Showing papers in "Journal of Heart and Lung Transplantation in 2016"

The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update

Abstract: Mandeep R. Mehra, MD (Chair), Charles E. Canter, MD, Margaret M. Hannan, MD, Marc J. Semigran, MD, Patricia A. Uber, PharmD, David A. Baran, MD, Lara Danziger-Isakov, MD, MPH, James K. Kirklin, MD, Richard Kirk, MD, Sudhir S. Kushwaha, MD, Lars H. Lund, MD, PhD, Luciano Potena, MD, PhD, Heather J. Ross, MD, David O. Taylor, MD, Erik A.M. Verschuuren, MD, PhD, Andreas Zuckermann, MD and on behalf of the International Society for Heart Lung Transplantation (ISHLT) Infectious Diseases, Pediatric and Heart Failure and Transplantation Councils

The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Heart Transplantation Report—2016; Focus Theme: Primary Diagnostic Indications for Transplant

Abstract: This section of the 19th Official Registry Report of 2016 summarizes data from pediatric lung transplant recipients and their donors for transplants that occurred through June 30, 2015. This report describes donor and recipient characteristics, transplant type and recipient outcomes data. The full Registry slide set available online (www.ishlt.org/ registries) provides more detail, additional analyses and other information not included in this printed report. This year’s report focuses on primary diagnostic indications for transplant. We present data on the distribution of diagnostic categories, demographics of patients with the different lung disorders leading to the need for transplant (Figure 1), associations of the diagnoses with outcomes, and other data of interest related to this topic. Data on heart-lung transplantation in children are not presented in this year’s report, as the number of pediatric heart–lung transplant procedures has remained very low. Only 11 pediatric heart–lung transplant procedures performed in 2014 were reported to the Registry. Data on pediatric heart–lung transplantation were presented in

Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation

Abstract: Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications.

Effect of the lung allocation score on lung transplantation in the United States

Abstract: Background On May 4, 2005, the system for allocation of deceased donor lungs for transplant in the United States changed from allocation based on waiting time to allocation based on the lung allocation score (LAS). We sought to determine the effect of the LAS on lung transplantation in the United States. Methods Organ Procurement and Transplantation Network data on listed and transplanted patients were analyzed for 5 calendar years before implementation of the LAS (2000–2004), and compared with data from 6 calendar years after implementation (2006–2011). Counts were compared between eras using the Wilcoxon rank sum test. The rates of transplant increase within each era were compared using an F -test. Survival rates computed using the Kaplan-Meier method were compared using the log-rank test. Results After introduction of the LAS, waitlist deaths decreased significantly, from 500/year to 300/year; the number of lung transplants increased, with double the annual increase in rate of lung transplants, despite no increase in donors; the distribution of recipient diagnoses changed dramatically, with significantly more patients with fibrotic lung disease receiving transplants; age of recipients increased significantly; and 1-year survival had a small but significant increase. Conclusions Allocating lungs for transplant based on urgency and benefit instead of waiting time was associated with fewer waitlist deaths, more transplants performed, and a change in distribution of recipient diagnoses to patients more likely to die on the waiting list.

Pulmonary artery pulsatility index predicts right ventricular failure after left ventricular assist device implantation

Abstract: Background Right ventricular failure (RVF) is a major cause of morbidity and mortality after left ventricular assist device (LVAD) implantation. The pulmonary artery pulsatility index (PAPi) is a novel hemodynamic index that predicts RVF in the setting of myocardial infarction, although it has not been shown to predict RVF after LVAD implantation. Methods We performed a retrospective, single-center analysis to examine the utility of the PAPi in predicting RVF and RV assist device (RVAD) implantation in 85 continuous-flow LVAD recipients. We performed a multivariate logistic regression analysis incorporating previously identified predictors of RVF after LVAD placement, including clinical and echocardiographic variables, to determine the independent effect of PAPi in predicting RVF or RVAD after LVAD placement. Results In this cohort, the mean PAPi was 3.4 with a standard deviation of 2.9. RVF occurred in 33% of patients, and 11% required a RVAD. Multivariate analysis, adjusting for age, blood urea nitrogen (BUN), and Interagency Registry for Mechanically Assisted Circulatory Support profile, revealed that higher PAPi was independently associated with a reduced risk of RVAD placement (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.07–0.89). This relationship did not change significantly when echocardiographic measures were added to the analysis. Stratifying the analysis by the presence of inotropes during catheterization revealed that PAPi was more predictive of RVAD requirement when measured on inotropes (OR, 0.21; 95% CI, 0.02–0.97) than without (OR, 0.49; 95% CI, 0.01–1.94). Furthermore, time from catheterization to LVAD did not significantly affect the predictive value of the PAPi (maximum time, 6 months). Receiver operating characteristic curve analysis revealed that optimal sensitivity and specificity were achieved using a PAPi threshold of 2.0. Conclusions In LVAD recipients, the PAPi is an independent predictor of RVF and the need for RVAD support after LVAD implantation. This index appears more predictive in patients receiving inotropes and was not affected by time from catheterization to LVAD in our cohort.

