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Black patients suffer higher rates of antibody-mediated rejection and have worse long-term graft survival after heart transplantation. Donor-derived cell free DNA (ddcfDNA) is released into the blood following allograft injury. This study analyzed %ddcfDNA in 63 heart transplant recipients categorized by Black and non-Black race, during the first 200 days after transplant. Immediately after transplant, %ddcfDNA was higher for Black patients (mean [SE]: 8.3% [1.3%] vs 3.2% [1.2%], p = 0.001). In the first week post-transplant, the rate of decay in %ddcfDNA was similar (0.7% [0.68] vs 0.7% [0.11], p = 0.78), and values declined in both groups to a comparable plateau at 7 days post-transplant (0.46% [0.03] vs 0.45% [0.04], p = 0.78). The proportion of Black patients experiencing AMR was higher than non-Black patients (21% vs 9% [hazard ratio of 2.61 [95% confidence interval: 0.651-10.43], p = 0.18). Black patients were more likely to receive a race mismatched organ than non-Black patients (69% vs 35%, p = 0.01), which may explain the higher levels of early allograft injury.

BackgroundThe Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new "Minor" category characterized by low-level inflammation in non-rejecting biopsies.MethodsUsing MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359).ResultsCompared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss.ConclusionsMany heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (ClinicalTrials.gov #NCT02670408).

BACKGROUND The ROADMAP study showed survival with improved functional status was better with left ventricular assist device (LVAD) therapy compared with optimal medical management (OMM) in ambulatory, non-inotrope-dependent (INTERMACS [IM] Profile 4 to 7) patients. To study more balanced cohorts and better define which patients may benefit from implantation of an LVAD, we re-evaluated the patients enrolled in ROADMAP when stratified by INTERMACS profile (Profile 4 and Profiles 5 to 7). METHODS The primary end-point (survival on original therapy with improvement in 6-minute walk distance ≥75 meters at 1 year), actuarial survival, adverse events (AEs) and health-related quality of life (HRQoL) were evaluated. RESULTS For INTERMACS Profile 4 (IM4), more LVAD patients met the primary end-point compared with OMM patients (40% vs 15%; odds ratio = 3.9 [1.2 to 12.7], p = 0.024), but there was no statistically significant difference for INTERMACS Profiles IM 5 to 7 (IM5-7). Event-free survival on original therapy at 2 years was greater for LVAD than for OMM patients in both IM4 (67% vs 28%; p < 0.001) and IM5-7 (76% vs 49%; p = 0.025) profile groups. Composite end-points of survival on original therapy with improved HRQoL or depression were better with LVAD than OMM in IM4, but not IM5-7. AEs trended higher in LVAD compared with OMM patients in both profile groups. Rehospitalization rates for LVAD vs OMM were similar between treatment arms in IM4 (82% vs 86%; p = 0.780), but were higher for LVAD in IM5-7 (93% vs 71%; p = 0.016). CONCLUSIONS LVAD patients in IM4, but not IM5-7, are more likely to meet the primary end-point and have improvements in HRQoL and depression compared with OMM, even with AEs generally being more frequent. LVAD therapy with current technology may be beneficial in select IM4 patients, but can be deferred for most IM5-7 patients, who should be followed closely due to the high frequency of treatment failures.

Purpose Heart Transplant recipients previously exposed to CMV infection are considered intermediate risk for post-transplant CMV complications. Many centers therefore utilize "universal" prophylaxis for 3-6 months to mitigate this risk. However, it remains unclear how long prophylaxis should be continued post-transplant in this population. In the present analysis, we compared post-transplant CMV outcomes in patients receiving 3 vs. 6 months of valganciclovir prophylaxis in a multicenter, retrospective analysis. Methods Retrospective analysis of 321 intermediate risk (CMV R+) HTx recipients from 6 U.S. centers between 2010-2018 treated with universal prophylaxis with valganciclovir for either 3 months (n = 277) or 6 months (n = 44). The primary endpoint was the development of CMV viremia or end-organ disease resulting in the escalation of anti-CMV therapy. The secondary endpoint was hospitalization for CMV-related infection. Results Of the 321 patients in the analysis, 13.4% (n = 43) developed CMV viremia or end-organ infection requiring escalation of anti-CMV therapy, and 3.4% (n = 11) were hospitalized for CMV infection. Overall, there was no significant difference in the primary endpoint in patients treated with 3 months of valganciclovir compared to 6 months (12.6% vs. 18.2%, p = 0.316; Figure 1A). There was a trend toward reduction in CMV hospitalization in the 6-month treatment group (Figure 1B), but this did not achieve statistical significance (3.6% vs. 2.3%, p = 0.651), potentially due to a low number of events. Conclusion We found no difference in the risk of CMV viremia or hospitalization for CMV using either a 3-month or 6-month regimen for prophylaxis in HTx recipients at intermediate risk for CMV (R+).

