Showing papers in "Journal of Heart and Lung Transplantation in 2011"

The registry of the international society for heart and lung transplantation: Twenty-eighth adult heart transplant report-2011

Abstract: This Twenty-eighth Report of the International Society for Heart and Lung Transplantation (ISHLT) Transplant Registry is based on data submitted by participating transplant centers worldwide. A total of 388 heart transplant centers have contributed information to the Registry. This year we have also achieved another important milestone: the 100,000 heart transplant recipient was registered in the database. This report reviews important statistics for the entire cohort of patients registered in the database. However, similar to prior reports, many of the more detailed analyses will focus on recent transplant recipients, exploring information relevant to contemporary heart transplantation practice. The first part of the report reviews important donor, recipient, and medical center demographics. The second part provides an overview of immunosuppressive therapies used after transplantation. The third part examines survival, mortality risk factors, and causes of death after adult heart transplantation. The last section focuses on quality of life after transplant.

The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Lung and Heart-Lung Transplant Report--2011.

Abstract: The Registry of the International Society for Heart and Lung Transplantation (ISHLT) has documented trends in clinical lung and heart-lung transplantation since the inception of these procedures. Detailed heart-lung transplantation data have been included in the Registry annual reports since 1984 and lung transplantation data since 1989. Through June 30, 2010, the Registry contains data on 4,248 heart-lung and 38,119 lung transplants from centers around the world. This 28th Lung and Heart-Lung Registry Report summarizes the current status of lung and heart-lung transplantation by reporting data on this international group of patients, focusing on adults. More detailed information is presented in the full set of more than 200 slides that can be found on the ISHLT Web site at www.ishlt.org/registries/.

Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction.

Abstract: Background Bronchiolitis obliterans syndrome (BOS) with small-airway pathology and obstructive pulmonary physiology may not be the only form of chronic lung allograft dysfunction (CLAD) after lung transplantation. Characteristics of a form of CLAD consisting of restrictive functional changes involving peripheral lung pathology were investigated. Methods Patients who received bilateral lung transplantation from 1996 to 2009 were retrospectively analyzed. Baseline pulmonary function was taken as the time of peak forced expiratory volume in 1 second (FEV 1 ) . CLAD was defined as irreversible decline in FEV 1 Results Among 468 patients, CLAD developed in 156; of those, 47 (30%) showed the RAS phenotype. Compared with the 109 BOS patients, RAS patients showed significant computed tomography findings of interstitial lung disease ( p p = 0.0003). The RAS phenotype was the most significant risk factor of death among other variables after CLAD onset (hazard ratio, 1.60; confidential interval, 1.23–2.07). Conclusions RAS is a novel form of CLAD that exhibits characteristics of peripheral lung fibrosis and significantly affects survival of lung transplant patients.

Third INTERMACS Annual Report: the evolution of destination therapy in the United States.

Abstract: The third annual report of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) provides documentation of the current landscape of durable mechanical circulatory support in the United States. With nearly 3,000 patients entered into the database, the transition to continuous-flow pump technology is evident and dramatic. This report focuses on the rapidly expanding experience with mechanical circulatory support as destination therapy. The current 1-year survival of 75% with continuous-flow destination therapy provides a benchmark for the evolving application of this therapy.

Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device.

Abstract: Background In this study we investigated gastrointestinal (GI) bleeding and its relationship to arteriovenous malformations (AVMs) in patients with the continuous-flow HeartMate II (HMII) left ventricular assist device (LVAD). Methods The records of 172 patients who received HMII support between November 2003 and June 2010 were reviewed. Patients were considered to have GI bleeding if they had 1 or more of the following symptoms: guaiac-positive stool; hematemesis; melena; active bleeding at the time of endoscopy or colonoscopy; and blood within the stomach at endoscopy or colonoscopy. The symptom(s) had to be accompanied by a decrease of >1 g/dl in the patient's hemoglobin level. The location of the bleeding was identified as upper GI tract, lower GI tract or both according to esophagogastroduodenoscopy, colonoscopy, small-bowel enteroscopy or mesenteric angiography. Post-LVAD implantation anti-coagulation therapy consisted of warfarin, aspirin and dipyridamole. Results Thirty-two of the 172 patients (19%) had GI bleeding after 63 ± 62 (range 8 to 241) days of HMII support. Ten patients had GI bleeding from an AVM; these included 3 patients who had 2 bleeding episodes and 2 patients who had 5 episodes each. Sixteen patients had upper GI bleeding (10 hemorrhagic gastritis, 4 gastric AVM, 2 Mallory–Weiss syndrome), 15 had lower GI bleeding (6 diverticulosis, 6 jejunal AVM, 1 drive-line erosion of the colon, 1 sigmoid polyp, 1 ischemic colitis) and 1 had upper and lower GI bleeding (1 colocutaneous and gastrocutaneous fistula). All GI bleeding episodes were successfully managed medically. Conclusions Arteriovenous malformations can cause GI bleeding in patients with continuous-flow LVADs. In all cases in this series, GI bleeding was successfully managed without the need for surgical intervention.

