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Orthotopic heart transplant is the gold standard therapeutic intervention for patients with end-stage heart failure. Conventionally, heart transplant has relied on donation after brain death for organ recovery. Donation after circulatory death (DCD) is the donation of the heart after confirming that circulatory function has irreversibly ceased. DCD-orthotopic heart transplant differs from donation after brain death-orthotopic heart transplant in ways that carry implications for widespread adoption, including differences in organ recovery, storage and ethical considerations surrounding normothermic regional perfusion with DCD. Despite these differences, DCD has shown promising early outcomes, augmenting the donor pool and allowing more individuals to benefit from orthotopic heart transplant. This review aims to present the current state and future trajectory of DCD-heart transplant, examine key differences between DCD and donation after brain death, including clinical experiences and innovations in methodologies, and address the ongoing ethical challenges surrounding the new frontier in heart transplant with DCD donors. [ABSTRACT FROM AUTHOR]

The increasing cost of health care is a major challenge around the world, but particularly in the United States. One reason for increased costs is the rapidly rising cost of oncology drugs. Potential solutions to this problem involve broad changes to health policy. However, an alternative solution is the development of lower-cost off-label treatment regimens, based on pharmacologic rationale, with significant potential economic impact. The pharmacologic and clinical properties of many drugs allow for a variety of different strategies. We describe this approach of interventional pharmacoeconomics and provide multiple individual examples. [ABSTRACT FROM AUTHOR]

BACKGROUND: Persistent low-level hemolysis (LLH) during continuousflow mechanical circulatory support is associated with subsequent thrombosis. Free hemoglobin from ongoing hemolysis scavenges nitric oxide (NO) to create an NO deficiency which can augment platelet function leading to a prothrombotic state. The phosphodiesterase-5 inhibitor, sildenafil, potentiates NO signaling to inhibit platelet function. Accordingly, we investigated the association of sildenafil administration and thrombotic events in patients with LLH during Heart Mate II support. METHODS AND RESULTS: A single-center review of all patients implanted with a Heart Mate II who survived to discharge (n=144). LLH was defined by a discharge lactate dehydrogenase level of 400 to 700 U/L. Patients were categorized as (1) LLH not on sildenafil, (2) LLH on sildenafil, (3) no LLH not on sildenafil, and (4) no LLH on sildenafil. Age, sex, platelet count, and mean platelet volume were similar between groups. Seventeen patients had either device thrombosis or ischemic stroke. Presence of LLH was associated with a greater risk of thrombosis (adjusted hazard ratio, 15; 95% confidence interval, 4.5-50; P<0.001 versus no LLH, not on sildenafil). This risk was reduced in patients with LLH on sildenafil (adjusted hazard ratio, 1.7; 95% confidence interval, 0.2-16.1; P=0.61). Device thrombosis and ischemic stroke were associated with an increase in mean platelet volume (9.6±0.5 to 10.9±0.8 fL, P<0.001). Patients with LLH not on sildenafil had a greater increase in mean platelet volume in comparison to those with LLH on sildenafil (P<0.001). CONCLUSIONS: Sildenafil is associated with reduced device thrombosis and ischemic stroke during ongoing LLH on Heart Mate II support. [ABSTRACT FROM AUTHOR]

Background--Despite a limited supply of organs, only 1 in 3 potential donor hearts is accepted for transplantation. Elevated donor troponin levels have generally been considered a contraindication to heart transplantation; however, the data supporting this practice are limited. Methods and Results--We identified 10 943 adult (=18 years) heart transplant recipients in the United Network of Organ Sharing (UNOS) database with preserved donor left ventricular ejection fraction (=50%) and where peak donor troponin I values were available. When analyzed as a continuous variable, there was no association between peak donor troponin levels and recipient mortality up to 1 year follow-up in unadjusted (hazards ratio, 0.999; 95% confidence interval, 0.997-1.002; P=0.856) and adjusted Cox models (hazards ratio, 1.000; 95% confidence interval, 0.997-1.002; P=0.950). Next, we divided the entire cohort into 3 groups based on donor troponin I values: <1 ng/mL (n=7812), 1 to 10 ng/mL (n=2770), and >10 ng/mL (n=361). Using unadjusted and adjusted Cox models and Kaplan-Meier analysis, there was no significant difference in recipient mortality at 30 days, 1 year, 3 years, or 5 years between the 3 groups. Similarly, cardiac allograft vasculopathy up to 5 years and primary graft failure up to 30 days of follow-up post transplant did not differ between the 3 donor troponin groups. The median length of hospital stay post transplant was also similar across groups. Conclusions--Elevated donor troponin I levels in the setting of preserved left ventricular ejection fraction were not associated with intermediate-term mortality, cardiac allograft vasculopathy, or primary graft failure rates in hearts accepted for transplantation. This finding could help expand the donor pool. [ABSTRACT FROM AUTHOR]

