or Class II antigens, and reduction in immunodominant DSA via MFI. 1-year survival, 1-year freedom from antibody-mediated rejection (AMR), 1-year freedom from hyperacute rejection, 1-year freedom from hemodynamic compromise rejection, and 1-year freedom from the development of de novo DSA were also assessed. The average cPRA prior to bortezomib treatment was 94.5%. Bortezomib did not lower cPRA, Class I or Class II antibodies or lower the immunodominant antibody. However, these highly sensitized patients who underwent HTx had 95% 1-year survival, 76% freedom from 1-year AMR and 65% freedom from 1-year de novo DSA development. Side effects of bortezomib included thrombocytopenia and/or pancytopenia (43%), treated infection (28%) and self-limited neuropathy (12%). The use of bortezomib in highly sensitized patients does not appear to be clinically effective in lowering circulating antibodies prior to heart transplantation. However, its use may have contributed to acceptable post-transplant outcomes. [ABSTRACT FROM AUTHOR]

Sensitized patients undergoing HTx have greater risk of antibody mediated rejection (AMR), cardiac allograft vasculopathy (CAV), and decreased survival. A prospective crossmatch is performed on highly sensitized patients pre-HTx. While a cytotoxicity-positive complement test may be prohibitive for HTx, patients with flow-positive but cytotoxicity-negative crossmatch undergo HTx at our program. We reviewed outcomes of these patients. 60 highly sensitized patients with flow-positive yet cytotoxicity-negative prospective crossmatches 2010-2021 were evaluated. Outcomes assessed: 5-year survival and 5-year freedom from CAV (stenosis ≥40% by angiography), non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, heart failure, percutaneous intervention, pacemaker, or stroke), and 1-year freedom from rejection [any treated rejection (ATR), acute cellular rejection (ACR), and AMR]. A subgroup was analyzed for the impact to outcome of T-cell and B-cell flow positivity (median channel shifts, MCS >200 and <200) and for Class I vs Class II donor-specific antibodies (DSA). A control group consisted of non-sensitized patients (n=540). 5-year survival, freedom from CAV and NF-MACE were comparable between flow-positive cytotoxicity-negative patients and controls. These patients, however, had lower freedom from ATR/AMR (Table). There was also lower freedom from ATR/AMR in those with higher flow MCS though no difference based on Class I vs II DSA. Patients with flow-positive cytotoxicity-negative prospective crossmatches have comparable 5-year outcomes to nonsensitized patients. Despite increased ATR, there is no impact on survival or CAV development. These findings support proceeding with transplantation in this high-risk group. [ABSTRACT FROM AUTHOR]

In many heart transplant (HTx) programs, patients greater than 65 years of age who have had a previous left ventricular assist device (LVAD) are not candidates for HTX. They are kept at destination therapy. It is believed that these patients will have complications if transplanted. It has not been well established as to the outcome of these older LVAD patients undergoing HTx. Between 2010 and 2021, we assessed 35 patients who underwent a previous LVAD placement and subsequently underwent HTx at ≥65 years of age (range 65 to 70). A control group was comprised of patients (≥65 years) who underwent HTx without LVAD support. Post-transplant outcomes included 30-day and 1-year survival as well as 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), cardiac allograft vasculopathy (CAV: stenosis ≥30%), acute cellular rejection (ACR), and antibody-mediated rejection (AMR). LVAD patients who underwent HTx at the age ≥65 years appear to have comparable outcomes compared to patients who underwent HTx without LVAD support ≥65 years. 1-year survival, freedom from NF-MACE, CAV, ACR, AMR were not significantly different. Older patients (≥65years) supported on an LVAD do not have compromised post-HTx outomes. These patients do not necessarily need to be committed to destination therapy. [ABSTRACT FROM AUTHOR]

Hemodynamic compromise rejection (HCR) after heart transplantation (HTx) historically is seen in approx. 5% of our HTx patients (pts). HCR is a form of severe rejection, defined as pulmonary capillary wedge ≥15, cardiac index ≤2.0, and requirement of inotropic support. In the current era of tacrolimus, mycophenolate mofetil, and corticosteroids, incidence of HCR has not been firmly established. Further, it is not known whether treatment for these pts affects outcomes and whether there are significant sequelae in terms of cardiac dysfunction, reduced survival, or development of cardiac allograft vasculopathy (CAV). We sought to answer these questions in a review of our large single center. Between 2010 and 2017, we assessed 20 HTx pts who developed HCR. Pts who developed primary graft dysfunction immediately post-HTx were excluded. Treatment at the time of HCR was characterized as well as the long-term sequelae of HCR. Long-term sequelae included 5-year survival, freedom from cardiac dysfunction (defined as LVEF ≤40% by echo), and development of CAV. Type of rejection was also characterized. These pts were compared to a contemporaneous case-control of pts (3:1) matched for age, gender, time from HTx and era who did not develop HCR. The incidence of HCR over this study period was 3.0%. Pts developed HCR at an average of 576 ± 385 days post-Htx and majority were treated with combinations of high dose steroids, ATG, plasmapheresis, and IVIg. HCR pts compared to controls had significantly lower survival at 5 years after HTx and a significantly lower 5-year freedom from cardiac dysfunction and freedom from CAV. At biopsy, 40% had acute cellular rejection, 5% had antibody-mediated rejection, 5% had mixed rejection and 50% had no rejection (biopsy-negative rejection). See table. In the current era, pts with HCR after HTx continue to have significant morbidity and mortality following an HCR event. These pts require intensive follow-up and a search for a more effective treatment. [ABSTRACT FROM AUTHOR]

