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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.

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.

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.

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.

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.

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.

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.

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 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 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 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.

Purpose The organ care system (OCS) has been found to have comparable 30-day mortality compared to standard of care (SOC) therapy for the donor heart. At our institution, we had previously shown comparable results on 1-year outcome in terms of rejection, antibody development and survival. In this current study, this cohort of patients were followed, and we evaluated long term results. Methods Between 2011 and 2013, we randomized 38 heart transplant (HTx) patients to either OCS or SOC. We assessed total ischemic time (TIT), cold ischemic time (CIT), development of de novo antibodies (abs) and donor specific antibodies (DSA) within 8 year post-HTx, 8-year survival, 8-year freedom from cardiac allograft vasculopathy (CAV), 8-year freedom from non-fatal major cardiac events (NF-MACE: Myocardial Infarction, Heart Failure, angioplasty, pacemaker/ICD, stroke), 8-year freedom from any-treated rejection (ATR), biopsy (bx) proven cellular rejection (ACR >2R), bx proven antibody-mediated rejection (AMR1, 2, or 3). Results OSC group had significant longer TIT but significantly shorter CIT compared to SOC. There was no statistically significant difference in 8-year freedom from CAV, NF-MACE, ATR, ACR and AMR. Moreover, 8-year survival was not statistically significant different between the two groups. There were total of 8 deaths in the OCS group and the cause of death included 3 immediate postoperative cases of hemorrhage and thrombotic event, two died of complications of malignancy, one due to multi-organ failure, one patient died due to complications of CMV infection and last patient died of unknown etiology. In the SOC group, there were 5 deaths. Causes of death included once case of rejection, one case of stroke, one patient died of CMV infection, one due to patient non-compliance, and one patient died of unknown cause at an outside hospital. Conclusion OCS appears to be a valid tool to extend total donor ischemic time without compromising long term outcomes.

Purpose Heart transplant patients develop many opportunistic infections due to chronic immunosuppression. One of the more common complications is that of Clostridium difficile (CDif) causing gastroenteritis, usually represented as diffuse diarrhea. It appears that these opportunistic infections such as CDif may have an impact on the immune system via the microbiome. It has not been demonstrated whether patients who develop CDif are at higher risk for the subsequent development of rejection or chronic rejection known as cardiac allograft vasculopathy (CAV) years after the event. Methods Between 2010 and 2018, we assessed 69 heart transplant patients who developed CDif within the first year post-transplant. These patients were assessed for subsequent 3-year survival, 3-year freedom from CAV (stenosis ≥30% by angiography), 3-year freedom from non-fatal major adverse cardiac event (NF-MACE: MI, new CHF, PCI, ICD implant, stroke), and 1-year freedom from acute cellular rejection (ACR) and antibody-mediated rejection (AMR). These patients were compared to a group (case controlled for time from transplant, age, gender) who did not develop CDif. Results The average time of infection following transplant was 2.2 ± 3.0 months. The heart transplant patients who developed CDif had significantly lower subsequent 3-year survival, 3-year freedom from NF-MACE, and lower 1-year freedom from AMR compared to the control group. There was no significant difference in the development of CAV (see table). Assessment of specific immunosuppression, antibiotic prophylaxis, and specific CDif treatment did not have an impact on outcome. Conclusion Heart transplant patients who developed first-year CDif appeared to have immune modulation that adversely affects subsequent outcome. Further investigation to study the microbiome is needed in order to elucidate the mechanisms that are in process.

