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Purpose Heartmate II risk score (HMRS) and MELD-Xi score are validated mortality risk predictors in Heartmate II left ventricular assist device (LVAD) patients. Prognostic utility of these risk scores remains unknown in patients considered for Heartmate 3 (HM3) LVAD therapy. Methods HMRS were calculated for 175 consecutive patients who underwent HM3 LVAD implantation at a single academic institution. Receiver operating characteristic (ROC) curve and logistic- and cox-regression models were developed to assess the impact of HMRS and MELD-Xi scores on short- and long-term outcomes in HM3 patients. Results Mean HMRS and MELD-Xi scores in HM3 population was 1.38±0.57 and 14.4±0.28, respectively. Pre-implant HMRS was not predictive of RVAD use (OR 1.25, p=0.392), CVVHD (OR 1.16, p=0.722), in-hospital mortality (OR 1.52, p=0.409), or 90-day mortality (OR 1.44, p=0.457). Pre-implant MELD-Xi score showed trend towards increased RVAD use (OR 1.09, p=0.056) and need for CVVH (OR 1.14, p=0.064), however was not predictive of in-hospital mortality (OR 1.02, p=0.836), or 90-day post-LVAD mortality (OR 0.958, p=0.636). Area under curve (AUC) for in-hospital mortality was 0.531 for HMRS and 0.525 for MELD-Xi score (Figure) . There was no difference in post-implant survival (88.6% vs. 85.7%, log-rank p=0.569), freedom from GI bleeding (73.5% vs. 65.1%, log-rank p =0.257) or freedom from stroke (93.3% vs. 90.8% log-rank p = 0.478) at 2-year follow-up in patients with below average vs. above average HMRS. Similarly, There was no difference in post-implant survival (91.3% vs. 82.3%, log-rank p=0.121), freedom from gastrointestinal bleeding (72.2% vs. 65.2%, log-rank p =0.257) or freedom from stroke (92.0% vs. 92.4% log-rank p = 0.820) at 2-year follow-up in patients with below average vs. above average MELD-Xi score. Conclusion HMRS and MELD-Xi scores do not predict mortality in patients undergoing HM3 implantation. New prediction models are required to optimize patient selection and outcomes in HM3 patients.

In heart transplantation (HT), although blood type O organs can go to any blood type, non-O organs may not be allocated to adult O recipients. Therefore, O candidates wait longer than non-O candidates and frequently require bridging with left ventricular assist devices (LVADs). The effects of this discrepancy are rarely investigated in a large registry. The purpose of this study was to assess the association between candidates' blood type and their outcomes after HT listing.This is a retrospective cohort study using the United Network for Organ Sharing Registry, including 34,352 candidates listed for a single-organ, primary HT from January 2000 through December 2015. Main outcome measures were waitlist mortality and post-HT mortality, using blood type A as reference. We conducted inverse-probability weighting to adjust for baseline profiles.Among 34,352 candidates (median age 55, interquartile range 46-62; female 24.8%; blood type A: 13,258, AB: 1,572, B: 4,599, O:14,923), 22,714 candidates (A: 71.5%, AB: 82.1%, B: 73.0%, O: 57.5%; p0.001) underwent HT during the study period. Among recipients, bridging LVAD rate was highest in O recipients (A: 23.0%, AB: 15.3%, B: 23.4%, O: 32.1%; p0.001). After inverse-probability weighting, O patients demonstrated a significantly higher hazard of death after listing (adjusted hazard ratio 1.11, 95% confidence interval [CI] 1.07-1.16) and after HT (adjusted hazard ratio 1.07, 95% CI 1.01-1.13) as compared with A.There is a survival discrepancy among blood types. Our findings should facilitate more prospective studies to revisit current policies regarding equity in allocation, where possible.

The intra-aortic balloon pump (IABP) neither benefits nor harms patients with acute myocardial infarction (AMI) with cardiogenic shock (CS) but may stabilize those with chronic heart failure who decompensate into CS. We sought to compare its hemodynamic effects in these 2 populations. We performed a retrospective analysis of the hemodynamic effects of IABP for AMI or acute decompensated heart failure (ADHF) patients with hemodynamic evidence of CS. The primary outcome was cardiac output (CO) change following insertion. In total, 205 patients were treated for CS resulting from AMI (73; 35.6%) or ADHF (132; 64.4%). At baseline, both cohorts had significant hemodynamic compromise with mean arterial pressure 75.6 ± 12.3 mm Hg, CO 3.02 ± 0.84 L/min, and cardiac power index 0.26 ± 0.06 W/m2; these parameters were nearly identical between groups though ADHF-CS patients had a higher pre-IABP mean pulmonary artery (PA) pressure than AMI-CS patients. After IABP insertion, ADHF-CS patients had moderate CO augmentation whereas AMI-CS experienced almost no improvement (0.58 ± 0.79 L/min vs 0.12 ± 1.00 L/min; p = 0.0009). Intracardiac filling pressures were reduced by similar amounts in both cohorts. Systemic vascular resistance was reduced in patients with ADHF-CS but not in those with AMI-CS. In conclusion, following IABP insertion, ADHF-CS patients experience roughly a 5-fold greater CO augmentation compared with AMI-CS patients. Pre-IABP PA pressure differences and differential systemic vascular resistance reduction may explain these results and shed light on recent evidence supporting IABP use in ADHF-CS and curbing it in AMI-CS.

Patients with antibodies to HLA wait longer for transplant and are at increased risk of adverse outcomes. For more than a decade, drug therapy approaches have been tested to modulate the immune system to prevent or reduce donor-specific antibody levels. Despite some studies reporting success in facilitating transplant, many patients do not respond or experience donor-specific antibody rebound, highlighting the diversity of the individual patient's immune response. While advances in immunomodulatory therapies have resulted in escalating efforts to successfully treat highly sensitized patients, further insight into the human immune system has uncovered its enormous complexity and diversity calling for a personalized approach. Yet, even defining the sensitized transplant candidate can be troublesome and much remains to be understood about the interaction between an individual's immune system as a whole and their response to our current desensitization strategies. The shift toward a personalized approach calls for a reevaluation of what we know and what remains to be determined; a process that will require iterative translational approaches. This review will focus on new insights into how the interaction between immune risk assessment, the patient's immunological history, and the clinical context can be reconciled to develop a precision-based approach to pretransplant management.

Background Left ventricular assist device (LVAD) therapy has revolutionized the treatment options for patients with advanced heart failure. Patient selection is essential for obtaining successful results. However, few data exist concerning the outcomes of patients evaluated for LVAD therapy but subsequently rejected or deferred. Methods and Results This is a retrospective review of all patients referred for LVAD therapy at our institution between January 2009 and December 2016. Baseline demographics and Interagency Registry for Mechanically Assisted Circulatory Support profiles were collected, and reasons for rejection or deferral for LVAD placement were investigated. A total of 669 patients were referred for LVAD therapy, and 228 patients (34%) were turned down. The yearly acceptance rate ranged between 57% and 75%. The average age of the turned-down cohort was 60.8 ± 12.5 years; 83% were men. Reasons for rejection included: patient being too sick (34%); psychosocial concerns (25%); patient declined (16%); decision was deferred for medical optimization (15%); or patient being too well (10%). The percentage of patients who were rejected due to psychosocial concerns has increased over time (P = 0.02), whereas the rate of deferral for medical optimization has remained stable (P = 0.10). One-year survival after initial LVAD consultation was 42% in those who were too sick, 64% in those with psychosocial concerns, 68% in patients who declined, 86% in those deferred for medical optimization; and 100% in those too well (P Conclusions One-year survival is reduced among patients who were initially turned down for LVAD therapy, except for those in whom this decision was deferred for medical optimization or because the patient was too well. Psychosocial concerns have become a significant barrier to LVAD therapy.

