Safety of bioelectrical impedance analysis in advanced heart failure patients.

BACKGROUND: Cardiac cachexia and frailty are major complications of advanced heart failure (AHF). Bioelectrical impedance analysis (BIA) may provide valuable information regarding fluid balance, muscle mass and prognosis. The main concerns regarding the use of BIA in AHF patients remain arrhythmias and electromagnetic interferences with cardiac implantable electronic devices (CIEDs). Reliable data regarding patients on continuous-flow ventricular assist device (cf-VAD) remain scarce. The aim of this study is to evaluate the safety of BIA in AHF patients on pro-arrhythmogenic therapy with an implanted CIED and/or with a cf-VAD. METHODS: We prospectively performed 217 BIA measurements in 143 AHF patients at risk of severe arrhythmias due to inotropic support/a history of ventricular arrhythmias and/or treated with CIED, including 104 patients with an ICD, CRT or pacemaker and 95 patients with a cf-VAD. All patients were under continuous Electrocardiogram (ECG) monitoring and clinical surveillance for 24 hours. RESULTS: No adverse events were observed during the 217 BIA measurements: No rhythm disturbances were documented in the telemetric monitoring during or within 30 minutes after the measurement. CIEDs showed no malfunction, regardless of the location measured or the device manufacturer. In particular, no inappropriate shocks were observed. No alarms, flow disturbances, or malfunctions of the cf-VAD occurred during or after the measurements. CONCLUSION: We consider BIA a safe measurement with major clinical relevance in our cohort of AHF patients, despite an increased arrhythmic potential on inotropic support or the presence of implanted electronic devices (ICD, CRT, pacemaker and cf-VAD).

Adjusting preoperative risk models of post heart transplant survival to a European cohort in the age of a new cardiac allocation score in Europe.

Background Several risk models target the issue of posttransplant survival, but none of them have been validated in a large European cohort. This aspect is important, in a time of the planned change of the Eurotransplant allocation system to a scoring system. Material and Methods Data of 761 heart transplant recipients from the Eurotransplant region with a total follow up of 5027 patient-years were analyzed. We assessed 30-day to 10-year freedom from graft failure. Existing post-transplant mortality risk models, IMPACT, Meld-XI and Columbia Risk Stratification Score were (RSS) were evaluated. A new risk model was created and the predictive accuracy was compared with the existing risk scores, with a focus on LVAD patients. Results Thirty-day, 1-year, 5-year and 10-year rates of freedom from graft failure were 78.3±1.5%, 68.8±1.71%, 59.1±1.8% and 44.1±1.9. The 1-year incidence of graft failure varied from 14.1% to 50% (RSS), from 22.9% to 57.1 (IMPACT) and from 24.9% to 42.6% using MELD-XI. Our newly adjusted risk score showed an improved area under the curve (AUC) of 0.69 (95% CI 0.64-0.72) with better discrimination in the intermediate to moderate risk cohort (CABDES Score). Conclusion IMPACT, Meld-XI and RSS were suitable to predict posttransplant graft failure only in a high and low risk cohort. CABDES Score, might be an alternative scoring system, with donor age and eGFR beeing the strongest predictors. Implementation of the IMPACT score within the new Eurotransplant Cardiac Allocation Score for patient prioritization for heart transplantation, should be reevaluated.

Effect of surgical incision management on wound infections in a poststernotomy patient population.

Skin breakdown and infiltration of skin flora are key causative elements in poststernotomy wound infections. We hypothesised that surgical incision management (SIM) using negative pressure wound therapy over closed surgical incisions for 6-7 days would reduce wound infections in a comprehensive poststernotomy patient population. 'All comers' undergoing median sternotomy at our institution were analysed prospectively from 1 September to 15 October 2013 (study group, n = 237) and retrospectively from January 2008 to December 2009 (historical control group, n = 3508). The study group had SIM (Prevena™ Therapy) placed immediately after skin suturing and applied at -125 mmHg for 6-7 days, whereas control group received conventional sterile wound tape dressings. Primary endpoint was wound infection within 30 days. Study group had a significantly lower infection rate than control group: 1·3% (3 patients) versus 3·4% (119 patients), respectively (P < 0·05; odds ratio 2·74). In the study group, when the foam dressing was removed after 6-7 days, the incision was primarily closed in 234 of 237 patients (98·7%). SIM over clean, closed incisions for the first 6-7 postoperative days significantly reduced the incidence of wound infection after median sternotomy. Based on these data SIM may be cost-effective in patients undergoing cardiac surgery.