Patients who undergo heart transplantation may be in need of a second heart transplant if they develop severe graft dysfunction. Due to the long periods of time that these patients have been on calcineurin inhibitors, chronic kidney disease may ensue. These patients who need a second heart transplant may also need a combined kidney transplant. It has not been established in these redo heart transplant patients as to what GFR places them at risk for chronic dialysis post redo heart transplant. Between 2010 and 2021, we assessed 41 heart transplant patients who underwent redo heart transplant alone. These patients were divided into GFR quintiles (<42, 42 to <52, 53 to <61, 61 to <80 and ≥80 cc/minutes) to assess subsequent need for chronic kidney dialysis post-redo heart transplant. A group of 22 combined heart-kidney transplant patients were also included for comparison. Other endpoints included post-transplant 1-year survival, freedom from cardiac allograft vasculopathy (CAV), freedom from acute cellular rejection (ACR) and freedom from antibody mediated rejection (AMR). Redo heart transplant patients undergoing a heart transplant alone in the lowest quintile had a trend toward increased need for chronic hemodialysis post-transplant. At 1-year post-transplant, GFR remained low for those redo heart patients with baseline GFR <52cc/minute. Among the GFR quintile groups, there was no significant difference in post-transplant 1-year survival, freedom from CAV, freedom from ACR and freedom from AMR. In comparison, the redo heart transplant with combined kidney transplant patients appeared to have good outcome. (see table) Redo heart transplant patients with GFR < 42 cc/min appear to be at high risk for chronic hemodialysis post redo heart transplant. These patients might be considered for a combined redo heart transplant with kidney transplantation. Larger number of patients are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

The number of homozygous human leukocyte antigen (HLA) loci has been associated with the risk of HLA sensitization in kidney transplant candidates, which is a risk factor for antibody-mediated rejection (AMR). We assessed the relationship between HLA homozygosity and sensitization and AMR in heart transplant (HT) recipients. The study cohort comprised 1238 HT recipients transplanted 2012 - 2019 (622 Paris, 616 Los Angeles). Calculated panel reactive antibody values were determined with a threshold of mean fluorescence intensity >= 2500 (Los Angeles) or 3000 (Paris) using an 11-locus CPRA calculator based on National Marrow Donor Program HLA genotype frequencies. Split antigens were mapped to the corresponding broad antigen. HLA genotypes were used to assess homozygosity for HLA-A, -B, -DR, and -DQ. "Low" or "high" HLA homozygosity was defined as 0/1/2 or 3/4 homozygous loci. Cox modeling was performed with biopsy-proven AMR by 3 years post-HT as the endpoint. 525 (42%) recipients had CPRA >=1% and 173 (14%) had CPRA >=50%. Homozygosity at HLA-A, -B, -DR, and -DQ occurred in 20%, 8%, 14%, and 29% of candidates, respectively. The number of homozygous HLA loci was associated with increasing CPRA in a linear model (β=2.39/homozygous locus, p=0.008) and in a stepwise fashion (FIG 1). Only the group with CPRA 50-100% and low homozygosity experienced an increased risk of AMR (HR 4.1, 95% CI 2.8-6.2, p<0.001, FIG 2). Homozygosity at multiple HLA loci is associated with an increased risk of sensitization but decreases the risk of AMR in sensitized candidates. Although the mechanism is unknown, we speculate that HLA homozygosity may limit the repertoire of alloreactive T cells. [ABSTRACT FROM AUTHOR]

