NMDA Receptor Antagonism for Neuroprotection in a Canine Model of Hypothermic Circulatory Arrest.

BACKGROUND: Hypothermic circulatory arrest (HCA) is associated with neurologic morbidity, in part mediated by activation of the N-methyl-D-aspartate glutamate receptor causing excitotoxicity and neuronal apoptosis. Using a canine model, we hypothesized that the N-methyl-D-aspartate receptor antagonist MK801 would provide neuroprotection and that MK801 conjugation to dendrimer nanoparticles would improve efficacy. MATERIALS AND METHODS: Male hound dogs were placed on cardiopulmonary bypass, cooled to 18°C, and underwent 90 min of HCA. Dendrimer conjugates (d-MK801) were prepared by covalently linking dendrimer surface OH groups to MK801. Six experimental groups received either saline (control), medium- (0.15 mg/kg) or high-dose (1.56 mg/kg) MK801, or low- (0.05 mg/kg), medium-, or high-dose d-MK801. At 24, 48, and 72 h after HCA, animals were scored by a standardized neurobehavioral paradigm (higher scores indicate increasing deficits). Cerebrospinal fluid was obtained at baseline, eight, 24, 48, and 72 h after HCA. At 72 h, brains were examined for histopathologic injury in a blinded manner (higher scores indicate more injury). RESULTS: Neurobehavioral deficit scores were reduced by low-dose d-MK801 on postoperative day two (P < 0.05) and by medium-dose d-MK801 on postoperative day 3 (P = 0.05) compared with saline controls, but free drug had no effect. In contrast, high-dose free MK801 significantly improved histopathology scores compared with saline (P < 0.05) and altered biomarkers of injury in cerebrospinal fluid, with a significant reduction in phosphorylated neurofilament-H for high-dose MK801 versus saline (P < 0.05). CONCLUSIONS: Treatment with MK-801 demonstrated significant improvement in neurobehavioral and histopathology scores after HCA, although not consistently across doses and conjugates.

Time-Resolved Echo-Particle Image/Tracking Velocimetry Measurement of Interactions Between Native Cardiac Output and Veno-Arterial ECMO Flows.

Determination of optimal hemodynamic and pressure-volume loading conditions for patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) would benefit from understanding the impact of ECMO flow rates (QE) on the native cardiac output in the admixing zone, i.e., aortic root. This study characterizes the flow in the aortic root of a pig with severe myocardial ischemia using contrast-enhanced ultrasound particle image/tracking velocimetry (echo-PIV/PTV). New methods for data preprocessing are introduced, including autocontouring to remove surrounding tissues, followed by blind deconvolution to identify the centers of elongated bubble traces in images with low signal to noise ratio. Calibrations based on synthetic images show that this procedure increases the number of detected bubbles and reduces the error in their locations by 50%. Then, an optimized echo-PIV/PTV procedure, which integrates image enhancement with velocity measurements, is used for characterizing the time-resolved two-dimensional (2D) velocity distributions. Phase-averaged and instantaneous flow fields show that the ECMO flow rate influences the velocity and acceleration of the cardiac output during systole, and secondary flows during diastole. When QE is 3.0 L/min or higher, the cardiac ejection velocity, phase interval with open aortic valve, velocity-time integral (VTI), and mean arterial pressure (MAP) increase with decreasing QE, all indicating sufficient support. For lower QE, the MAP and VTI decrease as QE is reduced, and the deceleration during transition to diastole becomes milder. Hence, for this specific case, the optimal ECMO flow rate is 3.0 L/min.

Left Ventricular Assist Device Exchange Increases Heart Transplant Wait-List Mortality.