Purpose Cardiac allograft vasculopathy (CAV) is one of the major factors limiting long-term survival. A severe form of CAV is small vessel disease which results in restrictive cardiac physiology (RCP). This RCP causes a very stiff heart which leads to significant reduction in cardiac index and elevation of cardiac pressures. The pathophysiology behind this RCP is most likely due to small vessel CAV with scarring and fibrosis. The outcome of patients with this RCP has not been well established. Methods Between 2010 and 2017 we assessed 23 heart transplant patients who developed RCP defined by right atrial pressure ≥ 15 mmHg, pulmonary artery diastolic pressure ≥ 15 mmHg, pulmonary capillary wedge ≥ 15 mmHg, and cardiac index ≤ 2.2 mm. Subsequent outcomes after diagnosis of RCP were 3-year survival, freedom from CAV (angiographic stenosis>30%), non-fatal major adverse cardiac events (NF-MACE: MI, new CHF, PCI, ICD implant, stroke), development of donor-specific antibodies (DSA) and re-hospitalizations. 1-year freedom from acute cellular rejection (ACR) was also assessed as risk factors for the development of RCP. The study group was compared with a case-controlled group 2:1 matched by age, gender, and era. Results The average time from transplant to the diagnosis of RCP was 1.5 ± 1.4 years. The RCP group compared to control had significantly lower subsequent 3-year survival, 3-year freedom from CAV, NF-MACE and hospitalizations. There was also a lower freedom from 1-year cellular rejection episodes and DSA in the RCP group compared to control. (See table) Conclusion Heart transplant patients who develop early RCP appear to have significantly reduced survival. ACR and DSA are associated with the development of RCP. As these patients do not appear to have a reversible cause, appropriate patients may be assessed for re-transplantation.

Introduction A patient presenting with biventricular failure was managed with Impella 5.5 as BTT. His course was complicated by HITT causing device failure, and he successfully underwent heart transplant (HTx) after plasmapheresis. Case Report A 44-year-old man with DM, HTN, and HLD was transferred to our center in cardiogenic shock. Coronary angiography revealed slow flow without obstruction. TTE showed biventricular dysfunction with LVEF 10%. Impella CP was placed, and on transfer the device was exchanged for a surgically placed axillary Impella 5.5. Filling pressures and RV function improved with diuresis. Platelets decreased from 230 (1000/uL) to 96 by hospital day 10, and a PF4 antibody was sent (Fig 1A). The next day, Impella purge pressure doubled and purge flow decreased, concerning for device thrombosis. The PF4 antibody returned positive, suggesting HITT. Heparin was stopped and argatroban administered systemically and through the purge. Pump power and hemodynamics were maintained. While awaiting results of a serotonin release assay, a suitable donor was identified. The risks and benefits of HTx included risk of cardiopulmonary bypass with heparin-PF4 antibodies, risk of Impella exchange, and risk of imminent device failure and stroke. Preliminary SRA was positive. The patient underwent two sessions of plasmapheresis and was transplanted on day 13. In the OR, there was extensive thrombus encasing the device (B). The driveline was transected proximally, and the distal catheter was removed with the native heart to decrease risk of embolization. After HTx, the patient was placed on argatroban and transitioned to apixaban. Summary We describe using Impella 5.5 as BTT in severe biventricular failure, where RV function improved with LV unloading. The case is notable for TCS failure due to HITT despite only modest thrombocytopenia (nadir 86,000), and for proceeding with HTx after plasmapheresis rather than Impella exchange. The patient was anticoagulated for a month post-HTx and is doing well.

Purpose The criteria for combined heart-liver transplant (HLiTx) has not been well established. Liver cirrhosis in a heart failure patient would require consideration for HLiTx. Investigators have used non-invasive testing (NIT) such as abdominal ultrasound and CT scans to assess for liver surface nodularity which suggests cirrhosis. Biopsies are then performed to assess for liver disease. However, pathology findings can be heterogeneous and, therefore, the biopsy may not be reliable to exclude cirrhosis due to sampling error. It is not known whether abnormal NIT suggesting cirrhosis alone renders poor outcome if heart alone transplant (HATx) proceeds. Methods Between 2012 and 2017, we identified 24 patients with an abnormal NIT demonstrating liver surface nodularity suggestive of cirrhosis but with liver biopsies showing no cirrhosis by pathology. Of these 24 patients, most patients had mild-moderate fibrosis with 3 patients who had severe 3-4+ fibrosis. Study endpoints included 3-year survival, freedom from non-fatal major adverse cardiac events (NF-MACE: MI, CHF, PCI, ICD implant, stroke), and freedom from cardiac allograft vasculopathy (CAV, defined by stenosis ≥30%). Freedom from 1-year rejection [acute cellular rejection (ACR), antibody-mediated rejection (AMR)] was also recorded. We compared these 24 patients to patients who underwent HATx without liver disease (n=523) during this same time period. Results Patients who had liver nodularity with HTx had similar 3-year survival, freedom from NF-MACE, and freedom from CAV compared to control patients who had HATx without liver disease. Furthermore, 1-year freedom from rejection was similar between study groups (see table). The 3 patients with 3-4+ fibrosis on liver biopsy had similar outcomes to the rest of the study group. Conclusion In our single center experience, surface nodularity suggesting cirrhosis by NIT but with no evidence of biopsy-proven cirrhosis does not appear to be a contraindication to proceed with HATx.

