RESUMO
Scientific barriers that have prevented successful xenotransplantation are being breached, yet many ethical issues remain. Some are broad issues that accompany the adoption of novel and expensive technologies, and some are unique to xenotransplantation. Major ethical questions include areas such as: viral transmission; zoonoses and lifetime surveillance; interfering with nature; efficacy, access, and expense; treatment of animals; regulation and oversight.
Assuntos
Zoonoses , Animais , Transplante Heterólogo , Zoonoses/prevenção & controleRESUMO
α-Synuclein is the major component of Lewy bodies and a candidate biomarker for neurodegenerative diseases in which Lewy bodies are common, including Parkinson's disease and dementia with Lewy bodies. A large body of literature suggests that these disorders are characterized by reduced concentrations of α-synuclein in cerebrospinal fluid (CSF), with overlapping concentrations compared to healthy controls and variability across studies. Several reasons can account for this variability, including technical ones, such as inter-assay and inter-laboratory variation (reproducibility). We compared four immunochemical methods for the quantification of α-synuclein concentration in 50 unique CSF samples. All methods were designed to capture most of the existing α-synuclein forms in CSF ('total' α-synuclein). Each of the four methods showed high analytical precision, excellent correlation between laboratories (R2 0.83-0.99), and good correlation with each other (R2 0.64-0.93), although the slopes of the regression lines were different between the four immunoassays. The use of common reference CSF samples decreased the differences in α-synuclein concentration between detection methods and technologies. Pilot data on an immunoprecipitation mass spectrometry (IP-MS) method is also presented. Our results suggest that the four immunochemical methods and the IP-MS method measure similar forms of α-synuclein and that a common reference material would allow harmonization of results between immunoassays.
Assuntos
Biomarcadores/líquido cefalorraquidiano , Imunoensaio/métodos , alfa-Sinucleína/líquido cefalorraquidiano , Feminino , Humanos , Doença por Corpos de Lewy/líquido cefalorraquidiano , Masculino , Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Valores de Referência , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Neuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinson's Disease Biomarkers Program to promote discovery of PD biomarkers for use in phase II and III clinical trials. METHODS: Using a novel consortium design, the Parkinson's Disease Biomarker Program is focused on the development of clinical and laboratory-based biomarkers for PD diagnosis, progression, and prognosis. Standardized operating procedures and pooled reference samples were created to allow cross-project comparisons and assessment of batch effects. A web-based Data Management Resource facilitates rapid sharing of data and biosamples across the research community for additional biomarker projects. RESULTS: Eleven consortium projects are ongoing, seven of which recruit participants and obtain biosamples. As of October 2014, 1,082 participants have enrolled (620 PD, 101 with other causes of parkinsonism, 23 essential tremor, and 338 controls), 1,040 of whom have at least one biosample. Six thousand eight hundred ninety-eight total biosamples are available from baseline, 6-, 12-, and 18-month visits: 1,006 DNA, 1,661 RNA, 1,419 whole blood, 1,382 plasma, 1,200 serum, and 230 cerebrospinal fluid (CSF). Quality control analysis of plasma, serum, and CSF samples indicates that almost all samples are high quality (24 of 2,812 samples exceed acceptable hemoglobin levels). CONCLUSIONS: By making samples and data widely available, using stringent operating procedures based on existing standards, hypothesis testing for biomarker discovery, and providing a resource that complements existing programs, the Parkinson's Disease Biomarker Program will accelerate the pace of PD biomarker research. © 2015 International Parkinson and Movement Disorder Society.
Assuntos
Biomarcadores , Estudos Multicêntricos como Assunto , National Institute of Neurological Disorders and Stroke (USA) , Doença de Parkinson/diagnóstico , Desenvolvimento de Programas , Humanos , Estados UnidosRESUMO
OBJECTIVE: Intervention for repair of secondary mitral valve disease is frequently associated with recurrent regurgitation. We sought to determine if there was sufficient evidence to support inclusion of anatomic indices of leaflet dysfunction in the management of secondary mitral valve disease. METHODS: We performed a systematic review and meta-analysis of published reports comparing anatomic indices of leaflet dysfunction with the complexity of valve repair and the outcome from intervention. Patients were stratified by the severity of leaflet dysfunction. A secondary analysis was performed comparing outcomes when procedural complexity was optimally matched to severity of leaflet dysfunction and when intervention was not matched to dysfunction. RESULTS: We identified 6864 publications, of which 65 met inclusion criteria. An association between the severity of leaflet dysfunction and the procedural complexity was highly predictive of satisfactory freedom from recurrent regurgitation. Patients were categorized into 4 groups based on stratification of leaflet dysfunction. Satisfactory results were achieved in 93.7% of patients in whom repair complexity was appropriately matched to severity of leaflet dysfunction and in 68.8% in whom repair was not matched to dysfunction (odds ratio, 0.148; 95% confidence interval, 0.119-0.184; P < .0001). CONCLUSIONS: For patients with secondary mitral valve disease, satisfactory outcome from valve repair improves when procedural complexity is matched to anatomic indices of leaflet dysfunction. Anatomic indices of leaflet dysfunction should be considered when planning interventions for secondary mitral regurgitation. Routine inclusion of anatomic indices in trial design and reporting should facilitate comparison of results and strengthen guidelines. There are sufficient data to support anatomic staging of secondary mitral valve disease.