Calcineurin inhibitors (CNIs) tacrolimus and cyclosporine, have improved outcomes of heart transplant (HTx) patients but unfortunately have many side effects which include nephrotoxicity, hypertension, and malignancy. CNI-free regimens may protect the kidneys but at the risk of rejection. The purpose of this study was to assess our center's experience with CNI minimization and discontinuation. We assessed 34 HTx patients transplanted between 2010-2020, who transitioned to CNI-free regimens 6m-2 years post HTx and 2-5 years post HTx. Outcomes assessed were any treated rejection (ATR; including acute cellular rejection [ACR], antibody-mediated rejection [AMR], and biopsy-negative rejection [BNR]), survival, cardiac dysfunction (ejection fraction ≤40%) in the 1 year following CNI-free initiation. We also assessed the need for antihypertensive medications, HgbA1c, and estimated glomerular filtration rate (eGFR). Of 34 HTx recipients, 89% of patients were successfully weaned off CNI at <2 years and 94% at 2-5 years after transplant. eGFR for both groups was markedly improved at 1-year post CNI-free initiation. There was no difference between groups in anti-hypertensive medications or HgbA1c. However, CNI had to be restarted in 50% of the CNI-free in <2 years group and in 31% of the CNI-free at 2-5 years group. Return to CNI was for: rejection, medication intolerance, and death. (Table). CNI-free regimens are safe and efficacious for select patients but may not be sustainable. Additional strategies for renal protection and immunosuppression optimization are warranted. [ABSTRACT FROM AUTHOR]

In heart transplantation, donor-to-recipient (D-R) size matching has been done by height and weight. Recently, predicted heart mass (PHM) has been found to be more clinically useful to predict outcome. Using PHM, under-sizing a donor heart for a larger recipient with high pulmonary artery pressures leads to increased mortality. It has recently been noted in the ISHLT registry that there may be increased risk in placing an oversized donor heart using weight into a smaller recipient. This clinical outcome has not been established using PHM. We sought to address this question in our large, single center experience using PHM. Between January 2010 and June 2020, we assessed 588 D-R heart matches. We used PHM to assess outcome differences when the donor hearts were oversized. We divided the D-R ratio by PHM into two categories: Normal (N: 90-110%, n=524), and markedly oversized (MO: greater than 140%, n=64). Outcomes included 1-year survival, freedom from 1-year rejection (acute cellular rejection [ACR], antibody-mediated rejection [AMR]), freedom from cardiac allograft vasculopathy (CAV: stenosis ≥30%), freedom from cardiac dysfunction (LVEF ≤40%), and 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). MO (n=64) compared to N (n=524) using PHM showed no difference in 1-year survival, freedom from ACR, freedom from CAV, freedom from NF-MACE, and freedom from cardiac dysfunction. There was a significantly lower freedom from 1-year AMR in the MO group due to more female recipients (sensitized due to previous pregnancies) in this group (71% MO group vs 20% N group). Markedly oversized donor to recipient matching using PHM does not result in poor outcomes after heart transplantation. This has potential to expand the donor pool, particularly for smaller patients. [ABSTRACT FROM AUTHOR]

It has been reported from the ISHLT registry that women have less optimal outcome after heart transplantation (HTx) compared to men. It is not known whether this difference is due to rejection, NF-MACE, or decreased survival. Between 2010 and 2020, we assessed 1071 HTx patients and divided them by male and female sex. 309 females and 762 males were included in the study. Post-transplant outcomes included 1-year survival, 1-year freedom from cardiac allograft vasculopathy (CAV, stenosis ≥30% by angiography), 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 rejection (acute cellular rejection [ACR], antibody-mediated rejection [AMR]), and 1-year freedom from de novo DSA production. Women were divided into two groups, sensitized (PRA >10%) or non-sensitized. When comparing women to men, women had similar survival, freedom from CAV, and freedom from NF-MACE, but significantly lower freedom from ATR, AMR, and de novo DSA production. Women who were sensitized had similar survival but lower freedom from rejection and DSA production compared to non-sensitized women. 26% of our female patients were sensitized. Major post-transplant outcomes are similar for women and men. However, sensitization may be the reason for more AMR in women but it does not affect short-term major outcomes. Longer follow-up and impact of these outcomes need to be assessed. [ABSTRACT FROM AUTHOR]

An acute abdomen (AA) may occur following heart transplantation (HTx). Patients (pts) with atherosclerotic vascular disease may also have risk for ischemic bowel associated with their surgeries. In addition, pts with gallstones are at increased risk for cholecystitis immediately following cardiac surgery. The frequency and outcomes of these abdominal complications that warrant urgent abdominal surgery after HTx has not been well established. Furthermore, the presence of increased inflammation in abdominal surgery may trigger an immune response and thereby cause rejection. We sought to evaluate these complications in our large, single center experience. Between 2010 and 2021, we assessed 1154 pts who underwent HTx and reviewed frequency of AA requiring surgical intervention (n=11) in the first month following HTx surgery. These pts were assessed for 30-day and 1-year survival, allograft rejection, and infectious complications requiring intravenous antibiotics and/or readmission in the ensuing 3 months. The AA pts were compared to a case-controlled group (n=22) matched for age, sex, and time of transplant. 11 of 1154 pts (1.0%) of our HTx pt population developed an AA and required surgical intervention within the 30 days following HTx. Surgical interventions included hemicolectomy, cholecystectomy, and exploratory laparoscopy. Compared to the control group, the AA group had significantly worse 30-day and 1-year survival. In the study group, further infectious complications occurred, with 36.4% requiring rehospitalization for intravenous antibiotics. Rejection episodes following these events were not different from the control population. Acute abdomen immediately post-HTx resulting in urgent abdominal surgery requiring hemicolectomy and/or cholecystectomy is rare but has significant morbidity/mortality. For pts awaiting HTx with gallstones, prophylactic laparoscopic cholecystectomy might be considered. [ABSTRACT FROM AUTHOR]

