Background-The ubiquitin proteasome system maintains a dynamic equilibrium of proteins and prevents accumulation of damaged and misfolded proteins, yet its role in human cardiac dysfunction is not well understood. The present study evaluated ubiquitin proteasome system function in human heart failure and hypertrophic cardiomyopathy (HCM). Methods and Results-Proteasome function was studied in human nonfailing donor hearts, explanted failing hearts, and myectomy samples from patients with HCM. Proteasome proteolytic activities were markedly reduced in failing and HCM hearts compared with nonfailing hearts (PϽ0.01). This activity was partially restored after mechanical unloading in failing hearts (PϽ0.01) and was significantly lower in HCM hearts with pathogenic sarcomere mutations than in those lacking these mutations (PϽ0.05). There were no changes in the protein content of ubiquitin proteasome system subunits (ie, 11S, 20S, and 19S) or in active-site labeling of the 20S proteolytic subunit ␤-5 among groups to explain decreased ubiquitin proteasome system activity in HCM and failing hearts. Examination of protein oxidation revealed that total protein carbonyls, 4-hydroxynonenylated proteins, and oxidative modification to 19S ATPase subunit Rpt 5 were increased in failing compared with nonfailing hearts. Conclusions-Proteasome activity in HCM and failing human hearts is impaired in the absence of changes in proteasome protein content or availability of proteolytic active sites. These data provide strong evidence that posttranslational modifications to the proteasome may account for defective protein degradation in human cardiomyopathies. Key Words: apoptosis Ⅲ cardiomyopathy Ⅲ heart failure Ⅲ hypertrophy Ⅲ myocardium Ⅲ proteins P roteolytic degradation is critical for maintaining a dynamic equilibrium of proteins and destroying damaged or misfolded proteins. As the major pathway for intracellular protein degradation, the ubiquitin proteasome system (UPS) requires precise control to sustain most biological processes. Regulation of proteasome function may occur by altered proteasome composition (ie, association of the 20S proteolytic core with different regulatory complexes such as the 19S or 11S) 1,2 or by posttranslational modifications (ie, phosphorylation, oxidation) that affect proteasome assembly, stability, and activity. [3][4][5][6] Proteasome regulation thus has the potential to provide highly dynamic responses to cellular signals and stresses. Clinical Perspective on p 1004Despite recognition that UPS function is dysregulated in many diseases, 7-11 the importance of UPS function in cardiac diseases is only beginning to gain attention. Desmin-related cardiomyopathy mouse models provide compelling data for UPS dysfunction, in which cardiomyocyte accumulation of protein aggregates is postulated to inhibit proteasome function by restricting entry of ubiquitinated proteins into the proteasome. 12,13 Another notable example is acute cardiac ischemia, in which proteasome inhibition is thought to occur as a resul...

Tables 5.6a -d, 6.6a-d, 7.6a-d, 8.6a-d, 9.6a-d, 10.6a-d, 11.6a-d, 12.6a-d, and 13.6a-d. All of these tables are also available online at http://www.ustransplant.org. Funding: The Scientific Registry of Transplant Recipients (SRTR) is funded by contract #231-00-0116 from the Health Resources and Services Administration (HRSA). The views expressed herein are those of the authors and not necessarily those of the US Government. This is a US Government-sponsored work. There are no restrictions on its use. inhibitor of choice; tacrolimus remained the predominant calcineurin inhibitor agent for intestine (since 1994). Use of antibody treatment for rejection during the first post-transplant year for most organs declined. Short-term outcomes have improved, based on the observation that rates of rejection within the first year post-transplant have diminished.

Background-Continuous-flow rotary pumps with axial design are increasingly used for left ventricular assist support. The efficacy of this design compared with pulsatile, volume displacement pumps, with respect to characteristics of left ventricular unloading, and exercise performance remains largely unstudied. Methods and Results-Thirty-four patients undergoing implantation with a pulsatile, volume displacement pump operating in a full-to-empty cycle (HeartMate XVE; Thoratec Inc, Pleasanton, Calif; nϭ16) or continuous-flow rotary pump with an axial design operating at a fixed rotor speed (HeartMate II; Thoratec Inc; nϭ18) were evaluated with right heart catheterization and echocardiography preoperatively and at 3 months postoperatively and cardiopulmonary exercise testing 3 months postoperatively.

This article highlights trends and changes in lung and heart-lung transplantation in the United States from 1999 to 2008. While adult lung transplantation grew significantly over the past decade, rates of heart-lung and pediatric lung transplantation have remained low. Since implementation of the lung allocation score (LAS) donor allocation system in 2005, decreases in the number of active waiting list patients, waiting times for lung transplantation and death rates on the waiting list have occurred. However, characteristics of recipients transplanted in the LAS era differed from those transplanted earlier. The proportion of candidates undergoing lung transplantation for chronic obstructive pulmonary disease decreased, while increasing for those with pulmonary fibrosis. In the LAS era, older, sicker and previously transplanted candidates underwent transplantation more frequently compared with the previous era. Despite these changes, when compared with the pre-LAS era, 1-year survival after lung transplantation did not significantly change after LAS inception. The long-term effects of the change in the characteristics of lung transplant recipients on overall outcomes for lung transplantation remain unknown. Continued surveillance and refinements to the LAS system will affect the distribution and types of candidates transplanted and hopefully lead to improved system efficiency and outcomes.