Functional assessment and transplantation of the donor heart after circulatory death.

Abstract: Background After a severe shortage of brain-dead donors, the demand for heart transplantation has never been greater. In an attempt to increase organ supply, abdominal and lung transplant programs have turned to the donation after circulatory-determined death (DCD) donor. However, because heart function cannot be assessed after circulatory death, DCD heart transplantation was deemed high risk and never adopted routinely. We report a novel method of functional assessment of the DCD heart resulting in a successful clinical program. Methods Normothermic regional perfusion (NRP) was used to restore function to the arrested DCD heart within the donor after exclusion of the cerebral circulation. After weaning from support, DCD hearts underwent functional assessment with cardiac-output studies, echocardiography, and pressure-volume loops. In the feasibility phase, hearts were transported perfused before evaluation of function in modified working mode extracorporeally. After the establishment of a reliable assessment technique, hearts with demonstrable good function were then selected for clinical transplantation. Results NRP was instituted in 13 adult DCD donors, median age of 33 years (interquartile range [IQR], 28–38 years), after a median ischemic time from withdrawal to perfusion of 24 minutes (IQR, 21–29; range, 17–146 minutes). Two of 4 hearts in the feasibility phase were unsuitable for transplantation after functional assessment. Nine DCD hearts were transplanted in the clinical phase, with 100% survival. The median intensive care duration was 5 days (IQR, 4–5 days), with 2 patients requiring mechanical support. There were no episodes of rejection (total, 1,436 patient-days; range, 48–297). During the same period, we performed 20 standard heart transplants using brain-dead donors. Conclusions NRP allows rapid reperfusion and functional assessment of the DCD donor heart, ensuring only viable hearts are selected for transplantation. This technique minimizes the risk of primary graft dysfunction and maximizes confidence in DCD heart transplantation, realizing a 45% increase in our heart transplant activity.

Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure.

Abstract: Background Cell-based therapies are being explored as a therapeutic option for patients with chronic heart failure following myocardial infarction. Extracellular vesicles (EV), including exosomes and microparticles, secreted by transplanted cells may orchestrate their paracrine therapeutic effects. We assessed whether post-infarction administration of EV released by human embryonic stem cell–derived cardiovascular progenitors (hESC-Pg) can provide equivalent benefits to administered hESC-Pg and whether hESC-Pg and EV treatments activate similar endogenous pathways. Methods Mice underwent surgical occlusion of their left coronary arteries. After 2–3 weeks, 95 mice included in the study were treated with hESC-Pg, EV, or Minimal Essential Medium Alpha Medium (alpha-MEM; vehicle control) delivered by percutaneous injections under echocardiographic guidance into the peri-infarct myocardium. functional and histologic end-points were blindly assessed 6 weeks later, and hearts were processed for gene profiling. Genes differentially expressed between control hearts and hESC-Pg–treated and EV-treated hearts were clustered into functionally relevant pathways. Results At 6 weeks after hESC-Pg administration, treated mice had significantly reduced left ventricular end-systolic (−4.20 ± 0.96 µl or −7.5%, p = 0.0007) and end-diastolic (−4.48 ± 1.47 µl or −4.4%, p = 0.009) volumes compared with baseline values despite the absence of any transplanted hESC-Pg or human embryonic stem cell–derived cardiomyocytes in the treated mouse hearts. Equal benefits were seen with the injection of hESC-Pg–derived EV, whereas animals injected with alpha-MEM (vehicle control) did not improve significantly. Histologic examination suggested a slight reduction in infarct size in hESC-Pg–treated animals and EV-treated animals compared with alpha-MEM–treated control animals. In the hESC-Pg–treated and EV-treated groups, heart gene profiling identified 927 genes that were similarly upregulated compared with the control group. Among the 49 enriched pathways associated with these up-regulated genes that could be related to cardiac function or regeneration, 78% were predicted to improve cardiac function through increased cell survival and/or proliferation or DNA repair as well as pathways related to decreased fibrosis and heart failure. Conclusions In this post-infarct heart failure model, either hESC-Pg or their secreted EV enhance recovery of cardiac function and similarly affect cardiac gene expression patterns that could be related to this recovery. Although the mechanisms by which EV improve cardiac function remain to be determined, these results support the idea that a paracrine mechanism is sufficient to effect functional recovery in cell-based therapies for post-infarction–related chronic heart failure.

Outcomes of children implanted with ventricular assist devices in the United States: First analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS)

Abstract: Background Use of mechanical circulatory support in children has increased as more options have become available. A national account of the use of mechanical support in children and adolescents is essential to understanding outcomes, refining patient selection and improving quality of care. Methods The Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS) is a National Heart, Lung, and Blood Institute-supported nationwide registry for temporary and durable ventricular assist device (VAD) use in patients Results Two hundred pediatric patients underwent 222 durable VAD implants. Patients' characteristics and outcomes of children supported with a temporary device ( n = 41) were not analyzed in this report. The etiology of heart disease included 146 (73%) patients with cardiomyopathy and 35 (18%) with congenital heart disease. Thirty patients (15%) transitioned from extracorporeal membrane oxygenation (ECMO) and 76 (38%) had previous cardiac surgery. Most patients were Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Level 1 (27%) or Level 2 (56%) at implant, with 13% at Level 3. Of the 200 patients supported with a durable device, 91 (46%) were supported with a pulsatile-flow device and 109 (55%) with a continuous-flow (CF) device. Patient age at first implant included 30 patients (15%) n = 78), bleeding ( n = 68), device malfu n ction ( n = 79) and neurologic dysfunction ( n = 52). Conclusions PediMACS constitutes the largest single data repository with detailed information of pediatric patients implanted with VADs. The first PediMACS report reveals favorable outcomes despite the varying patient characteristics and pump types. However, the rate of adverse events remains high. With further data collection, analysis of patient risk factors critical to improving outcomes will be possible.