Primary graft failure (PGF) after heart transplantation (HT) is a devastating and unexpected event characterized by failure of the graft to adequately support recipient circulation necessitating high doses of vasopressors and inotropes and/or temporary mechanical circulatory support. Although it represents an increasingly common event in the current era, there remains a high degree of variability in prevalence, reported risk factors, and approach to this clinical entity. The purpose of the current review is to highlight preoperative considerations including known incidence and risk factors, perioperative issues involving the identification and management of PGF, and postoperative decisions related to weaning of mechanical circulatory support and titration of immunosuppressive therapy. Lastly, we highlight future directions in PGF research, involving basic and translational research, that have the potential to uncover novel strategies of risk stratification and treatment. CASE: Our patient is a 53-year-old man with end-stage non-ischemic dilated cardiomyopathy complicated by ventricular tachycardia (VT), post-capillary pulmonary hypertension, and renal insufficiency. After progressing to NYHA Class IV symptoms, he underwent implantation of a durable left ventricular assist device (LVAD) as bridge to transplant (BTT). On device support, he developed recurrent VT resulting in multiple defibrillator discharges and hospital admission for intravenous anti-arrhythmic therapy. He is subsequently upgraded to a higher status on the waiting list. A suitable donor is identified, with an appropriate predicted heart mass and an anticipated ischemic time of

Introduction: Amiodarone use prior to heart transplant is independently associated with a higher rate of severe primary graft dysfunction and in-hospital mortality. Amiodarone may also alter the pharmacokinetics of medications metabolized via cytochrome P450. No data exist regarding the interaction between pretransplant amiodarone and tacrolimus concentrations. Design: Single-center retrospective study of transplant patients between January 1, 2014, and June 30, 2016. A therapeutic tacrolimus concentration was defined as a trough level between 8 and 15 ng/mL for 2 consecutive days. The primary outcome was the tacrolimus therapeutic weight-based dosing requirements (mg/kg/day) for patients receiving amiodarone prior to transplant when compared to those without prior receipt of amiodarone. Secondary outcomes include the incidence of cellular rejection and mortality within 6 months posttransplant. Results: Multi-organ transplant recipients (n = 3), retransplants (n = 9), those who died prior to a therapeutic level (n = 1), and those receiving amiodarone posttransplant (n = 7) were excluded from the analysis. Of the 80 patients included, 34 (42%) received amiodarone prior to transplant. Patient characteristics were similar, with the exception of primary graft dysfunction incidence (38% in amiodarone vs 8.5% in control, P = .001). The median therapeutic dose was 0.1 (interquartile range [IQR]: 0.07-0.12) versus 0.13 (IQR: 0.09-0.17) in the amiodarone and control groups, respectively, ( P < .01). No significant difference in mortality or rejection was noted. Conclusion: Patients receiving amiodarone prior to transplant require a lower weight-based dose of tacrolimus.

Although extremely high pulmonary vascular resistance (PVR) is a relative contraindication for heart transplantation (HTx), recent data with continuous-flow left ventricular assist devices (LVADs) indicate HTx outcomes may be different when high PVR is managed with an LVAD. This study clarifies the contemporary association between PVR at HTx and posttransplant survival in LVAD vs non-LVAD cohorts.We reviewed the United Network for Organ Sharing registry for adults who received a transplant from 2008 to 2015. In those with continuous-flow LVADs and those with no VADs at HTx, (non-VAD), we grouped patients by low PVR (PVR3), intermediate PVR (PVR 3 to6), and high PVR (PVR ≥6) groups. Adjusted hazard ratios (aHRs) for death after HTx were calculated by Cox regression.The non-LVAD cohort included 6270 patients (4385 in low, 1643 in intermediate, and 242 in high PVR), and the LVAD cohort included 4111 patients (3227 in low, 798 in intermediate, and 86 in high PVR). The high PVR LVAD group had the worst survival, which was not significant, likely to low power (P = .300). The aHR for death in non-LVAD was 1.047 (95% confidence interval, 1.010-1.088) and in LVAD was 1.063 (95% confidence interval, 1.010-1.119). Cubic spline analysis demonstrated nonlinear associations between PVR and the aHR, especially in the LVAD cohort.There was no significant evidence to conclude the effect of pretransplant PVR on posttransplant survival is higher in LVAD vs non-LVAD patients, based on analysis of the United Network for Organ Sharing database. However, further investigations are indicated to clarify HTx candidacy in those with extremely high PVR even after LVAD.

Importance Recipients of heart transplant (HT) may be at increased risk of adverse outcomes attributable to infection with coronavirus disease 2019 (COVID-19) because of multiple comorbidities and clinically significant immunosuppression. Objective To describe the characteristics, treatment, and outcomes of recipients of HT with COVID-19. Design, Setting, and Participants This case series from a single large academic heart transplant program in New York, New York, incorporates data from between March 1, 2020, and April 24, 2020. All recipients of HT followed up by this center who were infected with COVID-19 were included. Interventions Heart transplant and a confirmed diagnosis of COVID-19. Main Outcomes and Measures The primary measure was vital status at end of study follow-up. Secondary measures included patient characteristics, laboratory analyses, changes to immunosuppression, and treatment administered for COVID-19. Results Twenty-eight patients with HT received a confirmed diagnosis of COVID-19. The median age was 64.0 (interquartile range [IQR], 53.5-70.5) years, 22 (79%) were men, and the median time from HT was 8.6 (IQR, 4.2-14.5) years. Comorbid conditions included hypertension in 20 patients (71%), diabetes in 17 patients (61%), and cardiac allograft vasculopathy in 16 patients (57%). Twenty-two participants (79%) were admitted for treatment, and 7 (25%) required mechanical ventilation. Most (13 of 17 [76%]) had evidence of myocardial injury (median high-sensitivity troponin T, 0.055 [IQR, 0.0205-0.1345] ng/mL) and elevated inflammatory biomarkers (median peak high-sensitivity C-reactive protein, 11.83 [IQR, 7.44-19.26] mg/dL; median peak interleukin 6, 105 [IQR, 38-296] pg/mL). Among patients managed at the study institution, mycophenolate mofetil was discontinued in 16 patients (70%), and 6 (26%) had a reduction in the dose of their calcineurin inhibitor. Treatment of COVID-19 included hydroxychloroquine (18 patients [78%]), high-dose corticosteroids (8 patients [47%]), and interleukin 6 receptor antagonists (6 patients [26%]). Overall, 7 patients (25%) died. Among 22 patients (79%) who were admitted, 11 (50%) were discharged home, 4 (18%) remain hospitalized at the end of the study, and 7 (32%) died during hospitalization. Conclusions and Relevance In this single-center case series, COVID-19 infection was associated with a case fatality rate of 25% in recipients of HT. Immunosuppression was reduced in most of this group of patients. Further study is required to evaluate the optimal approach to management of COVID-19 infection in the HT population.

Background Left ventricular assist devices are increasingly being used in patients with advanced heart failure as both destination therapy and bridge to transplant. We aimed to identify histomorphometric, structural and inflammatory changes after pulsatile- and continuous-flow left ventricular assist device placement. Methods Clinical and echocardiographic data were collected from medical records. Aortic wall diameter, cellularity and inflammation were assessed by immunohistochemistry on aortic tissue collected at left ventricular assist device placement and at explantation during heart transplantation. Expression of adhesion molecules was quantified by Western blot. Results Decellularization of the aortic tunica media was observed in patients receiving continuous-flow support. Both device types showed an increased inflammatory response after left ventricular assist device placement with variable T-cell and macrophage accumulations and increased expression of vascular E-selectin, ICAM and VCAM in the aortic wall. Conclusions Left ventricular assist device implantation is associated with distinct vascular derangements with development of vascular inflammation. These changes are pronounced in patients on continuous-flow left ventricular assist and associated with aortic media decellularization. The present findings help to explain the progressive aortic root dilation and vascular dysfunction in patients after continuous-flow device placement.

Background Adults with congenital heart disease (CHD) are at increased risk for adverse outcomes after heart transplantation (HT). However, small cohorts have constrained the identification of factors associated with poor prognosis. We hypothesized that number of sternotomies and bystander organ dysfunction would be associated with an increased risk for early death after HT. Methods and Results We performed a retrospective observational study of all adult CHD patients who underwent HT at our institution from January 1997 to January 2014. Forty-eight adult CHD patients were followed for a mean of 5 years. Diagnoses included tetralogy of Fallot/pulmonary atresia/double-outlet right ventricle in 15 (31%), D-transposition of the great arteries (TGA) in 10 (21%), tricuspid atresia/double-inlet left ventricle in 9 (19%), ventricular or atrial septal defect in 4 (8%), heterotaxy in 3 (6%), congenitally corrected TGA in 2 (4%), and other diagnoses in 5 (10%). Survival at both 1 and 5 years was 77%. According to multivariate analysis, ≥3 sternotomies (hazard ratio [HR] 8.5; P = .02) and Model for End-Stage Liver Disease Excluding International Normalized Ratio (MELD-XI) score >18 (HR 6.2; P = .01) were significant predictors of mortality. Failed Fontan surgery was not a significant predictor of death ( P = .19). Conclusions In our cohort of adult CHD patients undergoing HT, ≥3 sternotomies and MELD-XI score >18 were significantly associated with death. These findings may be important in patient selection and decision regarding tolerable number of CHD surgeries before considering HT.