Despite significant efforts to predict and prevent right heart failure, it remains a leading cause of morbidity and mortality after implantation of left ventricular assist systems (LVAS). In this Perspective, we review the underappreciated anatomic and physiologic principles that govern the relationship between left and right heart function and contribute to this phenomenon. This includes the importance of considering the right ventricle (RV) and pulmonary arterial circuit as a coupled system; the contribution of the left ventricle (LV) to RV contractile function and the potential negative impact of acutely unloading the LV; the influence of the pericardium and ventricular twist on septal function; the role of RV deformation in reduced mechanical efficiency after device placement; and the potential of ongoing stressors of an elevated right-sided preload. We believe an appreciation of these complex issues is required to fully understand the expression of the unique phenotypes of right heart failure after LVAS implantation and for developing better prognostic and therapeutic strategies.

Purpose African American (AA) patients are at risk for increased rates of rejection after heart transplantation (HT).We compared cell-free DNA (cf-DNA) levels after HT by recipient race. Methods This was a retrospective analysis of 96 HT recipients from the Genomic Research Alliance for Transplantation (GRAFT) Registry, of which 63 patients had cf-DNA values. Cf-DNA values were compared by race withan exponential decay model and Kaplan-Meier (KM) analysis was performed to compare time-to-first rejection. Results Compared to non-AA patients, AA recipients had a similar prevalence of diabetes and hypertension,proportion of males, and donor characteristics. AA recipients had higher cf-DNA values compared to non-AA recipients for the first five days following transplant (8.3% vs. 3.2% p=0.001 Table 1/figure 1). The stable state cf-DNA values decayed rapidly for AA patients and equalized to non-AA patients over the first 7 days (0.46% vs 0.45%, p=0.8 Table 1). Cellular rejection did not differ by race (HR [CI]=1.4 [0.62,3.2], p=0.4). However AA were at higher risk of antibody mediated rejection (HR [CI]=3.8 [1.3,10.9], p=0.01). Conclusion African American patients had increased cf-DNA values in the first week following heart transplant. This may be a marker of early injury contributing to increased rates of allograft rejection in AA patients. Further analysisadjusting for confounding variables and determining predictors of clinical outcomes will be included at the time of presentation once follow-up of the GRAFT registry is complete.

Purpose This report describes an analysis of the complete experience using the Total Artificial Heart (TAH) Portable Driver (PD). Methods Comprehensive de-identified data were obtained from the TAH manufacturer. A review of customer complaints reported to the manufacturer and subsequent failure investigation findings relating to the TAH PD worldwide was conducted for the period 2010 through Q2 2019. A total of 316 PDs entered clinical service to support a total of 403 TAHs during this interval. 1375 PD complaints (835 included reported alarms) were analyzed and grouped by finding, component failure and patient impact. Demographics and outcomes were also reviewed. Results There were over 290 patient years observed. PD complaints: 54.8% (753/1375) were not associated with PD-malfunction, 39.3% (540/1375) were PD malfunctions and 6.0% (82/1375) were related to improper use. Electronic/Electrical components accounted for 51.9% (280/540) with 61.1% (171/280) caused by failure of a humidity-sensitive pressure sensor (replaced by a hermetically-sealed sensor) and 5.7% (31/540) by failure of the piston cylinder assembly. 60.7% (835/1375) of PD complaints reported device alarms: 55.2% (461/835) were not associated with malfunction, 6.3% (53/835) were attributed to improper use, and 38.4% (321/835) were device malfunctions. 64.8% (261/403) of patients were discharged. 74.9% (302/403) of all PD patients and 77% (201/261) of discharged PD patients were alive on device or had been transplanted. Of 540 confirmed driver malfunctions, 92.4% (1271/1375) had no patient impact, 4.1% (57/1375) reported an adverse event (AE), 2.6% (36/1375) reported a serious AE and 0.07% (11/1375) reported a death. Conclusion The majority of alarms and complaints are not associated with device malfunction. Overall safety and durability of the TAH Portable Driver is demonstrated by the low incidence of negative patient impact when device malfunctions do occur and an excellent BTT rate for PD patients.