The 2015 International Society for Heart and Lung Transplantation Guidelines for the management of fungal infections in mechanical circulatory support and cardiothoracic organ transplant recipients: Executive summary

Abstract: Shahid Husain, MD, MS, Amparo Sole, MD, PhD, Barbara D. Alexander, MD, MHS, Saima Aslam, MD, MS, Robin Avery, MD, Christian Benden, MD, Eliane M. Billaud, PharmD, PhD, Daniel Chambers, MBBS, MD, Lara Danziger-Isakov, MD, Savitri Fedson, MD, Kate Gould, MD, Aric Gregson, MD, Paolo Grossi, MD, PhD, Denis Hadjiliadis, MD, Peter Hopkins, MD, Me-Linh Luong, MD, Debbie J.E. Marriott, MD, Victor Monforte, MD, Patricia Munoz, MD, PhD, Alessandro C. Pasqualotto, MD, PhD, Antonio Roman, MD, Fernanda P. Silveira, MD, Jeffrey Teuteberg, MD, MS, Stephen Weigt, MD, Aimee K. Zaas, MD, MHS, Andreas Zuckerman, MD, and Orla Morrissey, MD, PhD

Evaluation of von Willebrand factor with a fully magnetically levitated centrifugal continuous-flow left ventricular assist device in advanced heart failure

Abstract: Background Contemporary continuous-flow left ventricular assist devices (CF-LVADs) are associated with degradation of von Willebrand factor (vWF) high-molecular-weight multimers (HMWMs), a critical factor supporting platelet function. We hypothesized that the HeartMate 3 fully magnetically levitated LVAD, designed to reduce circulatory shear stress, favorably influences these hemostatic parameters. Methods Fifteen consecutive HeartMate 3 LVAD patients were compared with 11 consecutive HeartMate II controls. Serial plasma samples were collected pre-implant and on Days 2, 7, 30 and 45 post-operatively. Changes in vWF HMWMs were evaluated by 2 independent, study-blind hematologists and confirmed using densitometry-based computerized software. Ristocetin cofactor (RiCO) and vWF antigen (vWF Ag) were measured using standard protocols with enzyme-linked immunosorbent assay. Results HeartMate 3 patients and HeartMate II controls had a mean age of 67.3 ± 1.4 and 52.8 ± 2.5 years, respectively (INTERMACS Profiles 2 to 4 in 93.3% and 91%, respectively). HeartMate 3 group demonstrated a significantly greater preservation of HMWMs compared with the HeartMate II group, with the most prominent decrease occurring by Day 2 post-operatively and sustained through 45 days (71.94% vs 31.16%, p = 0.001). Laboratory values (normalized to baseline) for RiCO activity, vWF Ag and RiCO:vWF Ag ratio remained in the functional range with no statistically significant differences observed between groups. Conclusion The HeartMate 3 LVAD is associated with enhanced hemocompatibility compared with the HeartMate II LVAD, as demonstrated by the improved preservation of vWF HMWMs, In contrast, effects on HMWM degradation appeared to be dissociated from functional attributes. Further confirmation of these findings in randomized clinical trials is warranted.

ALN-RSV01 for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients

Abstract: Background Respiratory syncytial virus (RSV) infection in lung transplant (LTx) patients is associated with an increased incidence of bronchiolitis obliterans syndrome (BOS) ALN-RSV01 is a small interfering RNA targeting RSV replication that was shown in an earlier Phase 2a trial to be safe and to reduce the incidence of BOS when compared with placebo Methods We performed a Phase 2b randomized, double-blind, placebo-controlled trial in RSV-infected LTx patients to examine the impact of ALN-RSV01 on the incidence of new or progressive BOS Subjects were randomized (1:1) to receive aerosolized ALN-RSV01 or placebo daily for 5 days Results Of 3,985 symptomatic patients screened, 218 were RSV-positive locally, of whom 87 were randomized to receive ALN-RSV01 or placebo (modified intention-to-treat [mITT] cohort) RSV infection was confirmed by central laboratory in 77 patients (ALN-RSV01, n = 44; placebo, n = 33), which comprised the primary analysis cohort (central mITT [mITTc]) ALN-RSV01 was found to be safe and well-tolerated At Day 180, in ALN-RSV01-treated patients, compared with placebo, in the mITTc cohort there was a trend toward a decrease in new or progressive BOS (136% vs 303%, p = 0058), which was significant in the per-protocol cohort (p = 0025) Treatment effect was enhanced when ALN-RSV01 was started Conclusions These results confirm findings of the earlier Phase 2a trial and provide further support that ALN-RSV01 reduces the risk of BOS after RSV in LTx recipients