Assuntos
Insuficiência da Valva Mitral , Prolapso da Valva Mitral , Humanos , Valva Mitral/diagnóstico por imagem , Valva Mitral/cirurgia , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/cirurgia , Fatores de Tempo , Resultado do TratamentoRESUMO
Cold static storage (CSS) for up to 6â h is the gold standard in heart preservation. Although some hearts stored over 6â h have been transplanted, longer CSS times have increased posttransplant morbimortality. Transmedics® Organ Care System (OCS™) is the only FDA-approved commercial system that provides an alternative to CSS using normothermic ex situ heart perfusion (NEHP) in resting mode with aortic perfusion (Langendorff method). However, it is also limited to 6â h and lacks an objective assessment of cardiac function. Developing a system that can perfuse hearts under NEHP conditions for >24â h can facilitate organ rehabilitation, expansion of the donor pool, and objective functional evaluation. The Extracorporeal Life Support Laboratory at the University of Michigan has worked to prolong NEHP to >24â h with an objective assessment of heart viability during NEHP. An NEHP system was developed for aortic (Langendorff) perfusion using a blood-derived perfusate (leukocyte/thrombocyte-depleted blood). Porcine hearts (n = 42) of different sizes (6-55â kg) were divided into five groups and studied during 24â h NEHP with various interventions in three piglets (small-size) heart groups: (1) Control NEHP without interventions (n = 15); (2) NEHP + plasma exchange (n = 5); (3) NEHP + hemofiltration (n = 10) and two adult-size (juvenile pigs) heart groups (to demonstrate the support of larger hearts); (4) NEHP + hemofiltration (n = 5); and (5) NEHP with intermittent left atrial (iLA) perfusion (n = 7). All hearts with NEHP + interventions (n = 27) were successfully perfused for 24â h, whereas 14 (93.3%) control hearts failed between 10 and 21â h, and 1 control heart (6.6%) lasted 24â h. Hearts in the piglet hemofiltration and plasma exchange groups performed better than those in the control group. The larger hearts in the iLA perfusion group (n = 7) allowed for real-time heart functional assessment and remained stable throughout the 24â h of NEHP. These results demonstrate that heart preservation for 24â h is feasible with our NEHP perfusion technique. Increasing the preservation period beyond 24â h, infection control, and nutritional support all need optimization. This proves the concept that NEHP has the potential to increase the organ pool by (1) considering previously discarded hearts; (2) performing an objective assessment of heart function; (3) increasing the donor/recipient distance; and (4) developing heart-specific perfusion therapies.
RESUMO
Objective: Donor hearts procured after circulatory death (DCD) may significantly increase the number of hearts available for transplantation. The purpose of this study was to analyze current DCD and brain-dead donor (DBD) heart transplantation rates and characterize organ refusal using the most up-to-date United Network for Organ Sharing (UNOS) and Organ Procurement and Transplantation Network data. Methods: We analyzed UNOS and Organ Procurement and Transplantation Network DBD and DCD candidate, transplantation, and demographic data from 2020 through 2022 and 2022 refusal code data to characterize DCD heart use and refusal. Subanalyses were performed to characterize DCD donor demographics and regional transplantation rate variance. Results: DCD hearts were declined 3.37 times more often than DBD hearts. The most frequently used code for DCD refusal was neurologic function, related to concerns of a prolonged dying process and organ preservation. In 2022, 92% (1329/1452) of all DCD refusals were attributed to neurologic function. When compared with DBD, DCD donor hearts were more frequently declined as the result of prolonged warm ischemic time (odds ratio, 5.65; 95% confidence interval, 4.07-7.86) and other concerns over organ preservation (odds ratio, 4.06; 95% confidence interval, 3.33-4.94). Transplantation rate variation was observed between demographic groups and UNOS regions. DCD transplantation rates are currently experiencing second order polynomial growth. Conclusions: DCD donor hearts are declined more frequently than DBD. DCD heart refusals result from concerns over a prolonged dying process and organ preservation. Heart transplantation rates may be substantially improved by ex situ hemodynamic assessment, adoption of normothermic regional perfusion guidelines, and quality initiatives.