Report from a consensus conference on antibody-mediated rejection in heart transplantation

Abstract: Background The problem of AMR remains unsolved because standardized schemes for diagnosis and treatment remains contentious. Therefore, a consensus conference was organized to discuss the current status of antibody-mediated rejection (AMR) in heart transplantation. Methods The conference included 83 participants (transplant cardiologists, surgeons, immunologists and pathologists) representing 67 heart transplant centers from North America, Europe, and Asia who all participated in smaller break-out sessions to discuss the various topics of AMR and attempt to achieve consensus. Results A tentative pathology diagnosis of AMR was established, however, the pathologist felt that further discussion was needed prior to a formal recommendation for AMR diagnosis. One of the most important outcomes of this conference was that a clinical definition for AMR (cardiac dysfunction and/or circulating donor-specific antibody) was no longer believed to be required due to recent publications demonstrating that asymptomatic (no cardiac dysfunction) biopsy-proven AMR is associated with subsequent greater mortality and greater development of cardiac allograft vasculopathy. It was also noted that donor-specific antibody is not always detected during AMR episodes as the antibody may be adhered to the donor heart. Finally, recommendations were made for the timing for specific staining of endomyocardial biopsy specimens and the frequency by which circulating antibodies should be assessed. Recommendations for management and future clinical trials were also provided. Conclusions The AMR Consensus Conference brought together clinicians, pathologists and immunologists to further the understanding of AMR. Progress was made toward a pathology AMR grading scale and consensus was accomplished regarding several clinical issues.

Working formulation for the standardization of definitions of infections in patients using ventricular assist devices.

Abstract: In 2009, the International Society for Heart and Lung Transplantation (ISHLT) recognized the importance of infectionrelated morbidity and mortality in patients using ventricular assist devices (VADs) and the growing need for a consensusbased expert opinion to provide standard definitions of infections in these patients. The aim of these standard definitions is to improve clinical-investigator communication, allowing meaningful comparison in practice and outcomes between different centers and different VAD devices. In 2010, a core group of experts, including infectious diseases specialists, cardiologists, pathologists, radiologists, and cardiothoracic surgeons, formed an ISHLT Infectious Diseases Working Group to develop agreed criteria for definitions of infections in VAD patients. These definitions have been created by adapting and expanding on existing standardized definitions, which are based on the pathophysiology of equivalent infectious processes in prosthetic devices, such as cardiac prosthetic valve infections, intravascular catheter-related infections, and prosthetic joint infections. These definitions have been divided into 3 sections: VAD-specific infections, VAD-related infections, and non-VAD infections. Owing to the constant shortage of donor organs, new allocation systems, and improved medical therapies for congestive cardiac failure, the overwhelming trend in cardiac transplantation has been toward listing principally the most critically ill patients, that is, those requiring inpatient inotropic therapy for mechanical circulatory support (MCS). The ventricular assist device (VAD) has an expanding role in the management of these patients, both as a bridge to transplantation and as a destination therapy (ie, alternative to transplantation). According to United Network of Organ Sharing (UNOS) registry data, 9,000 transplant candidates have undergone MCS since 1999, comprising 33% of all listed patients and 75% of all listed inpatients. 1

Clinical outcomes for continuous-flow left ventricular assist device patients stratified by pre-operative INTERMACS classification

Abstract: Background Risk stratification for mechanical circulatory support (MCS) has emerged as an important tool in patient selection and outcomes assessment. Most studies examining risk stratification have been limited to pulsatile devices. We use the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) to stratify patients with continuous-flow devices and assess outcomes in less severe, but functionally impaired, heart failure patients. Methods This study included 101 bridge-to-transplant and destination-therapy patients at 3 centers. Three groups were studied: Group 1, cardiogenic shock (INTERMACS Profile 1); Group 2, inotrope-dependent (INTERMACS Profile 2 or 3); and Group 3, ambulatory advanced heart failure (INTERMACS Profiles 4 to 7). The outcomes of interest were actuarial survival, survival to discharge and length of stay. Results Survival at 36 months was better in Group 3 than in Group 1 (95.8% vs 51.1%, p = 0.011), but not between Groups 2 and 3 (68.8 vs 95.8%, p = 0.065). Lengths of stay for Groups 1 to 3 were 44, 41 and 17 days: Groups 1 vs 3, p p p = 0.62. Lengths of stay for survivors were 49, 39 and 14 for the 3 groups: Groups 1 vs 3, p p p = 0.28. Conclusion INTERMACS classification is a useful metric for risk-stratifying candidates for MCS. Less acutely ill but functionally impaired heart failure patients receiving continuous-flow LVADs had longer short- and long-term survival and shorter lengths of stay compared with patients who were more acutely ill.

Bridging children of all sizes to cardiac transplantation: The initial multicenter North American experience with the Berlin Heart EXCOR ventricular assist device

Abstract: Background Beginning in 2000 and accelerating in 2004, the Berlin Heart EXCOR (Berlin Heart Inc Woodlands, TX) became the first pediatric-specific ventricular assist device (VAD) applied throughout North America for children of all sizes. This retrospective study analyzed the initial Berlin Heart EXCOR pediatric experience as a bridge to transplantation. Methods Between June 2000 and May 2007, 97 EXCOR VADs were implanted in North America at 29 different institutions. The analysis is limited to 73 patients (75%) from 17 institutions, for which retrospective data were available. Results Median age and weight at VAD implant were 2.1years (range, 12 days–17.8 years) and 11 kg (range, 3–87.6 kg), respectively. The primary diagnoses were dilated cardiomyopathy in 42 (58%), congenital heart disease in 19 (26%), myocarditis in 7 (10%), and other cardiomyopathies in 5 (7%). Pre-implant clinical condition was critical cardiogenic shock in 38 (52%), progressive decline in 33 (45%), or other in 2 (3%). Extracorporeal membrane oxygenation was used as a bridge to EXCOR in 22 patients (30%). Device selection was left VAD (LVAD) in 42 (57%) and biventricular assist devices (BiVAD) in 31 (43%). The EXCOR bridged 51 patients (70%) to transplant and 5 (7%) to recovery. Mortality on the EXCOR was 23% ( n = 17) overall, including 35% (11 of 31) in BiVAD vs 14% (6 of 42) in LVAD patients ( p = 0.003). Multivariate analysis showed younger age and BiVAD support were significant risk factors for death while on the EXCOR. Conclusions This limited but large preliminary North American experience with the Berlin Heart EXCOR VAD as a bridge to cardiac transplantation for children of all ages and sizes points to the feasibility of this approach. The prospective investigational device evaluation trial presently underway will further characterize the safety and efficacy of the EXCOR as a bridge to pediatric cardiac transplantation.