Pretransplant frailty is associated with decreased survival after lung transplantation

Abstract: Background Frailty is a condition of increased vulnerability to adverse health outcomes. Although frailty is an important prognostic factor for many conditions, the effect of frailty on mortality in lung transplantation is unknown. Our objective was to assess the association of frailty with survival after lung transplantation. Methods We performed a retrospective cohort analysis of all adult lung transplant recipients at our institution between 2002 and 2013. Frailty was assessed using the frailty deficit index, a validated instrument that assesses cumulative deficits for up to 32 impairments and measures the proportion of deficits present (with frailty defined as >0.25). We examined the association between frailty and survival, adjusting for age, sex, and bilateral (vs single) lung transplant using Cox proportional hazard regression models. Results Among 144 lung transplant patients, 102 (71%) completed self-reported questionnaires necessary to assess the frailty deficit index within 1 year before lung transplantation. Frail patients ( n = 46) had an increased risk of death, with an adjusted hazard ratio (HR) of 2.24 (95% confidence interval [CI], 1.22–4.19; p = 0.0089). Frailty was not associated with an increased duration of mechanical ventilation (median, 2 vs 2 days; p = 0.26), intensive care unit length of stay (median, 7.5 vs 6 days; p = 0.36) or hospital length of stay after transplantation (median, 14 vs 10.5 days; p = 0.26). Conclusions Pre-transplant frailty was independently associated with decreased survival after lung transplantation. Pre-transplant frailty may represent an important area for intervention to improve candidate selection and lung transplant outcomes.

Clinical trial design and rationale of the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) investigational device exemption clinical study protocol

Abstract: The HeartMate 3 left ventricular assist system (LVAS; St. Jude Medical, Inc., formerly Thoratec Corporation, Pleasanton, CA) was recently introduced into clinical trials for durable circulatory support in patients with medically refractory advanced-stage heart failure. This centrifugal, fully magnetically levitated, continuous-flow pump is engineered with the intent to enhance hemocompatibility and reduce shear stress on blood elements, while also possessing intrinsic pulsatility. Although bridge-to-transplant (BTT) and destination therapy (DT) are established dichotomous indications for durable left ventricular assist device (LVAD) support, clinical practice has challenged the appropriateness of these designations. The introduction of novel LVAD technology allows for the development of clinical trial designs to keep pace with current practices. The prospective, randomized Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) clinical trial aims to evaluate the safety and effectiveness of the HeartMate 3 LVAS by demonstrating non-inferiority to the HeartMate II LVAS (also St. Jude Medical, Inc.). The innovative trial design includes patients enrolled under a single inclusion and exclusion criteria , regardless of the intended use of the device, with outcomes ascertained in the short term (ST, at 6 months) and long term (LT, at 2 years). This adaptive trial design includes a pre-specified safety phase (n = 30) analysis. The ST cohort includes the first 294 patients and the LT cohort includes the first 366 patients for evaluation of the composite primary end-point of survival to transplant, recovery or LVAD support free of debilitating stroke (modified Rankin score >3), or re-operation to replace the pump. As part of the adaptive design, an analysis by an independent statistician will determine whether sample size adjustment is required at pre-specified times during the study. A further 662 patients will be enrolled to reach a total of 1,028 patients for evaluation of the secondary end-point of pump replacement at 2 years.

Outcomes of pediatric patients supported with continuous-flow ventricular assist devices: A report from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).

Abstract: Background Continuous-flow (CF) ventricular assist devices (VADs) have largely replaced pulsatile-flow VADs in adult patients. However, there are few data on CF VADs among pediatric patients. In this study we aimed to describe the overall use, patients' characteristics and outcomes of CF VADs in this population. Methods The Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS) is a national registry for U.S. Food and Drug Adminstration (FDA)-approved VADs in patients Results CF VADs were implanted in 109 patients at 35 hospitals. The median age at implantation was 15 years (2.8 to 18.9 years) and median weight was 62 kg (range 16 to 141 kg). The underlying disease was cardiomyopathy in 89 (82%) patients. The INTERMACS level at time of implant was Level 1 in 20 (19%), Level 2 in 64 (61%) and Levels 3 to 7 in 21 (20%) patients. Most were implanted as LVADs (n = 102, 94%). Median duration of support was 2.3 months (range Conclusions CF VADs are commonly utilized in older children and adolescents, with excellent survival rates. Further study is needed to understand impact of patient and device characteristics on outcomes in pediatric patients.