RESUMO
BACKGROUND: Cold static storage and normothermic ex vivo heart perfusion are routinely limited to 6 h. This report describes intermittent left atrial (LA) perfusion that allows cardiac functional assessment in a working heart mode. METHODS: Using our adult porcine model, general anesthesia was induced and a complete cardiectomy was performed following cardioplegic arrest. Back-table instrumentation was completed and normothermic ex vivo heart perfusion (NEHP) was initiated in a nonworking heart mode (Langendorff). After 1 h of resuscitation and recovery, LA perfusion was initiated and the heart was transitioned to a coronary flow-only working heart mode for 30 min. Baseline working heart parameters were documented and the heart was returned to nonworking mode. Working heart assessments were performed for 30 min every 6 h for 24 h. RESULTS: Twenty-four-hour NEHP on 9 consecutive hearts (280â ±â 42.1 g) was successful and no significant differences were found between working heart parameters at baseline and after 24 h of perfusion. There was no difference between initial and final measurements of LA mean pressures (5.0â ±â 3.1 versus 9.0â ±â 6.5 mm Hg, P â =â 0.22), left ventricular systolic pressures (44.3â ±â 7.2 versus 39.1â ±â 9.0 mm Hg, P â =â 0.13), mean aortic pressures (30.9â ±â 5.8 versus 28.1â ±â 8.1 mm Hg, P â =â 0.37), and coronary resistance (0.174â ±â 0.046 versus 0.173â ±â 0.066 mL/min/g, P â =â 0.90). There were also no significant differences between lactate (2.4â ±â 0.5 versus 2.6â ±â 0.4 mmol/L, P â =â 0.17) and glucose (173â ±â 75 versus 156â ±â 70 mg/dL, P â =â 0.37). CONCLUSIONS: A novel model using intermittent LA perfusion to create a coronary flow-only working heart mode for assessment of ex vivo cardiac function has been successfully developed.
Assuntos
Modelos Animais , Perfusão , Animais , Perfusão/métodos , Fatores de Tempo , Preparação de Coração Isolado , Suínos , Circulação Coronária , Preservação de Órgãos/métodos , Função Ventricular Esquerda , Transplante de Coração , Sus scrofaRESUMO
Background: Heart transplantation is always an emergency because the transplant needs to occur within 6 h after procurement to prevent primary graft dysfunction. Static cold storage (SCS) is the gold-standard preservation method. This study describes the outcomes of hearts preserved after prolonged SCS (12 and 24 h); those are then resuscitated with a novel normothermic ex situ heart perfusion (NEHP) system. Methods: Anesthetized piglets (nâ =â 10) were used as heart donors. Hearts were procured and stored at 5 °C CoStorSol following standard SCS protocols. Two groups were studied: SCS-12 h and SCS-24 h. After SCS, 8 h of NEHP (37 °C blood-based perfusate) was performed at 0.7-1.0 mL/min/g of cardiac tissue. NEHP parameters were monitored continuously. Results were corroborated with 3 additional hearts transplanted orthotopically in healthy recipients (nâ =â 3) after SCS (24 h) + NEHP (5 h). Recipients were observed for 90 min after weaning off cardiopulmonary bypass support. Results: All hearts (after 12 and 24 h of SCS) regained normal function and metabolism within 10 min and retained it throughout 8 h of NEHP. No differences were observed in NEHP parameters and histopathology between groups. Three hearts were successfully transplanted after a total ~30 h of preservation (24 h of SCS + 5 h of NEHP + 1 h of second cold ischemia time). The 3 recipients were weaned off cardiopulmonary bypass with mild vasopressor support. Conclusions: NEHP has the potential to routinely resuscitate porcine hearts that have undergone SCS for up to 24 h, restoring them to viable function. By objectively assessing heart function before transplant, NEHP may enhance the success rate of transplants. If these resuscitated hearts can be successfully transplanted, it would support the effectiveness of NEHP in ensuring heart viability.
