Metabolic reprogramming by immune-responsive gene 1 up-regulation improves donor heart preservation and function.

Preservation quality of donor hearts is a key determinant of transplant success. Preservation duration beyond 4 hours is associated with primary graft dysfunction (PGD). Given transport time constraints, geographical limitations exist for donor-recipient matching, leading to donor heart underutilization. Here, we showed that metabolic reprogramming through up-regulation of the enzyme immune response gene 1 (IRG1) and its product itaconate improved heart function after prolonged preservation. Irg1 transcript induction was achieved by adding the histone deacetylase (HDAC) inhibitor valproic acid (VPA) to a histidine-tryptophan-ketoglutarate solution used for donor heart preservation. VPA increased acetylated H3K27 occupancy at the IRG1 enhancer and IRG1 transcript expression in human donor hearts. IRG1 converts aconitate to itaconate, which has both anti-inflammatory and antioxidant properties. Accordingly, our studies showed that Irg1 transcript up-regulation by VPA treatment increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in mice, which was accompanied by increased antioxidant protein expression [hemeoxygenase 1 (HO1) and superoxide dismutase 1 (SOD1)]. Deletion of Irg1 in mice (Irg1-/-) negated the antioxidant and cardioprotective effects of VPA. Consistent with itaconate's ability to inhibit succinate dehydrogenase, VPA treatment of human hearts increased itaconate availability and reduced succinate accumulation during preservation. VPA similarly increased IRG1 expression in pig donor hearts and improved its function in an ex vivo cardiac perfusion system both at the clinical 4-hour preservation threshold and at 10 hours. These results suggest that augmentation of cardioprotective immune-metabolomic pathways may be a promising therapeutic strategy for improving donor heart function in transplantation.

Determining optimal donor heart ischemic times in adult cardiac transplantation.

OBJECTIVES: Unsupervised statistical determination of optimal allograft ischemic time (IT) on heart transplant outcomes among ABO donor heart types. METHODS: We identified 36,145 heart transplants (2000-2018) from the United Network for Organ Sharing database. Continuous and categorical variables were analyzed with parametric and nonparametric testing. Determination of IT cutoffs for survival analysis was performed using Contal and O'Quigley univariable method and Vito Muggeo multivariable segmented modeling. RESULTS: Univariable and multivariable IT threshold determination revealed a cutoff at about 3 h. The hourly increase in survival risk with ≥3 h IT is asymmetrically experienced at the early 90 days (hazard ratio [HR] = 1.29, p < .001) and up to 1-year time point (HR = 1.16, p < .001). Beyond 1 year the risk of prolonged IT is less impactful (HR = 1.04, p = .022). Longer IT was associated with more postoperative complications such as stroke (2.7% vs. 2.3, p = .042), dialysis (11.6% vs. 9.1%, p < .001) and death from primary graft dysfunction (1.8% vs. 1.2%, p < .001). O blood type donor hearts with IT ≥ 3 h has significantly increased hourly mortality risk at 90 days (HR = 1.27, p < .001), 90 days to 1 year (HR = 1.22, p < .001) and >1 year (HR = 1.05, p = .041). For non-O blood types with ≥3 h IT hourly mortality risk was increased at 90 days (HR = 1.33, p < .001), but not at 90 days to 1 year (HR = 1.09, p = .146) nor ≥1 year (HR = 1.08, p = .237). CONCLUSIONS: The donor heart IT threshold for survival determined from unbiased statistical modeling occurs at 3 h. With longer preservation times, transplantation with O donor hearts was associated with worse survival.

Advancing Quality Metrics for Durable Left Ventricular Assist Device Implant: Analysis of the Society of Thoracic Surgeons Intermacs Database.

BACKGROUND: Patients undergoing left ventricular assist device (LVAD) implantation are at risk for death and postoperative adverse outcomes. Interhospital variability and concordance of quality metrics were assessed using the Society of Thoracic Surgeons Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs). METHODS: A total of 22 173 patients underwent primary, durable LVAD implantation across 160 hospitals from 2012 to 2020, excluding hospitals performing <10 implant procedures. Observed and risk-adjusted operative mortality rates were calculated for each hospital. Outcomes included operative and 90-day mortality, a composite of adverse events (operative mortality, bleeding, stroke, device malfunction, renal dysfunction, respiratory failure), and secondarily failure to rescue. Rates are presented as median (interquartile range [IQR]). Hospital performance was evaluated using observed-to-expected (O/E) ratios for mortality and the composite outcome. RESULTS: Interhospital variability existed in observed (median, 7.2% [IQR, 5.1%-9.6%]) mortality. The rates of adverse events varied across hospitals: major bleeding, 15.6% (IQR, 11.4%-22.4%); stroke, 3.1% (IQR, 1.6%-4.7%); device malfunction, 2.4% (IQR, 0.8%-3.7%); respiratory failure, 10.5% (IQR, 4.6%-15.7%); and renal dysfunction, 6.4% (IQR, 3.2%-9.6%). The O/E ratio for operative mortality varied from 0.0 to 6.1, whereas the O/E ratio for the composite outcome varied from 0.28 to 1.99. Hospital operative mortality O/E ratios were more closely correlated with the 90-day mortality O/E ratio (r = 0.74) than with the composite O/E ratio (r = 0.12). CONCLUSIONS: This study reported substantial interhospital variability in performance for hospitals implanting durable LVADs. These findings support the need to (1) report hospital-level performance (mortality, composite) and (2) undertake benchmarking activities to reduce unwarranted variability in outcomes.