Fontan-associated liver disease: Implications for heart transplantation

Abstract: Chronic liver diseases are associated with multiple complications, including cirrhosis, portal hypertension, ascites, synthetic dysfunction and hepatocellular carcinoma, and these processes are increasingly recognized in post-Fontan patients. Fontan-associated liver disease (FALD) can be defined as abnormalities in liver structure and function that result from the Fontan circulation and are not related to another disease process. FALD arises due to chronic congestion of the liver created by the elevated venous pressure and low cardiac output of the Fontan circulation, which may be superimposed on previous liver injury. Pathology studies have generally shown that FALD worsens as time post-Fontan increases, but the prevalence of FALD is not well defined because the majority of Fontan patients, even those with significant hepatic fibrosis, appear to be asymptomatic and biochemical or functional hepatic abnormalities are usually subtle or absent. Alternate non-invasive investigations, derived from the study of other chronic liver diseases, have been tested in small series of pediatric and adult Fontan patients, but they have been confounded by congestion and do not correlate well with liver biopsy findings. Liver disease can complicate Fontan circulatory failure and may even be significant enough to be considered a contraindication to heart transplantation or require combined heart-liver transplantation. The search for the optimal management strategy continues in the setting of increasing numbers of Fontan patients surviving to adulthood and being referred for heart transplantation. Thus, in this review we attempt to define the scope and significance of FALD and address transplant-related assessment and management of this challenging disorder.

First Annual IMACS Report: A global International Society for Heart and Lung Transplantation Registry for Mechanical Circulatory Support

Abstract: The first annual report of the International Society for Heart and Lung Transplantation (ISHLT) Mechanically Assisted Circulatory Support (IMACS) registry provides global data on 5,942 patients from 31 countries. This initial report focuses on patient demographics, survival, device types, adverse events, competing outcomes, and a risk factor analysis.

Development of a three-dimensional pre-vascularized scaffold-free contractile cardiac patch for treating heart disease.

Abstract: Background The aim of our study was to develop a completely scaffold-free, viable, contractile cardiac tissue capable of being grafted into the damaged native heart. Methods Our technology is based on the fundamental characteristics of the self-assembling nature of cells. We created contractile cardiac spheroids by plating a mixture of rat neonatal ventricular cardiomyocytes, human dermal fibroblasts, and human coronary microartery endothelial cells in ultralow attachment plates. First, the optimal cell ratios for the 3 cell sources were determined. Next, approximately 1 × 10 4 optimal spheroids were fused into a patch-like construct, and the morphologic characteristics and mechanical functions of these patches were evaluated. Finally, the cardiac patches were grafted into the hearts of F344 nude rats, and histologic studies were performed after transplantation. Results Synchronous beating of the cardiac patch was confirmed electrophysiologically and mechanically. A micronetwork of endothelial cells was also demonstrated in the construct, and the histologic study performed 5 days after transplantation showed the grafts to be viable, with functioning microvascular structures inside the graft tissue. Conclusions We consider the application of our scaffold-free 3-dimensional tissue engineering technology to cardiac regeneration therapy is feasible and expect that this technology will become a promising tool for the treatment of end-stage heart failure.

Cognitive impairment improves the predictive validity of physical frailty for mortality in patients with advanced heart failure referred for heart transplantation

Abstract: Background The aim of this study was to identify whether the addition of cognitive impairment, depression, or both, to the assessment of physical frailty provides better outcome prediction in patients with advanced heart failure referred for heart transplantation (HT). Methods Beginning in March 2013, all patients with advanced heart failure referred to our Transplant Unit have undergone a physical frailty assessment using the Fried frailty phenotype. Cognition was assessed with the Montreal Cognitive Assessment and depression with the Depression in Medical Illness questionnaire. We assessed the value of 4 composite frailty measures: physical frailty (PF ≥ 3 of 5=frailty), "cognitive frailty" (CogF ≥ 3 of 6=frail), "depressive frailty" (DepF ≥ 3 of 6=frail), and "cognitive-depressive frailty" (ComF ≥ 3 of 7=frail) in predicting outcomes. Results Frailty was assessed in 156 patients (109 men, 47 women), aged 53 ± 13 years, and with a left ventricular ejection fraction of 27% ± 14%. Inclusion of cognitive impairment or depression in the definition of frailty increased the proportion classified as frail from 33% using PF to 42% using ComF. During follow-up, 28 patients died before ventricular assist device implantation or HT. Frailty was associated with significantly lower ventricular assist device- and HT-free survival, with CogF best capturing early mortality: 12-month survival for non-frail and frail cohorts was 81% ± 5% vs 58% ± 10% ( p p Conclusions The addition of cognitive impairment to the assessment of PF strengthened its capacity to identify advanced heart failure patients referred for HT who are at high risk of early death.