Purpose Higher rates of acute rejection in African American transplant recipients are reported across multiple organ types. Mechanisms underlying poorer outcomes vs. other races are poorly defined. Because race is a social construct, most studies use self-identified race to categorize patients. Reports of genetic unique to individuals of African ancestry (AA) led us to hypothesize that ancestry markers might enhance the precision of race categorization in studies of transplant injury and rejection. Methods Using the Genomic Research for Transplantation (GRAfT) cohort, we performed whole-genome genotyping assay and measured the donor-derived cell-free DNA (dd-cfDNA), a biomarker of graft injury. We genotyped 171 heart recipients and estimated the genetic ancestry proportions by GRAF-pop software referencing 1000Genome data. Applying the filters for African genetic ancestry proportion (AGAP), patients were categorized as AA if AGAP was > 85%, and not of AA if AGAP 15%. Serial post-transplant plasma samples were analyzed for dd-cfDNA by Illumina HiSeq3500. We consolidated the highest dd-cfDNA level along the time series to represent each individual; data are presented as median + the standard error. To assess potential relationship between AGAP and dd-cfDNA, we selected patients at two extremes: 31 AAs (>85% AGAP) and 97 non-AAs ( Results Among the 171 recipients, 69 self-reported as AAs (40%), while the AGAP reported 72 AAs (42 %). The consistence between self-reported and AGAP was 97.7% (167/171). AAs at the estimated extremes ( > 85% AGAP) had significantly higher dd-cfDNA level than non-AAs ( 15% AGAP): 3.64 + 0.73 vs. 1.79 + 0.41, p=0.03). Self-reported race showed a non-significant trend towards higher dd-cfDNA levels in AAs compared to non-AAs: 2.91 + 0.48 vs. 1.79 + 0.40, p=0.074). Conclusion This study documents a high consistence between self-reported race and genetic ancestry markers. It also confirms our prior reports of increased graft injury reflected as higher levels of dd-cfDNA in AAs at the extremes of genetic ancestry proportion. Supporting our hypothesis, ancestry markers might augment self-reported race data, warranting further studies on the interaction genetic heterogeneity with social determinants of health.

Purpose Heart transplant recipients with prior exposure to cytomegalovirus (CMV R+) are considered intermediate risk for CMV-related complications. Current guidelines allow for a pre-emptive approach to CMV prophylaxis (i.e. “watch and wait” strategy) in these patients; however, it remains unclear if this is a safe and effective strategy to mitigate the risks of CMV reactivation. In the present study, we assessed the utility of a pre-emptive approach to CMV prophylaxis compared to a universal prophylaxis strategy in an intermediate risk population. Methods Multi-center, retrospective analysis of 564 intermediate risk (CMV R+) HTx recipients from 6 U.S. centers between 2010-2018 with 18 months of follow-up. The primary endpoint was the development of CMV viremia or end-organ disease resulting in the initiation/escalation of anti-CMV therapy. The secondary endpoint was hospitalization for CMV-related infection. Results Of 564 intermediate risk (CMV R+) patients in the analysis, 123 (21.8%) were treated with a pre-emptive CMV prophylaxis strategy. Patient's treated with a pre-emptive approach had a significantly higher risk of both the primary (p Conclusion The use of a pre-emptive prophylaxis approach in intermediate risk CMV HTx recipients (CMV R+) is associated with a significantly higher risk of both the need for therapy escalation and hospitalization for CMV-related complications.

Purpose The rapid increase of the use of extracorporeal membrane oxygenation (ECMO) as a direct bridge to heart transplantation (HT) raises concerns. The objective of this study is to describe the outcomes after HT using a bridge-to-bridge strategy with a sequence of ECMO support followed by temporary total artificial heart (t-TAH) implantation. Methods A retrospective, multicentric analysis of 54 patients who underwent t-TAH (SynCardia) implantation following the use of an ECMO for cardiogenic shock was performed (ECMO-t-TAH group). A control group of 163 patients who underwent t-TAH implantation as a direct bridge to transplantation (t-TAH group) was used to assess the impact of this strategy. Results Fifty-four patients, averaging 47±13 years old underwent implantation of a t-TAH after 5.3±3.4 days of ECMO perfusion for cardiogenic shock. In the ECMO-t-TAH group, 20 patients (20/54,37%) died after t-TAH implantation and 57 patients (57/163,35%) died in the t-TAH group (p=0.4968). Overall, 32 patients (32/54, 59%) underwent heart transplantation in the ECMO-t-TAH group, compared to 106 patients (106/163, 65%) in the t-TAH group (p=0.4449). No significant difference in survival was observed at 6 months, 1 and 3 years after heart transplant (ECMO-t-TAH group: 94%, 87%, and 80% vs. 87%, 83%, and 76% in the t-TAH group, respectively). Deterioration of liver function tests under t-TAH was associated with increased mortality before heart transplant in both groups. Conclusion The present series suggests that sequential bridging from ECMO to t-TAH followed by heart transplantation is a viable alternative for a group of highly selected patients.