Background-The effects of continuous blood flow and reduced pulsatility on major organ function have not been studied in detail. Methods and Results-We evaluated renal (creatinine and blood urea nitrogen) and hepatic (aspartate transaminase, alanine transaminase, and total bilirubin) function in 309 (235 male, 74 female) advanced heart failure patients who had been supported with the HeartMate II continuous-flow left ventricular assist device for bridge to transplantation. To determine whether patients with impaired renal and hepatic function improve over time with continuous-flow left ventricular assist device support or whether there are any detrimental effects in patients with normal organ function, we divided patients into those with above-normal and normal laboratory values before implantation and measured blood chemistry over time during left ventricular assist device support. There were significant improvements over 6 months in all parameters in the above-normal groups, with values in the normal groups remaining in the normal range over time.Mean blood urea nitrogen and serum creatinine in the above-normal groups decreased significantly from 37Ϯ14 to 23Ϯ10 mg/dL (PϽ0.0001) and from 1.8Ϯ0.4 to 1.4Ϯ0.8 mg/dL (PϽ0.01), respectively. There were decreases in aspartate transaminase and alanine transaminase in the above-normal groups from 121Ϯ206 and 171Ϯ348 to 36Ϯ19 and 31Ϯ22 IU (PϽ0.001), respectively. Total bilirubin for the above-normal group was 2.1Ϯ0.9 mg/dL at baseline; after an acute increase at week 1, it decreased to 0.9Ϯ0.5 mg/dL by 6 months (PϽ0.0001). Both renal and liver values from patients in the normal groups remained normal during support with the left ventricular assist device. Conclusions-The HeartMate II continuous-flow left ventricular assist device improves renal and hepatic function in advanced heart failure patients who are being bridged to transplantation, without evidence of detrimental effects from reduced pulsatility over a 6-month time period. Clinical Trial Registration Information-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00121472.

Background-The use of extracorporeal life support (extracorporeal membrane oxygenation [ECMO]) as a direct bridge to heart transplant in adult patients is associated with poor survival. Similarly, the use of an implantable left ventricular assist device (LVAD) to salvage patients with cardiac arrest, severe hemodynamic instability, and multiorgan failure results in poor outcome. The use of LVAD implant in patients who present with cardiogenic shock who have not been evaluated for transplantation or who have sustained a recent myocardial infarction also raises concerns. ECMO may provide reasonable short-term support to patients with severe hemodynamic instability, permit recovery of multiorgan injury, and allow time to complete a transplant evaluation before long-term circulatory support with an implantable LVAD is instituted. After acquisition of the HeartMate LVAD (Thermo Cardiosystems, Inc), we began using ECMO as a bridge to an implantable LVAD and, subsequently, to transplantation in selected high-risk patients. adult patients who presented with refractory cardiogenic shock (cardiac index Ͻ2.0 L ⅐ min Ϫ1 ⅐ m Ϫ2 , with systolic blood pressure Ͻ100 mm Hg and pulmonary capillary wedge pressure Ն24 mm Hg and dependent on Ն2 inotropes with or without intra-aortic balloon pump) were evaluated and accepted as candidates for mechanical assistance as a bridge to transplant. Of the 32 patients, 14 (group I) had a cardiac arrest or severe hemodynamic instability (systolic blood pressure Յ75 mm Hg) with evidence of multiorgan failure (defined as serum creatinine level Ͼ3 mg/dL or oliguria; international normalized ratio Ͼ1.5 or transaminases Ͼ5 times normal or total bilirubin Ͼ3 mg/dL; and needing mechanical ventilation). Group I patients were placed on ECMO support; 7 underwent subsequent LVAD implant and 1 was bridged directly to transplant. Six patients in group I survived to transplant hospitalization discharge. The remaining 18 patients (group II) underwent LVAD implant without ECMO support; 12 survived to transplant hospitalization discharge and 2 remained alive with ongoing LVAD support and awaited transplant. One-year actuarial survival from the initiation of circulatory support was 43% in group I and 75% in group II. One-year actuarial survival from the time of LVAD implant in group I, conditional on surviving ECMO, was 71% (PϭNS compared with group II). Conclusions-In appropriately selected high-risk patients, the rate of LVAD survival after initial ECMO support was not significantly different from the survival rate after LVAD support alone. An initial period of resuscitation with ECMO is an effective strategy to salvage patients with extreme hemodynamic instability and multiorgan injury. Use of LVAD resources is improved by avoiding LVAD implant in a very-high-risk cohort of patients who do not survive ECMO. (Circulation. 1999;100[suppl II]:II-206 -II-210.)

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There was a significant association between transplant center volume and 1-year survival. Patients who undergo cardiac transplantation at very low-volume centers are at higher risk for early mortality than those who undergo transplantation in higher-volume centers.