Wholly vascularized millimeter-sized engineered tissues by cell-sized microscaffolds.

The in vitro fabrication of wholly vascularized millimeter-sized engineered tissues is still a key challenge in the tissue engineering field. Recently we reported a unique approach 'sedimentary culture' using a collagen microfiber (CMF) to fabricate large-scale engineered tissues. The millimeter-sized tissues with high extracellular matrix (ECM) density were easily obtained by centrifugation of cells and CMFs and subsequent cultivation because the CMFs acted as a micrometer-sized scaffold. However, cell distribution in the obtained tissues was not homogeneous because of the different sedimentation velocity of the cells and CMFs because of their size difference. Here we report the fabrication of wholly vascularized millimeter-sized engineered tissues using cell-sized CMFs. To avoid dissolving, vacuum drying was performed at 200 °C for 24 h for thermal crosslinking of primary amine groups of type I collagen. The 200- and 20-µm-sized CMFs (CMF-200 and CMF-20) were obtained by homogenization and subsequent sonication of the crosslinked collagen. Interestingly, the CMF-20 indicated a similar sedimentation velocity with cells because of their same size range, thus uniform millimeter-sized tissue with homogeneous cell distribution was fabricated by the sedimentary culture method. To form a whole blood capillary structure in the tissues, fibronectin (FN) was adsorbed on the surface of CMF-20 to stimulate endothelial cell migration. The distribution of the blood capillary network in 1.6-mm-sized tissues was markedly improved by FN-adsorbed CMF-20 (FN-CMF-20). Sedimentary culture using FN-CMF-20 will create new opportunities in tissue engineering for the in vitro fabrication of wholly vascularized millimeter-sized engineered tissues.

Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis.

Working memory capacity, a critical component of executive function, expands developmentally from childhood through adulthood. Anomalies in this developmental process are seen in individuals with autism spectrum disorder (ASD), schizophrenia and intellectual disabilities (ID), implicating this atypical process in the trajectory of developmental neuropsychiatric disorders. However, the cellular and neuronal substrates underlying this process are not understood. Duplication and triplication of copy number variants of 22q11.2 are consistently and robustly associated with cognitive deficits of ASD and ID in humans, and overexpression of small 22q11.2 segments recapitulates dimensional aspects of developmental neuropsychiatric disorders in mice. We capitalized on these two lines of evidence to delve into the cellular substrates for this atypical development of working memory. Using a region- and cell-type-selective gene expression approach, we demonstrated that copy number elevations of catechol-O-methyl-transferase (COMT) or Tbx1, two genes encoded in the two small 22q11.2 segments, in adult neural stem/progenitor cells in the hippocampus prevents the developmental maturation of working memory capacity in mice. Moreover, copy number elevations of COMT or Tbx1 reduced the proliferation of adult neural stem/progenitor cells in a cell-autonomous manner in vitro and migration of their progenies in the hippocampus granular layer in vivo. Our data provide evidence for the novel hypothesis that copy number elevations of these 22q11.2 genes alter the developmental trajectory of working memory capacity via suboptimal adult neurogenesis in the hippocampus.

Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study.

BACKGROUND: Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II study assessed the clinical benefit of rebamipide in reducing the incidence of severe chemoradiotherapy-induced oral mucositis in patients with head and neck cancer (HNC). METHODS: Patients aged 20-75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo. The primary endpoint was the incidence of grade ≥ 3 oral mucositis determined by clinical examination and assessed by central review according to the Common Terminology Criteria of Adverse Events version 3.0. Secondary endpoints were the time to onset of grade ≥ 3 oral mucositis and the incidence of functional impairment (grade ≥ 3) based on the evaluation by the Oral Mucositis Evaluation Committee. RESULTS: From April 2014 to August 2015, 97 patients with HNC were enrolled, of whom 94 received treatment. The incidence of grade ≥ 3 oral mucositis was 29% and 25% in the rebamipide 2% and 4% groups, respectively, compared with 39% in the placebo group. The proportion of patients who did not develop grade ≥ 3 oral mucositis by day 50 of treatment was 57.9% in the placebo group, whereas the proportion was 68.0% in the rebamipide 2% group and 71.3% in the rebamipide 4% group. The incidences of adverse events potentially related to the study drug were 16%, 26%, and 13% in the placebo, rebamipide 2%, and rebamipide 4% groups, respectively. There was no significant difference in treatment compliance among the groups. CONCLUSIONS: The present phase II study suggests that mouth washing with rebamipide may be effective and safe for patients with HNC receiving chemoradiotherapy, and 4% liquid is the optimal dose of rebamipide. TRIAL REGISTRATION: ClinicalTrials.gov under the identifier NCT02085460 (the date of trial registration: March 11, 2014).