Clinical usefulness of a novel C1q assay to detect immunoglobulin G antibodies capable of fixing complement in sensitized pediatric heart transplant patients.

Abstract: Background Donor-specific antibodies (DSA) against human leukocyte antigens complicate transplantation with the potential for acute antibody-mediated rejection (AMR). Complement-fixing antibodies are required to initiate the complement cascade. Not all DSAs, however, can fix complement. Methods A novel C1q assay was developed to detect the sub-set of immunoglobulin G (IgG) antibodies capable of fixing complement. Sera from 18 pediatric heart transplant patients were analyzed for DSAs using a Luminex platform (Luminex Inc, Austin, TX) and commercially available single-antigen bead assay kits. Biopsy specimens were assessed for AMR using histopathologic criteria and immunohistochemical staining. Results During the study period, 5 patients had AMR; of these, 2 were C1q virtual crossmatch positive (VXM+) and had persistent C1q DSAs after transplant, and 3 were C1q VXM– but antibody developed immediately after transplant. A positive C1q assay in the immediate post-transplant period had a positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 100%, with 100% sensitivity and 100% specificity (Fisher exact p = 0.001). Of 11 patients who were IgG VXM+, 5 had AMR; the IgG VXM had a PPV of 45% and NPV of 100%, with 100% sensitivity and 54% specificity (Fisher exact p = 0.101). Conclusions The C1q assay can detect a sub-set of antibodies capable of fixing complement and predicts AMR early after transplant. Avoiding only the donor antigens that would be recognized by the C1q assay may accelerate time to transplant by expansion of the donor pool and potentially allows transplantation of previously "incompatible" organs.

The ISHLT working formulation for pathologic diagnosis of antibody-mediated rejection in heart transplantation: evolution and current status (2005-2011)

Abstract: From the Department of Pathology, Stanford University, Stanford, California; Universita of Padua Medical School, Padua, Italy; Royal Brompton and Harefield NHS Trust, London, United Kingdom; Hopital Europeen Georges Pompidou, Paris, France; David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, California; Intermountain Medical Center, Salt Lake City, Utah; Queen Elizabeth Hospital, Birmingham, United Kingdom; University of Utah, Salt Lake City, Utah; Cleveland Clinic, Cleveland, Ohio; Papworth Hospital, Papworth, United Kingdom; Brigham & Women’s Hospital, Boston, Massachusetts; Cedars Sinai Heart Institute, Los Angeles, California; University of Maryland School of Medicine, Baltimore, Maryland.

A 2010 working formulation for the standardization of definitions of infections in cardiothoracic transplant recipients.

Abstract: Shahid Husain, MD, MS, Martha L. Mooney, MD, MS, FACP, Lara Danziger-Isakov, MD, MPH, Frauke Mattner, MD, PhD, Nina Singh, MD, Robin Avery, MD, FIDSA, Michael Ison, MD, MS, Atul Humar, MD, MSc, Robert F. Padera, MD, PhD, Leo P. Lawler, MD, FRCR, Andy Fisher, PhD, FRCP, Richard J. Drew, MD, Kate F. Gould, MBBS, MRCP, FRCP, Amparo Sole, MD, PhD, Sean Studer, MD, MSc, Patricia Munoz, MD, Lianne G. Singer, MD, FRCPC, and Margaret Hannan, MD, FRCP, FRCPath, for the ISHLT Infectious Diseases Council Working Group on Definitions From the Division of Infectious Diseases, Transplant Infectious Diseases, University Health Network, University of Toronto, Toronto, Ontario, Canada; Eastern Virginia Medical School, Sentara Norfolk Transplant Center, Norfolk, Virginia; Center for Pediatric Infectious Diseases, Department of Infectious Disease, Medicine Institute, The Cleveland Clinic, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio; Infection Control and Hospital Epidemiology, Institute for Medical Microbiology, Hannover Medical School, Hannover, Germany; Division of Infectious Diseases, Veteran Affairs Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania; Divisions of Infectious Diseases and Organ Transplantation, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Department of Medicine, Division of Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada; Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; Respiratory Transplant Medicine, Newcastle University, Institute of Transplantation, Freeman Hospital, Newcastle Upon Tyne, UK; Mater Misericordiae University Hospital, Dublin, Ireland; Health Protection Agency Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK; Hospital Universitario La Fe, Valencia, Spain; Division of Pulmonary & Critical Care, Newark Beth Israel Medical Center, Newark, New Jersey; and Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Maranon, Universidad Complutense, Madrid, Spain.

Right-to-left ventricular end-diastolic diameter ratio and prediction of right ventricular failure with continuous-flow left ventricular assist devices.