Purpose Diversity in the United States is a point of keen interest within the communities. In the heart transplant selection committees, most programs believe they have no bias in accepting patients for heart transplantation. However, there may be some inherent biases that are not due to the program's decisions, but rather institutional decisions or limitations. Such limitations may include lack of medical insurance, gender, age or geography that may be present without foreknowledge. Therefore, we assessed our heart transplant selection committee decisions to assess whether there is any inherent, institutional or voluntary bias within committee decisions. Methods Between 2016 and 2020 we assessed 296 heart transplant candidates that were presented to the heart transplant selection committee. We assessed for various factors that may be associated with patients declined for transplant for age, gender, race, social support (SIPAT score), health insurance (Medicaid), and state of residence. The standard for comparison included a Caucasian with non-Medicaid health insurance, social support, and ability to travel. Results The declined patients compared to the accepted patients were significantly older (64.4 vs 54.6 years) and had a higher SIPAT score (13.7 vs 11.2). There was no difference between groups in % female, % non-Caucasian, % w/non-Medicaid health insurance and % from outside California. (see table) Conclusion Inherent bias within a selection committee is difficult to interpret as older patients are held to a higher standard as older age is a risk factor for lower post-transplant survival. Higher SIPAT scores are also known to be a risk for lower survival due to higher psychosocial risk. It is comforting to appreciate that there does not appear to be inherent bias in gender, race, type of health insurance and region. Larger studies are needed.

Purpose Patients who are awaiting heart transplantation (HTx) have blood screened for circulating antibodies. Antibodies can sometimes come and go and not be detected at the time of HTx. However, there are instances when the patient has demonstrated donor specific antibodies (DSA) in the past but yet are not present at the time of HTx. It is not known whether these historical DSA have an impact on post-HTx outcomes. Methods Between 2010 and 2019, we assessed 11 patients awaiting HTx who had historical DSA but none detected at the time of HTx. These patients were compared to patients with DSA at the time of HTx and also compared to a non-sensitized group of patients undergoing HTx in a contemporaneous era. Post-HTx detection of DSA was performed and assessed if there was an amnestic response to the historical DSA. DSA are routinely checked post-HTx at 1, 3, 6, 12 months post-operatively. Other endpoints included 1-year freedom from any treated rejection, acute cellular rejection, and antibody-mediated rejection. 1-year survival, 1-year freedom from non-fatal major adverse cardiac event (NF-MACE, defined as MI, new CHF, PCI, ICD/pacemaker placement, stroke) and 1-year freedom from cardiac allograft vasculopathy were also recorded. Results Patients with historical DSA did not have an amnestic response with an increase of that specific DSA post-HTx. The historical DSA group compared to the non-sensitized group had no significant differences in 1-year survival, freedom from DSA, CAV, NF-MACE or rejections. Specifically, the historical DSA group did not appear to have an increase in any type of rejection in the first year post-HTx compared to (crossing) DSA at transplant group or the non-sensitized group. (See table) Conclusion Historical DSA does not appear to be a factor in terms of an amnestic response possibly due to the immunosuppression that is being administered. Therefore, crossing historical DSA at heart transplant does not appear to have adverse sequelae.

