Search

Background Allosensitization in heart transplant candidates is associated with longer transplant wait times and post-transplant complications. We summarize our experience with desensitization using carfilzomib , an irreversible proteasome inhibitor that causes plasma cell apoptosis . Methods One cycle of desensitization consisted of plasmapheresis and carfilzomib 20 mg/m 2 on days 1, 2, 8, 9, 15, and 16 with intravenous immune globulin 2 g/kg after carfilzomib on day 16. Patients underwent repeat cycles as indicated. We compare calculated panel-reactive antibody (cPRA) for neat combined Class I and II IgG and C1q pre- and post-treatment using a cutoff for cPRA entry of ≥ 4000 and 500 MFI, respectively. Results From June 2013 to October 2019, 9 patients underwent 20 cycles of carfilzomib-based desensitization. Each cycle resulted in an average cPRA decrease of 24% (95% CI: 6-42) for IgG and 36% (95% CI: 17-55) for C1q. From treatment start to finish, mean cPRA fell from 76% to 40% (p = 0.01) for IgG and 56% to 4% (p = 0.017) for C1q. Six of 9 patients have been transplanted with 5 of the transplanted hearts crossing preoperative donor-specific antibodies. During a median follow-up of 35.1 months, all transplanted patients have survived with only 1 occurrence of treated rejection. Side effects of desensitization included acute kidney injury (67%) and thrombocytopenia (33%) with all episodes self-resolving. Conclusions A carfilzomib-based desensitization strategy among heart transplant candidates reduces the level of HLA antibodies and complement binding , facilitates successful transplantation, and is associated with excellent outcomes at 3 years.

Background Institutional factors have been shown to impact outcomes following orthotopic heart transplantation (OHT). This study evaluated center variability in the utilization of induction therapy for OHT and its implications on clinical outcomes. Methods Adult OHT patients between 2010 and 2018 were identified from the United Network for Organ Sharing registry. Transplant centers were stratified based on their rates of induction therapy utilization. Mixed-effects logistic regression models were created with drug-treated rejection within 1 year as primary endpoint and individual centers as a random parameter. Risk-adjusted Cox regression was used to evaluate patient-level mortality outcomes. Results In 17,524 OHTs performed at 100 centers, induction therapy was utilized in 48.6% (n = 8411) with substantial variability between centers (interquartile range, 21.4%-79.1%). There were 36, 30, and 34 centers in the low ( 67%) induction utilization terciles groups, respectively. Induction therapy did not account for the observed variability in the treated rejection rate at 1 year among centers after adjusting for donor and recipient factors (p = .20). No differences were observed in postoperative outcomes among induction utilization centers groups (all, p > .05). Furthermore, there was a weak correlation between the percentage of induction therapy utilization at the center-level and recipients found to have moderate (r = .03) or high (r = .04) baseline risks for acute rejection at 1 year. Conclusions This analysis demonstrates that there is substantial variability in the use of induction therapy among OHT centers. In addition, there was a minimal correlation with baseline recipient risk or 1-year rejection rates, suggesting a need for better-standardized practices for induction therapy use in OHT.

Temporary mechanical circulatory support (tMCS) devices are used for the management of cardiogenic shock. The Impella 5.0 (Abiomed; Danvers, MA) (IMP5) is a commonly used, surgically implanted, tMCS device that requires systemic anticoagulation and purge solution to avoid pump failure. To avoid heparin-induced thrombocytopenia (HIT) from unfractionated heparin (UFH) use, our program has explored the utility of bivalirudin (BIV) for systemic anticoagulation in IMP5. This single center, retrospective study included patients supported on IMP5 with BIV based AC. The efficacy and safety end points were recovery, bridge to left ventricular assist device (LVAD), cardiac transplant (HTX), or death as well as clinically significant bleeding, incidence of Tissue Plasminogen Activator (tPA) use for suspected pump thrombosis, stroke, and device failure. There were 31 patients included, and 26 (84%) received BIV purge solutions. The median duration of IMP5 was 6 (IQR 4–10) days. Most patients were bridged to LVAD (39%, 12); 16% (5) were bridged to HTX, 16% (5) recovered, and 29% (9) died. One patient (3%) suffered from ischemic stroke and 12% (4) patients developed clinically significant bleeding. tPA was administered to 8 (26%) patients. Logistic regression analysis demonstrated that duration of IMP5 was a significant predictor of tPA use (OR 1.28; 95% Confidence Interval 1.04–1.56). There were no cases of pump failure. Our experience highlights the feasibility of utilizing BIV for routine AC use in IMP5.