IntroductionEffective tacrolimus (TAC) dosing is hampered by complex pharmacokinetics and significant patient variability. The gut microbiome, a key mediator of endotoxemia, inflammation and oxidative stress in advanced heart failure (HF) patients, is a possible contributor to interindividual variations in drug efficacy. The effect of alterations in the gut microbiome on TAC dosing requirements after heart transplant (HT) has not been explored.MethodsWe enrolled 24 patients (mean age = 55.8 ±2.3 years) within 3 months post-HT. Biomarkers of endotoxemia ((lipopolysaccharide (LPS)), inflammation (tumor necrosis factor-α (TNF-α)) and oxidative stress (8,12-iso-Isoprostane F-2alpha-VI) were measured in 16 blood samples. 22 stool samples were analyzed using 16S rRNA sequencing. TAC dose and serum trough level were measured at the time of stool and blood collection. TAC doses were reported in mg/kg/day and as level-to-dose (L/D) ratio, and categorized as ≤ vs. > median.ResultsThe median TAC dose was 0.1 mg/kg/day and L/D ratio was 100.01. Above the median daily weight-based TAC dose was associated with higher gut microbial alpha diversity (p = 0.03); similarly, TNF-α and 8,12-iso-Isoprostane F-2alpha-VI levels were lower and LPS levels were higher in the above median TAC group, although these findings were only marginally statistically significant and dependent on BMI adjustment. We observed n = 37 taxa to be significantly enriched among patients with > median TAC dose (all FDRConclusionsOur pilot study observed gut microbial alpha diversity to be increased while inflammation and oxidative stress were reduced among patients requiring higher TAC doses early after HT.

Purpose Cardiac allograft vasculopathy (CAV) is a pan-arterial disease, characterized by intimal thickening, fibrosis, and decreased coronary blood flow. It is common (50-65% 10 years post-HT) and is among the leading causes of death following heart transplantation (HT). Screening has traditionally evaluated the epicardial coronary arteries and microvascular dysfunction has been largely overlooked. Recent data suggests poor outcomes among HT patients with low myocardial flow reserve (MFR), a parameter capable of assessing microvascular function. We sought to identify the impact of MFR on death, retransplantation (ReTx), or cardiovascular (CV) hospitalization. Methods This prospective study enrolled 181 (206 screened, 3 studies were technically limited, 22 had high rest flows) patients who underwent 13N ammonia PET with CT attenuation correction between 2016-2017. Patients were followed for clinical outcomes including rejection (cellular or antibody mediated rejection [AMR]), graft function, and CAV. The optimal MFR cut off was determined by a receiver operator characteristic curve. Results Among the cohort, MFR was highly predictive of the combined endpoint (HR 7.58, p Conclusion Decreased MFR following heart transplant is associated with an increased risk of death, ReTx, or CV hospitalization.

Purpose Whether C-reactive protein (CRP) levels prior to left ventricular assist device implantation (LVAD) are predictive of post-implantation outcomes is not well established. Current data are limited to small, single-center studies. Methods 5,183 adult recipients of continuous-flow left ventricular assist devices with pre-implant CRP measurement were identified from INTERMACS. Patients were divided into three groups based on pre-implant CRP levels: CRP of 0 to 10 mg/L (low), 11 to 30 mg/L (intermediate), and >30 mg/L (high). Outcomes of interest were mortality, gastrointestinal bleeding, device thrombosis, infection, stroke, and right heart failure. Analyses included Kaplan-Meier survival estimates and Cox proportional hazards models. Results Patients with higher pre-implant CRP were younger (55.3 vs 56.5 vs 57.8 yrs), had sicker INTERMACS profiles (Class I: 33.7% vs 22.6% vs 9.5%); higher use of IABP (34.1% vs 26.0% vs 14.5%) and ECMO (12.0% vs 6.9% vs 2.1%) compared to patients with intermediate and low CRP levels (all p Conclusion Higher CRP levels indicate comorbidity prior to LVAD implantation and predict higher risk of post-implant right heart failure and mortality. These findings suggest that baseline CRP may be a useful predictor of clinical outcome after LVAD implantation.

Purpose In October 2018, a new heart transplantation (HT) allocation system was implemented with the intent of prioritizing the most medically urgent candidates, including those with cardiogenic shock requiring percutaneous support, extracorporeal membrane oxygenation (ECMO), and surgical support devices. We hypothesized that utilization of acute mechanical circulatory support (MCS) increased nationwide as a result of the new allocation system. Methods The UNOS database were queried to identify patients listed for HT on or after January 2017. Patients were categorized into: 1) old allocation (listed and removed before 10/18/2018) and 2) new allocation (listed on or after 10/18/2018) groups. Patients who crossed over from old to new allocation were excluded from the analysis. MCS utilization and post-transplant graft survival were compared in the two eras. Results 4663 patients were waitlisted during the old allocation compared to 1759 waitlisted patients in the new allocation system. There was a significant increase in the utilization of intra-aortic balloon pump (IABP) (6.1% to 9.7%, p Conclusion Use of acute circulatory support devices has increased as bridge to HT. Early post-transplant graft survival is significantly better for patients bridged with IABP support compared to ECMO or other surgical support devices.

Purpose MOMENTUM 3 trial demonstrated superiority of Heartmate 3 (HM 3) compared to Heartmate II (HM 2) with regards to hemocompatibility, however, their differential effects on de-novo HLA allosensitization, which may create a challenge for future transplantation, remains unknown. Methods Patients who underwent HM2 or HM3 implantation and had no prior HLA antibodies by solid-phase assay (Luminex) testing at a major academic center were included for the study. Complement dependent cytotoxicity (CDC) panel reactive antibody (PRA) levels as well as Luminex antibody profiles were followed until cardiac transplantation, device explantation, or death. Results 34 HM3 and 34 HM2 patients with no HLA antibodies by Luminex testing prior to LVAD implant were identified with a mean follow-up duration of 1.71 ± 1.1 years on device support. HM3 and HM2 groups had similar age at implant (56.1±8.6 vs 54.7±12.0, p=0.575), female gender (11.8% vs. 14.7%, p=0.720), ischemic HF etiology (38.2% vs 35.3%, p=0.801), and bridge strategy at implant (44.1% vs 58.8%, p=0.225). Over the follow-up period, 41.2% of HM3 and 47.1% of HM2 patients had detectable HLA antibodies by Luminex testing (p=0.625). Development of high level (MFI>10, 000) Class I HLA antibodies were significantly lower in HM3 patients (2.9% vs 17.9%, p=0.046) compared to high-level Class II HLA antibodies which were similar in two device groups (2.9% vs 5.9%, p=0.555). CDC PRA testing showed lower proportion of HM3 patients with a positive result (PRA >0%) for T cell (32.4% vs. 55.9%, p=0.050) compared to positive B cell panel which was comparable in two groups (32.4% vs 47.1%, p=0.215). Peak PRA levels in patients who turned positive was comparable for T cell (5.8% vs 6.5%, p=0.775) and B cell (10.2% vs. 12.4%, p=0.568) in HM3 vs. HM2 patients. Conclusion Our findings suggest that HM3 is associated with a lower likelihood of de-novo HLA sensitization than HM2 specifically against Class I antigens.

Purpose In addition to goal-directed therapies, advanced therapies for heart failure including left ventricular assist devices (LVADs) remain underutilized in women. Sex-specific data in the area of mechanical circulatory support remains sparse and women are often underrepresented in heart failure trials. Even less is known about sex differences in outcomes with the HeartMate 3 LVAD, an FDA approved centrifugal-flow device. Methods Consecutive patients who received HeartMate 3 LVAD as bridge-to-transplant or destination therapy at a single institution were included in the study. Demographics, co-morbidities, device-related factors, and outcomes were comparatively examined between women and men. Results 175 patients (28 women, 16.0%) were identified. Women were significantly younger than men (53.9 vs. 60.1 years, p=0.023) with smaller body surface area (1.83 vs 2.08, p Conclusion In our single-center experience with HeartMate 3 LVADs, there were no significant differences in early morbidity and mortality between women and men.

Purpose Antibody mediated rejection (AMR) is an increasingly studied cause of graft failure after heart transplantation. AMR diagnostic criteria previously required serum donor specific antibodies (DSA). However, the most recent criteria only requires pathological findings independent of DSA. This classification defined a subset of patients with AMR without known antibodies. To investigate this complication, we performed RNA sequencing using endomyocardial biopsy samples taken at the time of pathology confirmed AMR in the presence and absence of DSA. Methods We evaluated the transcriptome profile of the paraffin-embedded endomyocardial biopsy specimens of 30 representative heart transplant recipients. Patients were categorized as having no evidence of AMR (controls), immunohistochemical findings of AMR (pAMR1i) in the presence of DSA (1i+D), pAMR1i in the absence of DSA (1i-D), histopathological findings of AMR (pAMR1h) in the presence of DSA (1h+D), pAMR1h in the absence of DSA (1h-D) or presence of both immunohistochemical and histopathological findings of AMR (pAMR2) in the presence of DSA. A total of 5 patients were analyzed per group. All were matched for previous mechanical circulatory support and time from transplant to biopsy. Results There was no differential RNA expression between patients with no AMR and those in the 1i-D group. There was also no differential expression between patients in the 1h+D and pAMR2 groups. The largest difference was seen between the no AMR and 1i+D groups and the no AMR and pAMR2 groups. In addition, there was RNA expression differences between patients with immunohistochemical evidence of AMR compared to those with histopathological findings, suggesting distinct mechanisms. Conclusion These studies demonstrate that RNA expression profiling can be performed on endomyocardial biopsy tissue preserved in paraffin from the time of a rejection episode and that different expression patterns are observed dependent on the criteria used to diagnose AMR. In particular, AMR in the presence of DSA showed a different RNA expression profile than AMR without DSAs. The RNA expression associated with histological markers of AMR also appeared different than that associated with immunological markers. Overall, our findings suggest the existence of different subtypes of AMR that may rely on distinct mechanisms of injury.