Older donor hearts ≥60 years old have been reported to have less than optimal outcome after heart transplantation. However, careful selection of these donor hearts may result in acceptable outcomes. We sought to assess the outcome of our patients receiving these older donor hearts. Between 2010

The use of stem cell therapy in combination with a left ventricular assist device (LVAD) for patients with advanced heart failure (HF) is an attractive concept with the potential to alter the natural history of HF. Cell therapy trials for HF have demonstrated excellent safety and encouraging results, but current rates of myocardial recovery after LVAD implantation are limited. Early trials combining these 2 therapies to increase the likelihood of recovery and to potentially obviate the need for subsequent transplantation appear promising. Additionally, the application of cell therapy to patients undergoing LVAD implantation as a bridge to cardiac transplantation creates an opportunity to examine cardiac tissue before and after treatment and to study the mechanism of benefit. Despite the promise, there is a paucity of data for the combination of stem cell therapy with LVAD insertion in patients with HF. Of 11 case series or clinical trials, the largest enrolled 30 patients. We highlight clinical trials using stem cell therapy for end-stage HF most relevant to an LVAD patient population and comprehensively review the preclinical and clinical studies of combined stem cell therapy and long-term mechanical circulatory support. Based on the available clinical trials, the combination of stem cell therapy and LVAD support is a promising approach but requires further clinical refinement, with additional clinical data and larger numbers of patients required to support its clinical application.

Objective: We determined, in stable ambulatory heart failure with reduced ejection fraction (HFrEF) subjects and matched controls, the capability of a novel blood based cardiac-specific cBIN1 Score (CS), which assesses the health of cardiac muscle, to identify patients with known heart failure (HF) and to prognosticate future hospitalization. Background: Limited clinical tools are available in assessing cardiac muscle health in stable ambulatory patients. Cardiac bridging integrator 1 (cBIN1) is a cardiomyocyte t-tubule membrane scaffolding protein which regulates calcium signaling in cardiomyocytes, decreases in failing muscle, and is present in plasma in levels that correlate with cardiac content. We hypothesize that CS, a normalized index of plasma cBIN1 concentration, can function as a diagnostic and prognostic biomarker of HF. Methods: Plasma cBIN1 concentration is measured by an ELISA test, and CS is calculated as the natural log of the ratio of a constant population mean cBIN1 to measured cBIN1 concentration. We determined CS among 125 clinically stable individuals with HFrEF (LVEF ≤ 40%) (mean age 56 ± 10 years old, 79% men) and 125 age, sex matched volunteers with no known history of HF. We obtained plasma concentrations of NT-proBNP, a marker of volume status, as comparison. Baseline co-morbidities and 18-month longitudinal clinical information were obtained through electronic medical records. Results: CS follows a normal distribution with a median of 0 in the control population and median is significantly increased among HFrEF patients to 1.8 (IQR 1.4 – 2.1, p < 0.0001). CS diagnosed HFrEF with a receiver operating characteristic (ROC) area under the curve (AUC) of 0.93 (AUC is 0.98 for NT-proBNP, and combined CS and NT-proBNP AUC is 0.99). Unlike NT-proBNP, CS does not correlate with body mass index (BMI) in either the control or HFrEF population (Pearson’s r = -0.15, p = 0.12; Pearson’s r = 0.003, p = 0.97, respectively). NT-proBNP significantly correlates with renal function (Pearson’s r = -0.37, p = 0.001), while CS also has no correlation (Pearson’s r = 0.03, p = 0.71). During an 18-month follow-up, a high CS ≥ 1.8 at the initial visit predicted future cardiovascular hospitalizations (38% vs. 21%, p = 0.04, hazard ratio 2.0). NT-proBNP did not predict future cardiovascular hospitalizations. Conclusions: Plasma cBIN1 based CS is insensitive to BMI and renal function and differentiates myocardial health between patients with HFrEF versus matched controls. An abnormally high CS reflected poor intrinsic myocardial health and can predict future 18-month cardiac hospitalization in stable ambulatory patients.