Abstract: Background Left ventricular assist device (LVAD) implantation is an accepted therapy for patients with end-stage heart failure. Post-operative right ventricular failure (RVF) still remains a major cause of morbidity and mortality in these patients. This study sought to identify echocardiography parameters to select patients with high risk of RVF after LVAD implantation. Methods Prospectively collected pre-operative transesophageal echocardiography (TEE) and clinical data were evaluated in patients pre-selected for isolated LVAD or biventricular assist device (BiVAD) implantation. According to prevalence of RVF during the first post-operative 48 hours, patients were divided into those who developed RVF (isolated LVAD with RVF) and those who did not (isolated LVAD without RVF). Echocardiographic parameters for RV geometry, RV function, LV geometry, and the RV-to-LV end-diastolic diameter ratio (R/L ratio) were evaluated. For identification of the optimal cutoff of R/L ratio, receiver operating characteristics curves were constructed. Results An isolated LVAD was implanted in 115 patients and BiVAD in 22 patients. RVF developed in 15 patients (13%) after isolated LVAD implantation. The R/L ratio was markedly increased in the isolated LVAD with RVF and BiVAD groups compared with the isolated LVAD without RVF group. According to the receiving operating curve, the cutoff for the R/L ratio to predict RVF was 0.72. The odds ratio that RVF will develop is 11.4 in patients with an R/L ratio >0.72 ( p = 0.0001). Conclusions Increased R/L ratio successfully identifies patients with high risk of RVF after isolated LVAD implantation. Beyond standard measurements of RV function, the consideration of R/L ratio may be useful to improve risk stratification in patients before isolated LVAD implantation.

Alloimmunity-induced autoimmunity as a potential mechanism in the pathogenesis of chronic rejection of human lung allografts

Abstract: Background Bronchiolitis obliterans syndrome (BOS) is a major cause of morbidity and mortality after lung transplantation (LTx). We sought to better understand the relationship between alloimmune responses and autoimmunity and, subsequently, how autoimmunity leads to chronic rejection. Methods We analyzed the development of donor-specific antibodies (Abs) in LTx by flow PRA and the development of Abs to K-α1 tubulin (K-α1T) and collagen V (ColV) by ELISA. The frequency of K-α1T- and ColV-specific T cells that secrete IFN-γ, IL-17 and IL-10 in LTx recipients was measured by ELISPOT. Results In a retrospective analysis of 42 LTx recipients, we demonstrated a strong correlation between development of donor-specific anti-HLA Abs, Abs to self-antigens and BOS ( p + patients had higher frequency of T cells secreting IL-17 ( p p p − patients. Conclusions Based on these results we propose that alloimmune responses to donor HLA can induce autoimmune responses to airway epithelial self-antigens, characterized by activation of the IL-17 pathway. These immune responses to self-antigens along with alloimmunity contribute to the pathogenesis of BOS. Strategies to prevent development of autoimmunity may be play a key role in preventing the development of chronic rejection.

Impact of extracorporeal life support on outcome in patients with idiopathic pulmonary arterial hypertension awaiting lung transplantation

Abstract: Background Our management of patients with idiopathic pulmonary arterial hypertension (iPAH) awaiting lung transplantation changed in 2006 with the introduction of extracorporeal life support (ECLS) as an option to bridge these patients to transplantation (BTT). Methods To study the effect of this change on waiting list mortality and post-transplant outcome, 21 consecutive iPAH patients listed for lung transplantation between January 2006 and September 2010 (second cohort) were compared with 23 consecutive iPAH patients listed between January 1997 and December 2005 (first cohort). Results Between the first and second cohort, the number of patients admitted to the hospital as BTT increased from 4% (1 of 23) to 48% (10 of 21; p = 0.0009). Six patients were BTT with ECLS in the second cohort, including 4 with the Novalung device (Novalung GmbH, Hechingen, Germany) connected as a pumpless oxygenating right-to-left shunt between the pulmonary artery and left atrium. While on the waiting list, 5 patients (22%) died in the first cohort and none in the second cohort ( p = 0.03). Time on the waiting list decreased from 118 ± 85 to 53 ± 40 days between the first and second cohort ( p = 0.004). After lung transplantation, the 30-day mortality was 16.7% in the first cohort and 9.5% in the second cohort ( p = 0.5). The postoperative intensive care unit stay increased from 17 ± 13 to 36 ± 30 days between the first and second cohort ( p = 0.02). The long-term outcome after lung transplantation remained similar between both cohorts. Conclusions Aggressive management with ECLS of iPAH patients awaiting lung transplantation could have a major impact to reduce the waiting list mortality. This may, however, be associated with longer intensive care unit stay after transplant.

Survival after biventricular assist device implantation: An analysis of the Interagency Registry for Mechanically Assisted Circulatory Support database

Abstract: Background Patients requiring biventricular assist device (BiVAD) for mechanical circulatory support (MCS) have substantially worse outcomes than patients requiring left VAD (LVAD) support only. Patient-specific risk factors have yet to be consistently identified in a large, multicenter registry, which may underlie the poorer outcomes for BiVAD patients. The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) is a registry of U.S. Food and Drug Administration–approved durable MCS devices used for bridge-to-transplantation, destination therapy, or recovery. The purposes of this study were to 1) identify the underlying pre-implant characteristics of the population requiring BiVAD support that contribute to reduced survival, and 2) identify differences in postoperative outcomes with respect to adverse events compared with patients supported with LVAD alone. Methods From June 2006 to September 2009, 1,646 patients were entered into the INTERMACS database in which adverse events and outcomes were recorded for primary implants with LVAD or BiVAD. Competing outcomes methodology was used to estimate the time-related probability of death, transplant, or recovery. Overall survival for all groups was analyzed with Kaplan-Meier methods and Cox proportional regression analysis. Results The distribution of primary device implants included 1,440 LVADs and 206 BiVADs. BiVAD patients presented with a lower INTERMACS profile 93% in INTERMACS 1 or 2, compared with 73% for LVAD patients ( p p Conclusions Patients requiring BiVAD support at the time of durable MCS implant are more critically ill at the time of MCS implant. BiVAD patients experience worse survival than patients supported with LVAD alone and higher rates of serious adverse events. Characteristics of the population present at the time of BiVAD implant likely influence post-implant MCS outcomes.