Purpose Recipient race remains a powerful risk factor for mortality after heart transplantation (HT), with African Americans (AA) having worse survival than Caucasians. The aim of this analysis was to evaluate racial differences in gene expression profiling (GEP) and donor derived cell free DNA (dd-cfDNA) after HT using the Surveillance HeartCare Outcomes Registry (SHORE). Methods SHORE is an ongoing registry with >1200 patients enrolled at 60 HT centers in the United States. The registry includes HT recipients aged ≥15 years and ≥55 days post-transplant who had routine GEP and dd-cfDNA testing for rejection surveillance. Since patient sampling is from multiple centers, a linear mixed effects model, an extension of the linear model, was used to accommodate both fixed and random effects in the data. Results Among 956 recipients included in the analysis, 198 (20.7%) were AA, median age 57.0 years [0, 74.0] and 73.9% male. Overall, median GEP values demonstrated a borderline difference (p=0.07, Kolmogorov Smirnov test) for AA versus non-AA patients (Figure). This is evident by the cumulative distribution function, where a slightly higher rise in slope is observed for the non-AA cohort. Using linear mixed effects models, there was a statistically significant difference in GEP score when grouped by months post-transplant, demonstrating an early difference between AA and non-AA patients between months 2-5, but not subsequently. For dd-cfDNA analysis, median values were similar between AA (0.12%; Range 0.1-3.9%) and non-AA (0.12%; 0.1-3.5%) patients within the first year post-transplant (p=0.87, 2-sided K-S test) (Figure). Conclusion AA race is associated with higher GEP scores early post-transplant. This may be related to differential expression of the MARCH8 and FLT3 genes following HT, as previously described. Further analysis of specific GEP clusters and covariates across racial groups may shed light on these observed differences. In contrast, dd-cfDNA values do not appear to be influenced by race.

Introduction As patients live longer on mechanical circulatory support (MCS), it is crucial to recognize long term device complications. We present a case of an unusual late complication after an HVAD implantation. Case Report A 51 year old female implanted with HVAD 6.5 years ago as a bridge to transplant presented with hypotension and UTI. She received IV fluids and antibiotics, and antihypertensive medications were held with clinical improvement. Surveillance RHC showed high filling pressures (RA 25 mmHg, Wedge 38 mmHg) and low cardiac index (1.8 mL/kg/m2). After diuresis, she developed acute hypotension, low flows and a pulsatility waveform consistent with suction for which device speed was decreased. Despite volume resuscitation she had PEA arrest requiring CPR and inotrope support. An echocardiogram showed near complete compression of the RA and RV by a fluid collection adjacent to the outflow tract. An emergent CT showed a 5.2 × 8.4 × 9.7 cm fluid collection around the outflow graft, extending from the proximal conduit to the aortic anastomosis. There was mass effect causing effacement of the IVC-RA junction and compression of SVC consistent with tamponade. The outflow graft was patent without signs of compression. Due to concern for bleeding from the graft, the patient was taken to surgery. Intraoperatively, there was a large amount of gelatinous material within the Gore-Tex wrapping of the conduit and no bleeding. The biodebris was evacuated with immediate relief of cardiac compression. Gore-Tex membranes were removed, and the chest was closed. The patient recovered and is doing well. Summary We present the first case of biodebris within Gore-Tex outflow graft wrapping causing cardiac tamponade. Gore-Tex wrapping of MCS devices is used to facilitate future explanting but may cause accumulation of biodebris over time. The phenomenon was previously described with HeartMate devices owing to the design of the bend relief resulting in outflow graft compression, but is unusual for HVAD devices, and has not been reported to cause tamponade.