Background This study evaluated the impact of hepatitis C–positive ( HCV +) donors on outcomes of heart transplantation in the United States. Methods and Results Adults undergoing isolated heart transplantation in the United States between January 1, 2016, and December 31, 2018, were included. The primary outcome was 1‐year post‐transplant survival. Multivariable Cox regression and 2:1 propensity matching were used to compare outcomes between transplants with HCV + and hepatitis C–negative ( HCV −) donors. A subanalysis was performed to evaluate the impact of nucleic acid amplification test positivity on outcomes. Of 7889 isolated heart transplants performed during the study period, 343 (4.4%) used HCV + donors. Overall unadjusted 1‐year posttransplant survival was not statistically different between HCV − versus HCV + donors (91.1% versus 90.2%; P =0.86), a finding that persisted after risk adjustment (hazard ratio, 1.05; 95% CI, 0.70–1.58; P =0.80). Propensity matching resulted in 675 well‐balanced patients (437 HCV − and 238 HCV +). Overall 1‐year posttransplant survival was not statistically different in propensity‐matched analysis (89.8% HCV − versus 89.2% HCV +; P =0.88). Rates of 1‐year drug‐treated rejection (21.1% versus 22.1%; P =0.84), postoperative dialysis (11.4% versus 14.7%; P =0.22), and stroke (4.6% versus 2.1%; P =0.10) were also not statistically different between HCV − and HCV + groups, respectively. Outcomes were not statistically different between nucleic acid amplification test–negative and nucleic acid amplification test–positive HCV + donors. Conclusions Adult heart transplants using HCV + donors, including those that are nucleic acid amplification test positive, can be performed without an adverse impact on 1‐year survival. Wider implementation of protocols for using HCV + donors and an assessment of longer‐term outcomes including seroconversion rates will be important in maximizing the effect of HCV + donors on national donor shortages.

Purpose The Impella 5.0 (IMP5) is a surgically implanted axial flow pump used in cardiogenic shock. Anticoagulation (AC) strategy with unfractionated heparin (UFH) is used for pump patency. Alternative AC strategies have not been well defined. This study examines the outcomes of patients treated with bivalirudin (BIV) for AC during IMP5 utilization. Methods This single center, retrospective study included patients supported on IMP5 with BIV based AC. The primary end points were recovery, bridge to left ventricular assist device (LVAD), cardiac transplant (HTX), or death. Secondary end points included clinically significant bleeding (TIMI major or minor), incidence of tPA (Tissue Plasminogen Activator) use for suspected pump thrombosis, stroke, and device outcomes. Results 31 patients were included with a mean age of 57.4 years and 19.4% female. 26 patients (84%) received BIV purge solution. The median duration of IMP5 was 6 days. Most patients (38.7%) were bridged to LVAD; 16.1% were bridged to HTX, 16.1% recovered, and 29% died. 1 patient (3.2%) suffered ischemic stroke and 12 patients (38.7%) developed TIMI major or minor bleeding. . tPA was administered to 8/31 (25.8%) of patients. There was no difference in time to therapeutic AC between patients given or not given tPA(p=0.18). Of those given tPA, 37.5% had therapeutic aPTTs (61-75 seconds) immediately prior to tPA. 17/23 (73.9%) of patients not given tPA had therapeutic aPTTs (Fig. 1). Overall time to therapeutic range for all subjects is displayed in Figure 2. Logistic regression analysis demonstrated that duration of IMP5 was a significant predictor of tPA use (OR 1.28; 1.04-1.56). There were no cases of pump failure. Conclusion Use of BIV as an alternative to UFH for IMP5 was proven to be feasible with most patients surviving to recovery, LVAD, or HTX.