Report From the American Society of Transplantation Conference on Donor Heart Selection in Adult Cardiac Transplantation in the United States.

Cardiac transplantation remains the only definitive treatment for end-stage heart failure. Transplantation rates are limited by a shortage of donor hearts. This shortage is magnified because many hearts are discarded because of strict selection criteria and concern for regulatory reprimand for less-than-optimal posttransplant outcomes. There is no standardized approach to donor selection despite proposals to liberalize acceptance criteria. A donor heart selection conference was organized to facilitate discussion and generate ideas for future research. The event was attended by 66 participants from 41 centers with considerable experience in cardiac donor selection. There were state-of-the-art presentations on donor selection, with subsequent breakout sessions on standardizing the process and increasing utilization of donor hearts. Participants debated misconceptions and established agreement on donor and recipient risk factors for donor selection and identified the components necessary for a future donor risk score. Ideas for future initiatives include modification of regulatory practices to consider extended criteria donors when evaluating outcomes and prospective studies aimed at identifying the factors leading to nonacceptance of available donor hearts. With agreement on the most important donor and recipient risk factors, it is anticipated that a consistent approach to donor selection will improve rates of heart transplantation.

Cardiac Donor Risk Factors Predictive of Short-Term Heart Transplant Recipient Mortality: An Analysis of the United Network for Organ Sharing Database.

INTRODUCTION: To address the shortage of donor hearts for transplantation, there is significant interest in liberalizing donor acceptance criteria. Therefore, the aim of this study was to evaluate cardiac donor characteristics from the United Network for Organ Sharing (UNOS) database to determine their impact on posttransplantation recipient outcomes. METHODS: Adult (≥18 years) patients undergoing heart transplantation from July 1, 2004, to December 31, 2012, in the UNOS Standard Transplant Analysis and Research (STAR) database were reviewed. Patients were stratified by 1-year posttransplantation status; survivors (group S, n = 13,643) and patients who died or underwent cardiac retransplantation at 1-year follow-up (group NS/R = 1785). Thirty-three specific donor variables were collected for each recipient, and independent donor predictors of recipient death or retransplantation at 1 year were determined using multivariable logistic regression analysis. RESULTS: Overall 1-year survival for the entire cohort was 88.4%. Mean donor age was 31.5 ± 11.9 years, and 72% were male. On multivariable logistic regression analysis, donor age >40 years (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.27 to 1.64), graft ischemic time >3 hours (OR 1.32, 1.16 to 1.51), and the use of cardioplegia (OR 1.17, 1.01 to 1.35) or Celsior (OR 1.21, 1.06 to 1.38) preservative solution were significant predictors of recipient death or retransplantation at 1 year posttransplantation. Male donor sex (OR 0.83, 0.74 to 0.93) and the use of antihypertensive agents (OR 0.88, 0.77 to 1.00) or insulin (OR 0.84, 0.76 to 0.94) were protective from adverse outcomes at 1 year. CONCLUSIONS: These data suggest that donors who are older, female, or have a long projected ischemic time pose greater risk to heart transplant recipients in the short term. Additionally, certain components of donor management protocols, including antihypertensive and insulin administration, may be protective to recipients.

Stimulation of neuronal neurite outgrowth using functionalized carbon nanotubes.

Low concentrations (0.11-1.7 microg ml(-1)) of functionalized carbon nanotubes (CNTs), which are multi-walled CNTs modified by amino groups, when added with nerve growth factor (NGF), promoted outgrowth of neuronal neurites in dorsal root ganglion (DRG) neurons and rat pheochromocytoma cell line PC12h cells in culture media. The quantity of active extracellular signal-regulated kinase (ERK) was higher after the addition of both 0.85 microg ml(-1) CNTs and NGF than that with NGF alone. CNTs increased the number of cells with neurite outgrowth in DRG neurons and PC12h cells after the inhibition of the ERK signaling pathway using a mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor. Active ERK proteins were detected in MEK inhibitor-treated neurons after the addition of CNTs to the culture medium. These results demonstrate that CNTs may stimulate neurite outgrowth by activation of the ERK signaling pathway. Thus, CNTs are biocompatible and are promising candidates for biological applications and devices.