Unrecognized glucose intolerance is common in pulmonary arterial hypertension

Abstract: Background Animal and human data suggest insulin resistance is common in pulmonary arterial hypertension (PAH). Although routine assessment of insulin resistance is difficult, hemoglobin A 1c (HbA 1c ) is a sensitive test to detect diabetes mellitus (DM) and those at high risk for DM. We aimed to define the prevalence of elevated HbA 1c in PAH patients and to correlate HbA 1c levels with functional assessment. Methods HbA 1c was measured in 41 PAH patients without a diagnosis of DM, along with demographic, functional, and hemodynamic data. Using published criteria, HbA 1c ≤ 5.9% defined normal, 6.0% to 6.4% was glucose intolerance, and ≥ 6.5% was DM. Results Twenty-three patients (56%) had HbA 1c ≥ 6.0%, and 6 (15%) had unrecognized DM (HbA 1c ≥ 6.5%). Age and body mass index were similar in patients with HbA 1c ≥ 6.0% vs 1c (331.0 ± 126.6 vs 413.6 ± 74.9 meters, p = 0.07). The 6-month event-free survival was not significantly different in patients with elevated HbA 1c . Conclusions Unrecognized glucose intolerance as assessed by HbA 1c is common in PAH. Further studies are needed to discern if glucose or insulin dysregulation mediates PAH pathogenesis or is secondary to advanced PAH.

Reduction of alloantibodies via proteosome inhibition in cardiac transplantation

Abstract: Background The presence of alloantibodies in patients awaiting heart transplantation is associated with increased waiting time to transplant, increased risk of rejection after transplant, an increased risk of cardiac allograft vasculopathy, and decreased survival. So far, treatments to reduce circulating antibodies to allow transplantation have been limited. We report the first clinical experience using a plasma-cell-depleting strategy with bortezomib to reduce anti-HLA antibodies in the heart transplant population. Methods Six patients awaiting cardiac transplantation demonstrated persistently elevated anti-HLA antibodies, despite receiving a course of treatment with intravenous immunoglobulin (IVIg) and rituximab. These patients then underwent supplemental therapy with bortezomib in conjunction with plasmapheresis. One additional patient awaiting cardiac transplantation with elevated anti-HLA antibodies required bortezomib treatment for amyloidosis. Antibody strength was monitored after completion of treatment by solid-phase (single-antigen-bead) assay. Results The mean calculated panel-reactive antibody (cPRA) was reduced from 62% to 35% following a course of bortezomib ( p = 0.01). Six of 7 patients demonstrated a significant decline in antibody levels. One patient remained refractory to desensitization therapy and died from sepsis while awaiting heart transplantation. Four patients successfully underwent cardiac transplantation without evidence of rejection or graft dysfunction. One patient developed early post-transplant graft dysfunction and died at 1 month from sepsis. Infection was the most common adverse effect associated with desensitization. Conclusions In this pilot study, use of plasmapheresis and bortezomib appeared to decrease cPRA, even in patients refractory to desensitization with IVIg/rituximab, thus increasing the chances that an acceptable donor heart will be available for the sensitized patient awaiting heart transplantation. However, desensitization is associated with an increased risk of infection. Further studies are warranted to determine whether the benefits of desensitization using this strategy outweigh the risks.

Results of HeartMate II left ventricular assist device implantation on renal function in patients requiring post-implant renal replacement therapy.

Abstract: Background Renal function is often compromised in patients with advanced heart failure. Methods We evaluated renal function in heart failure patients supported by the HeartMate II (Thoratec Corporation, Pleasanton, CA) continuous-flow left ventricular assist device (LVAD) who required renal replacement therapy (RRT) by continuous venovenous hemofiltration dialysis (CVVHD) or hemodialysis, or both. Indications for RRT included oliguria (urine 24 hours with a creatinine level > 2.0 mg/dl or 1.5 times that of the pre-implant creatinine level, severe acidemia, and volume overload. Results Of 107 consecutive patients who underwent HeartMate II implantation at our center and had been supported for > 30 days, 15 (13 men and 2 women) required post-implant RRT. Of the 15 patients, 3 received CVVHD and 12 received CVVHD and hemodialysis. Renal function improved within 2 months of support compared with average values before support (creatinine clearance, 64 ± 39 vs 92 ± 55 ml/min, p = 0.041; glomerular filtration rate, 46.9 ± 20.7 vs 73.2 ± 38.9 ml/min/1.73 m 2 ; p = 0.032). Renal function improved after HeartMate II implantation in 10 patients, and RRT was removed. Of these 10 patients, 2 underwent heart transplantation 4 months after RRT was removed, 1 underwent heart and kidney transplantation 4 years later, 2 died at home of conditions unrelated to renal function 6 months after RRT was removed, and 5 are awaiting heart transplantation, with good quality of life. Conclusions In this study, patients who experienced clinical recovery after the LVAD implant had subsequent recovery of renal function after continuous-flow LVAD support.

Early outcomes of bilateral sequential single lung transplantation after ex-vivo lung evaluation and reconditioning.