Introduction Anti-body mediated rejection (AMR) after cardiac transplantation is a difficult entity to diagnose and treat. Mortality rates in AMR remain high and treatment strategies vary but consist of therapies that aim to remove circulating antibodies, decrease antibody production, suppress T and B-cell responses, and inhibit complement. We report a case of AMR associated cardiogenic shock supported on Impella 5.0. Case Report : A 51-year-old man who received a cardiac transplant in 2018 was admitted for chest pain and dyspnea. Six weeks prior, he had similar symptoms with a right heart catherization (RHC) showing normal hemodynamics. Endomyocardial biopsy did not show cellular or AMR. On admission, he was found to be in cardiogenic shock SCAI stage D with severe bi-ventricular failure. RHC confirmed elevated right and left-sided filling pressures and low cardiac output (cardiac power output 0.7). Biopsy showed grade 1R cellular rejection and infiltrative quilty lesions with focal endocardial inflammation and C3d positive capillaries. He was intubated for hypoxemic respiratory failure and an Impella 5.0 was placed for left ventricular unloading and tissue perfusion in addition to milrinone and epinephrine drips. Labs were significant for new class II DSA (DQ7, DR53 immunodominant antibodies). He was treated with intravenous solumedrol, plasmapheresis, and antithymocyte globulin-rabbit (rATG, Thymoglobulin). He received multiple sessions of bortezomib infusion with plasmapheresis while supported with Impella 5.0. He improved over the following three weeks and was extubated with explant of the Impella 5.0 on day 16. His DSA's continued to decrease and graft function improved with ejection fraction up to 50% (Figure 1). He was discharged with plans for further bortezomib and plasmapheresis sessions. Summary This case demonstrates the successful treatment of cardiogenic shock precipitated by AMR with an Impella 5.0 as a bridge to recovery.

Purpose Allosensitization in heart transplant (HT) candidates is associated with longer transplant wait times and post-transplant complications. We summarize our experience with desensitization using carfilzomib (CFZ), an irreversible proteasome inhibitor that causes plasma cell apoptosis. Methods One cycle of desensitization consisted of plasmapheresis and CFZ 20mg/m2 on days 1, 2, 8, 9, 15, and 16 with intravenous immune globulin 2g/kg after CFZ on day 16. Patients underwent repeat cycles as indicated. We summarize treatment impact by depicting calculated PRA (cPRA) for neat combined Class I and II IgG and C1q pre- and post-treatment using a cutoff for cPRA entry of ≥ 4000 and 500 MFI, respectively. We fit a linear mixed model to evaluate treatment effect. Results From June 2013 to October 2019, 9 patients underwent 20 cycles of CFZ with 6 requiring multiple cycles. Each cycle of CFZ resulted in an average cPRA decrease of 33% (95% CI: 16-50) for combined IgG and 36% (95% CI: 17-55) for C1q. An example is shown in Figure 1. From treatment start to finish, mean cPRA fell from 76% to 35% (p=0.005) for combined IgG and 56% to 4% (p=0.017) for C1q (Table 1). Six of 9 patients have been transplanted with 5 of the transplanted hearts crossing historical antibodies. HT survival at 1 year was 100%. Patient 6 has not been transplanted due to obesity. Patients 3 and 4 only received 4 doses of CFZ due to acute kidney injury, which resolved. Neutropenia, thrombocytopenia, neuropathy, and hepatotoxicity did not occur. Conclusion CFZ, as part of a desensitization regimen, appears to be safe and effective in sensitized patients awaiting HT. The number of cycles may depend on the HLA antibody titer prior to treatment.