BACKGROUND: The new heart transplant allocation criteria prioritize inpatients who require temporary mechanical circulatory support and give lower urgency to candidates on a durable left ventricular assist device (LVAD) who require a device exchange. This study explores whether the latter group should warrant higher priority to reduce wait-list mortality. METHODS: This is a retrospective observational study of 13,113 adult heart transplant candidates in the Organ Procurement and Transplantation Network database who underwent LVAD implantation between 2007 and 2017. It evaluates the impact of LVAD exchange on the composite endpoint of death or removal from the wait list owing to worsening medical condition 1 y after device implantation. RESULTS: There were 1085 pump exchanges in 954 patients (7% of candidates), of which 22% were women. The pump exchange rate was 5.92 events per 100 patient-years. One-year survival was lower for those who required a pump exchange (76.3% versus 88.5%, logrank P < 0.001). This was congruent with the risk-adjusted mortality 1-y after implantation (hazards ratio: 2.56, 95% confidence interval: 2.18-3.00, P < 0.001). CONCLUSIONS: These findings indicate that among candidates awaiting heart transplantation with a durable LVAD, undergoing pump exchange doubles the risk of 1-y mortality. Giving priority to these candidates may reduce wait-list mortality.

Effects of Systemic and Device-Related Complications in Patients Bridged to Transplantation With Left Ventricular Assist Devices.

BACKGROUND: The use of left ventricular assist devices (LVADs) as a bridge to heart transplantation has increased rapidly over the last 2 decades. We aim to explore the effect of pretransplant systemic and device-related complications on posttransplant survival for patients bridged with LVADs. MATERIALS AND METHODS: The United Network of Organ Sharing (Organ Procurement and Transplantation Network) database was queried for all adult heart transplant recipients (aged ≥ 18 y) transplanted from April 1, 2015, to June 31, 2018. Device-related complications included thrombosis, device infection, device malfunction, life-threatening arrhythmia, and other device complications. Systemic complications included a new dialysis need or ventilator dependence between the time of listing and transplantation, transfusion, or systemic infection requiring treatment with intravenous antibiotics within 2 wk of transplantation. RESULTS: A total of 2131 patients were identified as requiring LVAD support before transplantation. LVAD patients had high rates of preoperative systemic complications (53%) and high rates of device-related complications (42.7% experienced at least one device-related complication). Kaplan-Meier analysis revealed a significantly decreased 1-y survival for LVAD patients bridged to transplantation who experienced a pretransplant systemic complication (P = 0.041). Interestingly, preoperative device-related complications had no effect on 1-y posttransplantation survival (P = 0.93). Multivariate Cox modeling revealed that systemic complications were associated with a significantly increased risk of posttransplant mortality for LVAD patients (hazard ratio 1.45; P = 0.033). CONCLUSIONS: Recipients who suffered a systemic complication while awaiting heart transplantation experienced higher short-term mortality rates. Device-related complications do not appear to impact posttransplantation outcomes.

Impact of cytomegalovirus serologic status on heart transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection has been associated with increased risk of mortality, cardiac allograft vasculopathy, and de novo malignancy following heart transplantation in prior institutional reports. This study examines the impact of the recipient and donor CMV status on heart recipients in the United States. METHODS: Adult heart transplant recipients were identified in the OPTN registry between 2005-2016. Recipients were stratified based on the recipient (R) and donor (D) CMV serologic status (+/-). The primary endpoint was survival 5-years after transplantation. The secondary endpoint was cardiac allograft vasculopathy 5-years after transplantation. Separate Cox proportional hazards regression models were developed to evaluate independent associations between CMV status and each of the study endpoints. RESULTS: A total of 21 878 recipients met the inclusion criteria. The breakdown of study arms by CMV serologic status was R-/D- = 3412, R+/D- = 4939; R-/D+ = 5230, and R+/D+ = 8,297. Five-year survival estimates were similar across groups (77-79%). CMV status was associated with increased mortality at 5-years (23%-41% increased risk) which was most evident in the first 3 months. The use of valganciclovir was associated with decreased risk of mortality (HR 0.56; 95% CI, 0.52-0.60). The cumulative incidence of cardiac allograft vasculopathy (R-/D- = 31%, R+/D- = 30%, R-/D+ = 31%, and R+/D+ = 30%) was similar across groups. CONCLUSIONS: CMV seropositivity at the time of transplantation is associated with increased long-term risk of mortality. Chemoprophylaxis with antivirals seems to mitigate this risk. There was no association with an increased risk of allograft vasculopathy.