Purpose Cardiac allograft vasculopathy (CAV) is a major complication that affects long-term survival after heart transplantation (HT). Multiple factors contribute to the development of CAV, with inflammation playing an important role. Endothelin-1 (ET1) is a pro-inflammatory mediator that has been implicated in development of CAV. Trimethylamine-N-oxide (TMAO) is a gut-derived metabolite, recently linked to accelerated risk of atherosclerosis in non-HT pts. Herein, we sought to investigate the association of ET1 and TMAO with CAV in HT. Methods Blood was collected in 116 HT pts (52.8±12.6 yo; F 19%). Plasma TMAO and serum ET1 were measured via LC-MS and ELISA, respectively. Presence of CAV on angiography was defined using the current ISHLT criteria or an intravascular ultrasound measurement of a maximal intimal thickness of >0.5mm. We used Wilcoxon test and logistic regression analyses to assess the association between CAV and TMAO/ET1 levels, controlling for several covariates. Results TMAO and ET1 were measured at a median [IQR] of 9.3 [4.7-52.7] months post-HT. CAV was assessed at a median of 4.70 [1.08-8.17]y. Median TMAO and ET1 levels were 4.79 [2.49-9.15] µM and 1.93 [1.36-2.61] pg/mL, respectively. CAV was present in 59 (51%) pts. There was no difference in baseline characteristics in pts with (CAV+) and without CAV (CAV-). CAV+ pts had a longer median follow up (5.98 [2.99-9.75] vs 1.92 [1.01-6.02]y). TMAO levels were similar in both groups (5.50 [2.67-11.5] vs 4.44 [2.61-7.58] µM, p = 0.56), while ET1 was significantly higher in the CAV+ group (2.20 [1.69-2.93] vs 1.68[1.21- 2.31] pg/mL, p Conclusion Our findings indicate that ET1, but not TMAO, is independently associated with CAV in HT.

Purpose Number of adult congenital heart disease (ACHD) patients who require heart transplantation (HT) has increased. However, transplant rate for these patients has remained low. The potential reason of this phenomenon could be surgical complexity related to anatomical abnormalities and multiple prior surgeries. In this study, we sought to determine the HT outcomes of ACHD patients who had prior cardiac surgery using United Network for Organ Sharing (UNOS) database. Methods Between January 2008 and March 2019, ACHD patients who had prior cardiac surgery and subsequent HT were identified from the UNOS database. As a control group, adult patients without congenital heart disease who had prior sternotomy and subsequent HT were extracted.Propensity score matching (PSM) was used to compare outcomes between two groups. Results There were 793 ACHD group and 8400 control. Unadjusted comparison shows that ACHD were younger (p Conclusion ACHD patients with prior intracardiac repair carried higher operative risk but long-term outcome was equivalent to non-ACHD patients with prior sternotomy.

Purpose Gastrointestinal bleeding (GIB) remains a common and vexing complication of left ventricular assist device (LVAD) support. Recent single-center analyses suggest that ACE inhibitors (ACEi)/angiotensin receptor blockers (ARB) and digoxin may prevent GIB in LVAD patients. Here we evaluate the effect of heart failure (HF) drug therapies on rates of GIB through analysis of the INTERMACS registry database. Methods 13,732 patients who received a continuous-flow LVAD and were on antiplatelet therapy coupled with warfarin anticoagulation at 3 months of pump support were included in the analysis. GIB events beyond 3 months following implant were assessed receipt of ACEi/ARB, beta-blockers (BB), aldosterone antagonists (AA), amiodarone (Amio), digoxin, loop diuretics, and phosphiesterase inhibitors (PDE5) at 3 months of support. Backwards stepwise cox regression was used to control for confounding of each drug class on each other, as well as for clinical variables like age, gender, renal function, HF etiology, and device strategy. Results Medication use in LVAD patients were BB (65.0%), ACEi/ARB (51.7%), Amio (43.7%), AA (37.9%), and loop diuretics (70.1%) at 3 months of pump support. In patients with available data, PDE and digoxin use were 18.2% and 16.9% respectively. The overall incidence of GIB was 23.7% at 2 years of support. After adjustment for other clinical variables, loop diuretics (HR 1.274, p Conclusion Despite recent reports, ACEi/ARB, AA, Amio, and digoxin use have minimal association with GIB on LVAD support. The heightened risk seen in those on loop diuretics may reflect venous congestion in these patients, while antiplatelet effects of PDE5 could drive the higher risk of GIB.

Purpose Serum creatinine (sCr) is routinely used in the assessment of renal function among heart transplant (HT) pts. However, changes in muscle mass and nutritional status early post-HT may affect the accuracy of sCr estimated glomerular filtration rate (eGFRsCr). While Cystatin C (CysC) is independent from the above mentioned confounders, an increase in CysC with steroid use has been reported. The ratio sCr/CysC has been validated as a marker of muscle mass. Herein, we aimed to: i) longitudinally compare post-HT changes in CysC eGFR (eGFRCysC) and eGFRsCr; and ii) investigate the relation of muscle mass, nutritional status and steroid use with the difference between eGFRCysC and eGFRsCr. Methods Pts transplanted between 6/2016 and 4/2019 had serial, concurrent measurements of CysC and sCr pre- and post-HT. Albumin (a marker of nutritional status) and prednisone dose at the time of sample collection were recorded. Adjusted linear mixed models were used to: i) regress post-HT changes in eGFRCysC, eGFRsCr and sCr/CysC ratio; ii) study associations of albumin and prednisone dose with the difference between eGFRsCr and eGFRCysC (ΔeGFRsCr-CysC = [eGFRsCr - eGFRCysC]/eGFRsCr). Results 313 samples were collected in 84 pts (age 54±12, 20% female). While eGFRsCr declined long-term, eGFRCysC showed an opposite trend with a gradual improvement (Figure). The temporal decline in eGFRsCr mirrored the progressive rise in sCr/CysC ratio, suggesting a contribution of an increase in muscle mass to this decline. Albumin was inversely related to ΔeGFRsCr-CysC (β= -0.51, p Conclusion eGFRCysC and eGFRsCr markedly differ early post-HT. Changes in muscle mass and nutritional status as well as steroid use may account for the observed discrepancies. Future studies are warranted to address these inconsistencies as accurate estimation of renal function carries important clinical implications (e.g. medication dosing).

Purpose Creatinine clearance (CrCl) is the accepted clinical standard for the assessment of renal function and dosing of renally-excreted medications such as valganciclovir (VGC) among heart transplant (HT) pts. Cystatin C (CysC) has recently shown superiority to serum creatinine (sCr) for the estimation of renal function in advanced diseases. We hypothesize that CysC-estimated glomerular filtration rate (Cys-eGFR) more accurately guides VGC dosing than CrCL, and thereby may prevents drug overdosing and leukopenia in HT pts. Methods Pts transplanted between 11/2016 and 4/2019 who received VGC for CMV prophylaxis were included. eGFR was assessed using CrCl and CysC-eGFR as a time-varying covariate at 1-,3-, and 6-months post-HT. The primary endpoint was rate of leukopenia (WBC Results 119 samples were available in 58 pts (age 54±13 y, 20% female). Based on CrCl, VGC was inappropriately dosed in 43 samples: 21 underdosed, 22 overdosed. Based on CysC-eGFR, VGC was inappropriately dosed in 62 samples: 12 underdosed, 50 overdosed (Figure 1). 32 episodes of leukopenia were observed in 27 pts within 1-month of sampling. Half (n=16) of the events occurred in samples with VGC overdosed by CysC-eGFR. In adjusted models, CysC but not sCr was associated with a significant 1.48 times greater odds of leukopenia (per 0.3 mg/L CysC 95%CI 1.05-2.08; OR per 0.3 mg/dL sCr 1.17, 95%CI 0.78-1.73.) Conclusion CysC-eGFR may more accurately estimate VGC dosing compared to CrCL thereby resulting in lower rates of leukopenia after HT.

Purpose MOMENTUM 3 trial excluded patients with planned biventricular support prior to enrollment and 4.2% right ventricular failure requiring RVAD in Heartmate 3 (HM 3) patients. The aim of this study was to assess the use of RVAD in the real-world post-approval era. Methods HM3 implantation at a major academic center were categorized into two era: HM 3 implanted 1) before FDA approval (8/23/2017) [N=67] and 2) after FDA approval [N=107]. Baseline patient characteristics, RVAD utilization patterns, and LVAD complications and mortality were analyzed in the pre- vs. post-approval era. Results In the post-approval era, HM3 patients were younger (57.5±14.1 vs 61.7±11.2 yrs, p=0.031), more likely to have ischemic etiology of heart failure (55.6% vs 34.3%, p=0.006), to be INTERMACS Class I (21.3% vs. 1.5%, p=0.002), and to have VA-ECMO or paracorporeal VAD support (12.0% vs 0.0%, p=0.012) prior to HM3 implant. 8 (11.9%) patients out of 67 required RVAD in the pre-approval era as opposed to 47 patients out of 108 (43.5%) in the post-approval era (p Conclusion Level of sickness at the time of device implantation as well as need for RVAD utilization increased substantially in HM3 patients following the FDA approval. However, the change in practice did not adversely affect post-LVAD morbidity or mortality.