Polymorphisms for VKORC1 and CYP2C9 are associated with increased warfarin sensitivity. The prevalence of these polymorphisms in patients with mechanical circulatory support (MCS) is unknown. Polymorphisms for VKORC1 and CYP2C9 were determined in 65 patients undergoing MCS surgery. Postoperative warfarin dose, international normalized ratio (INR), and bleeding events were measured until discharge, 6 months, or composite end point (in-hospital MCS recovery, heart transplant, or death). A total of 67.7% (44/65) had at least one polymorphism: VKORC1 (44.6%), CYP2C9*2 (7.7%), CYP2C9*3 (4.6%), CYP2C9*2 and VKORC1 (3.1%), or CYP2C9*3 and VKORC1 (7.7%). At discharge or before composite end point, patients with any polymorphism received a lower mean warfarin dosage than patients having no polymorphism (3.21 ± 1.47 vs. 5.57 ± 3.72 mg, p = 0.015) and achieved a similar mean INR (2.20 ± 0.67 vs. 2.19 ± 0.69, p = 0.96). There was no significant difference in bleeding rates within 6 months or before composite end point (6.13 vs. 8.02 events/patient-year, p = 0.13). One or more polymorphisms for VKORC1 or CYP2C9 (associated with warfarin sensitivity) were found in 67.7% of MCS patients. By using a warfarin genotype-guided approach, MCS patients with polymorphisms received a lower warfarin dosage to achieve a similar INR, with similar bleeding rates, in comparison with no polymorphisms. A warfarin genotype-guided approach avoided excessive anticoagulation and its attendant bleeding risks.

Background : Hypertension (HTN) is one of the causes of cardiovascular disease (CVD) in Africa, and may be associated with lower socio-economic status (SES). The prevalence of HTN is not well established in the Gambia or in Sierra Leone. Methods : A cross-sectional, population-based study of adults was conducted in the Gambia in 2000 and in Sierra Leone from 2001 to 2003 and in 2009. The study was conducted as part of the annual visit to countries in western Africa sponsored by a medical delegation from California. People from the Gambia and Sierra Leone were examined by the medical delegation and blood pressures were measured. Results : A total of 2 615 adults were examined: 1 400 females and 1 215 males. The mean systolic blood pressure (SBP) of the females was 134.3 ± 29.7 mmHg, mean diastolic blood pressure (DBP) was 84.5 ± 17.5 mmHg, and 46.2% were hypertensive. The mean SBP of the males was 132.8 ± 28.5 mmHg, mean DBP was 82.8 ± 16.2 mmHg, and 43.2% were hypertensive. Overall prevalence of HTN in the subjects was 44.8%. Mean SBP, mean DBP and HTN prevalence increased with age decade, both in males and females. In addition, after age adjustment (known age), females had higher mean SBP (p = 0.042), mean DBP (p = 0.001) and rate of occurrence of HTN (p = 0.016) when compared with males. Conclusions : Prevalence rates of HTN in the Gambia and Sierra Leone were higher than 40% in males and females, and may be a major contributor to CVD in both countries. Due to the association of HTN with low SES, improvements in educational, public health, economic, non-governmental and governmental efforts in the Gambia and Sierra Leone may lead to a lower prevalence of HTN. The cause of the higher prevalence in women may be due to post-menopausal hormonal changes.

Evolving technology and improvements in the design of modern, continuous-flow left ventricular assist devices have substantially reduced the rate of device malfunction. As the number of implanted devices increases and as survival prospects for patients with a device continue to improve, device malfunction is an increasingly common clinical challenge. Here, we present our initial experience with an endovascular microaxial flow left ventricular assist device as a successful bridge to transplantation in a 54-year-old man who experienced left ventricular assist device malfunction.