Association of preoperative spinal drain placement with spinal cord ischemia among patients undergoing thoracic and thoracoabdominal endovascular aortic repair.

OBJECTIVE: Spinal cord ischemia (SCI) is among the most devastating complications of thoracic endovascular aortic repair (TEVAR). Spinal fluid drainage has been proposed as a viable means to reduce SCI, but few data exist to support its routine use. This study investigated the association of preoperative spinal fluid drainage with the risk of SCI after TEVAR. METHODS: The Vascular Quality Initiative TEVAR module was queried for adult patients (≥18 years) undergoing TEVAR (coverage of zones 0-5) between September 2014 and March 2018 (inclusive). Patients with preoperative spinal malperfusion, aortic rupture on presentation, and connective tissue disorders were excluded. One-to-one propensity matching was used to balance patients on 44 separate dimensions by the nearest neighbor principle to compare those with vs those without preoperative spinal drainage. The primary end point was SCI still present at the time of discharge. Secondary outcomes were 30-day mortality and prolonged intensive care unit stay (>7 days). RESULTS: Among 4287 patients who underwent TEVAR (mean age, 67.1 [standard deviation, 13.7] years; 1665 [38.8%] women and 2622 [61.2%] men), 2076 had a spinal drain placed. Propensity matching yielded 1292 pairs with adequate covariate balance (all 44 absolute standardized differences <0.1). In the 2584 propensity-matched patients, spinal drain placement was associated with a reduced risk of SCI (1.5% vs 2.5%; risk-adjusted odds ratio [OR], 0.47; 95% confidence interval [CI], 0.24-0.89; P = .02). The rates of 30-day mortality (4.5% vs 5.0%; risk-adjusted OR, 0.67; 95% CI, 0.44-1.01; P = .05) and prolonged intensive care unit stay (7.0% vs 5.7%; risk-adjusted OR, 1.10; 95% CI, 0.84-1.45; P = .48) did not differ on the basis of spinal drain placement. The crossover rate was 10% (127/1292), and those with postoperative drain placement had a 20% (26/127) SCI rate on discharge. CONCLUSIONS: Among patients undergoing thoracic and thoracoabdominal endovascular aortic repair, preoperative placement of a spinal drain, compared with no drain, was associated with reduced risk of SCI. Cerebrospinal fluid drainage as a rescue measure does not provide the same protection offered by routine preoperative placement. Further investigation, including randomized controlled trials, is needed to more definitively determine the role for spinal drainage in TEVAR.

Five-Year Mortality Hazard Is Reduced In Chronic Obstructive Pulmonary Disease Patients Receiving Double- versus Single-Lung Transplants.

BACKGROUND: Previous studies suggest double-lung transplant (DLT) may be associated with superior survival compared to single-lung transplantation (SLT) in chronic obstructive pulmonary disease (COPD) recipients. The purpose of this study was to compare survival in patients with COPD undergoing DLT versus SLT since the inception of the lung allocation score. METHODS: We used the United Network for Organ Sharing database to retrospectively identify adult patients with COPD who underwent isolated lung transplantation from 5/4/2005-12/31/2014. We then separated patients into DLT versus SLT. Short-term (1 y) and long-term survival (5 y) were compared between DLT and SLT cohorts by the method of Kaplan-Meier, and Cox proportional hazards modeling was used to adjust for case mix. RESULTS: Four thousand eight hundred thirty-two COPD patients were listed, and 3554 underwent lung transplantation over the study period, including 1358 SLTs (38%) and 2196 DLTs (62%). Survival 1 y after listing was 93% for those remaining wait listed (n = 1892) versus 91% for SLT (n = 1093) versus 89% for DLT (n = 1847) (log-rank P < 0.01). Survival at 1 y after transplant was 88% for both SLT and DLT groups (log-rank P = 0.93); however, 5-y survival was significantly lower after SLT (51% versus 59%, log-rank P < 0.01). After risk adjustment, hazard for 1-y mortality after DLT was not significantly reduced compared to SLT (hazard ratio 0.89 [0.69-1.14], P = 0.36) but was significantly reduced 5 y after DLT (hazard ratio 0.88 [0.78-0.99], P = 0.04). CONCLUSIONS: In the largest survival analysis of COPD recipients since the inception of the lung allocation score, the hazard for 5-y mortality was significantly reduced in recipients who underwent DLT as compared to SLT.

