Faculty Bibliography

HLA antibodies pose a significant barrier to transplantation and current strategies to reduce allosensitization are limited. We hypothesized that augmenting proteasome inhibitor (PI) based desensitization with costimulation blockade (belatacept) to mitigate germinal center (GC) responses might increase efficacy and prevent rebound. Four highly sensitized (calculated panel reactive antibody [cPRA] class I and/or II >99%, complement-dependent cytotoxicity panel reactive antibody [CDC PRA+], C1q+) heart transplant candidates were treated with the combination of belatacept and PI therapy, which significantly reduced both class I and II HLA antibodies and increased the likelihood of identifying an acceptable donor. Three negative CDC crossmatches were achieved against 3, 6, and 8 donor-specific antibodies (DSA), including those that were historically C1q+ binding. Posttransplant, sustained suppression of 3 of 3, 4 of 6, and 8 of 8 DSA (cases 1-3) was achieved. Analysis of peripheral blood mononuclear cells before and after desensitization in one case revealed a decrease in naïve and memory B cells and a reduction in T follicular helper cells with a phenotype suggesting recent GC activity (CD38, PD1, and ICOS). Furthermore, a shift in the natural killer cell phenotype was observed with features suggestive of activation. Our findings support synergism between PI based desensitization and belatacept facilitating transplantation with a negative CDC crossmatch against historically strong, C1q binding antibodies.

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.

Continuous-flow left ventricular assist devices (CF-LVADs) are increasingly used in advanced heart failure patients. Recent studies suggest that low socioeconomic status (SES) predicts worst survival after heart transplantation. Both individual-level and neighborhood-level SES (nSES) have been linked to cardiovascular health; however, the impact of SES in CF-LVAD patients remains unknown. We hypothesized that SES is a major determinant of CF-LVAD candidacy and postimplantation outcomes. A retrospective chart review was conducted on 362 patients between February 2009 and May 2016. Neighborhood-level SES was measured using the American Community Survey data and the Agency for Healthcare Research and Quality SES index score. Individual-level SES was self reported. Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression determined survival statistics. Patients in the highest SES tertile were older (58 ± 13 vs. 53 ± 14; p < 0.001), less likely to be black or Hispanic (26% vs. 70%; p < 0.001), more likely to be married (87% vs. 65%; p < 0.001), more likely to have private insurance (50% vs. 39%; p < 0.001), and more likely to have employment (29% vs. 15%; p < 0.001) compared with patients in the lowest tertile. Low nSES was associated with a decreased risk of death (hazard ratio [HR], 0.580; 95% confidence interval [CI], 0.347-0.970; p = 0.038) in comparison to the high nSES. However, after adjusting for baseline clinical morbidities, the relationship was no longer present. When selecting patients for a LVAD, SES should not be thought of as an immutable risk factor. Carefully selected low-SES patients could be safely implanted with CF-LVAD with outcomes comparable to high-SES patients.

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.

Chronic systolic heart failure (HF) with acute decompensation can result in cardiogenic shock (CS) requiring short-term mechanical circulatory support. We sought to identify predictors of survival for acute decompensated HF (ADHF) patients requiring veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Patients >18 years old treated at our institution with VA-ECMO from 2009 to 2018 for ADHF with CS were studied. Demographic, hemodynamic, and echocardiographic data were collected. The primary outcome was survival to discharge. Fifty-two patients received VA-ECMO for ADHF with CS; 24 (46.2%) survived. Seventeen (32.7%) had suffered cardiac arrest, and 37 (71.2%) were mechanically ventilated. Mean lactate was 4.33 ± 3.45 mmol/L, and patients were receiving 2.7 ± 1.2 vasopressor/inotropic infusions at ECMO initiation; these did not differ significantly between survivors and nonsurvivors. Pre-ECMO cardiac index was 1.84 ± 0.56L/min/m and 1.94 ± 0.63L/min/m in survivors and nonsurvivors, respectively (p = 0.57). In multivariable analysis, only diabetes mellitus (DM; OR, 13.25; CI, 1.42-123.40; p = 0.02) and mineralocorticoid receptor antagonist use (OR, 0.12; CI, 0.02-0.78; p = 0.03) were independent predictors of mortality. Nineteen (79.2%) survivors required durable ventricular assist device. Among ADHF patients receiving VA-ECMO, DM is a powerful predictor of outcomes while markers of clinical acuity including hemodynamics, vasopressor/inotrope use, and lactate are not. The vast majority of survivors required durable left-ventricular assist devices.

Women with advanced heart failure (HF) are underrepresented in trials of short-term and durable mechanical circulatory support although they derive similar benefit. In acute HF, intensive medical and interventional therapies are effective but underutilized. The smaller, newer generation, left ventricular assist devices (LVADs) have increased the feasibility of durable support in women. Women frequently present late, with more comorbidities, emphasizing the need for timely referral. Compared with men, the stroke risk is higher in women with an LVAD. Increased representation in clinical trials and a better understanding of the psychosocial issues affecting women is essential.

BACKGROUND:Heart rate (HR) is a prognostic marker that is increasingly used as a therapeutic target in patients with cardiovascular disease. The association between resting and mean HR remains unclear. We therefore set out to determine the relationship between resting HR on the electrocardiogram (ECG) obtained at a single time point, and mean HR on implantable cardioverter defibrillator (ICD) interrogation amongst patients with a reduced left ventricular ejection fraction (LVEF). METHODS:Prospective ICD data were obtained from 54 patients with LVEF < 40%. Mean HR determined using the ICD HR histograms was compared with resting HR measured on the ECG performed in the clinic. RESULTS:Average resting and ICD mean HRs were 67.9 ± 10.1 and 67.8 ± 9.6 bpm respectively. There was good correlation in the overall cohort (r = 0.79), in those with resting ECG HRs ≤ 70 bpm (r = 0.62), and amongst the 27 patients on intermediate-to-high dose beta-blockers (r = 0.91). However, Bland-Altman analysis demonstrated wide limits of agreement in the overall cohort (- 12.5, 12.7 bpm), at resting HRs ≤ 70 bpm (- 12.7, 9.8 bpm), and on intermediate-to-high dose beta-blockers (- 8.9, 7.4 bpm). Moreover, resting HR did not predict the 10-bpm interval where the most time was spent. CONCLUSIONS:While resting HR correlated with mean HR in patients with reduced LVEF, and in important subgroups, the limits of agreement were unacceptably wide raising concern over the use of single time point resting HR as a therapeutic target.

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.