Background--Management of hemolysis in the setting of suspected device thrombosis in continuous-low left ventricular assist device patients varies widely, ranging from watchful waiting with intensified antithrombotic therapy to early surgical device exchange. The aim of this study was to compare the outcomes of hemolysis events treated with surgical interventions versus medical management alone. Methods and Results--A retrospective review of Heartmate II continuous-low left ventricular assist device patients at 2 centers from January 2009 to September 2014 was completed. Patients were categorized as surgical management if hemolysis refractory to intensification of standard antithrombotic therapy was treated surgically. The primary end point was the first occurrence of cerebrovascular accident (CVA) or death. Sixty-four hemolysis events occurred in 49/367 patients implanted with Heartmate II continuous-low left ventricular assist devices. Of 49 primary hemolysis events, 24 were treated with surgical interventions. After surgical treatment, 1 patient died and 2 experienced CVAs, as compared with 3 deaths and 9 CVAs in the 25 patients who remained on intensified antithrombotic therapy alone. The 1-year freedom from CVA or death was 87.5% and 49.5% in the surgical and medical cohorts, respectively (P=0.027). Resolution of a primary hemolysis event without CVA or death occurred in 21/24 patients treated with surgical interventions and in 13/25 who remained on medical therapy alone. A similar association between treatment and outcome was noted in the 15 recurrent hemolysis events. Conclusions--Hemolysis refractory to intensification of antithrombotic therapy identifies continuous-low left ventricular assist device patients at major risk for CVA and death. Early device exchange should be considered to minimize these risks. [ABSTRACT FROM AUTHOR]

Background--Hematologic adverse events are common during continuous flow left ventricular assist device support; yet, their relation to antiplatelet therapy, including aspirin (ASA) dosing, is uncertain. Methods and Results--A single-center retrospective review of all patients supported by a continuous flow left ventricular assist device (Heart Mate II) from June 2006 to November 2014 was conducted. Patients were categorized into 3 groups: (1) ASA 81 mg+dipyridamole 75 mg daily (n=26) with a target international normalized ratio (INR) of 2 to 3 from June 2006 to August 2009; (2) ASA 81 mg daily (n=18) from September 2009 to August 2011 with a target INR of 1.5 to 2; and (3) ASA 325 mg daily from September 2011 to November 2014 with a target INR of 2 to 3 (n=70). Hemorrhagic and thrombotic outcomes were retrieved ≤365 days after implantation. Cumulative survival free from adverse events was calculated using Kaplan-Meier curves and Cox proportional hazard ratios were generated. Hemorrhagic events occurred in 6 patients on ASA 81 mg+dipyridamole (26%; 0.42 events per patient year; mean INR at event, 2.2), 4 patients on ASA 81 mg (22%; 0.38 events per patient year; mean INR at event, 2.0), and in 38 patients on ASA 325 mg (54%; 1.4 events per patient year; mean INR at event, 2.2); P=0.004. Patients on ASA 325 mg had a higher adjusted hazard ratio of 2.9 (95% confidence interval, 1.2-7.0 versus ASA 81 mg+dipyridamole; P=0.02) and 3.4 (95% confidence interval, 1.2-9.5 versus ASA 81 mg; P=0.02) for hemorrhagic events. Thrombotic events rates were not different between groups. Conclusions--High-dose ASA in Heart Mate II patients treated concomitantly with warfarin is associated with an increased hazard of bleeding but does not reduce thrombotic events. [ABSTRACT FROM AUTHOR]