Purpose To study the safety and efficacy of the portable pneumatic driver [Freedom™ Driver] in clinically stable patients supported with a total artificial heart (TAH). Methods This is a multi-center, non-randomized study of the Freedom™ Driver System between 2010 and 2015. Patients who had a TAH implanted and were clinically stable were enrolled then followed from the initiation of Freedom™ Driver support until transplant, 90 days post-discharge, 90 days of in-hospital Freedom™ support, or death, whichever occurred first. The criteria for study success are that 95% of study subjects maintain an average cardiac index ≥ 2.2 L/min/m2 during Freedom™ Driver support and that the overall out-of-hospital to in-hospital adverse event profiles are clinically comparable while on Freedom™ Driver support. Results A total of 96 subjects were enrolled from 22 institutions in the United States. Of the 96 subjects, 73 (76%) were discharged after an average of 15 ± 15 days in the hospital after Freedom™ Driver initiation (median 11 days, range 3 - 86 days). For both in-hospital and discharged subjects, the overall mean cardiac index was 3.4 ± 0.4 L/min/m2 (median 3.4 L/min/m2, range 2.5 - 4.7 L/min/m2). There were 154 adverse events, 69 (45%) while inpatient and 85 (55%) while outpatient, 39 (46%) of which required readmission. There were approximately 1.2 readmissions for each of the 73 discharged subjects, with a mean 11 days length of stay (median 5 days, range 0 - 130 days). Most common causes for readmission were anemia/hemolysis/bleeding (17.7%), alarms (11.1%), infection (11.1%), and sub-therapeutic INR (10%). The mortality rate was 2.7% within 90 days post-discharge and was not associated with device failure. This is comparable to the event rate for in-hospital subjects. No preclusion from transplant occurred through the respective study endpoint. Conclusion All subjects with the Freedom™ Driver maintained a cardiac index above 2.2 L/min/m2 without preclusions from transplant and minimal death rate. The Freedom™ Driver is a safe portable pneumatic driver system for clinically stable TAH patients in both hospital and outpatient settings when used per the manufacturer's instructions.

Purpose In heart transplantation (HT), antibodies directed against Angiotensin II type 1 receptor (AT1RAb) have been associated with antibody-mediated rejection (AMR), acute cellular rejection (ACR), and microvasculopathy. The effect of AT1RAb detected pre-HT on immediate post-HT allograft injury remains poorly defined. In this study, we leverage a validated and sensitive blood based biomarker for allograft injury, donor-derived cell-free DNA (ddcfDNA), to examine the association of pre-HT AT1RAb to post-HT allograft injury. Methods AT1RAb testing was performed on pretransplant plasma from HT recipients in the Genomic Research Alliance for Transplantation (GRAfT) multicenter, prospective cohort study, using a quantitative ELISA (One Lambda, ThermoFisher). After HT, serial plasma samples were collected and used to quantitate %ddcfDNA by shotgun sequencing. AT1RAb concentration (units/ml) was used to categorize patients as AT1RAb 30 (n=17). A mixed linear model was used to examine post-HT %ddcfDNA trajectories across AT1RAb groups. Histopathology slides were read by a consensus of pathologists to define AMR using ISHLT criteria. Results Age, gender and clinical features were similar between AT1RAb 30 groups. AT1RAb>30 had a greater proportion of White recipients compared to AT1RAb 30 (p=0.6), in the first year post-HT, ddcfDNA declined by 87% (95% CI 79%-92%) among patients with AT1RAb 30 (p = 0.04) (Figure). AMR in the first year post-HT was more common among AT1RAb>30 than AT1RAb Conclusion Preliminary analysis of this heart transplant cohort suggest that high pre-HT AT1RAb is associated with increased early post-HT allograft injury.

Summary of Objectives Genomic biomarkers are used to non-invasively screen cardiac transplant recipients for allograft rejection. Gene expression profiling has no ability to diagnose antibody-mediated rejection (AMR) and has a poor positive predictive value for T-cell mediated rejection (TCMR). An emerging class of genomic biomarkers are circulating, cell-free microRNAs (cf-miR). MicroRNAs modulate gene expression and have been implicated in rejection, they are found in the circulation, and early studies, using targeted genomic approaches suggest that cf-miRs may be a helpful biomarker to detect rejection. We hypothesize that cf-miRs can non-invasively diagnose rejection and distinguish AMR from TCMR. Methods The Genomic Research Alliance for Transplantation (GRAfT) is a prospective, multicenter study enrolling transplant recipients since 2014. All patients with AMR or TCMR were included and a group of controls without rejection were selected based on age, sex and race. Each biopsy was reviewed by two blinded, independent, expert cardiac pathologists. Plasma aliquots will undergo small molecular RNA isolation and the circulating cf-miR transcriptome will be sequenced using a next-generation platform. We expect to generate ∼6 million, single-end, 50bp reads per sample. Sequence data will be annotated using the FASTX_Toolkit and DESeq2 will be used to identify differentially expressed cf-miRs. Machine learning algorithms will be used to refine the cf-miR panel and maximize the C-statistic. Endpoints The study includes 35 patients with allograft rejection and 70 controls (Table). For the TCMR cohort there were 27 episodes of grade ≥ 2R rejection. For AMR there are 11 episodes of ≥ pAMR2 and 16 episodes of pAMR1 h or i. In total ∼300 plasma samples will be sequenced. Our primary objective is to develop a cf-miR panel that diagnoses allograft rejections, distinguishes rejection subtypes and allows for a blood-based, biochemical assessment of rejection severity.