Case of trigger finger related to an intertendinous connection between the flexor tendons.

We report a rare cause of trigger finger related to an anatomical variation of an intertendinous connection between the flexor digitorum superficialis and flexor digitorum profundus tendons in the palmar region.

HeartMate VE LVAS design enhancements and its impact on device reliability.

OBJECTIVE: The HeartMate VE left ventricular assist system (LVAS) has supported more than 2300 patients and has been shown to be effective for bridge to cardiac transplantation and has demonstrated improved outcomes in survival as a destination therapy. Improvements in device durability are needed as bridge to transplant times increase and as we move into the era of LVAD as destination therapy. The purpose of this study is to determine if design enhancements to the HeartMate LVAS have improved device reliability and durability. METHODS: A retrospective analysis of serious mechanical failures was performed in 1865 devices (1458 VE, 407 XVE). The analysis of data included devices used to support patients from September 1998 for bridge to transplantation and destination therapy. Serious mechanical failures were defined as inflow valve dysfunction, percutaneous lead breaks, diaphragm fractures or punctures, bearing failures, outflow graft erosion and pump disconnects. RESULTS: Median device duration for the VE was 97 days (max 1206 days), and 85 days (max 517 days) for the XVE. A total of 134 serious mechanical failures occurred and included inflow valve dysfunction (5.3% VE, 2.4% XVE) (P = 0.853) percutaneous lead breaks (1.9% VE, 0% XVE) (P < 0.001) diaphragm fractures (0.1% VE, 0% XVE) (P = 0.134) outflow graft erosion (0.2% VE, 0% XVE) (P = 0.1096), pump disconnects (0.1% VE, 0% XVE) (P = 0.1336) and bearing failures (0.6% VE, 0.2% XVE) (P = 0.5538). Of the XVEs 97% were free of serious mechanical failures at 6 months and 82% at 1 year compared to 92 and 73% for the VE, respectively. The 6-month difference between the devices was statistically significant (P = 0.0063) and there was no statistically significant difference at 1 year (P = 0.1492). CONCLUSIONS: Preliminary experience with the HeartMate XVE LVAS demonstrated a significant reduction in percutaneous lead breaks. Early trends indicate positive impact of recent design modifications on XVE performance. These design modifications may improve device durability and reliability, which is crucial as we enter the era of LVADs as an alternative to medical therapy.

Endotoxaemia during left ventricular assist device insertion: relationship between risk factors and outcome.

BACKGROUND: Endotoxaemia, caused by splanchnic ischaemia during surgery, is believed to trigger systemic inflammation and cause postoperative organ dysfunction. A relationship between the plasma concentration of endotoxin during surgery and known risk factors for postoperative morbidity and mortality (e.g. age, abnormal gastric tonometric variables) and adverse outcome after surgery has not been demonstrated. METHODS: In a prospective study, the plasma concentration of endotoxin was measured in 12 patients undergoing implantation of a left ventricular assist device. Automated air gastric tonometry was performed in all patients. The relationship between plasma endotoxin concentration, risk factors, and postoperative outcome was explored. RESULTS: Carbon dioxide gap increased from 0.7 (0.3) to 3.6 (1.6) kPa at the end of surgery. Endotoxin was detected in one of 12 patients at baseline and in nine of 12 patients at the end of surgery (P=0.003). A high plasma concentration of endotoxin at the end of surgery was associated with a higher carbon dioxide gap (r=0.59, P<0.05), and a higher postoperative multiple organ dysfunction score (r=0.7, P=0.01). CONCLUSIONS: The finding of an association between high intraoperative plasma concentrations of endotoxin, abnormal gastric tonometric variables and adverse outcome supports the view that endotoxaemia is caused by gut hypoperfusion during surgery and is associated with postoperative organ dysfunction.

Validation of continuous thermodilution cardiac output in patients implanted with a left ventricular assist device.