OBJECTIVES Previous studies have demonstrated that preheart transplant mechanical circulatory support (MCS) can lead to a small but significant increase in mortality. However, data on outcomes of patients with MCS who require simultaneous heart-kidney transplant are limited. METHODS A retrospective review of simultaneous heart-kidney transplantations (HKTxs) performed at a single institution over a 5-year period was performed. Patients were divided based on the preoperative use of durable MCS. Renal graft-related end points were evaluated, including glomerular filtration rate following transplantation, prevalence of delayed renal graft function and freedom from antibody and cellular-mediated graft rejection. Patient-specific outcomes, including survival and frequency of non-fatal major adverse cardiac events at 1 year, were additionally assessed. RESULTS During the study period, 50 HKTxs were performed, 14 of which had preoperative MCS. HKTx patients with and without MCS implantations had a similar prevalence of delayed graft function (57.1% vs 50.0%; P = 0.757). A numerical trend was observed towards a reduced glomerular filtration rate 1-month post-transplant in patients without an MCS device (81.2 ± 32.8 vs 64.4 ± 27.5; P = 0.072), but no significant difference was observed at 6 and 12 months. No significant difference was observed on the need for post-transplant renal replacement therapy, non-fatal major adverse cardiac events, freedom from graft rejection and overall survival at 1 year. CONCLUSIONS The use of preoperative MCS in patients undergoing combined HKTx was not found to affect renal graft function post-transplantation and does not seem to be associated with increase in morbidity or mortality.

Background: Acquired heart failure (HF) originates with failing heart muscle, yet it is currently not possible to assay the biochemical health of cardiomyocytes. A key pathophysiology of HF is weakened calcium transient under the regulation of a membrane deformation protein bridging integrator 1 (BIN1). BIN1 decreases with HF and is blood available. We hypothesized that a recently cloned cardiac BIN1 isoform (cBIN1, BIN1+13+17) can be selectively measured to diagnose heart muscle health. Methods: Expression of cBIN1 in human heart and plasma was determined by immunoprecipitation, western blotting, and mass spectrometry analysis. A cBIN1 specific ELISA was developed using the combination of anti-BIN1 exon 17 (clone 99D from Sigma) and 13 (gift from Sarcotein Diagnostics) antibodies. Plasma cBIN1 concentration was then measured in a large clinical cohort of HFrEF (N=180) patients and compared to a sex and age matched cohort of healthy volunteers. Plasma cBIN1 concentration was also compared to NT-proBNP for its ability to detect patients with HFrEF. Results: Biochemistry and mass spectrometry confirms that cBIN1 is expressed in human myocardium. An ELISA assay selects for the cBIN1 isoform which significantly reduced in HFrEF (3.0±0.3, n=286, mean±SEM, ng/ml, p Conclusions: A cBIN1 specific ELISA can quantify cBIN1 in human plasma. Low plasma cBIN1 diagnoses diseased heart muscle in HFrEF patients and predicts future hospitalization and death.

Background Vasoplegia is characterized as a severe vasodilatory shock after cardiac surgery, and can be associated with substantial morbidity. Increased systemic inflammation and endothelial dysfunction, often related to prolonged cardiopulmonary bypass times, anesthesia, or mechanical circulatory support have been shown to be associated with the development of vasoplegia. We sought to identify risk factors and the impact of various degrees of vasoplegia after heart transplantation. Methods A retrospective review was conducted of 244 consecutive patients who underwent heart transplantation over a 3-year period. Patients were divided into three groups: no vasoplegia, mild vasoplegia (requiring one vasopressor), and moderate/severe vasoplegia (more than two vasopressors). One-year survival, freedom from rejection, and postoperative complication rates were assessed. Risk factors for vasoplegia subgroups were retrospectively identified. Results Vasoplegia syndrome was observed in 34.3% of patients after heart transplantation (mild, 74.1%; moderate/severe, 25.9%). Cardiopulmonary bypass time was significantly longer and pretransplant creatinine was significantly higher in the moderate/severe vasoplegia group. There was a strong trend toward greater use of mechanical circulatory support among moderate/severe vasoplegia patients compared with mild and no vasoplegia patients. After heart transplantation, 1-year survival, freedom from rejection, and need for hemodialysis were not significantly different between groups. Conclusions Vasoplegia syndrome is common after heart transplantation. Risk factors for increased severity include longer cardiopulmonary bypass times and elevated preoperative creatinine. Although higher rates of mortality or graft rejection were not detected, vasoplegia was associated with prolonged intubation, greater blood product usage, and lengthened hospital stay. Further studies involving larger cohorts are warranted.