The production of pharmaceutical proteins in plants, particularly in maize (corn), offers solutions to the limited production capacity and flexibility of current cell culture technologies. Implementation of this technology presents unique challenges to industrial hygiene, safety, and occupational medicine, including the handling of pharmaceuticals in the context of agricultural production and the processing of grain for extraction. Protein-related challenges include: (1) widely varying potential for hazard depending upon the activity of the protein and nature and location of the target molecule; (2) limited data related to industrial routes of exposure; and (3) the inability to obtain relevant animal data because of high species-specificity. These challenges necessitate the development of novel approaches to industrial hygiene and safety. Realizing that much remains to be learned, our approach uses conservative assumptions to assure protection of employee health. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Heart failure disproportionately affects Black patients. Whether differences among race influence outcomes in advanced heart failure with use of a fully magnetically levitated continuous-flow left ventricular assist device remains uncertain. Methods: We included 515 IDE (Investigational Device Exemption) clinical trial patients and 500 Continued Access Protocol patients implanted with the HeartMate 3 left ventricular assist device in the MOMENTUM 3 study (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3). Outcomes were compared between Black and White left ventricular assist device recipients for the primary end point of survival free of disabling stroke or reoperation to replace or remove a malfunctioning device at 2 years, overall survival, adverse events, 6-minute walk distance, and quality of life scores. Results: Of 1015 HeartMate 3 patients, 675 were self-identified as White and 285 as Black individuals. The Black patient cohort was younger, more obese and with a history of hypertension, and more nonischemic cause of heart failure, relative to the White patient group. Black and White patients did not experience a difference in the primary end point (81.1% versus 77.9%; hazard ratio, 1.08 [95% CI, 0.76–1.54], P =0.6568). Black patients were at higher risk of adverse events (calculated as events per 100 patient-years), including bleeding (75.4 versus 63.5; P <0.0001), stroke (9.5 versus 7.2; P =0.0183), and hypertension (10.1 versus 3.2; P <0.0001). The 6-minute walk distance was not different at baseline and 6 months between the groups, however, the absolute change from baseline was greater for White patients (median: +183.0 [interquartile range, 42.0–335.3] versus +163.8 [interquartile range, 42.3–315.0] meters, P =0.01). The absolute quality of life measurement (EuroQoL group, 5-dimension, 5-level instrument visual analog scale) at baseline and 6 months was better in the Black patient group, but relative improvement from baseline to 6 months was greater in White patients (median: +20.0 [interquartile range, 5.0–40.0] versus +25.0 [interquartile range, 10.0–45.0]; P =0.0298). Conclusions: Although the survival free of disabling stroke or reoperation to replace/remove a malfunctioning device at 2 years with the HM 3 left ventricular assist device did not differ by race, Black HeartMate 3 patients experienced a higher morbidity burden and smaller gains in functional capacity and quality of life when compared with White patients. These findings require efforts designed to better understand and overcome these gaps through systematic identification and tackling of putative factors. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02224755 and NCT02892955. [ABSTRACT FROM AUTHOR]

During the last 10 years, several cases of myocardial infarction associated with anabolic steroid use have been reported. Postulated mechanisms to explain this association have included changes in lipid levels, the fibrinolytic system, and platelet aggregation. Clenbuterol is a beta 2-agonist with anabolic properties that has not been seen previously with myocardial infarction. We report a case of myocardial infarction in an otherwise healthy 26-year-old body-builder who recently used clenbuterol and anabolic steroids. In this case, synergistic effects of the two agents seem likely to have played a role in the infarct. The normal coronary arteriograms before any anticoagulant or thrombolytic therapy strongly suggest coronary spasm as the mechanism of the infarct. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Ischemic tolerance of donor hearts has a major impact on the efficiency in utilization and clinical outcomes. Molecular events during storage may influence the severity of ischemic injury. Methods: RNA sequencing was used to study the transcriptional profile of the human left ventricle (LV, n=4) and right ventricle (RV, n=4) after 0, 4, and 8 hours of cold storage in histidine-tryptophan-ketoglutarate preservation solution. Gene set enrichment analysis and gene ontology analysis was used to examine transcriptomic changes with cold storage. Terminal deoxynucleotidyl transferase 2´-Deoxyuridine, 5´-Triphosphate nick end labeling and p65 staining was used to examine for cell death and NFκB activation, respectively. Results: The LV showed activation of genes related to inflammation and allograft rejection but downregulation of oxidative phosphorylation and fatty acid metabolism pathway genes. In contrast, inflammation-related genes were down-regulated in the RV and while oxidative phosphorylation genes were activated. These transcriptomic changes were most significant at the 8 hours with much lower differences observed between 0 and 4 hours. RNA velocity estimates corroborated the finding that immune-related genes were activated in the LV but not in the RV during storage. With increasing preservation duration, the LV showed an increase in nuclear translocation of NFκB (p65), whereas the RV showed increased cell death close to the endocardium especially at 8 hours. Conclusions: Our results demonstrated that the LV and RV of human donor hearts have distinct responses to cold ischemic storage. Transcriptomic changes related to inflammation, oxidative phosphorylation, and fatty acid metabolism pathways as well as cell death and NFκB activation were most pronounced after 8 hours of storage. [ABSTRACT FROM AUTHOR]