OBJECTIVE: To assess the accuracy of a continuous cardiac output (CCO) monitor against an independent, intravascular measurement of flow as can be performed in patients fitted with a left ventricular assist device (LVAD). DESIGN: A prospective cohort study. SETTING: Academic tertiary-care center. PARTICIPANTS: Adult patients (n = 15) presenting for LVAD placement. INTERVENTIONS: Consenting patients presenting for LVAD placement for end-stage cardiac failure were anesthetized, and a CCO pulmonary artery catheter was placed (OptiQ, CCO/SvO(2); Abbott Critical Care, North Chicago, IL). Patients were monitored with transesophageal echocardiography and excluded from analysis if aortic regurgitation was found. Cardiac output was determined using a Q-Vue, CCO/SvO(2) computer with digital readout (Abbott Critical Care, North Chicago, IL). The LVAD was placed in standard fashion during cardiopulmonary bypass. The Thoratec vented electric Heartmate (Thoratec Co, Pleasanton, CA) incorporates an LVAD flow console, which computes LVAD flow within +/- 5% (range, 1.8 to 10 L/min). MEASUREMENTS AND MAIN RESULTS: Cardiac output flow measurements were made from both systems at the following time points: 5 minutes and 30 minutes after protamine administration, at chest closure, and after skin closure. Mean cardiac output for each device did not differ at any time point. Regression analysis (Pearson's) showed acceptable correlation (r(2) = 0.79, p < 0.0001), whereas a bias of 529 mL with limits of agreement of 1,208 mL were shown for CCO measurement compared with LVAD flow. CONCLUSION: The data indicate that the CCO system tends to overestimate cardiac output by approximately 500 mL/min when compared with LVAD flow. Nevertheless, this bias is within the range found by other less-invasive studies done to assess the accuracy of this system and further serves to confirm its relative accuracy.

Current options for mechanical heart technology.

Heart transplantation remains the treatment of choice for end-stage heart failure despite limited donor availability and allograft durability. Artificial heart technology was initially developed as a replacement for transplantation but the initial experience with these technologies was disappointing. The quest for a total artificial heart has largely been abandoned in favor of ventricular assist devices (VADs). VADs have gained widespread acceptance as bridge to transplant and bridge to recovery therapy. After more than a decade of clinical use, several FDA approved device designs have proved effective in treating patients with various causes of heart failure. This review describes the current, clinically available ventricular replacement and assist devices and defines the adult patient populations in which they are useful. The next generation of these devices will soon become available and their clinical utility will likely shape the future direction of heart failure therapy. Ultimately the concept of a long-term total artificial heart may be revisited.

Intravenous allicin improves pulmonary blood flow after ischemia-reperfusion injury in rats.

BACKGROUND: Allicin is a sulfur-containing compound extracted from garlic, with antiaggregatory, anti- migratory, anti-oxidant and pulmonary vasodilator actions. We hypothesized that allicin might be beneficial in lung ischemia-reperfusion. METHODS: A non-nothermic rat lung ischemia-reperfusion model was established by clamping left pulmonary artery (PA) for 1 hr, followed by reperfusion for 2 hrs by clamping right PA to reflect solely the function of left lung. Groups were control (n=7), allicin 0.1 mg (n=8) and allicin 0.01 mg (n=4). In the beginning of reperfusion allicin/saline were injected. Pulmonary artery pressures (PAP), pulmonary artery flow (PAF), left atrial pressure (LAP) were monitored. At the end of reperfusion period arterial blood gas (ABG) analysis was done. RESULTS: Six of 7 control and 3 of 8 group 2 animals died before completing the experiment. In group 1 all animals completed the experiment (p=0.015 vs control). PAF was significantly increased after 30, 60 and 120 min of reperfusion in group 1 (p=0.0028, 0.0009, 0.0003 respectively vs control) and after 60 and 120 minutes in group 2 (p=0.0453, 0.018 respectively vs control). Pulmonary vascular resistance was lower at 30 min in allicin 0.01 mg group (p=0.0017 vs control). PAP was increased after 60 and 120 min of reperfusion in group 1 (p=0.016, 0.0029 respectively vs control) and after 120 min in group 2 (p=0.0104 vs control). CONCLUSIONS: This study shows that allicin improves postischemic PAF in this model. Allicin needs further investigation of potential utility and mechanism(s) of action.

Novel technique to repair type A acute aortic dissection in patients with a left ventricular assist device.

Acute type A aortic dissection is an uncommon complication with left ventricular assist device insertion, but is often fatal even if successfully repaired with conventional techniques including aortic valve repair. Residual aortic insufficiency is common because this valve is now subjected to systolic pressure. We present a novel technique for the repair of type A acute aortic dissection in patients with a left ventricular assist device with no chance of residual aortic insufficiency.