Purpose Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality post heart transplant (HT). Coronary calcium has a sensitivity of 91% for the presence of >50% angiographic stenosis among the general population. Given the different pathophysiology of CAV and atherosclerosis, it is unclear whether visually estimated coronary artery calcification (VECAC) on CT attenuation correction (CTAC) scans can be used to detect CAV post HT and whether there is an association with long-term outcomes in patients with CAV. Methods Consecutive HT recipients who underwent 13 N-ammonia positron emission tomography with CTAC to assess for CAV between 2016-2017 were included. CAC was reported using the estimated Agatson score. CAV on paired angiography (within 1 year of PET/CTAC) was defined using the ISHLT nomenclature, CAV0-3, and compared to visually estimated CAC (VECAC). Events recorded were time to cardiovascular (CV) hospitalization, retransplantation or death. Results Complete data was available for 179 patients. Forty-seven (26.3%) had CAC of any severity. The CAC group were older (62 ± 12.7 vs 58 ± 15.6 y), with longer time post-transplant (127 ± 68 vs 88 ± 58 months) and older donor age (42.9 ± 12.3y vs. 30.6 ± 11.5y), all significant p Conclusion Visually estimated CAC may be useful to screen for advanced CAV (NPV >95%) among HT recipients. The presence of CAC was not associated with adverse outcomes.

Purpose Coronary allograft vasculopathy (CAV) following heart transplantation (HT) is a major cause of morbidity and mortality. Assessment of myocardial flow reserve (MFR) by positron emission tomography (PET) is increasingly used in clinical practice; reduced MFR has been associated with adverse cardiovascular (CV) outcomes. Little is known regarding sex differences in MFR and associated outcomes in HT recipients. Methods Consecutive HT recipients who underwent rest and stress N13 ammonia PET as part of standardized protocol for assessment of CAV were included. Clinical characteristics including demographics, medications, and co-morbidities were recorded. Imaging characteristics including MFR, visually estimated coronary artery calcium (VECAC) scores, and degree of ischemia were examined. Coronary angiograms performed within 1 year of PET were reviewed for degree of CAV. Events including CV hospitalizations and death were captured. Results Complete clinical and imaging information was available for 181 patients (48 women, 26.5%) from 2016-2017. Women and men differed with respect to age [54.7±16.0 vs 52.0±16.3 years, p 1.96 and women irrespective of MFR (Figure, p Conclusion Reduced MFR on PET following HT may not be as predictive of CV events in women. These findings need to be validated in other cohorts.

Purpose Treatment of cardiogenic shock associated with late allograft failure after heart transplant (HT) is poorly characterized and infrequently reported. In this study, we examined the role of mechanical circulatory support (MCS) as a method to treat patients with severe late graft failure. Methods From 2000 - 2018, there were 1275 adult HT at our institution. Of those, 26 patients (2.0%) were identified who required MCS for cardiogenic shock due to late allograft failure. Patient demographics and outcomes were retrospectively reviewed. Results Median age of the cohort was 37.3 years (IQR: 17.3) and 69% were male. Median time from initial transplant to MCS was 2.9 years. At the time of shock, median hemodynamic values were as follows: CVP 18 mmHg, mean PA pressure 29 mmHg, PCWP 25 mmHg, and CI 1.87 L/min/m2. On echocardiogram, median LVEF was 25% and 77% of patients had moderate or severe right ventricular dysfunction. Seven patients (27%) had severe allograft coronary disease, while all remaining patients had chronic or acute worsening rejection. Initial MCS used included veno-arterial extracorporeal membrane oxygenation in 15 patients (58%), biventricular assist device in 10 patients (38%), and total artificial heart in 1 patient (4%). 8 patients underwent revision of MCS during the same hospitalization, on average 18 days after initial placement. While on MCS, the most common treatments for rejection were pulse dose steroids (69%), thymoglobulin (54%), and plasmapheresis (31%), with nearly all patients receiving combination therapy. Six patients (23%) weaned from MCS following medical therapy. Median duration of MCS was 33 days (IQR 55). Major morbidities included bleeding events in 39%, new renal replacement therapy in 23%, major infection in 27%, and stroke in 23%. Eight patients (31%) underwent re-heart transplant, all within one year of MCS, and survival for this cohort was 100% at 1 year. However, for those patients who were not offered re-transplant or who died while awaiting re-transplant, 1 year survival was only 22%, with 61% of deaths occurring in the hospital. Conclusion Late graft failure resulting in cardiogenic shock carries significant morbidity and mortality, despite use of contemporary MCS.

Purpose Myocardial flow reserve (MFR) compares hyperemic to resting myocardial blood flow to evaluate the effects of coronary stenosis or microvascular disease on myocardial blood flow (MBF). Positron emission tomography (PET) is the most accurate noninvasive modality for assessing MBF and diagnosing coronary disease. Impaired MFR by PET is also predictive of adverse events, including mortality, for both atherosclerosis and cardiac allograft vasculopathy (CAV). Prior studies assessing MFR in CAV included patients an average of 10 years post heart transplant (HT). We sought to assess whether the prognostic effect of MFR was consistent both early and late after HT. Methods From 2016-2017 206 patients underwent rest/stress 13N ammonia PET with CT attenuation correction. The cohort was divided into quartiles: 0-4y, 4-7y, 7-11y, >11y post-HT. MFR data were compared over time. Results 181 patients (Exclusions: 3 technically limited, 22 had high rest flows) were enrolled in the study. Overall MFR values (median, IQR) were consistent among the first three quartiles, but were lower for the >11y quartile (2.16 [1.82-2.66], 2.11 [1.75-2.77], 2.19 [1.82-2.77], 2.01 [1.52-2.76] p Conclusion Decreased MFR is associated with an increased risk of death, retransplantation, or cardiovascular hospitalization following HT. This effect is seen both early and late after transplant, with a dramatically increased risk after 7 years.

Purpose Pulmonary artery pulsatility index (PAPi) recently emerged as a predictor of right ventricular failure after Heartmate II LVAD Implantation. Clinical utility of this marker in Heartmate 3 patients is unknown. We hypothesized that PAPi is a stronger predictor of RV failure compared to central venous pressure to pulmonary artery capillary wedge pressure ratio (CVP/PCWP) or RV stroke work index (RVSWI) in Heartmate 3 population. Methods 175 patients who received a Heartmate 3 LVAD at a single academic center between 2014 - 2019 were included in the study. Primary outcome was right ventricular assist device (RVAD) use following HM3 implant. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis determined predictors of RVAD use in HM3 patients. Results 55 patients (31.4%) required RVAD following HM3 implantation including 19 percutaneous, 24 paracorporeal, and 2 durable RVADs. Age, gender, and implant strategy were comparable between RVAD and no RVAD groups. Patients requiring RVAD were more likely to be INTERMACS Class I or II (78.2% vs. 56.6%), have a higher WBC count (9.2±3.4 vs. 8.1±2.8) and C-reactive protein (57.7±59.2 vs. 38.4±34.7) prior to device implant (all p Conclusion PAPi is an independent predictor of RV failure in Heartmate 3 patients. Incorporating PAPi in clinical decision-making may improve patient selection and perioperative outcomes in this population.

High pulmonary vascular resistance (PVR) has been associated with early postoperative morbidity and mortality after heart transplantation (HT). Left ventricular assist device (LVAD) or chronic vasodilator therapy can lower PVR sufficiently to allow eligibility for HT. This study assessed whether

Venoarterial extracorporeal membrane oxygenation is a useful treatment for severe primary graft dysfunction after heart transplant. The ideal timing of initiation is unknown.We retrospectively reviewed 362 adult heart transplant recipients at our center between January 2011 and December 2017. Thirty-eight patients (10.5%) experienced severe primary graft dysfunction treated with venoarterial extracorporeal membrane oxygenation. As our institution adopted a prompt venoarterial extracorporeal membrane oxygenation policy in 2015, patients were stratified into pre-2015 (conservative extracorporeal membrane oxygenation: n = 18) and post-2015 (prompt extracorporeal membrane oxygenation: n = 20) cohorts. Clinical outcomes were compared.Baseline characteristics were similar (conservative vs prompt) except for age (51.82 vs 59.96 years, P = .036), aspartate transaminase (32 vs 21.5 U/L, P = .038), male donor (44.4 vs 80%, P = .042), and donor ejection fraction (60 vs 65%, P = .047). Median ischemic time was significantly longer in the conservative extracorporeal membrane oxygenation cohort (210 vs 148 minutes, P = .005). Median time to initiation of extracorporeal membrane oxygenation was significantly shorter in the prompt extracorporeal membrane oxygenation cohort (7.26 vs 1.95 hours, P .0001). There was no difference in intensive care unit stay or major complications. In-hospital mortality improved from 28% (conservative) to 5% (prompt, P = .083). Post-transplant survival at 1 year was 67% in the conservative extracorporeal membrane oxygenation cohort and 90% in the prompt extracorporeal membrane oxygenation cohort (P = .117). There was no difference in the Kaplan-Meier survival curves (P = .071), although Cox regression suggested, but certainly did not prove, a 74.6% lower risk of mortality in the prompt extracorporeal membrane oxygenation group (P = .094).Prompt venoarterial extracorporeal membrane oxygenation use for primary graft dysfunction after heart transplant results in excellent myocardial recovery and a possible decrease in mortality without increased risk of complications.