Nutritional Support in Postcardiotomy Shock Extracorporeal Membrane Oxygenation Patients: A Prospective, Observational Study.

BACKGROUND: Despite the 6000 patients treated with extracorporeal membrane oxygenation (ECMO) annually, there is a paucity of data regarding the nutritional management of these patients. MATERIALS AND METHODS: We performed a prospective, observational study of nutrition in postcardiotomy shock patients at our institution. Over a 3.5-year study period, we identified 50 ECMO patients and 225 non-ECMO patients. We identified type, amount, duration, and disruption of nutritional delivery by cohort. The primary outcome was percent of caloric goal met, and secondary outcome was gastrointestinal complications. RESULTS: ECMO patients met less of their caloric (29% versus 40%, P = 0.017) and protein goals (34% versus 55%, P < 0.001) compared with non-ECMO patients. Tube feeds were administered more slowly (26 versus 37 mL/h, P < 0.001) and held for longer (8.3 versus 4.5 h/d, P < 0.001) in ECMO patients because of procedures (60%) and high-dose pressors (20% versus 7%, P < 0.001). Multivariate analysis demonstrated that ECMO decreased caloric intake by 14%, with no detected increased risk of gastrointestinal complications. CONCLUSIONS: -ECMO patients received significantly less nutrition support compared with a non-ECMO population. Tube feed hold deficits could potentially be avoided by utilizing postpyloric tubes to feed through procedures, by eliminating holds for vasopressors/inotropes in hemodynamically stable patients, or by establishing volume-based feeding protocols. Further clinical studies are needed to establish efficacy of these interventions and to understand the impact of nutrition on outcomes in ECMO patients.

Impact of Traumatically Brain-Injured Donors on Outcomes After Heart Transplantation.

BACKGROUND: Heart transplant recipients of traumatically brain-injured (TBI) donors have been reported to have inferior survival and increased rates of cardiac allograft vasculopathy in single-center studies. This study sought to examine the impact of TBI donors on outcomes after heart transplantation across all transplantation centers. METHODS: We identified all adult heart transplants performed during 2007-2016 in the OPTN database. Recipients were dichotomized based on donor cause of death (TBI versus non-TBI), propensity-scored across 22 variables with known associations with mortality, and matched 1:1 without replacement. The primary endpoint was all-cause mortality. Secondary endpoints were conditional survival and rates of cardiac allograft vasculopathy. RESULTS: In total, 20,244 patients underwent heart transplantation. TBI was the primary cause of death in 53.4% of donors (10,816/20,244), and among TBI donors, blunt injury (59.6%; 6443/10,816) and gunshot wound (35%; 3781/10,816) were the most common mechanisms of injury. Propensity matching generated 6919 pairs (all absolute mean differences < 0.07). Risk-adjusted survival was similar between recipients of TBI donors and non-TBI donors at 5 y (78.1% versus 77.5%, log-rank P = 0.34). Risk-adjusted survival conditional on 1-y survival was also similar at 5 y (86.2% versus 86.1%, log-rank P = 0.74). The 5-y risk-adjusted rates of cardiac allograft vasculopathy did not differ either (30.6% versus 30.4%; log-rank P = 0.78). CONCLUSIONS: In the largest analysis of TBI donors in heart transplantation, we found similar survival and rates of cardiac allograft vasculopathy to those who received hearts from non-TBI donors out to 5 y. These findings should allay concerns over continued transplantation with this unique donor population.