Purpose Nearly 30% of heart transplant recipients develop de novo donor-specific antibodies post-transplant, leading to an increased risk of antibody mediated rejection, graft failure, and death. Given poor response rates to therapies targeting dnDSA once present, therapies preventing dnDSA altogether could impact transplant outcomes. It remains unclear if the use of induction therapy at the time of transplant mitigates the risk of dnDSA development. The present study attempts to address this question in a multicenter, retrospective analysis. Methods Multicenter, retrospective analysis of 319 heart transplant recipients from 4 participating centers in the U.S. The primary endpoint was the development of dnDSA. Results In the overall cohort, 206 of 319 (65%) patients received induction therapy at the time of transplant, with 200 (62%) receiving basiliximab and 6 (3%) receiving thymoglobulin. Overall 93 of 319 (29%) patients developed dnDSA post-transplant. The use of induction therapy reduced the risk of dnDSA (Kaplan Meier log rank p = 0.009, Figure 1). When assessing induction type, basiliximab reduced the risk of dnDSA compared to no induction, whereas thyroglobulin did not (Figure 2). However, in a multivariable Cox Regression model incorporating the use of an LVAD as BTT, the use of any induction was no longer statistically significant. Conclusion Although induction therapy, particularly with basiliximab, reduces the risk of dnDSA post-heart transplant in univariate analysis, this effect is no longer significant in a model incorporating LVAD as BTT.

Purpose Antibody to angiotensin-II type 1 receptor (AT1R-Ab) may be implicated in allograft dysfunction in patients who are bridged to heart transplant (BTT) with a continuous flow left ventricular assist device (VAD). We studied AT1R-Ab level following VAD implantation on event-free survival in BTT patients and whether AT1R-Ab elevation is independent from inflammation as measured through C-reactive protein (CRP). Methods Sera of 77 BTT patients from 2009 to 2017 were tested for AT1R-Ab and CRP prior to and after VAD placement. Elevated AT1R-Ab level was defined as greater than 10.0 U/mL. For statistical analysis, the value of 40 U/mL was assigned to AT1R-Ab level greater than 40 U/mL. Events were defined as acute cellular rejection, antibody-mediated rejection, cardiac allograft vasculopathy, reduced EF, and death. Results Median follow-up time after transplant was 3.3 years (range 0.4-9.0 years). After VAD implantation, AT1R-Ab was increased as compared to baseline (Fig 1A). Univariate regression analysis revealed that age, female gender, African-American race, time to transplant, type of VAD, HLA sensitization, and positive donor specific antibodies were not risk factors for AT1R-Ab sensitization. The elevated post-VAD AT1R-Ab cohort had more events than the normal AT1R-Ab group (61% vs 29%, Fig 1B). On Kaplan Meier analysis, there was a statistically decrease in 5-year event-free survival in patients who had elevated AT1R-Ab levels (Fig 1C). Multivariate Cox regression analysis showed increased post-VAD AT1R-Ab as an independent risk factor for developing events. Though CRP was high before and after VAD implantation, CRP had no statistically significant correlation with AT1R-Ab level (Fig 1D). Conclusion Increase in AT1R-Ab was seen in BTT patients after VAD implantation and was associated with adverse outcomes after heart transplant. The AT1R-Ab elevation does not appear to be an epiphenomenon related to CRP, a marker of inflammation.

Purpose Previous studies have indicated that the Model for End-stage Liver Disease (MELD) score as a metric for liver congestion and right heart failure predicts survival in patients undergoing left ventricular assist device (LVAD) implantation. The predictive value of the MELD has never been evaluated for predicting postoperative survival for patients implanted with the total artificial heart (TAH), where right heart failure does not exist. The goal was to evaluate the preoperative MELD for predicting survival after TAH. Methods This was a single center study that analyzed 100 patients who were implanted with the TAH between March 2006 and March 2017. We calculated the preoperative MELD scores using laboratory data closest to device implantation and compared a high and low MELD group using the median value as a cutoff. Results The median MELD score was 14.4 (IQR: 12.2, 19.4) and patients in the high and low MELD groups were of similar age and proportion of male gender and Caucasian race. Patients with a higher MELD score had lower eGFR (72.5 ± 20.8 vs 45.8 ± 30.8 mL/min/1.73 m², p Conclusion The MELD score was not predictive of mortality in patients undergoing TAH implantation. These data may reflect the benefits of bi-ventricular replacement in a patient population exhibiting laboratory data associated with congestive hepatopathy, however the analysis must be applied in a larger patient cohort for validation.