Leukocytosis following heart transplantation (HTx) is common and most likely is due to high dose corticosteroid therapy immediately post-HTx. However, infection must be excluded with pan cultures. The use of anti-T lymphocyte globulin (ATG) induction may also cause leukocytosis due to an inflammatory reaction. We sought to determine whether culture negative leukocytosis in the first week after HTx has deleterious consequences. Between 2010 and 2020, we assessed 114 patients who developed leukocytosis within the first week following HTx. Patients were divided into groups by the severity of leukocytosis (WBC 11-14.9 x 109/L, 15-19.9 x 109/L, ≥20 x 109/L). Patients were asymptomatic, had negative cultures, and were not treated with antibiotics. The study population was compared to patients without leukocytosis following HTx. Development of infections in the ensuing 1-6 weeks postoperatively were assessed. Furthermore, 1-year outcomes including survival, freedom from cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), and rejection (any treated rejection [ATR], acute cellular rejection [ACR], antibody-mediated rejection [AMR]) were evaluated. Higher levels of asymptomatic leukocytosis (>15 x 109/L) immediately after HTx appears to signal possible subsequent infection. However, it does not lead to unacceptable 1-year outcomes including survival, or freedom from CAV, NF-MACE, or rejection. Induction therapy with ATG does not contribute to the leukocytosis. (See table.) Continued monitoring should be pursued for asymptomatic culture negative leukocytosis immediately after heart transplantation. [ABSTRACT FROM AUTHOR]

In the past, light chain (AL) amyloid has been associated with poor outcomes after heart transplantation (HTx), mainly due to its complicated course. Many AL amyloid patients will require stem cell transplant following HTx. It is not known whether these patients have acceptable outcomes after HTx. Between 2008 and 2020, we assessed all AL amyloid patients undergoing HTx. Patients were divided into those that required stem cell therapy and those that did not. Both groups were compared to age-matched control that did not have amyloid. Endpoints included 1-year survival, freedom from cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), and rejection (any treated rejection [ATR], acute cellular rejection [ACR], antibody-mediated rejection [AMR], biopsy-negative rejection [BNR]). There was no difference between AL amyloid patients with and without stem cell therapy in 1-year survival, or freedom from CAV, NF-MACE, or ATR. Compared to matched controls, post-transplant outcomes were similar. (See table.) In the current era, therapies for AL amyloid post-heart transplant appear successful with acceptable outcome compared to non-amyloid patients. AL amyloid is not a contraindication for heart transplantation. [ABSTRACT FROM AUTHOR]

The use of eculizumab, which is a complement blockade inhibitor, has been demonstrated to be efficacious in highly sensitized patients undergoing heart transplantation (HTx). The hypothesis is that the complement blockade protects the heart from hyperacute rejection and from other potential adverse responses. It is postulated that the complement blockade may downregulate antibody production. We reviewed our single center study using eculizumab for highly sensitized patients to assess for post-transplant outcomes. Between 2013 and 2020, we assessed 29 HTx patients who are highly sensitized, defined as calculated panel reactive antibody (cPRA) greater than 70% who underwent HTx with eculizumab therapy perioperatively. In all cases, donor-specific antibody (DSA) was crossed at the time of transplant but with a negative CDC prospective crossmatch. Eculizumab was given intraoperatively, post-op day 1, post-op day 7, and then given weekly for the first month and monthly for the second and third months post-transplant. The development of hyperacute rejection, antibody-mediated rejection, hemodynamic compromise rejection, and development of de novo DSA in the first-year post-transplant were assessed. Eculizumab use in highly sensitized patients resulted in 93.1% 1-year survival and no patient developing hyperacute rejection. There were 11 first-year AMR episodes noted, with one episode associated with hemodynamic compromise. All antibody levels began to wane in the first-year post-transplant. The use of eculizumab in highly sensitized patients (crossing DSA at transplant) appears to be effective in allowing these patients to undergo safe heart transplantation. [ABSTRACT FROM AUTHOR]