Abstract: Background Ex vivo lung perfusion (EVLP) is a novel approach for extended evaluation and/or reconditioning of donor lungs not meeting standard International Society for Heart and Lung Transplantation criteria for transplantation. Methods We retrospectively evaluated 13 consecutive EVLP runs between January 2009 and December 2010. Lungs rejected for routine transplantation were implanted to the EVLP circuit and reperfused using acellular supplemented Steen Solution (Vitrolife, Goteborg, Sweden) up to a target flow rate of 40% of the donor's calculated flow at a cardiac index of 3.0 liters/min/m 2 ; target left atrial pressure 2 O. Hemodynamic and respiratory data monitoring with hourly clinical assessment were performed. Donor data, conversion rate to transplantation, and recipient outcome were analyzed. Results Donor data ( n = 13) were: age, 44.23 ± 8.33 years; female/male, 8:5; cause of death: intracranial hemorrhage, 11 (85%), stroke, 1 (7.5%), hypoxic brain injury, 1 (7.5%); smoking history, 9 (69%), 17.44 ± 8.92 pack-years; mechanical ventilation, 102.6 ± 91.92 hours; chest x-ray imaging: abnormal, 12 (92.5%); normal, 1 (7.5%). EVLP: mean 141 ± 28.83 minutes. Arterial partial pressure of oxygen/fraction of inspired oxygen 100% before termination of the circuit vs pre-retrieval value: 57.32 ± 9.1 vs 42.36 ± 14.13 kPa ( p Conclusions EVLP may facilitate assessment and/or reconditioning of borderline lungs, with a conversion rate of 46 % and good short-term survival.

Right heart failure and “failure to thrive” after left ventricular assist device: Clinical predictors and outcomes

Abstract: Background This study determined predictors of early post-operative right heart failure (RHF) and its consequences, as well as predictors of those who clinically thrive longer term after insertion of a continuous-flow left ventricular assist device (LVAD). Methods Pre-operative and latest follow-up data were analyzed for 40 consecutive patients who received third-generation centrifugal-flow LVADs. RHF was defined using previously described criteria, including post-operative inotropes, pulmonary vasodilator use, or right-sided mechanical support. Patients were also categorized according to clinical outcomes after LVAD insertion. Results LVADs were implanted as a bridge to transplantation (BTT) in 33 patients and as destination therapy in 7. Before LVAD implant, 22 patients were Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level 1, and 17 were at level 2. Temporary mechanical assistance was present in 50% of the cohort at LVAD implantation. The 6-month survival/progression to transplant was 92.5%. Average LVAD support time was 385 days (range, 21–1,011 days). RHF developed postoperatively in 13 of 40 patients (32.5%). RHF patients had more severe pre-operative tricuspid incompetence than non-RHF patients. The BTT patients with evidence of RHF had poorer survival to transplant (6 of 11 [54.5%]) than those without RHF (20 of 22 [90.9%]), p = 0.027). There were no other hemodynamic or echocardiographic predictors of short-term RHF. After LVAD, 22 of the 40 patients (55%) thrived clinically. For BTT patients, 20 of 21 (95%) of those who thrived progressed to transplant or were alive at latest follow-up vs 6 of 12 (50%) of those who failed to thrive (FTT; p p p Conclusions Early post-operative RHF results in poorer survival/progression to transplantation for BTT patients and is predicted by greater pre-operative tricuspid incompetence. The most important predictor for those who will clinically thrive longer-term after LVAD insertion is younger age.

Infectious complications after pulsatile-flow and continuous-flow left ventricular assist device implantation

Abstract: BACKGROUND: Infection is a significant source of morbidity and mortality after left ventricular assist device (LVAD) implantation. Newer generation continuous-flow (CF) LVADs are smaller, requiring smaller pump pockets and drive-line exit sites as compared with pulsatile-flow (PF) devices. With their recent adoption, CF device patients benefit from improved provider experience in the detection and treatment of infectious complications. Given these advances in design and experience, we examined the incidence of infectious complications in patients receiving CF and PF devices. METHODS: We reviewed patients who received CF or PF LVADs (June 2000 to May 2009) at our institution. Incidences and timing of systemic infections (bacteremia, sepsis, severe sepsis, septic shock), device-associated infections (drive-line, LVAD pocket, sternal wound) and non-device-associated infections (catheter-related bloodstream, pneumonia, urinary tract) were compared between devices. Primary outcomes were sepsis, severe sepsis, a composite of drive-line and LVAD pocket infection, and catheter-related bloodstream infection. RESULTS: Of 133 LVADs, 86 were CF. CF patients had lower pre-operative risk, more recent device implantation, and longer LVAD support time. Device type was highly correlated with reduced infections; however, on multivariate analysis, implantation date appeared to drive this association. Kaplan-Meier estimates of freedom from all primary outcomes were improved with more recent implantation (p < 0.05). On multivariate analysis, implantation date was predictive of all primary outcomes except severe sepsis, for which advanced age and worse Seattle Heart Failure Model score were predictive. CONCLUSION: In this institutional review of post-LVAD infections, a decrease in infectious complications in CF patients was likely related to increased provider experience associated with a more recent date of implantation.

Usefulness of extracorporeal membrane oxygenation as a bridge to lung transplantation: A descriptive study

Abstract: Background This retrospective study investigated early outcome in patients with end-stage pulmonary disease bridged with extracorporeal membrane oxygenation (ECMO) with the intention of lung transplantation (LTx) in 2 Scandinavian transplant centers. Methods ECMO was used as a bridge to LTx in 16 patients between 2005 and 2009 at Sahlgrenska and Helsinki University Hospitals. Most patients were late referrals for LTx, and all failed to stabilize on mechanical ventilation. Thirteen patients (7 men) who were a mean age of 41 ± 8 years (range, 25–51 years) underwent LTx after a mean ECMO support of 17 days (range, 1–59 days). Mean follow-up at 25 ± 19 months was 100% complete. Results Three patients died on ECMO while waiting for a donor, and 1 patient died 82 days after LTx; thus, by intention-to-treat, the success for bridging is 81% and 1-year survival is 75%. All other patients survived, and 1-year survival for transplant recipients was 92% ± 7%. Mean intensive care unit stay after LTx was 28 ± 18 days (range, 3–53 days). All patients were doing well at follow-up; however, 2 patients underwent retransplantation due to bronchiolitis obliterans syndrome at 13 and 21 months after the initial ECMO bridge to LTx procedure. Lung function was evaluated at follow-up, and mean forced expiratory volume in 1 second was 2.0 ± 0.7l (62% ± 23% of predicted) and forced vital capacity was 3.1 ± 0.6 l (74% ± 21% of predicted). Conclusion ECMO used as a bridge to LTx results in excellent short-term survival in selected patients with end-stage pulmonary disease.