Purpose Cognitive impairment (CI) in heart failure pts. may affect performance of everyday activities that impact ability to manage chronic illness. Anticholinergic drugs are a risk factor for CI. Higher anticholinergic burden (ACB) can occur with specific medications with high anticholinergic activity or an accumulation of drugs with low, medium, and high anticholinergic burden. The ACB of drugs in HF pts. may be a factor contributing to a high prevalence of CI; however, no studies have compared ACB and CI based on severity of HF. This study aims to compare CI and ACB in pts. with Class II vs. Class III/IV HF. Methods 113 adult pts. were recruited from a HF/Transplant Program. Exclusion criteria included diagnosis of dementia, LVAD or total artificial heart. Demographic data were obtained using a self-report questionnaire; clinical data were retrieved using a medical record review. Cognitive function was measured with the MOS Cognitive Function Scale. ACB was calculated using the Anticholinergic Cognitive Burden Scoring Scale. Comorbidity was measured with the Charlson Index. Polypharmacy (>=5 drugs) was determined using a medication count. Data were analyzed using mean (SD) for continuous variables f (%) for categorical variables. Significant differences between groups were examined using Chi Square and independent t-tests. Results Participants (Class II=48, Class III/IV=65) were 62% male, 50% AA, and 56 years old. There were no sig, differences between groups based on EF (p=.116), comorbidity (p=.485), evaluation for transplant (p=.235), IV inotrope therapy (p=.132), or ACB (Class II=2.47 vs Class III/IV-2.67; p=.811). There were between group differences based on age (p=.006), listed for transplant (p=.001), evaluation for MCS (p=.007), ICD (p=.002), polypharmacy ( n=105; Class II=9.5 vs 10.03, p=.034), and CI (Class II=11.06 vs Class III/IV-16.3, p=.035). Conclusion Findings support significant CI and ACB in NYHA Class II-IV pts. with greater CI in Class III/IV pts. Pts. with HF have substantial polypharmacy that may lead to high anticholinergic drug exposure which has been correlated with increased risk for CI. Future studies should target factors influencing CI in patients with greater severity of HF.

Purpose Previous reports have suggested an association between pre-transplant mechanical circulatory support (MCS) and an increased risk for post-transplant de novo donor specific antibodies (dnDSA). However, it is unclear if specific MCS devices pose a greater risk for dnDSA. The present study seeks to better understand the risk of dnDSA posed by a variety of MCS devices in a multicenter, collaborative study. Methods Multicenter, retrospective analysis of 319 heart transplant recipients from 4 U.S. centers between 2011 - 2017. The primary outcome was the development of post-transplant dnDSA. Results 145 of 319 (45%) patients were supported with durable MCS devices prior to transplant, including 47 Heartware (HVAD), 73 Heartmate II (HM2), and 25 total artificial hearts (TAH). MCS patients had a higher risk of dnDSA compared to those transplanted without mechanical support (37% vs. 23%, p = 0.006; Kaplan Meier log rank p Conclusion Pre-transplant MCS is associated with higher risk for dnDSA. Similar risk is seen regardless of device type; however, the risk associated with TAH was not significantly increased compared to no MCS.

Background Patients with severe pulmonary arterial hypertension (PAH) face significant morbidity and death as a consequence of progressive right heart failure. Surgical shunt placement between the left PA and descending aorta (Potts shunt) appears promising for PAH palliation in children; however, surgical mortality is likely to be unacceptably high in adults with PAH. Methods We describe a technique for transcatheter Potts shunt (TPS) creation by fluoroscopically guided retrograde needle perforation of the descending aorta at the site of apposition to the left PA to create a tract for deployment of a covered stent between these vessels. This covered stent—anchored by the vessel walls and surrounding tissue—serves as the shunt. Results TPS creation was considered in 7 patients and performed in 4. The procedure was technically successful in 3 patients; 1 patient died during the procedure as a result of uncontrolled hemothorax. One acute survivor, critically ill at the time of TPS creation, later died of comorbidities. The 2 mid-term survivors (follow-up of 10 and 4 months) are well at home, with symptomatic improvement and no late complications. The 3 candidate patients in whom the procedure was not performed died within 1 month of consideration, underscoring the tenuous nature of this population. Conclusions TPS creation is feasible and may offer symptomatic relief to select patients with refractory PAH. Further study of this innovative approach is warranted.

From the Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland; the Division of Cardiothoracic Surgery, Virginia Commonwealth University Hospital System, Richmond, Virginia; Division of Cardiology, Virginia Commonwealth University Hospital System, Richmond, Virginia; and the Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.