Background Although implantation of a left ventricular assist device ( LVAD ) generally improves tricuspid regurgitation ( TR ) in short‐term follow‐up, the clinical significance of residual TR in patients with mid‐ to long‐term LVAD support is unknown. This study aimed to identify the prevalence, predictors, and prognostic value of residual TR in LVAD patients in association with tricuspid valve ( TV ) deformation. Methods and Results The study cohort consisted of 127 patients who underwent LVAD implantation without TV procedure and were supported with LVAD at least 1 year. All patients underwent echocardiographic examination preoperatively and 1 year after LVAD implantation. TR was quantitatively assessed by ratio of TR color jet area/right atrial area, and significant residual TR was defined as ≥20% of % TR at follow‐up echocardiographic examination. Detailed echocardiographic measurements were also performed, including TV annulus diameter, TV leaflet displacement, and left ventricular and right ventricular systolic function. LVAD implantation significantly improved ratio of TR color jet area/right atrial area as well as left ventricular and right ventricular systolic function and tethering distance (all P TV annulus diameter ( P =0.002). Significant residual TR was observed in 30 (23.6%) patients. Age, preoperative TV annulus diameter, and residual mitral regurgitation were significantly associated with significant residual TR (all P TV tethering was not. During a mean follow‐up of 21±17 months, patients with residual TR had significantly higher mortality than those without residual TR (log‐rank P Conclusions Significant residual TR was observed in ≈25% patients supported with LVAD over 1 year and was associated with unfavorable outcome.

Background: There is mixed evidence of racial and socioeconomic disparities in heart transplant outcomes. Their underlying cause—and whether individual- or community-level traits are most influential—remains unclear. The current study aimed to characterize socioeconomic disparities in outcomes and identify time trends and mediators of these disparities. Methods and Results: We used United Network for Organ Sharing registry data and included 33 893 adult heart transplant recipients between 1994 and 2014. Socioeconomic status (SES) indicators included insurance, education, and neighborhood SES measured using a composite index. Black race and multiple indicators of low SES were associated with the primary outcome of death or retransplant, independent of baseline clinical characteristics. Blacks had lower HLA and race matching, but further adjustment for these and other graft characteristics only slightly attenuated the association with black race (HR, 1.25 after adjustment). This and the associations with neighborhood SES (HR, 1.19 for lowest versus highest decile), Medicare (HR, 1.17), Medicaid (HR, 1.29), and college education (HR, 0.90) remained significant after full adjustment. When comparing early (1994–2000) and late (2001–2014) cohorts, the disparities associated with the middle (second and third) quartiles significantly decreased over time, but those associated with lowest SES quartile and black race persisted. Low neighborhood SES was also associated with higher risks of noncompliance (HR, 1.76), rejection (HR, 1.28), hospitalization (HR, 1.13), and infection (HR, 1.10). Conclusions: Racial and socioeconomic disparities exist in heart transplant outcomes, but the latter may be narrowing over time. These disparities are not explained by differences in clinical or graft characteristics.

Primary graft dysfunction (PGD) remains a significant cause of post-transplant morbidity and mortality. The exact mechanism and risk factors for this phenomenon remain unknown in the contemporary era.In this study we reviewed adult patients undergoing heart transplantation (HT) at our institution between 2009 and 2017. Severe PGD was defined as the need for mechanical circulatory support (MCS) within the first 24 hours after HT. Multivariate logistic regression analysis was used to identify risk factors for severe PGD, focusing on those bridged to transplant (BTT) with a continuous-flow left ventricular assist device (CF-LVAD).Fifty-six of 480 (11.7%) HT patients experienced severe PGD. Eighty percent of the severe PGD patients were BTT with a CF-LVAD (odds ratio [OR] 3.86, 95% confidence interval [CI] 1.94 to 7.68, p0.001). Among the BTT patients, significant associations between1 year of CF-LVAD support (OR 2.48, 95% CI 1.14 to 5.40, p = 0.022), pre-HT creatinine (OR 3.35, 95% CI 1.42 to 7.92, p = 0.006), elevated central venous pressure/pulmonary capillary wedge pressure (CVP/PCWP) ratio (OR 3.32, 95% CI 1.04 to 10.60, p = 0.043), use of amiodarone before HT (OR 2.69, 95% CI 1.20 to 6.20, p = 0.022), and severe PGD were identified. RADIAL score did not accurately predict severe PGD in this contemporary cohort. Those patients who developed severe PGD had decreased 1-year post-transplant survival (78.3% vs 91.8%, p = 0.007).Use of CF-LVAD as BTT is associated with an increased risk of severe PGD. Increased time on device support, renal dysfunction, right ventricular dysfunction as assessed by CVP/PCWP ratio, and pre-transplant amiodarone may identify those patients at high risk. Further research is warranted focusing on optimal timing of device implantation and transplantation, as well as the underlying mechanisms of PGD.

With the impending United Network for Organ Sharing (UNOS) heart allocation policy giving VA-ECMO supported heart transplant (HT) candidates highest priority status (Tier 1), identifying patients in cardiogenic shock (CS) with severe and irreversible heart failure (HF) appropriate for urgent HT is critically important. In a center where wait times currently preclude this approach, we retrospectively reviewed 119 patients (ages 18-72) with CS from 1/2014 to 12/2016 who required VA-ECMO for >24 hours. Underlying aetiologies included postcardiotomy shock (45), acute coronary syndromes (33), and acute-on-chronic HF (16). Eighty-four percent of patients (100) had ≥1 contraindication to HT with 61.3% (73) having preexisting contraindications (eg, multiorgan dysfunction and substance abuse), and 68.1% (81) experienced preclusive complications (eg, renal failure, coagulopathy, and infection). Potential HT candidates were significantly more likely to survive to discharge (potential HT candidates 84.2% vs preexisting contraindications 43.8% vs contraindications developing on VA-ECMO 33.3%, P = 0.001). Among potential HT candidates, 11 (68.8%) were discharged without advanced therapies and 4 received durable left ventricular assist device (25.0%). Importantly, 1-year survival was 100% for the 11 patients with follow-up. Thus, further work is critical to define appropriate candidates for HT from VA-ECMO while avoiding preemptive transplantation in those with otherwise favorable outcomes.

Blood type O heart transplant recipients wait longer than non-O recipients and frequently require bridging left ventricular assist devices (LVADs). However, rarely has the effect of this disparity been shown in a large registry. This study used Markov simulation to clarify the outcome difference between O and non-O candidates and how allocation change could affect survival.We reviewed the United Network for Organ Sharing registry for adults listed for heart transplantation from 2008 to 2015. Cumulative incidences of death or transplant and survival after listing were compared between O and non-O using propensity matching. A four-state Markov model-waiting without LVAD, waiting with LVAD, transplantation, and death-was created to simulate survival after listing. Sensitivity analysis was performed to see how the percentage of O hearts in non-O recipients would affect survivals.A total of 8,187 O and non-O candidates were included after matching. The cumulative incidence of transplantation was lower in O (p0.001), and death after listing was significantly higher (p0.001). During a median follow-up of 2.1 years, 69.6% of non-O candidates were transplanted, compared with 54.9% of O candidates (p 0.001). Despite this disparity, 19% of non-O recipients received O hearts. Our simulated survival demonstrated that decreasing the O heart percentage in non-O recipients from the current 19% to 5% would provide similar survival in O and non-O after listing.Under the current strategy, there are death and transplant rate differences between O and non-O candidates. Our simulation-based allocation strategy might aid in mitigating this discrepancy across blood types.