RESUMO
OBJECTIVE: Racial disparities in health care have come to the forefront. We hypothesized that Black race was associated with worse preoperative risk, lower repair rates, and worse outcomes among patients who underwent mitral valve surgery. METHODS: All patients who underwent mitral valve repair or replacement with or without coronary artery bypass grafting from 2011 to 2020 in a statewide collaborative database were stratified into 3 racial groups, White, Black, and other. Preoperative characteristics, procedure type, and outcomes were evaluated. RESULTS: A total of 9074 mitral valve operations were performed at 33 centers (Black 1009 [11.1%], White 7862 [86.6%]). Preoperative combined Society of Thoracic Surgeons morbidity and mortality was higher for Black patients (Black 32%, White 22%, other 23%, [P < .001]) because of a greater proportion of diabetes, hypertension, and chronic lung disease. White patients were more likely to undergo mitral repair (White 66%, Black 53.3%, other 57%; P < .001). Operative mortality was similar across racial groups (White 3.7%, Black 4.6%, other 4.5%; P = .36). After adjusting for preoperative factors, mitral etiology, and hospitals, race was not associated with mitral valve repair, complications, or mortality, but Black patients had higher odds of extended care facility utilization and readmission. CONCLUSIONS: Contrary to our hypothesis, there was no difference in the odds of repair or operative mortality across races after accounting for risk and etiology. However, Black patients were more likely to be readmitted after discharge. These findings support a greater focus on reducing disparities in mitral valve surgery.
Assuntos
Implante de Prótese de Valva Cardíaca , Valva Mitral , Humanos , Valva Mitral/cirurgia , Resultado do Tratamento , Grupos Raciais , Ponte de Artéria Coronária , Hospitais , Implante de Prótese de Valva Cardíaca/métodosRESUMO
BACKGROUND: Historically, cardiac transplantation relied on cold static storage at 5 °C for ex vivo myocardial preservation. Currently, machine perfusion is the standard of care at many transplant centers. These storage methods are limited to 12 hours. We sought to evaluate the efficacy of hemofiltration and filtrate replacement in adult porcine hearts using normothermic heart perfusion (NEVHP) for 24 hours. METHODS: We performed 24-hour NEVHP on 5 consecutive hearts. After anesthetic induction, sternotomy, cardioplegia administration, explantation, and back-table instrumentation, NEVHP was initiated in beating, unloaded mode. After 1 hour, plasma exchange was performed, and hemofiltration was initiated. Heart function parameters and arterial blood gasses were obtained hourly. RESULTS: All hearts (n = 5) were viable at the 24-hour mark. The average left ventricular systolic pressure at the beginning of the prep was 36.6 ± 7.9 mm Hg compared with 27 ± 5.5 mm Hg at the end. Coronary resistance at the beginning of prep was 0.79 ± 0.10 mm Hg/L/min and 0.93 ± 0.28 mm Hg/L/min at the end. Glucose levels averaged 223 ± 13.9 mg/dL, and the lactate average at the termination of prep was 2.6 ± 0.3 mmol/L. CONCLUSIONS: We successfully perfused adult porcine hearts at normothermic temperatures for 24 hours with results comparable to our pediatric porcine heart model. The next step in our research is NEVHP evaluation in a working mode using left atrial perfusion.
Assuntos
Transplante de Coração , Hemofiltração , Humanos , Adulto , Criança , Suínos , Animais , Coração , Transplante de Coração/métodos , Perfusão/métodos , Ácido Láctico , Preservação de Órgãos/métodosAssuntos
Implantação Dentária Endóssea/métodos , Implantes Dentários , Odontologia Geral , Arcada Parcialmente Edêntula/reabilitação , Tomografia Computadorizada de Feixe Cônico , Falha de Restauração Dentária , Estética Dentária , Feminino , Humanos , Maxila/diagnóstico por imagem , Maxila/cirurgia , Pessoa de Meia-IdadeRESUMO
A pumpless artificial lung has the potential to provide a bridge to recovery or transplantation in children with respiratory failure. Pulmonary artery inflow and left atrial outflow are necessary for low-gradient, pumpless systems; however, long-term cannulation of the fragile left atrium remains problematic. In this technique, the left atrium and pulmonary artery were exposed through a left anterior thoracotomy. Inflow to the artificial lung was created using an end-to-side anastomosis with the pulmonary artery. Device outflow was established through the left atrium. A single-stage venous cannula was passed through a free PTFE graft. Using polypropylene with pledgets, two concentric purse-string sutures were placed in the dome of the left atrium. The venous cannula was inserted. The graft was slid down the cannula and circumferentially secured to the adjacent left atrial tissue and pledgets. The other end of the graft was secured to the cannula with silk ties. The procedure was successful in 10 sheep. Initial device blood flow was 969 ± 222 ml/min, which remained stable for up to 7 days with no anastomotic complications. This is an effective method of achieving secure, long-term left atrial cannulation without cardiopulmonary bypass for use in a low-resistance, pumpless artificial lung. And, most importantly, improves the ease and safety of cannula replacement and final decannulation when AL support is no longer required.