Reports of cardiac surgery in the elderly have focused primarily on septuagenarians and octogenarians. There are very limited data regarding risk-adjusted models in nonagenarians.From 1983 to 2011, patients with age 90 years or greater at the time of coronary artery bypass grafting (CABG) or valve surgery (aortic or mitral) were retrieved from a prospective institutional database. A Cox proportional hazard model was used to determine significant predictors of 5-year survival. In addition, a 12-month assessment of quality of life was conducted.The CABG-only (n = 46), valve-only (n = 55), or CABG-valve (n = 53) surgery was conducted in 154 patients. Demographic characteristics were similar in all groups except for congestive heart failure, which was more prominent in the valve-only or CABG-valve groups (p0.0001). The 30-day mortality was 8.8%, 12.8%, and 18.9% in the CABG-only, valve-only, and CABG-valve groups, respectively, without significant difference among groups (p = 0.35). At 5-years follow-up, the Kaplan-Meier survival curves do not show a difference among groups (p = 0.62). Cox proportional hazard model for 5-year survival identified age (hazard ratio [HR] = 1.25, confidence interval [CI] 1.09 to 1.43, p = 0.001, for 1-year increase), prior surgery (HR = 2.23, CI 1.23 to 4.64, p = 0.007), and prior stroke (HR = 2.39, CI 1.25 to 3.98, p = 0.01), as significant predictors of mortality. The 12-month quality of life questionnaire revealed an improvement in 83% of the patients, whereas only 4% reported a decline in cardiac status.Survival in nonagenarians is comparable after CABG or valve surgery. Redo surgery, stroke, and increasing age are significant hazards for mortality. Nonagenarians can undergo cardiac surgery with acceptable mortality and quality of life.

Heart transplantation (HTx) surgically interrupts the parasympathetic vagal neurons and the intrinsic postganglionic sympathetic nerve fibers traveling from the stellate ganglia to the myocardium, causing axonal Wallerian degeneration and thus extrinsic cardiac denervation.[1][1], [2][2], [3][3], [4

BackgroundDepression after cardiac surgery (CS) is associated with increased pain and decreased sleep quality. While cognitive behavioral therapy (CBT) aimed at depression is effective in relieving depressive symptoms after cardiac surgery, little is known about its ability to ameliorate other common postoperative problems that affect recovery and quality of life.AimsThe purpose of this study was to evaluate the effects of CBT for depression on pain severity, pain interference, sleep, and perceived control in patients recovering from CS.MethodsDepressed patients recovering from CS were randomized to receive either eight weeks of CBT or usual care. At baseline and post-intervention, patients completed questionnaires for depressive symptoms, pain, sleep, and perceived control. Group comparisons were conducted using t-tests or chi square analysis. Repeated measures analysis was used to assess the effect of the intervention in changes over time.ResultsThe sample (n=53) included 16.9% women and had a mean age of 67.8±9.2 years. CBT for depression increased perceived control (p

OBJECTIVES Vasoplegia syndrome is a potentially life-threatening condition that can occur following cardiopulmonary bypass. Heart transplantation is a recognized risk factor for developing this vasodilatory state. The objective of this study was to determine the effects of vasoplegia syndrome on 1-year heart transplant outcomes. METHODS A retrospective review of orthotopic heart transplants at a single institution between November 2010 and December 2014 was performed. Of the 347 consecutive adult patients, 107 patients (30.8%) met criteria for vasoplegia syndrome. Preoperative factors and intraoperative variables were collected and compared between vasoplegia and non-vasoplegia cohorts. The incidence of postoperative complications, transplant rejection and patient survival within 1 year were evaluated. RESULTS Demographics and preoperative medication profiles were similar in both groups, while mechanical circulatory support device use was associated with vasoplegia syndrome (30.8% vs 20.0%; P = 0.039). Perioperative characteristics such as longer cardiopulmonary bypass [165.0 (interquartile range [IQR] 74) min vs 140.0 (IQR 42.7) min; P