Effects of dexamethasone and FK506 on Helicobacter pylori-induced gastritis and bacterial viability in Mongolian gerbils.

FK506 and dexamethasone were used to investigate whether or not immunosuppression affects H. pylori colonization and gastric mucosal damage induced by Helicobacter pylori in Mongolian gerbils. Two weeks after H. pylori infection, FK506 and dexamethasone or vehicle alone were subcutaneously administered once daily for the following 2 weeks. FK506 or vehicle alone was administered subcutaneously once daily for 5 weeks (1 week before and 4 weeks after infection). In H. pylori-infected animals for 4 weeks, hemorrhagic erosions and inflammatory responses (neutrophil infiltration and lymphoid follicle formation) were induced in gastric mucosa at an incidence of 100%. Both FK506 and dexamethasone administered for 2 weeks markedly reduced such mucosal changes. In these animals, H. pylori viability in the stomach was significantly elevated. FK506 administered for 5 weeks also significantly inhibited the hemorrhagic erosions, edema and neutrophil infiltration in the stomach. H. pylori viability was slightly elevated as compared with the control. It was concluded that the host immune responses might play dual roles both by deteriorating gastritis induced by H. pylori and by protecting against H. pylori infection in its early stage.

Comparison of right and left ventricular responses to left ventricular assist device support in patients with severe heart failure: a primary role of mechanical unloading underlying reverse remodeling.

BACKGROUND: Left ventricular assist devices (LVAD) reverse ventricular, myocardial, and systemic abnormalities characteristic of severe heart failure (reverse remodeling). The relative contributions of hemodynamic unloading and normalized biochemical milieu to reverse remodeling are unknown. METHODS AND RESULTS: Structural and functional characteristics were measured from 53 hearts of patients undergoing transplantation without LVAD support (medical support) and 33 hearts from patients receiving a median of 46 days of LVAD support (range, 8 to 360 days). Compared with medical support alone, patients receiving LVAD support for >/=30 days had higher central venous pressures (11+/-6 versus 8+/-5 mm Hg, P=0.04), lower pulmonary artery diastolic pressures (14+/-9 versus 21+/-9 mm Hg, P=0.01), and higher cardiac outputs (5.1+/-1.6 versus 3.7+/-1.0 L/min, P<0.001). In LVAD versus transplantation hearts, V(30) (ex vivo volume yielding ventricular pressure of 30 mm Hg) was decreased in the left ventricle (LV) (179+/-75 versus 261+/-118 mL, P=0.005) but not in the right ventricle (RV) (140+/-59 versus 148+/-52 mL, P=NS). LV myocyte diameter decreased more significantly after LVAD support (17%, P=0.05) than in the RV (11%, P=NS). Compared with transplantation, LVAD support increased normalized SERCA2a content in the LV (0.51+/-0.26 versus 1.04+/-0.34, P<0.001) but not in the RV (0.48+/-34 versus 0.67+/-0.55, P=NS). Finally, LVAD support improved force-frequency relations of isolated superfused LV trabeculae (P=0.01) but not RV trabeculae. CONCLUSIONS: Reduction of hemodynamic load is a primary factor underlying several important features of reverse remodeling. These findings do not preclude a possible primary role of neurohormonal factors underlying other facets of reverse remodeling during LVAD support.

Long-term outcomes after cardiac transplantation: an experience based on different eras of immunosuppressive therapy.

BACKGROUND: Constantly changing practices in heart transplantation have improved posttransplant survival in patients with end-stage heart disease. The objective of this study was to evaluate long-term outcomes in different eras of immunosuppressive therapy after cardiac transplantation at a single center during a two-decade period. METHODS: A retrospective review of 1,086 consecutive cardiac allograft recipients who underwent transplantation between 1977 to 1999 was performed. Patients were divided into four eras based on type of immunosuppressive therapy: era 1 = steroids, azathioprine (n = 26, February 1977 to March 1983), era II = steroids, cyclosporine (n = 43, April 1983 to April 1985), era III = cyclosporine, steroids, azathioprine (n = 752, April 1985 to December 1995), era IV = cyclosporine, steroids, mycophenolate mofetil (n = 315, January 1996 to October 1999). RESULTS: The actuarial survival of the entire cohort of 1,086 patients undergoing cardiac transplantation was 79%, 66%, and 49% at 1, 5, and 10 years, respectively. There were significant trends in recipient age and gender distribution among the four eras with increasing proportion of older age (> 60 years) and female recipients in eras III and IV (p = 0.001 and 0.02). Early mortality and long-term survival improved significantly over all eras (p < 0.001). Rejection as a cause of death decreased over time (era I, 24%; era II, 21%; era III, 15%; era IV, 9%; p = 0.02), whereas the contribution of transplant coronary artery disease as a cause of death remained unchanged. CONCLUSIONS: Cardiac transplantation provides satisfactory long-term survival for patients with end-stage heart failure. The improving outcomes in survival correlate with improved immunosuppressive therapy in each era. Although the reasons for improvement in survival over time are multifactorial, we believe that changes in immunosuppressive therapy have had a major impact on survival as evidenced by the decreasing number of deaths due to rejection.