Combined pulmonary endarterectomy and balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension

Abstract: Background Pulmonary endarterectomy (PEA) is a curative treatment option for more than 60% of patients with chronic thromboembolic pulmonary hypertension (CTEPH). For selected inoperable patients, interventional balloon pulmonary angioplasty (BPA) has recently been established in addition to medical treatment. This approach disrupts scar tissue occluding the pulmonary arteries, leading to an improvement in parenchymal perfusion. CTEPH is occasionally heterogeneous, with operable disease on one side but peripheral, inoperable changes on the contralateral side. Performing unilateral PEA (on the operable side only) in these patients may lead to a worse hemodynamic outcome and increased mortality compared with patients who that can be surgically corrected bilaterally. We sought to determine the feasibility, safety, and benefits of BPA applied to the contralateral lung in several patients with predominantly unilateral disease that was amenable to treatment by PEA. Methods Standard unilateral PEA in deep hypothermic circulatory arrest was performed in 3 CTEPH patients with poor pulmonary hemodynamics, and inoperability of the contralateral pulmonary artery obstructions was confirmed. The inoperable side was treated by BPA. The intervention was performed during the rewarming phase of cardiopulmonary bypass. Results A dramatic improvement in pulmonary hemodynamics, with a mean reduction in pulmonary vascular resistance of 842 dyne · sec/cm 5 , was achieved in all patients. World Health Organization Functional Class was also significantly improved at the midterm follow-up. Conclusions The combination of surgical PEA and interventional BPA is a new treatment option for highly selected high-risk CTEPH patients. A multidisciplinary CTEPH expert team is a basic pre-requisite for this complex concept.

Ventricular assist devices in a contemporary pediatric cohort: Morbidity, functional recovery, and survival.

Abstract: Background Limited availability of donor organs has led to the use of ventricular assist devices (VADs) to treat heart failure in pediatric patients, primarily as bridge to transplantation. How effective VAD therapy is in promoting functional recovery in children is currently not known. Methods We report morbidity and mortality as defined by the Interagency Registry for Mechanically Assisted Circulatory Support Modified for Pediatrics (PediMACS) and the use of the Treatment Intensity Score to assess functional status for 50 VAD patients supported at a single pediatric program from 2004 to 2013. Results In this cohort, 30-day survival on VAD was 98%, and 180-day survival was 83%. Stroke occurred in 11 patients (22%), with 8 (16%) resulting in persistent neurologic deficit or death. The adverse event rate was 2-fold to 3-fold higher in the first 7 days of support compared with the subsequent support period. Functional status, as measured by the Treatment Intensity Score, improved with duration of support. Successful bridge to transplantation was associated with fewer adverse events during support and greater improvement in the Treatment Intensity Score during the period of support. Conclusions Overall survival in this cohort is excellent. The risk of serious adverse events decreases over the first month of support. However, a clinically significant risk of morbidity and mortality persists for the duration of pediatric VAD support. Measures of functional status improve with duration of support and are associated with survival to transplantation.

Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation

Abstract: Background Ex vivo lung perfusion (EVLP) presents a unique therapeutic opportunity to administer mesenchymal stromal cells (MSCs) to lung grafts before transplantation. We sought to determine the optimal route and dose of viable human umbilical cord–derived MSCs to be delivered into ex vivo–perfused damaged swine lungs, and to measure their effect on concentration of growth factors and inflammatory mediators. Methods Pig lungs were conventionally retrieved, cold preserved for 18 hours, and perfused normothermically ex vivo for 12 hours. Physiologic data were recorded. No cells were administered to a control group of animals ( n = 5). To examine the routes of administration, lungs were administered 50 × 10 6 MSCs endobronchially ( n = 3) or via the pulmonary artery ( n = 3). To determine the doses, a dose-escalation study was performed wherein lungs were administered 50 × 10 6 ( n = 3), 150 × 10 6 ( n = 5) and 300 × 10 6 ( n = 3) MSCs via the pulmonary artery. Concentrations of human growth factors and pig cytokines were measured in lung biopsies and perfusate. Results Intravascular administration of 50 × 10 6 MSCs was associated with significant and sustained retention of MSCs in lung parenchyma, whereas intrabronchial administration was not. Intravascular administration of 150 × 10 6 MSCs was the optimal tolerated dose and was associated with increased concentrations of human vascular endothelial growth factor (VEGF) in lung biopsies and decreased concentrations of pig interleukin-8 (IL-8) in the perfusate during 12 hours of EVLP. Conclusions Intravascular delivery of 150 × 10 6 MSCs showed preferred outcome compared with intrabronchial delivery to damaged lungs perfused ex vivo. The method was well tolerated and associated with an increased concentration of human VEGF in the lung tissue and a decreased concentration of pig IL-8 in the perfusate.

Five-year experience with intraoperative extracorporeal membrane oxygenation in lung transplantation: Indications and midterm results.

Abstract: Background Since April 2010, extracorporeal membrane oxygenation (ECMO) has replaced cardiopulmonary bypass for intraoperative support during lung transplantation at our institution. The aim of this study was to present our 5-year experience with this technique. Methods Records of patients who underwent transplantation between April 2010 and January 2015 were retrospectively reviewed. Patients who underwent transplantation without ECMO formed Group A. Patients in whom the indication for ECMO support was set a priori before the beginning of the operation formed Group B. The remaining patients in whom the indication for ECMO support was set during transplantation formed Group C. Results Among 595 patients, 425 (71%) patients (Group A) did not require intraoperative ECMO; the remaining 170 (29%) patients did. Among these patients, 95 (56%) patients formed Group B, and the remaining 75 (44%) patients comprised Group C. Pulmonary fibrosis and pre-operative dilated or hypertrophied right ventricle emerged as risk factors for the indication of non–a priori intraoperative ECMO. Patients in Groups B and C showed a higher pre-operative risk profile and higher prevalence of post-operative complications than patients in Group A. Overall survival at 1 year was 93%, 83%, and 82% and at 4 years was 73%, 68%, and 69% in Groups A, B, and C ( p = 0.11). The intraoperative use of ECMO did not emerge as a risk factor for in-hospital mortality or mortality after hospital discharge. Conclusions Intraoperative ECMO filled the gap between pre-operative and post-operative ECMO in lung transplantation. Although complications and in-hospital mortality were higher in patients who received ECMO, survival was similar among patients who underwent transplantation with or without ECMO.