The total artificial heart (TAH) consists of two implantable pneumatic pumps that replace the heart and operate at a fixed ejection rate and ejection pressure. We evaluated the blood pressure (BP) response to exercise and exercise performance in patients with a TAH compared to those with a with a continuous-flow left ventricular assist device (LVAD).We conducted a single-center, retrospective study of 37 patients who received a TAH and 12 patients implanted with an LVAD. We measured the BP response during exercise, exercise duration and change in tolerated exercise workload over an 8-week period.In patients with a TAH, baseline BP was 120/69 ± 13/13, exercise BP was 118/72 ± 15/10 and post-exercise BP was 120/72 ± 14/12. Mean arterial BP did not change with exercise in patients with a TAH (88 ± 10 vs 88 ± 11; p = 0.8), but increased in those with an LVAD (87 ± 8 vs 95 ± 13; p0.001). Although the mean arterial BP (MAP) was negatively correlated with metabolic equivalents (METs) achieved during exercise, the association was not statistically significant (β = -0.1, p = 0.4). MAP correlated positively with METs achieved in patients with LVADs (MAP: β = 0.26, p = 0.04). Despite the abnormal response to exercise, patients with a TAH participated in physical therapy (median: 5 days; interquartile range [IQR] 4 to 7 days) and treadmill exercise (19 days; IQR: 13 to 35 days) early after device implantation, with increased exercise intensity and duration over time.During circulatory support with a TAH, the BP response to exercise was blunted. However, aerobic exercise training early after device implantation was found to be safe and feasible in a supervised setting.

The total artificial heart (TAH) orthotopically replaces a recipient’s native ventricles and all four cardiac valves, interrupting neural and hormonal signaling pathways that are dependent upon the intact ventricular myocardium. Btype natriuretic peptide (BNP) is a cardiac neurohormone primarily secreted from ventricular cardiomyocytes in response to cardiac stretch. In healthy individuals, BNP decreases vascular tone, increases renal blood flow, promotes natriuresis and suppresses the renin–aldosterone axis. The influence of nesiritide (exogenous BNP) on renal function after ventriculectomy and removal of endogenous of BNP is poorly understood and we and others have observed that renal function declines after placement of the total artificial heart. We hypothesized that infusion of exogenous BNP after ventriculectomy would improve renal function as marked by an increase in urine output. We screened 8 consecutive patients who received the TAH (December 2010 to May 2011) with the intention of bridge to heart transplantation. To remove the confounding influence of calcineurin inhibitor exposure on renal function, 3 patients who had devices implanted for retransplantation were not included in the study. All patients met criteria for infusion of nesiritide ( 50% decrease in the estimated glomerular filtration rate [eGFR] or urine output 30 ml/h) based on their evolved oliguria pattern

Figure 1 Laboratory evidence of severe persistent hemolysis in a patient supported witha TAH for 130 days. A 62-year-old man with non-ischemic cardiomyopathy developed cardiogenic shock, and a total artificial heart (TAH) was implanted due to profound biventricular failure. Within days of device implantation the patient developed severe hemolysis. Over the subsequent weeks, despite aggressive anticoagulation with bivalirudin, aspirin, dipyridamole and pentoxyfilline, he continued to have hemolytic anemia (mean hemoglobin [Hb] 5.7 g/dl, nadir Hb 3.1 g/dl; mean lactate dehydrogenase [LDH] 1,693 U/liter, peak LDH 2,628 U/liter) (Figure 1), receiving 37 units of packed red blood cells (RBC) and several infusions of intravenous iron sucrose over the 130 days of TAH support. The TAH parameters were within normal limits. No device malfunction or thrombosis was detected on intracardiac echocardiography or upon direct inspection of the TAH at the time of heart transplantation. Post-transplantation recovery was uneventful. Later, the patient presented with a febrile illness. Computer tomography of the abdomen revealed a hepatic lesion. Abdominal magnetic resonance imaging (MRI) demonstrated secondary hemochromatosis to the liver and spleen. The previously identified hepatic lesion represented an area of normal tissue sparing. The pancreas was not affected, favoring a secondary, rather than primary, etiology of hemochromatosis (Figure 2). In addition, iron deposition was noted in the renal cortex, a finding specific to intravascular hemolysis (Figure 3). Ferritin concentration was markedly elevated. Liver function studies showed mild transaminitis that normalized within 1 week. Because total iron concentration and transferrin saturation remained within normal limits, and there was no liver dysfunction, both hematology and hepatology consultants did not recommend treatment with phlebotomy or iron chelation as long as no further blood transfusions were required. We retrospectively identified a 68-year-old woman who was supported with TAH for 254 days. The patient had chronic hemolytic anemia, alveolar hemorrhage and