Clinical application of vacuum-assisted cardiopulmonary bypass with a pressure relief valve.

OBJECTIVES: Hemodilution induced by cardiopulmonary bypass (CPB) often prevents open heart operations without blood transfusion because of a large CPB-priming volume. A vacuum-assisted venous drainage system appears to overcome this problem and our previous experimental study demonstrated the beneficial effect of a vacuum-assisted CPB with a pressure relief valve. In this study, we clinically applied this novel system, and evaluated its efficacy by comparing it with the results of a conventional siphon-dependent drainage system. METHODS: Sixty patients undergoing open heart operation were divided into Group V (vacuum-assisted system, n=30) and Group S (siphon-dependent system, n=30). The vacuum-assisted system contains a powerful vacuum generator and a pressure relief valve to keep the negative pressure in the reservoir constant when the blood suction is used. RESULTS: The CPB-priming volume was significantly smaller in Group V (V vs. S: 1071+/-88 vs. 1405+/-137 ml; P<0.01), resulting in the lower hemodilution in Group V evidenced by the minimum hemoglobin level (V vs. S: 6.83+/-1.06 vs. 5.78+/-0.79 mg/dl; P<0.01) and blood transfusion rate (V vs. S: 9 vs. 20%; P<0.01). There were no significant differences in the plasma free hemoglobin level and the reduction ratio of plasma haptoglobin between the groups. CONCLUSIONS: These data demonstrate that this vacuum-assisted CPB can provide simplification of the CPB circuit, resulting in a smaller CPB-priming volume and lower hemodilution. This vacuum-assisted CPB may attenuate the negative effect of CPB by minimizing hemodilution and appears to be a useful modification to accomplish no blood-requiring open heart operations.

Pretransplant cachexia and morbid obesity are predictors of increased mortality after heart transplantation.

BACKGROUND: Extremes in body weight are a relative contraindication to cardiac transplantation. METHODS: We retrospectively reviewed 474 consecutive adult patients (377 male, 97 female, mean age 50.3+/-12.2 years), who received 444 primary and 30 heart retransplants between January of 1992 and January of 1999. Of these, 68 cachectic (body mass index [BMI]<20 kg/m2), 113 overweight (BMI=>27-30 kg/m2), and 55 morbidly obese (BMI>30 kg/m2) patients were compared with 238 normal-weight recipients (BMI=20-27 kg/m2). We evaluated the influence of pretransplant BMI on morbidity and mortality after cardiac transplantation. Kaplan-Meier survival distribution and Cox proportional hazards model were used for statistical analyses. RESULTS: Morbidly obese as well as cachectic recipients demonstrated nearly twice the 5-year mortality of normal-weight or overweight recipients (53% vs. 27%, respectively, P=0.001). An increase in mortality was seen at 30 days for morbidly obese and cachectic recipients (12.7% and 17.7%, respectively) versus a 30-day mortality rate of 7.6% in normal-weight recipients. Morbidly obese recipients experienced a shorter time to high-grade acute rejection (P=0.004) as well as an increased annual high-grade rejection frequency when compared with normal-weight recipients (P=0.001). By multivariable analysis, the incidence of transplant-related coronary artery disease (TCAD) was not increased in morbidly obese patients but cachectic patients had a significantly lower incidence of TCAD (P=0.05). Cachectic patients receiving oversized donor hearts had a significantly higher postoperative mortality (P=0.02). CONCLUSIONS: The risks of cardiac transplantation are increased in both morbidly obese and cachectic patients compared with normal-weight recipients. However, the results of cardiac transplantation in overweight patients is comparable to that in normal-weight patients. Recipient size should be kept in mind while selecting patients and the use of oversized donors in cachectic recipients should be avoided.