Long-term biventricular HeartWare ventricular assist device support—Case series of right atrial and right ventricular implantation outcomes

Abstract: Background There is limited information on outcomes using the HeartWare ventricular assist device (HVAD; HeartWare, Framington, MA) as a biventricular assist device, especially with respect to site of right ventricular assist device (RVAD) implantation. Methods Outcomes in 13 patients with dilated cardiomyopathy and severe biventricular failure who underwent dual HVAD implantation as bridge to transplantation between August 2011 and October 2014 were reviewed. Results Of 13 patients, 10 were Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Level 1, and 3 were INTERMACS Level 2. Mean age was 45 ± 11 years, and mean body mass index was 26 ± 4 kg/m 2 . There were 7 patients on temporary mechanical support pre-operatively (extracorporeal life support, n = 5; intra-aortic balloon pump, n = 2). The median hospital length of stay was 53 days (interquartile range [IQR] 33–70 days) with a median intensive care unit length of stay of 14 days (IQR 8–36 days). The median length of support on device was 269 days (IQR 93–426 days). The right HVAD was implanted in the right ventricular (RV) free wall in 6 patients and in the right atrial (RA) free wall in 7 patients. Transplantation was successfully performed in 5 patients, and overall survival for the entire cohort was 54%. RVAD pump thrombosis occurred in 3 of 6 RV pumps and 1 of 7 RA pumps. No left ventricular assist device pump thrombosis was observed. Bleeding tended to be higher in the RV implantation group (3 of 6 vs 0 of 7). During follow up, 6 patients died (4 of 7 in the RA group vs 2 of 6 in the RV group). Cause of death was multiple-organ failure in 3 patients, sepsis in 2 patients, and intracerebral hemorrhage in 1 patient. Conclusions Critically ill patients who require biventricular support can be successfully bridged to transplant using 2 HVADs. RA implantation may allow right heart support with lower pump thrombosis and bleeding complications, although this was at the expense of a higher mortality in this cohort.

Outcomes after stroke complicating left ventricular assist device

Abstract: Background Stroke is one of the leading complications during continuous flow-left ventricular assist device (CF-LVAD) support. Risk factors have been well described, although less is known regarding treatment and outcomes. We present a large single-center experience on stroke outcome and transplant eligibility by stroke sub-type and severity in CF-LVAD patients. Methods Between January 1, 2008, and April 1, 2015, 301 patients underwent CF-LVAD (266 HeartMate II [HM I], Thoratec Corp, Pleasanton, CA; 35 HeartWare [HVAD], HeartWare International Inc, Framingham, MA). Stroke was defined as a focal neurologic deficit with abnormal neuroimaging. Intracerebral hemorrhage (ICH) definition excluded sub-dural hematoma and hemorrhagic conversion of an ischemic stroke (IS). Treatment in IS included intra-arterial embolectomy when appropriate; treatment in ICH included reversal of coagulopathy. Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). Outcomes were in-hospital mortality and transplant status. Results Stroke occurred in 40 patients: 8 ICH (4 HM II, 4 HVAD) and 32 IS (26 HM II, 6 HVAD). Among 8 ICH patients, there were 4 deaths (50%), with NIHSS of 18.8 ± 13.7 vs 1.8 ± 1.7 in survivors ( p = 0.049). Among 32 IS patients, 12 had hemorrhagic conversion and 5 were treated with intra-arterial embolectomy. There were 9 deaths (28%), with NIHSS of 16.2 ± 10.8 vs 7.0 ± 7.6 in survivors ( p = 0.011). Among the 32 IS patients, 12 underwent transplant, and 1 is awaiting transplant. No ICH patients received a transplant. Conclusions In-hospital mortality after stroke is significantly affected by the initial neurologic impairment. Patients with IS appear to benefit the most from in-hospital treatment and often make sufficient recovery to be able to progress to transplant.

A multicenter study of the HeartWare ventricular assist device in small children

Abstract: A multicenter study of the HeartWare ventricular assist device in small children Oliver Miera, MD, Richard Kirk, MD, Holger Buchholz, MD, Katharina R.L. Schmitt, MD, Christina VanderPluym, MD, Ivan M. Rebeyka, MD, Neil Wrightson, MD, Felix Berger, MD, Massimo Griselli, MD, and Jennifer Conway, MD From the Department of Congenital Heart Disease/Pediatric Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany; Department of Pediatric Cardiology, Freeman Hospital, Newcastle Upon Tyne, UK; Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada; and the Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts, USA

De-novo donor-specific anti-HLA antibodies 30 days after lung transplantation are associated with a worse outcome.