Spontaneous Aortoesophageal Fistula in an Acute Type B Aortic Dissection and a Right-Sided Arch.

Primary aortoesophageal fistula (AEF) in the absence of prosthetic graft replacement or aortic endovascular therapy can develop as a rare but life-threatening complication of acute aortic dissection. This case demonstrates that primary AEF should be maintained on the clinical differential of a patient presenting with massive gastrointestinal bleed in the context of an aortic dissection.

Outcomes after heart transplantation in sensitized patients bridged with ventricular assist devices.

OBJECTIVE: Sensitization has been associated with worse outcomes following heart transplantation (HTx). The use of ventricular assist devices (VAD) is a risk factor for the development of sensitization. We investigated the impact of left ventricular assist devices (LVAD) and sensitization in HTx recipients. METHODS: We queried the UNOS database for all heart transplants performed from January 2000 through December 2016. Patients were considered highly sensitized and included if panel-reactive antibody (PRA) activity was 25% or higher. Patients were separated by pretransplant LVAD utilization and subgroup analysis was performed by device type (HeartMate II or HeartWare). Outcomes included Kaplan-Meier survival and episodes of rejection within 1 year of HTx. RESULTS: Of 18 009 recipients, 2434 (14%) were highly sensitized. 1055 (43.3%) were bridged with a VAD. In multivariate analysis, LVAD use did not impact 1-year (hazards ratio [HR], 1.30; P = 0.052) or 5-year survival (HR, 1.18; P = 0.112) in highly sensitized recipients. Furthermore, episodes of rejection were not affected by LVAD status (P = 0.765). Of the 1055 sensitized LVAD-bridged transplant recipients, 624 (59%) were implanted with a HeartMate II and 99 (9.4%) were bridged with a HeartWare device. In multivariate analysis, no differences were observed in 1-year survival (HR, 0.86; P = 0.664), 5-year survival (HR, 1.35; P = 0.209), or episodes of rejection (P = 0.497). CONCLUSIONS: The use of ventricular assist devices did not impact survival or rejection within 1 year of HTx in highly sensitized patients. Highly sensitized recipients have similar outcomes regardless of prior LVAD support or type of LVAD used as a bridge to transplantation.

Discrepancies in access and institutional risk tolerance in heart transplantation: A national open cohort study.

BACKGROUND: The impact of center volume on heart transplantation is widely recognized and serves as a benchmark for certification and reimbursement. STUDY AIMS: Study sociodemographic variables associated with access to high-volume centers and substantiate the importance of extending access to underserved populations. METHODS: This study focused on adults undergoing heart transplantation between 2006 and 2015. Centers were clustered into terciles (>25, 14-25, or <14 transplants per year) and factors associated with receiving care in different terciles were identified through multinomial regression. RESULTS: During the study period, 18 725 patients were transplanted at 145 centers. Younger age (<30 years) (P = .005), lower educational level (P < .001), and government-based insurance (P < .001) were associated to lower odds of receiving care at a high-volume center. These centers had higher risk recipients and accepted organs from higher risk donors, when compared to intermediate- and low-volume centers. Receiving care at high (odds ratio [OR], 1.212; P = .017) and intermediate-volume centers (OR, 1.304; P = .001) was associated with greater odds of 1-year survival when compared with low-volume centers. CONCLUSION: Social, demographic, and geographic factors affect access to high- and intermediate-volume centers. High-volume centers tolerate more risk while providing excellent survival. Awareness of this impact should prompt an extension of access to care for underserved patient populations.

Predictors of operative mortality among cardiac surgery patients with prolonged ventilation.