Impact of donor blood type on outcomes after prolonged allograft ischemic times.

OBJECTIVE: The study objective was to determine the influence of allograft ischemic time on heart transplant outcomes among ABO donor organ types given limited prior reports of its survival impact. METHODS: We identified 32,454 heart transplants (2000-2016) from the United Network for Organ Sharing database. Continuous and categoric variables were analyzed by parametric and nonparametric testing. Survival was determined using log-rank or Cox regression tests. Propensity matching adjusted for preoperative variables. RESULTS: By comparing allograft ischemic time less than 4 hours (n = 6579) with 4 hours or more (n = 25,875), the hazard ratios for death at 15 years after prolonged ischemic time (≥4 hours) for blood types O, A, B, and AB were 1.106 (P < .001), 1.062 (P < .001), 1.059 (P = .062), and 1.114 (P = .221), respectively. Unadjusted data demonstrated higher mortality for transplantation of O versus non-O donor hearts for ischemic time 4 hours or more (hazard ratio, 1.164; P < .001). After propensity matching, O donor hearts continued to have worse survival if preserved for 4 hours or more (hazard ratio, 1.137, P = .008), but not if ischemic time was less than 4 hours (hazard ratio, 1.042, P = .113). In a matched group with 4 hours or more of ischemic time, patients receiving O donor organs were more likely to experience death from primary graft dysfunction (2.5% vs 1.7%, P = .052) and chronic allograft rejection (1.9% vs 1.1%, P = .021). No difference in death from primary graft dysfunction or chronic allograft rejection was seen with less than 4 hours of ischemic time (P > .150). CONCLUSIONS: Compared with non-O donor hearts, transplantation with O donor hearts with ischemic time 4 hours or more leads to worse survival, with higher rates of primary graft dysfunction and chronic rejection. Caution should be practiced when considering donor hearts with the O blood type when anticipating extended cold ischemic times.

Use of Argatroban in Donor Lung Procurement: A Case Report.

BACKGROUND Heparin-induced thrombocytopenia (HIT) is an immunological response to heparin exposure that predisposes patients to hypercoagulable reactions with subsequent heparin administration. Traditionally, heparin is the standard anticoagulant used during organ procurement to prevent clot formation in grafts. This creates a problem in donors or recipients that develop HIT as they are at risk of developing life-threatening coagulopathy. This raises the question of how to use alternative anticoagulation therapies, such as argatroban, that provide rapid-onset prophylaxis by reversibly inhibiting thrombin. Additionally, there are few studies that have assessed how recipients of multiorgan donors treated with argatroban do post-operatively. CASE REPORT In this report, we discuss the procurement protocol and hospital course of a lung transplant recipient who received a graft treated with argatroban due to a HIT-positive liver recipient. The post-operative course for our patient was uneventful, with improved lung function and no complications attributable to argatroban use. Further, none of the 4 other recipients who received organs from the same donor experienced graft dysfunctions secondary to coagulopathy, including the HIT-positive liver recipient. CONCLUSIONS The ultimate success of grafts without thromboembolic complications suggests the use of argatroban in multiorgan procurement in the setting of a HIT-positive recipient is safe and effective. This case report highlights an alternative to the traditional process of organ procurement with heparin, in which patients at risk of coagulopathies secondary to HIT are able to receive organs when traditional protocols would otherwise be prohibitive.

Left Ventricular Assist Device Implantation in Patients with Preoperative Severe Mitral Regurgitation.