Introduction There is renewed interest in the utility of the intra-aortic balloon pump (IABP) for short-term and durable support in patients with chronic systolic heart failure (HF) who present with acute decompensation and cardiogenic shock (CS). However, the clinical characteristics of IABP-responders and non-responders remain incompletely defined. We sought to identify predictors of early IABP response to guide optimal use of IABP therapy in this population. Methods We retrospectively analyzed the records of chronic systolic HF patients who presented at our institution between 2011-2018 with acute decompensated HF with hemodynamic evidence of CS and underwent IABP placement. IABP-responder was defined as having an immediate increase in cardiac output (CO) and an immediate decrease in mean pulmonary artery pressure (MPAP) above the median values of the cohort. Logistic regression was used to identify predictors of hemodynamic response. Results During the study period, 218 chronic systolic HF patients underwent IABP insertion for acute decompensation with CS. The mean age was 59.4 ±13.4 years, 79.8% were men, and 38.5% had ischemic cardiomyopathy (ICM). The average hemodynamic response to IABP in the whole cohort was a CO increase of 0.57 ±0.85L/min and a MPAP reduction of 5.1 ±7.6mmHg; IABP-responders had a CO increase of 1.21 ±0.87L/min and a MPAP reduction of 12.1 ±5.9mmHg (figure). Univariable predictors of IABP-response were ICM, presence of severe mitral regurgitation, baseline heart rate, elevated MPAP, and elevated systemic vascular resistance (SVR). Following multivariable logistic regression, independent predictors of IABP-response were elevated baseline SVR (OR 2.05, 95% CI 1.01 - 4.17; p=0.047) and elevated MPAP (OR 2.47, 95% CI 1.23 - 5.00; p=0.01). MPAP reduction decreased the odds of death or need for escalation to another short-term circulatory support device while CO increase did not [OR 0.52 (0.28 - 0.97; p=0.04) vs. 0.83 (0.45 - 1.54; p=0.56)]. Conclusions A subset of chronic systolic HF patients had a robust hemodynamic response to IABP insertion with CO augmentation and MPAP reduction. Elevated baseline SVR and MPAP are predictors of robust response following device insertion. These parameters may be used to identify patients who may respond favorably to IABP counterpulsation therapy.

Purpose With increasing organs available in light of the national opioid epidemic and the availability of direct acting-antiviral (DAA) therapy for Hepatitis C virus (HCV), HCV antibody (Ab)+ organs serve as an important potential supply to the donor pool. We sought to examine trends over time in the utilization of HCV Ab+ organs both nationally and regionally. Methods We queried the United Network for Organ Sharing registry data in the DAA era between January 2012 and March 2018 for adults ≥18 years who had undergone heart transplantation with a HCV Ab+ donor as well as donor recovery data. Results The incidence of HCV Ab+ deceased donors have increased from 4.6% in 2012 to 8.7 in 2018 (p Conclusion Over the last two years, with the availability of DAA therapy, there has been increased nationwide recovery and utilization of HCV Ab+ donor hearts that is accompanied by significant regional variability. Adopting standardized protocols across UNOS regions and transplant centers may increase utilization of these donors more effectively and potentially lead to better outcomes.

Purpose T-cells are implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), yet their clonal composition and function are incompletely defined. We examined the T-cell receptor β (TCRβ) repertoire from explanted grafts with CAV and characterized their phenotype at the single-cell level. Methods TCRβ repertoire analysis was carried out in 4 cardiac explants with CAV by next generation sequencing using DNA extracted from 1) coronary artery (CA), 2) endomyocardium (endo) 3) peripheral blood and 4) cardiac biopsies from the same patients. Blood and intragraft T cells were also phenotyped at the single cell level using a strategy combining index sorting, 13-colour flow cytometry and single-cell RT/PCR for key cytokines, transcription markers and TCRβ chain sequencing. Unique TCRβ chain gene rearrangements were used to link single-cell and TCR repertoires. Results Overlap between intragraft and blood T cell repertoires was observed in all 4 cases with most high frequency rearrangements present in both compartments (Fig. 1a). The clonality index was higher in the blood compared to the graft. In contrast, there was minimal overlap in the B cell repertoire from the same samples (example in 1b). Strikingly, in each case, a common high frequency TCRβ in the blood was also amongst the top rearrangements in the CA, endo, and a previous biopsy (Quilty lesion or cellular rejection) obtained 2 to 6 years earlier (1c). Using their unique TCRβ sequence as a link to the single-cell phenotype data, we identified these clones as CD8+CD45RA+Tbet+ T-cells evocative of effector memory RA T cells (Temra). Conclusion Our studies demonstrated considerable overlap between the graft and blood TCR repertoire in CAV suggestive of a bystander T cell response in situ. However, these findings do not rule out the existence of individual clones being expanded in the graft. Moreover, the Temra phenotype of persistent high frequency clones offers a first indication of the type of T cells infiltrating cardiac allografts.

Purpose Effective tacrolimus (TAC) dosing is hampered by complex pharmacokinetics and significant intra- and interpatient variability. One prior report suggests that TAC dosing is influenced by gut microbiota, while the effects of systemic inflammation and oxidative stress are unknown. We evaluated these relationships in adult heart transplant (HT) pts. Methods We prospectively enrolled 24 HT pts (age=56±2 years, 88% male, 25% AA). Stool samples were analyzed using 16S rRNA sequencing. Alpha diversity metrics (number and evenness of bacterial taxa within samples) were estimated using Shannon index. TAC dose and serum trough level were measured at the time of gut and blood analysis. TAC doses were reported in mg/kg/day and as level-to-dose (L/D) ratio; pts were categorized as above vs. below the median. Biomarkers of inflammation (tumor necrosis factor-α (TNF-α)) and oxidative stress (Isoprostane) were measured in blood. Gut diversity and blood biomarkers were compared by TAC dose using ANOVA. DESeq regression analyses explored differences in individual taxa by weight-based TAC dose - false discovery rate (FDR) adjusted for multiple comparisons. Results The average time from HT to sample collection was 63±6 days. The median TAC dose was 0.1 mg/kg/day, while the median L/D ratio was 1.15. Above the median daily weight-based TAC dose was associated with higher Shannon index (p=0.03), lower TNF-α (p=0.05) and lower isoprostane levels (p=0.02) (Figure). These findings were similar when analyzed using the L/D ratio. We observed n=38 taxa to be significantly enriched among pts with >median TAC dose (all FDR Conclusion Our pilot study observed gut microbial diversity to be increased while inflammation and oxidative stress were reduced among pts requiring higher TAC dosing.

Purpose ISHLT guidelines recommend serial right heart catheterization (RHC) to survey pulmonary hypertension in patients awaiting heart transplant. In LVAD as BTT patients the ideal surveillance frequency is unknown in those without prior pulmonary hypertension or whose pre-LVAD PVR normalized after surgery. Here, we review the utility of our surveillance RHC protocol. Methods Between January 2017 and July 2018, 69 patients who received an LVAD as BTT were studied. Routine RHC was performed every six months irrespective of prior PVR. Hemodynamic variables were retrospectively collected and reviewed. Results In 69 patients, 217 RHCs were analyzed. The median age was 55 years (IQR=15), and 55 (80%) were male. Median follow-up period was 18.4 months, and hemodynamic variables were largely unchanged post-LVAD (Table). Post-LVAD, overall PVR decreased from 3.5 ± 2.1 to 2.4 ± 1.0 Wood units (p = 7.2e-5) at six months and stabilized below 3 at all time points. Thirty-three patients (48%) had PVR ≤ 3 (1.8 ± 0.7), and 36 patients (52%) had PVR > 3 (4.9 ± 2.0) pre-LVAD. Both groups exhibited stabilization of PVR with mean 3 at any point after LVAD implantation, 13 (81%) had a pre-LVAD PVR > 3. No patients with a PVR ≤ 3 six months post-LVAD implantation presented with a PVR > 3 at any subsequent RHC. Of the 40 patients (58%) transplanted, one patient developed severe primary graft dysfunction with right ventricular failure. Conclusion Routine RHC every six months may not be necessary for BTT patients, particularly for those with PVR ≤ 3 six months post LVAD.

Purpose Sudden cardiac death may occur in the setting of acute rejection or later in patients with allograft vasculopathy. The role of implantable cardioverter-defibrillators (ICDs) in heart transplant recipients with allograft failure is unknown. Methods We analyzed the United Network for Organ Sharing registry between January 2008 and March 2018 to include adults ≥18 who had undergone heart transplantation and were listed for retransplantation for the indication of allograft failure. Results Between January 2008 and March 2018, 1201 heart transplant recipients were re-listed for transplant of whom 229 (19%) had an ICD. Indications for re-listing included coronary artery disease (n = 699, 58%), primary graft failure (n = 188, 15.7%), chronic rejection (n = 141, 11.7%), acute rejection (n = 60, 5.0%), non-specific reason (n = 57, 4.7%), restrictive or constrictive disease (n = 49, 4.1%), and hyperacute rejection (n = 7, 0.6%). Allograft failure patients with ICDs were younger than those without (47.3 vs 43.5 years, p Conclusion Approximately 1 in 5 heart transplant recipients re-listed for primary allograft failure received an ICD. The use of ICDs does not appear to be associated with increased waitlist survival. More research is needed regarding the role of ICDs in this unique population.