BACKGROUND: Prolonged ventilation after cardiac surgery affects survival and increases morbidity. Previous studies have focused on predicting this complication preoperatively; however, indicators of poor outcome in those requiring prolonged ventilation remain ill-defined. We sought to identify predictors of operative mortality in cardiac surgery patients who experience prolonged mechanical ventilation. METHODS: 1698 patients who underwent cardiac surgery (CAB, aortic valve replacement ± CAB, or mitral valve repair/replacement ± CAB) required prolonged postoperative mechanical ventilation (>24 hours) between 2012 to 2016 in a statewide consortium. Perioperative factors were evaluated to identify the association with operative mortality. Covariates were selected through bootstrap aggregation to fit multivariable logistic regression models. The relative strength of association was determined by the Wald chi-square statistic. RESULTS: Median patient age was 68 years [IQR 61 to 76], 38% (644/1,698) were female, median duration of mechanical ventilation was 65 hours [IQR 38 to 143], median STS predicted risk of mortality was 3.1% [IQR 1.4 to 6.9%], and 15.7% (266/1698) suffered operative mortality. Among preoperative and operative characteristics, patient age and intraoperative initiation of extracorporeal membrane oxygenation (ECMO) were the strongest correlates of operative mortality on the multivariate analysis. Among postoperative factors, cardiac arrest and renal failure requiring dialysis were the strongest predictors of risk-adjusted operative mortality. Type of operation or surgical center had no association to mortality after risk adjustment. CONCLUSION: Prolonged ventilation following cardiac surgery is associated with a five-fold increase in operative mortality. In these patients, operative mortality is associated with older age, intraoperative initiation of ECMO, postoperative cardiac arrest, and renal failure requiring dialysis.

Foetal right atrial aneurysm and aortic coarctation with left ventricular dysfunction.

Aneurysms of the right atrium are rare in the paediatric population. We report a case of a foetal diagnosis of right atrial aneurysm with associated atrial tachycardia in foetal and postnatal life. Unique to our case are the findings of isolated pericardial effusion without hydrops fetalis and the development of aortic coarctation in postnatal life.

Recent Changes in Durable Left Ventricular Assist Device Bridging to Heart Transplantation.

This study evaluates the impact of the recent United Network for Organ Sharing (UNOS) allocation policy change on outcomes of patients bridged with durable left ventricular assist devices (LVADs) to orthotopic heart transplantation (OHT). Adults bridged to OHT with durable LVADs between 2010 and 2019 were included. Patients were stratified based on the temporal relationship of their OHT to the UNOS policy change on October 18, 2018. The primary outcome was early post-OHT survival. In total, 9,628 OHTs were bridged with durable LVADs, including 701 (7.3%) under the new policy. Of all OHTs performed during the study period, the proportion occurring following durable LVAD bridging decreased from 45% to 34% (p < 0.001). The more recent cohort was higher risk, including more extracorporeal membrane oxygenation bridging (2.6% vs. 0.3%, p < 0.001), more mechanical right ventricular support (9.7% vs. 1.4%, p < 0.001), greater pretransplant ICU admission (22.8% vs. 8.7%, p < 0.001) more need for total functional assistance (62.8% vs. 53.0%, p < 0.001), older donor age (33.3 vs. 31.7 years, p < 0.001), and longer ischemic times (3.38 vs. 3.13 hours, p < 0.001). Despite this, early post-OHT survival was comparable at 30 days (96.1% vs. 96.0%, p = 0.89), 90 days (93.7% vs. 94.0%, p = 0.76), and 6 months (91.0% vs. 93.0%, p = 0.96), findings that persisted after risk-adjustment. In this early analysis, OHT following bridging with durable LVADs is performed less frequently and in higher risk recipients under the new allocation policy. Despite this, short-term posttransplant outcomes appear to be unaffected in this patient cohort in the current era.

Diazoxide preserves myocardial function in a swine model of hypothermic cardioplegic arrest and prolonged global ischemia.