We examined cardiac features associated with residual mitral regurgitation (MR) following continuous-flow left ventricular assist device (cfLVAD) implant. From 2003 to 2017, 134 patients with severe MR underwent cfVLAD implant without mitral valve (MV) intervention. Echocardiographic (echo) assessment occurred pre-cfLVAD, early post-cfLVAD, and at last available echo. Ventricular and atrial volumes were calculated from established formulas and normalized to be predicted. Cluster analysis based on preoperative normalized left ventricular and atrial volumes, and MV height identified grades 1, 2, and 3 with progressively larger cardiac chamber sizes. Median early echo follow-up was 0.92 (0.55, 1.45) months and the last follow-up was 15.12 (5.28, 38.28) months. Mitral regurgitation improved early after cfLVAD by 2.10 ± 1.16 grades (p < 0.01). Mitral regurgitation severity at the last echocardiogram positively correlated with the preoperative left ventricular volume (p = 0.014, R = 0.212), left atrial volume (p = 0.007, R = 0.233), MV anteroposterior height (p = 0.032, R = 0.185), and MV mediolateral diameter (p = 0.043, R = 0.175). Morphologically, smaller grade 1 hearts were correlated with MR resolution at the late follow-up (p = 0.023). Late right ventricular failure (RVF) at the last clinical follow-up was less in grade 1 (4/48 [8.3%]) compared with grades 2 and 3 (26/86 [30.2%]), p = 0.004). Grade 1 cardiac dimensions correlates with improvement in severe MR and had less late RVF.

One-Year Functional, Cognitive, and Psychological Outcomes Following the Use of Extracorporeal Membrane Oxygenation in Coronavirus Disease 2019: A Prospective Study.

To prospectively describe 1-year outcomes, with a focus on functional outcome, cognitive outcome, and the burden of anxiety, depression, and post-traumatic stress disorder, in coronavirus disease 2019 patients managed with extracorporeal membrane oxygenation. DESIGN: Prospective case series. SETTING: Tertiary extracorporeal membrane oxygenation center in the United States. PATIENTS: Adult coronavirus disease 2019 acute respiratory distress syndrome patients managed with extracorporeal membrane oxygenation March 1, 2020, to July 31, 2020. INTERVENTIONS: Baseline variables, treatment measures, and short-term outcomes were obtained from the medical record. Survivors were interviewed by telephone, a year following the index intensive care admission. Functional outcome was assessed using the modified Rankin Scale and the World Health Organization Disability Assessment Scale 2.0. Cognitive status was assessed with the 5-minute Montreal Cognitive Assessment. The Hospital Anxiety and Depression Scale was used to screen for anxiety and depression. Screening for post-traumatic stress disorder was performed with the Posttraumatic Stress Disorder Checklist 5 instrument. MEASUREMENTS AND MAIN RESULTS: Twenty-three patients were managed with extracorporeal membrane oxygenation, 14 (61%) survived to hospital discharge. Thirteen (57%) were alive at 1 year. One patient was dependent on mechanical ventilation, another intermittently required supplemental oxygen at 1 year. The median modified Rankin Scale score was 2 (interquartile range, 1-2), median World Health Organization Disability Assessment Scale 2.0 impairment score was 21% (interquartile range, 6-42%). Six of 12 previously employed individuals (50%) had returned to work, and 10 of 12 (83%) were entirely independent in activities of daily living. The median Montreal Cognitive Assessment score was 14 (interquartile range, 13-14). Of 10 patients assessed with Hospital Anxiety and Depression Scale, 4 (40%) screened positive for depression and 6 (60%) for anxiety. Four of 10 (40%) screened positive for post-traumatic stress disorder. CONCLUSIONS: Functional impairment was common a year following the use of extracorporeal membrane oxygenation in coronavirus disease 2019, although the majority achieved independence in daily living and about half returned to work. Long-term anxiety, depression, and post-traumatic stress disorder were common, but cognitive impairment was not.

Lobar lung transplantation: a relevant surgical option in the current era of lung allocation score.

BACKGROUND: With the implementation of the lung allocation score (LAS) system, an increased number of critically ill patients are considered for transplantation. However, LAS does not take size matching between donor and recipient lungs into consideration. Mortality on the waiting list is high (as high as 25%) for short-stature patients and for patients with restrictive lung disease. Here, we review our experience using cadaveric lobar lung transplantation as a surgical option in an attempt to decrease mortality while waiting. METHODS: We retrospectively reviewed patients with end-stage lung diseases and an LAS greater than 70 who underwent cadaveric lobar lung transplantation between 2010 and 2012 (n = 25) at our institution, a high-volume lung transplant center. Anatomic lobectomy was performed on all donor lungs before double lung transplantation. RESULTS: Median LAS was 85.6 (range, 72 to 94). Average waiting time after the patients' LAS was updated to greater than 70 was 10 days (range, 1 to 41). There were 2 in-hospital deaths. The 90-day and 1-year survivals were 88% and 76%, respectively. Patient major comorbidities included severe primary graft dysfunction requiring postoperative extracorporeal membrane oxygenation (7 patients), acute renal insufficiency (4 patients), and bleeding requiring reoperation (4 patients). No technical problems were identified, and repeated bronchoscopy demonstrated satisfactory healing of the bronchial stump after lobectomy. The average posttransplant peak for forced expiratory volume in 1 second was 85%. CONCLUSIONS: Our initial experience supports the option of lobar lung transplantation for critically ill patients whose opportunities for transplant are limited by their stature. Long-term functional studies are warranted.