Mesenchymal stem cell conditioned media attenuates in vitro and ex vivo myocardial reperfusion injury.

Abstract: Background Previous studies have suggested that implantation of mesenchymal stem cells (MSC) or their conditioned media (MSC CM) improves heart function after myocardial infarction. We sought to determine whether MSC and MSC CM added at the onset of reperfusion attenuates myocardial reperfusion injury. Methods Rat MSC and neonatal rat cardiomyocytes (NRC) were isolated and cultured separately. NRC were subjected to simulated in vitro ischemia/reperfusion (I/R). At the onset of reperfusion, NRC received either fresh medium (control group) or one of the following treatments: MSC in fresh medium; MSC CM alone (without MSC); MSC CM + inhibitors of PI3K (LY294002 or Wortmannin); MSC CM + antibodies neutralizing IGF-1 or VEGF; MSC + inhibitors of PI3K; or cyclosporine. Cell injury was assessed by LDH activity and MTT staining at the end of reperfusion. VEGF, IGF-1 and HGF were measured in each experimental treatment preparation. Ex vivo experimentation on isolated rat hearts subjected to I/R were performed to evaluate the protective effects of MSC CM on myocardial reperfusion injuries measured through CK release and infarct size after TTC staining. Results In vitro cell injury was significantly reduced by MSC, MSC CM and CsA. PI3K inhibitors significantly attenuated the protection afforded by MSC CM but not growth factor inhibitors. Ex vivo experimentation showed that MSC CM significantly reduced myocardial I/R injury. Conclusion Our data suggest that MSC CM added at the onset of reperfusion can protect myocardium from I/R injury. In vitro data suggest a protection mediated by paracrine activation of the PI3K pathway.

Would access to device therapies improve transplant outcomes for adults with congenital heart disease? Analysis of the United Network for Organ Sharing (UNOS).

Abstract: Background Patients with congenital heart disease (CHD) now survive into adulthood and often present with end-stage heart failure (HF). HF management and approach to orthotopic heart transplant (OHT) may differ from adults without CHD. We sought to compare OHT waitlist characteristics and outcomes for these 2 groups. Methods The Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) database was used to identify adults (≥18 years) listed for OHT from 2005 to 2009. The cohort was divided into those with or without CHD. Results Of 9,722 adults included, 314 (3%) had CHD. Adults with CHD were younger (35 ± 13 vs 52 ± 12 years, p p p p p p p = 0.15), patients with CHD were more likely to experience cardiovascular death (60% vs 40%, p = 0.03), including sudden in 44% and due to HF in 16%. Conclusions Despite lower urgency status, patients with CHD have greater cardiovascular mortality awaiting OHT than those without. Increased defibrillator use could improve survival to OHT, because sudden death is common. VAD support may benefit select patients, but experience in CHD is limited. Referral to specialized adult congenital heart centers can enhance utilization of device therapies and potentially improve waitlist outcomes.

Health-related quality of life and exercise tolerance in recipients of heart transplants and left ventricular assist devices: A prospective, comparative study

Abstract: Background The aim of this study was to evaluate and compare health-related quality of life (HRQoL) and physical exercise tolerance in patients after heart transplantation (HTx) or implantation of a left ventricular assist device (LVAD). Methods A prospective, comparative design was used to characterize changes over time in HRQoL (SF-36) and exercise tolerance in patients after HTx ( n = 54) and during LVAD support ( n = 36). Nine LVAD patients were lost for follow-up. The majority of patients in both groups were male (97%); the LVAD cohort tended to be younger ( p = 0.06). Results HRQoL improved significantly in HTx patients in the SF-36 physical ( p = 0.02), but not in the psychosocial ( p = 0.27) component score during follow-up. In the LVAD group, HRQoL showed improvements for both the SF-36 physical and psychosocial component scores (both p = 0.04). Between-group comparisons revealed better HRQoL for the HTx cohort than the LVAD cohort for 2 of 8 SF-36 subscales. Age-, gender- and body mass index (BMI)-adjusted exercise tolerance (workload; VO 2max ) showed significant improvements for both HTx ( p = 0.01) and LVAD ( p = 0.01) patients. Adjusted maximum oxygen consumption was higher for HTx patients ( p = 0.05) relative to LVAD patients at 8 ± 1 months after implant. Conclusion HRQoL and exercise capacity increased in both groups over the time-course of the study. After adjusting for relevant variables, HTx patients showed a higher exercise tolerance compared with the LVAD group during follow-up. Thus, future large-scale intervention studies should emphasize the specific needs of these patient cohorts.

Allosensitization and outcomes in pediatric heart transplantation.

Abstract: Background Allosensitization among children being considered for heart transplantation remains a great challenge. Controversy exists as to the best approach for those with elevated panel-reactive antibody (PRA) titers. We sought to define the association between elevated PRA and outcomes using data from the multi-institutional Pediatric Heart Transplant Study Group. Methods Between January 1993 and December 2008, 3,016 patients (>1 month of age) were listed for heart transplantation. PRA data at listing were available for 2,500 (83%) patients, and 2,237 underwent transplantation with PRA data being available for 1,904 (85%). Because various PRA assays were employed (e.g., cell-based and solid phase) we entered the highest value regardless of methodology. Results Among the factors associated with high PRA at transplant were Status 1 at listing, previous sternotomy and prior Norwood procedure. An elevated PRA at listing was associated with higher risk of death while waiting. Of subjects with PRA ≥50% only 57% were transplanted by 1 year on the waitlist, as compared with 76% of those with PRA p Conclusions Significant allosensitization is associated with more than a 2-fold increased risk of death within the first transplant year. Although prospective crossmatching abrogates the risk of post-transplant mortality, it may contribute to higher pre-transplant attrition due to longer waitlist times. There is a critical need for strategies to minimize the impact of allosensitization and antibody-mediated rejection immediately after transplantation.

Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension.

Abstract: Background Tadalafil 40 mg orally once daily, was shown to be well-tolerated and efficacious for pulmonary arterial hypertension in a 16-week, double-blind, placebo (PBO)-controlled trial. Inclusion criteria included the option for background bosentan. Analyses of tadalafil in treatment-naive patients and as add-on to bosentan were pre-specified. Objectives were to provide safety and efficacy data for both groups. Methods Groups analyzed included: treatment-naive + PBO; treatment-naive + tadalafil; background bosentan + PBO; and background bosentan + tadalafil. Patients randomized to tadalafil or PBO ( N = 405) were analyzed by bosentan use (yes = 216, no=189). Treatment differences in 6-minute walk distance (6MWD, PBO-adjusted), functional class (FC), clinical worsening (CW) and adverse events were assessed. Hazard ratios (HRs) with 95% confidence intervals (CIs) are presented for FC and CW. Results At Week 16, PBO-adjusted 6MWD increases were 44 m (CI: 20 to 69 m; n = 37) for tadalafil 40 mg in treatment-naive patients and 23 m (CI: −2 to 48 m; n = 42) for tadalafil 40 mg add-on to bosentan. The 6MWD for treatment-naive and background bosentan PBO patients decreased by 3 m and increased by 19 m, respectively, at Week 16 compared with baseline. Two (5%) treatment-naive patients had CW with tadalafil 40 mg vs 8 (22%) with PBO (HR = 3.3, CI: 1.1 to 10.0). Two (5%) background bosentan patients had CW with tadalafil 40 mg add-on vs 5 (11%) for PBO add-on (HR = 1.9, CI: 0.4 to 10.2). Adverse events for tadalafil monotherapy and as add-on were similar. Conclusion Tadalafil 40 mg was well-tolerated and provided clinical benefit in patients as monotherapy. It was also well-tolerated when added to background bosentan, but data are insufficient to conclude additional benefit.

Comparison of outcomes in women versus men using a continuous-flow left ventricular assist device as a bridge to transplantation.

Abstract: Background The use of large, pulsatile left ventricular assist devices (LVADs) has been limited in women because of their small body size. Methods We compared the survival outcomes, quality of life, and adverse events in 465 patients (104 women, 361 men) with advanced systolic heart failure in their first 18 months of support with the HeartMate II (Thoratec Corp, Pleasanton, CA) continuous-flow LVAD for bridge to transplantation. Results During the first 18 months, there were no differences in survival between women and men while on LVAD support (73% ± 3% vs 73% ± 5%, p = 0.855) but fewer women (40%) underwent heart transplantation than did men (55%; p = 0.001). More women continued on support after 18 months ( p = 0.007). Median duration of support was 238 days for women and 184 days for men ( p = 0.003). Mortality was 20% for women and 19% for men ( p = 0.89). Adverse events were similar, with the exception of hemorrhagic stroke, which occurred more frequently in women (0.10 vs 0.04 events/patient-year, p = 0.02), and device-related infections, which occurred less frequently in women (0.23 vs 0.44, p = 0.006). Functional capacity and quality of life at 6 months improved significantly in women and men. Conclusions Continuous-flow left ventricular assistance as a bridge to transplantation is associated with similar survival rates in women and men. Differences observed in higher stroke rates and fewer infections among women require further study.

Age and CYP3A5 genotype affect tacrolimus dosing requirements after transplant in pediatric heart recipients.

Abstract: Background Tacrolimus is one of the commonly used immunosuppressive drugs for pediatric heart transplants. Large variation exists in pharmacokinetics during the direct post-transplant period, resulting in an increased risk of adverse events. Limited data are available on the interaction of age, CYP3A5 and ABCB1 genotype, and disease severity on the variation in disposition and outcome in pediatric heart transplant recipients. Method We studied the relationship between age and CYP3A5 and ABCB1 genotype and the Pediatric Risk of Mortality (PRISM) score on tacrolimus dose (mg/kg), steady-state trough concentrations, and concentration/dose ratio, as well as rejection and renal function for 14 days after heart transplant in children. Results Tacrolimus was administered to 39 children (median age, 6.0 years) after transplant. A correlation was found between the age at the time of transplant and the tacrolimus dosing requirements ( r s = –0.447, p = 0.004) and the concentration/dose ratio (r s = 0.351, p = 0.029). CYP3A5 expressors required median (interquartile range) higher doses of tacrolimus (0.14 [0.09] vs 0.06 [0.04] mg/kg/12 hours, p = 0.001), and had lower concentration/dose ratios (45.34 [44.54] vs 177.78 [145.38] ng/ml per mg/kg/12 hours, p ABCB1 genotype. Age and CYP3A5 genotype predicted the tacrolimus dosing requirements as well as the concentration/dose ratio ( R 2 = 0.351, p = 0.001 and R 2 = 0.521, p CYP3A5 or ABCB1 genotypes and the estimated glomerular filtration rate. Conclusion Younger age and CYP3A5 expressor genotype were independently associated with higher dosing requirements and lower tacrolimus concentration/dose ratios.