OBJECTIVE: Adenosine triphosphate potassium sensitive channels provide endogenous myocardial protection via coupling of cell membrane potential to myocardial metabolism. Adenosine triphosphate potassium sensitive channel openers, such as diazoxide, mimic ischemic preconditioning, prevent cardiomyocyte swelling, preserve myocyte contractility after stress, and provide diastolic protection. We hypothesize that diazoxide combined with hyperkalemic cardioplegia provides superior myocardial protection compared with cardioplegia alone during prolonged global ischemia in a large animal model. METHODS: Twelve pigs were randomized to global ischemia for 2 hours with a single dose of cold blood (4:1) hyperkalemic cardioplegia alone (n = 6) or with diazoxide (500 µmol/L) (n = 6) and reperfused for 1 hour. Cardiac output, myocardial oxygen consumption, left ventricular developed pressure, left ventricular ejection fraction, diastolic function, myocardial troponin, myoglobin, markers of apoptosis, and left ventricular infarct size were compared. RESULTS: Four pigs in the cardioplegia alone group could not be weaned from cardiopulmonary bypass. There were no differences in myoglobin, troponin, or apoptosis between groups. Diazoxide preserved cardiac output versus control (74.5 vs 18.4 mL/kg/min, P = .01). Linear mixed regression modeling demonstrated that the addition of diazoxide to cardioplegia preserved left ventricular developed pressure by 36% (95% confidence interval, 9.9-61.5; P < .01), dP/dt max by 41% (95% confidence interval, 14.5-67.5; P < .01), and dP/dt min by 33% (95% confidence interval, 8.9-57.5; P = .01). It was also associated with higher (but not significant) myocardial oxygen consumption (3.7 vs 1.4 mL O2/min, P = .12). CONCLUSIONS: Diazoxide preserves systolic and diastolic ventricular function in a large animal model of prolonged global myocardial ischemia. Diazoxide as an adjunct to hyperkalemic cardioplegia may allow safer prolonged ischemic times during increasingly complicated cardiac procedures.

Extruded poly (glycerol sebacate) and polyglycolic acid vascular graft forms a neoartery.

In the ongoing search for the optimal biomaterial for tissue engineered vascular grafts (TEVGs), poly (glycerol sebacate) (PGS) has emerged as a new potential candidate. We have utilized a novel method to create unique, pore-free, extruded PGS grafts with and without a supportive exterior layer of polyglycolic acid (PGA). The 1 mm diameter by 5 mm length TEVGs were implanted in a rat model of infrarenal abdominal aorta interposition grafting. Three months after implantation, TEVGs comprised of extruded PGS with an external PGA braid demonstrated a patency rate of 9/10 (90%) with no signs of dilatation, dehiscence, or rupture. The PGS/PGA graft was remodeled into a neoartery with complete endothelialization of the neoartery lumen and formation of smooth muscle actinin multilayers as demonstrated via immunohistochemistry. Formation and maturation of extracellular matrix material were also observed, with amounts of elastin and collagen comparable to native rat aorta. No significant host inflammatory response was observed. These findings suggest the combination of an extruded PGS tube with an external reinforcing PGA braid is a promising material for small diameter TEVGs.

Mechanical stimulation enhances development of scaffold-free, 3D-printed, engineered heart tissue grafts.

Current efforts to engineer a clinically relevant tissue graft from human-induced pluripotent stem cells (hiPSCs) have relied on the addition or utilization of external scaffolding material. However, any imbalance in the interactions between embedded cells and their surroundings may hinder the success of the resulting tissue graft. Therefore, the goal of our study was to create scaffold-free, 3D-printed cardiac tissue grafts from hiPSC-derived cardiomyocytes (CMs), and to evaluate whether or not mechanical stimulation would result in improved graft maturation. To explore this, we used a 3D bioprinter to produce scaffold-free cardiac tissue grafts from hiPSC-derived CM cell spheroids. Static mechanical stretching of these grafts significantly increased sarcomere length compared to unstimulated free-floating tissues, as determined by immunofluorescent image analysis. Stretched tissue was found to have decreased elastic modulus, increased maximal contractile force, and increased alignment of formed extracellular matrix, as expected in a functionally maturing tissue graft. Additionally, stretched tissues had upregulated expression of cardiac-specific gene transcripts, consistent with increased cardiac-like cellular identity. Finally, analysis of extracellular matrix organization in stretched grafts suggests improved remodeling by embedded cardiac fibroblasts. Taken together, our results suggest that mechanical stretching stimulates hiPSC-derived CMs in a 3D-printed, scaffold-free tissue graft to develop mature cardiac material structuring and cellular fates. Our work highlights the critical role of mechanical conditioning as an important engineering strategy toward developing clinically applicable, scaffold-free human cardiac tissue grafts.