Although late-onset right-sided heart failure is recognized as a clinical problem in the treatment of patients with left ventricular assist devices (LVADs), the mechanism and predictors are unknown. Tricuspid valve (TV) deformation leads to the restriction of the leaflet motion and decreased coaptation, resulting in a functional tricuspid regurgitation that may act as a surrogate marker of late right-sided heart failure. This study aimed to investigate the association of preoperative TV deformation (annulus dilatation and leaflet tethering) with late right-sided heart failure development after continuous-flow LVAD implantation. The study cohort consisted of 274 patients who underwent 2-dimensional echocardiography before LVAD implantation. TV annulus diameter and tethering distance were measured in an apical 4-chamber view. Late right-sided heart failure was defined as right-sided heart failure requiring readmission and medical and/or surgical treatment after initial LVAD implantation. During a mean follow-up of 25.1 ± 19.0 months after LVAD implantation, late right-sided heart failure occurred in 33 patients (12.0%). Multivariate Cox proportional hazard analysis demonstrated that TV annulus diameter (hazard ratio 1.221 per 1 mm, p

Impaired cardiac function is considered a contraindication for lung transplantation (LT). Because right ventricular (RV) function is expected to improve after LT, poor left ventricular (LV) function is often the determinant for LT eligibility. However, the changes in cardiac function before and after LT have not yet been elucidated. Therefore, we reviewed echocardiograms obtained from 67 recipients before and after LT. In a subset of 49 patients, both RV and LV longitudinal strains based on 2-dimensional speckle tracking echocardiography were analyzed. The cardiopulmonary exercise tests were also reviewed. All patients showed significant improvements in their exercise capacity after LT. RV echo parameters improved in all patients after LT (RV fractional area change: 36.7 ± 5.6% to 41.5 ± 2.7%, RV strain: -15.5 ± 2.9% to -18.0 ± 2.1%, RV E/E': 8.4 ± 1.8 to 7.7 ± 1.8; all p0.05). Overall, the left ventricular ejection fraction (LVEF) did not change (58.7 ± 6.0% to 57.5 ± 9.7%, p = 0.385); however, 20 patients (30%) showed10% decrease in LVEF after LT (61.5 ± 6.1% to 47.3 ± 4.2%, p0.001) and an increase in LV E/E' (11.8 ± 1.8 to 12.9 ± 2.2, p = 0.049). Multivariate logistic regression analysis revealed that pre-LT LV E/E' was associated with decrease in LVEF after LT (odds ratio 1.381, 95% confidence interval 1.010 to 1.947, p = 0.043). Furthermore, patients with strain data showed that lower pre-LT LV strain was independently associated with LVEF decrease after LT (odds ratio 1.293, 95% confidence interval 1.088 to 1.614, p = 0.002). Although RV function improves after LT, LV systolic and diastolic functions deteriorate in a sizable proportion of patients. Impaired LV diastolic function before transplant appears to increase the risk of LVEF deterioration after LT.

Functional and structural liver abnormalities may be found in patients with advanced heart failure (HF). The Model of End-Stage Liver Disease Excluding INR (MELD-XI) score allows functional risk stratification of HF patients on and off anti-coagulation awaiting heart transplantation (HTx), but these scores may improve or worsen depending on bridging therapies and during time on the waiting list. Liver biopsy is sometimes performed to assess for severity of fibrosis. Uncertainty remains whether biopsy in addition to MELD-XI improves prediction of adverse outcomes in patients evaluated for HTx.Sixty-eight patients suspected of advanced liver disease underwent liver biopsy as part of their HTx evaluation. A liver risk score (fibrosis-on-biopsy + 1) × MELD-XI was generated for each patient.Fifty-two patients were listed, of whom 14 had mechanical circulatory support (MCS). Thirty-six patients underwent transplantation and 27 patients survived ≥1 year post-HTx (74%, as compared with 88% average 1-year survival in HTx patients without suspected liver disease; p0.01). Survivors had a lower liver risk score at evaluation for HTx (31.0 ± 20.4 vs 65.2 ± 28.6, p0.01). A cut-point of 45 for liver risk score was identified by receiver-operating-characteristic (ROC) analysis. In the analysis using Cox proportional hazards models, a liver risk score ≥45 at evaluation for HTx was associated with greater risk of death at 1 year post-HTx compared with a score of45 in both univariable (HR 3.94, 95% CI 1.77-8.79, p0.001) and multivariable (HR 4.35, 95% CI 1.77-8.79, p0.001) analyses. Patients who died1 year post-HTx had an increased frequency of acute graft dysfunction (44.4% vs 3.7%, p = 0.009), longer ventilation times (55.6% vs 11.1%, p = 0.013) and severe bleeding events (44.4% vs 11.1%, p = 0.049). The liver risk score at evaluation for HTx also predicted 1-year mortality after HTx listing (p0.001).Patients with HF and advanced liver dysfunction are high-risk HTx candidates. Liver biopsy in addition to MELD-XI improves risk stratification of patients with advanced HF and suspected irreversible liver dysfunction.

Background Cardiac retransplantation is increasing in frequency. Recent data have shown that retransplantation outcomes are now comparable with primary transplantation. The use of mechanical circulatory support (MCS) as a bridge to retransplantation has similar post-retransplant outcomes to those without MCS, but the success of bridging patients to retransplant with MCS has not been well studied. Methods From January 2000 to February 2014 at Columbia University Medical Center, 84 patients were listed for retransplantation. Of this cohort, 48 patients underwent retransplantation, 15 were bridged with MCS, 24 died, and 6 clinically improved. A retrospective analysis was performed examining waiting list time, survival to retransplantation, and survival after retransplant. The effect of the United Network of Organ Sharing (UNOS) allocation policy change in 2006 on waiting list time and MCS use was also investigated. Results Of 48 patients who underwent retransplantation, 11 were bridged with MCS. Overall 1-year survival to retransplantation was 81.3%. There was no significant difference in waiting list survival ( p = 0.71) in those with and without MCS. Death from cardiac arrest or multiorgan failure with infection was more frequent in the medically managed group ( p = 0.002). After the UNOS 2006 allocation policy change, waiting list time (599 ± 936 days in Era 1 vs 526 ± 498 days in Era 2, p = 0.65) and waiting list survival ( p = 0.22) between eras were comparable, but there was a trend toward greater use of MCS ( p = 0.13). Survival after retransplant was acceptable. Conclusion The use of MCS as a bridge to cardiac retransplantation is a reasonable strategy.

Induction therapy with interleukin-2 receptor antagonists has been established as an effective immunosuppressive strategy in the management of heart transplant (HTx) recipients. We compared outcomes following HTx in patients receiving basiliximab, daclizumab, or no induction therapy.We investigated post-transplant prognosis of patients receiving basiliximab (n=67), daclizumab (n=98) or no induction therapy (n=70). Patients treated with daclizumab (50.3 ± 14.7 years) were younger than those receiving basiliximab (55.8 ± 11.2 years) or no induction therapy (54.9 ± 14.1 years; both P0.05). Patients receiving either induction therapy showed better survival 1 year after HTx (95%) than those without induction therapy (82%; P0.001). Survival was similar between patients receiving basiliximab and daclizumab. The incidence of acute cellular or antibody-mediated rejections did not differ among the groups. The main reason that patients did not receive induction therapy was ongoing infection (65.7%), which was more common in patients on ventricular assist device (VAD) support than those without VAD (76.1% vs. 45.8%; P=0.004). The VAD-related infection rate in the entire study cohort was 29.7% (35/118 VAD recipients).Survival following HTx was worse in patients not receiving induction therapy. No differences were noted in survival or the incidence of rejection between the daclizumab- and basiliximab-treated groups. Induction therapy was less used in patients with infection, which was related to prior VAD support.

Patients with end-stage liver disease in need of liver transplantation increasingly are older with a greater burden of cardiac disease and other co-morbidities, which may increase perioperative risk and adversely affect long-term prognosis. Cirrhosis of any etiology manifests hemodynamically as a state of low systemic vascular resistance, with high peripheral, but low central blood volume, leading to a state of neurohormonal activation and high cardiac output, which may adversely affect cardiac reserve under extreme perioperative stress, aptly termed cirrhosis-associated or cirrhotic cardiomyopathy. Evidence of asymptomatic cirrhotic cardiomyopathy may be found in subtle electrocardiographic and echocardiographic changes, but may progress to severe heart failure under the demands of bleeding and transfusions, vasopressors, rebounding peripheral vascular resistance, withdrawal of cardioprotective beta-blockers and mineralocorticoid antagonists, exacerbated by sepsis or systemic inflammatory response syndrome. This review will add to the current body of literature on cirrhotic cardiomyopathy by focusing on the role of advanced echocardiographic imaging techniques, cardiac biomarkers, and advanced heart failure therapies available to manage patients with cirrhotic cardiomyopathy while waiting for liver transplant and during the perioperative period.