Assuntos
Cateterismo , Coração Auxiliar , Animais , Ponte Cardiopulmonar , Átrios do Coração/cirurgia , Pulmão , OvinosRESUMO
OBJECTIVE: Cross-circulation of plasma from a paracorporeal animal allows successful ex vivo heart perfusion (EVHP) for 3 days. Little is known about the feasibility of prolonged EVHP without a paracorporeal animal. These experiments evaluated plasma exchange (PX) that infuses fresh plasma, whereas an equal amount is removed to replace paracorporeal cross-circulation. METHODS: Ten hearts were procured from 8 to 10 kg piglets and maintained with EVHP. The EVHP circuit was primed with platelet- and leukocyte-reduced blood. Plasma obtained from stored porcine blood (4°C for ≤7 days) was infused and removed with a plasma separator at 1 mL/h/g cardiac tissue (n = 5) in the PX group. Controls (n = 5) used the same EVHP without PX. Antegrade aortic perfusion was adjusted to reach physiologic coronary flow of 0.7 to 1.2 mL/min/g, normothermia (37°C), and hemoglobin ≥8 g/dL. Viability was assessed by hemodynamic metrics, metabolic assays, and histopathology. RESULTS: All PX hearts remained viable for 24 hours compared with only 1 control (P = .015). Coronary resistance was higher in the PX versus controls (1.06 ± 0.06 mm Hg/mL/min; 0.58 ± 0.02 mm Hg/mL/min [P < .05]). Lactate levels were lower in PX (2.8-4.2 mmol/L) versus controls (3.6-7.6 mmol/L) (P < .05). PX demonstrated a trend toward preservation of left ventricle systolic pressure (63.0 ± 10.9 mm Hg) versus controls (37 ± 22.0 mm Hg) (P > .05). In mixed effect models, oxygen consumption was higher with PX (P < .05). Histopathologic evaluation confirmed extensive myocardial degeneration and worse interstitial edema in controls. CONCLUSIONS: These results demonstrate that EVHP can be successfully maintained for at least 24 hours using continuous PX. This eliminates the need for a paracorporeal animal and provides an important step toward clinical application.
Assuntos
Transplante de Coração , Preservação de Órgãos , Animais , Coração/fisiologia , Humanos , Preservação de Órgãos/métodos , Perfusão/efeitos adversos , Perfusão/métodos , Troca Plasmática , SuínosRESUMO
Currently, normothermic ex vivo heart perfusion (NEVHP) is limited to 6-12 hours. NEVHP for 24 hours or more would allow organ treatment, assessment of organ function, and near-perfect recipient matching. We present a model of NEVHP using continuous hemofiltration (HFn) with sustained myocardial viability up to 24 hours. Twenty hearts from 6-10 kg piglets were procured and maintained on our NEVHP circuit. HFn hearts (n = 10) underwent NEVHP with HFn, whereas controls (n = 10) used NEVHP alone. All HFn vs. four controls were viable at 24 h (p = 0.004). At end perfusion, HFn hearts had higher left ventricular systolic pressure (51.5 ± 6.8 mm Hg, 38.3 ± 5.2 mm Hg, p = 0.05), lower coronary resistance (0.83 ± 0.11 mm Hg/mL/min, 1.18 ± 0.21mmHg/mL/min, p < 0.05), and lower serum lactate levels (2.9 ± 0.4 mmol/L, 4.1 ± 0.6 mmol/L, p < 0.0001) when compared to control hearts. HFn hearts also had less extensive myocardial damage and significantly less edema than control hearts with lower weight gain and wet-dry ratios. Using our circuit, NEVHP for 24 hours is possible with HFn and allows for preservation of myocardial function, improved tissue viability, decreased tissue edema, and less myocardial injury.