Abstract: Background The impact of de-novo donor-specific anti-HLA antibodies (DSA) on patient and graft survival after lung transplantation remains controversial. We analyzed DSA that developed at Day 7 and Month (M) 1, M3, M6 and M12 after lung transplantation and evaluated their impact on chronic lung allograft dysfunction (CLAD) development and survival. Methods One hundred thirty-four patients who underwent lung transplantation at our institution between November 2007 and August 2013 were included in this study. During the first post-transplant year, 82 (61%) patients developed de novo DSA and 52 (39%) patients did not. Three mean fluorescence intensity (MFI) intervals were used to define scores of anti-HLA antibody positivity: score 4 if MFI was 500 to 1,000; score 6 if MFI was 1,000 to 3,000; and score 8 if MFI was ≥3,000. Patients' records were retrospectively reviewed. Results DSA with MFI scores of ≥4 (hazard ratio [HR] 2.21, 95% confidence interval [CI] 1.08 to 4.54, p = 0.03), 6 (HR 2.63, 95% CI 1.27 to 5.20, p p P = 0.01); and with post-operative extracorporeal membrane oxygenation (HR 0.09, 95% CI 0.01 to 0.28, p = 0.02) were significantly associated with CLAD. Multivariate analysis identified score 8 at M1 (HR 2.71, 95% CI 1.34 to 5.47, p p = 0.02). Conclusion Early de-novo DSA may significantly impact long-term outcomes after lung transplantation and should therefore prompt regular screening.

Racial and ethnic disparities in outcomes after heart transplantation: A systematic review of contributing factors and future directions to close the outcomes gap

Abstract: The demographics of patients undergoing heart transplantation in the United States have shifted over the last 10 years, with an increasing number of racial and ethnic minorities undergoing heart transplant. Multiple studies have shown that survival of African American patients after heart transplantation is lower compared with other ethnic groups. We review the data supporting the presence of this outcome disparity and examine the multiple mechanisms that contribute. With an increasingly diverse population in the United States, knowledge of these disparities, their mechanisms, and ways to improve outcomes is essential.

Right ventricular afterload sensitivity dramatically increases after left ventricular assist device implantation: A multi-center hemodynamic analysis

Abstract: Background Right ventricular (RV) failure is a source of morbidity and mortality after left ventricular assist device (LVAD) implantation. In this study we sought to define hemodynamic changes in afterload and RV adaptation to afterload both early after implantation and with prolonged LVAD support. Methods We reviewed right heart catheterization (RHC) data from participants who underwent continuous-flow LVAD implantation at our institutions (n = 244), excluding those on inotropic or vasopressor agents, pulmonary vasodilators or additional mechanical support at any RHC assessment. Hemodynamic data were assessed at 5 time intervals: (1) pre-LVAD (within 6 months); (2) early post-LVAD (0 to 6 months); (3) 7 to 12 months; (4) 13 to 18 months; and (5) very late post-LVAD (18 to 36 months). Results Sixty participants met the inclusion criteria. All measures of right ventricular load (effective arterial elastance, pulmonary vascular compliance and pulmonary vascular resistance) improved between the pre- and early post-LVAD time periods. Despite decreasing load and pulmonary artery wedge pressure (PAWP), RAP remained unchanged and the RAP:PAWP ratio worsened early post-LVAD (0.44 [0.38, 0.63] vs 0.77 [0.59, 1.0], p Conclusions Despite reducing RV load, LVAD implantation leads to worsened RV adaptation. With continued LVAD support, both RV afterload and RV adaptation improve, and their relationship remains constant over time post-LVAD. These findings suggest the RV afterload sensitivity increases after LVAD implantation, which has major clinical implications for patients struggling with RV failure.

Clinical myocardial recovery during long-term mechanical support in advanced heart failure: Insights into moving the field forward.

Abstract: Myocardial remodeling induced by pressure and volume overload drives the vicious cycle of progressive myocardial dysfunction in chronic heart failure (HF). Mechanical volume and pressure unloading induced by implantable cardiac assist devices allows a reversal of stress-related compensatory responses of the overloaded myocardium so that selected patients requiring long-term mechanical circulatory support for advanced HF can achieve clinically meaningful degrees of improvement in the structure and function of their native heart. Insights from clinical and translational studies on myocardial recovery with mechanical circulatory support may enhance the understanding of how the pathophysiologic mechanisms of HF progression might be reversed. The end points of ongoing and future translational and clinical studies are discussed to identify specific investigational strategies that may advance the field of myocardial recovery driven by hemodynamic unloading of the heart.

Major advantages and critical challenge for the proposed United States heart allocation system

Abstract: The proposed new United States allocation system incorporates extensive research into an elegant plan designed to reduce wait list mortality while preserving post-transplant outcomes. All architects are to be congratulated. However, the future cannot be reliably modeled from the past as listing practices will evolve in response to new criteria. The new system should provide a major advance if and only if it is combined with a commitment to limit the number of listed patients overall and within each high priority status to the number that could reasonably undergo timely transplantation.