Evaluation of Extracorporeal Membrane Oxygenation Therapy as a Bridging Method.

BACKGROUND: With the implementation of the new heart allocation system, heart transplantation teams are prompted to reevaluate management of patients requiring mechanical circulatory support. The purpose of our study is to compare the outcomes of patients supported with extracorporeal membrane oxygenation (ECMO) before transplantation. METHODS: The United Network for Organ Sharing database was queried for all adult patients (aged 18 years or more) who required support with ECMO before heart transplantation from 2001 to 2018. Patients were stratified into patients who did not require ECMO before transplantation, who were weaned off ECMO before transplantation, who were bridged immediately to transplantation from ECMO, and who were bridged to a left ventricular assist device (LVAD) before transplantation. Demographics and outcomes including 1-year survival, postoperative stroke, postoperative renal failure requiring dialysis, episodes of rejection, and graft failure were compared. RESULTS: Overall, 29,370 patients did not require ECMO before transplantation, 101 patients were weaned off ECMO before transplantation, 118 were bridged from ECMO directly to transplantation, and 55 patients were successfully bridged from ECMO to LVAD before transplantation. Kaplan-Meier survival estimates found a statistically significant decrease in 1-year survival for patients who were bridged from ECMO to transplantation compared with patients who were bridged to LVAD before subsequent transplantation (P < .001). CONCLUSIONS: Our study suggests bridging ECMO patients to an LVAD before transplantation will result in improved 1-year survival compared with patients bridged to immediate transplantation. With the new heart allocation system, continued evaluation of outcomes is required to inform management strategies.

Long-term Survival After Heart Transplantation: A Population-based Nested Case-Control Study.

BACKGROUND: Heart transplantation is the mainstay of treatment for patients in end-stage heart failure. This study sought to contrast survival after transplantation with that of the general population to quantify standardized mortality rates using a nested case-control study design. METHODS: Control subjects were noninstitutionalized inhabitants of the United States identified through the National Longitudinal Mortality study. Case subjects were adults who underwent heart transplantation between 1990 and 2007 and identified through the Organ Procurement and Transplantation Network. Propensity-matching (5:1, nearest neighbor, caliper = 0.1) was utilized to identify suitable control subjects based on age, sex, race, and state of permanent residency. The primary study endpoint was 10-year survival. RESULTS: In all, 31,883 heart transplant recipients were matched to 159,415 noninstitutionalized residents of the United States. The 10-year survival of heart transplant recipients was 53%. The population expected mortality rate was 15.9 deaths per 100 person-years with an observed rate of 45.1 deaths per 100 person-years (standardized mortality rate [SMR] 2.84; 95% confidence interval, 2.82 to 2.87). The broadest gaps between observed and expected survival were evident in female (SMR 3.63), black (SMR 3.67), and Hispanic (SMR 4.12) recipients. Standardized mortality ratios declined over time (1990 to 1995, 3.09; 1996 to 2000, 2.90; 2001 to 2007, 2.58). The long-term standardized survival of older recipients was closest to that expected for their age. CONCLUSIONS: Heart transplant recipients have considerable long-term survival and have a threefold higher standardized long-term mortality rate than that of the noninstitutionalized population. Long-term mortality rates have consistently declined over time and will likely continue to decrease.