Purpose Patients with heart failure (HF) requiring advanced therapies (AT) or palliative inotropes have been well described in the literature, but less is known regarding their earlier clinical course. Patients started on inotropes may be appropriate candidates for AT, yet do not always receive timely evaluations. Given the high mortality associated with end stage HF, we investigated the clinical characteristics and outcomes of HF patients after initiation of inotrope therapy. Methods We retrospectively evaluated 3,948 patients with HF admitted to the University of Pittsburgh Medical Center's 40 hospital network between 2010-2015 from the time of their first identified inotrope therapy to present. Patients post-cardiotomy or with prior heart transplant (HT) or ventricular assist device (VAD) were excluded. Results The patients were predominantly male (61%), white (80%) with a mean age of 68 (±15). Common comorbidities included ventricular arrhythmia (9%), atrial fibrillation (21%) and CKD (59%). 13% had an ICD and 7% had biventricular pacing. Initial EF was reduced (32%±18). During hospitalization 38% were treated with milrinone, 52% with dobutamine and 10% had been on either. Overall, median survival was 6.2 months (95% CI 5.2-7.4). On index hospitalization 1,005 (26%) patients died, 83 (2%) received AT (13 HT and 70 VAD), 491 (12%) were discharged on home inotrope therapy (HI) and 2369 (60%) without HI. Excluding patients that received AT after discharge, Kaplan-Meier analysis showed significantly worse 1-year mortality in patients discharged with HI (51%) versus those without HI (41%) (p Conclusion Most HF patients admitted for inotrope therapy were discharged without HI, with survival remaining low in this group. Patients discharged without HI have longer median survival time yet few go on to follow-up with outpatient cardiology or receive AT. This may represent an opportunity for earlier AT evaluation before further clinical deterioration.

Given the cognitive-promoting properties of the nicotinic acetylcholinergic receptor (nAChR) agonist, nicotine, the increased prevalence of smoke-inhaled nicotine in schizophrenia has been interpreted as an attempt to self-correct cognitive deficits, which have been particularly pronounced in the attentional domain. As glutamatergic abnormalities have been implicated in these attentional deficiencies, this study attempted to shed light on the separate and interactive roles of the N-methyl- d -aspartate receptor (NMDAR) and nAChR systems in the modulation of attention by investigating, in healthy volunteers, the separate and combined effects of nicotine and the NMDAR antagonist ketamine on neural and behavioural responses in a sustained attention task. In a randomized, double-blind, placebo controlled study, performance and the P300 event-related brain potential (ERP) in a visual information processing (RVIP) task were examined in 20 smokers and 20 non-smokers (both male and female). Assessment involved intravenous injection of a low subperceptual bolus dose (.04 mg/kg) of ketamine or placebo, which was accompanied by acute treatment with nicotine (4 mg) or placebo gum. Nicotine-enhanced attentional processing was most evident in nonsmokers, with both performance accuracy and P300 amplitude measures. Ketamine's detrimental effects on these behavioural and electrophysiologic measures were negatively moderated by acute nicotine, the synergistic effects being expressed differently in smokers and nonsmokers. These findings support the view that acute alterations and individual differences in nAChR function can moderate even subtle glutamatergic-driven cognitive deficiencies in schizophrenia and can be important therapeutic targets for treating cognitive impairments in schizophrenia.

In Pennsylvania on February 16, 2006, a New York City resident collapsed with rigors and was hospitalized. On February 21, the Centers for Disease Control and Prevention and the New York City Department of Health and Mental Hygiene were notified that Bacillus anthracis had been identified in the patient's blood. Although the patient's history of working with dried animal hides to make African drums indicated the likelihood of a natural exposure to aerosolized anthrax spores, bioterrorism had to be ruled out first. Ultimately, this case proved to be the first case of naturally occurring inhalational anthrax in 30 years. This article describes the epidemiologic and environmental investigation to identify other cases and persons at risk and to determine the source of exposure and scope of contamination. Because stricter regulation of the importation of animal hides from areas where anthrax is enzootic is difficult, public healthcare officials should consider the possibility of future naturally occurring anthrax cases caused by contaminated hides. Federal protocols are needed to assist in the local response, which should be tempered by our growing understanding of the epidemiology of naturally acquired anthrax. These protocols should include recommended methods for reliable and efficient environmental sample collection and laboratory testing, and environmental risk assessments and remediation.