Comparison of feasibility and results of frailty assessment methods prior to left ventricular assist device implantation.

AIMS: Assessing frailty and sarcopenia is considered a valuable cornerstone of perioperative risk stratification in advanced heart failure patients. The lack of an international consensus on a diagnostic standard impedes its implementation in the clinical routine. This study aimed to compare the feasibility and prognostic impact of different assessment tools in patients undergoing continuous-flow left ventricular assist device (cf-LVAD) implantation. METHODS AND RESULTS: We prospectively compared feasibility and prognostic values of six frailty/sarcopenia assessment methods in 94 patients prior to cf-LVAD implantation: bioelectrical impedance analysis (BIA), computed tomography (CT)-based measurement of two muscle areas/body surface area [erector spinae muscle (TMESA/BSA) and iliopsoas muscle (TPA/BSA)], physical performance tests [grip strength, 6 min walk test (6MWT)] and Rockwood Clinical Frailty Scale (RCFS). Six-month mortality and/or prolonged ventilation time >95 h was defined as the primary endpoint. BIA and CT showed full feasibility (100%); physical performance and RCFS was limited due to patients' clinical status (feasibility: 87% grip strength, 62% 6MWT, 88% RCFS). Phase angle derived by BIA showed the best results regarding the prognostic value for 6 month mortality and/or prolonged ventilation time >95 h (odds ratio (OR) 0.66 [95% confidence interval (CI): 0.46-0.92], P = 0.019; area under the curve (AUC) 0.65). It provided incremental value to the clinical risk assessment of EuroSCORE II: C-index of the combined model was 0.75 [95% CI; 0.651-0.848] compared with C-index of EuroSCORE II alone, which was 0.73 (95% CI: 0.633-0.835). Six-month survival was decreased in patients with reduced body cell mass derived by BIA or reduced muscle area in the CT scan compared with patients with normal values: body cell mass 65% (95% CI: 51.8-81.6%) vs. 83% (95% CI: 74.0-93.9%); P = 0.03, TMESA/BSA 65% (95% CI: 51.2-82.2%) vs. 82% (95% CI: 73.2-93.0%); P = 0.032 and TPA/BSA 66% (95% CI: 53.7-81.0%) vs. 85% (95% CI: 75.0-95.8%); P = 0.035. CONCLUSIONS: Bioelectrical impedance analysis parameters and CT measurements were shown to be suitable to predict 6-month mortality and/or prolonged ventilation time >95 h in patients with advanced heart failure prior to cf-LVAD implantation. Phase angle had the best predictive capacity and sarcopenia diagnosed by reduced body cell mass in BIA or muscle area in CT was associated with a decreased 6 month survival.

The effects of bilateral lung transplantation on ventilatory efficiency, oxygen uptake and the right heart: a two-yr follow-up.

BACKGROUND: This study was to examine the course of ventilation/perfusion mismatch (VE/VCO(2)-slope) before and during two-yr follow-up after bilateral lung transplantation (BLTx) and to relate exercise parameters with the reverse right ventricular remodeling. METHODS: We prospectively examined 20 patients (nine women; age 46.0 ± 13.0 yr) by cardiopulmonary exercise testing (before and at 3, 6, 12, and 24 months after BLTx), and by echocardiography and blood gas analysis. Etiology of pulmonary failure was chronic obstructive pulmonary disease as well (n = 8), pulmonary hypertension (n = 7), idiopathic fibrosis (n = 3), others (n = 2). RESULTS: The VE/VCO(2)-slope before BLTx was 47.5 (interquartile range 24.5) and declined at 3 months -25.9%, 6 months -30.9%, 12 months -33.9%, and 24 months -35.1% (all p ≤ 0.003) and was then not different from normal. The right ventricular end diastolic diameter RVEDd narrowed from 35.0 (22.5) before to 31.0 (9.0) mm at 3 months after LTx. Similarly, right ventricular systolic pressure (RV(sys)) decreased from 53.6 ± 28.3 to 26.2 ± 5.2 mmHg (all p < 0.01). RVEDd correlated with VE/VCO(2)-slope before (p < 0.0001) but not after BLTx. PeakVO(2) increased from 10.0 ± 2.3 mL/min per kg before BLTx by 86.5% at 24 months (p < 0.01). CONCLUSIONS: The functional status (VE/VCO(2)-slope, peakVO(2)) improves quickly after lung transplantation and is accompanied by reverse remodeling of the right heart. A correlation between exercise parameters and right heart function was found before BLTx only.

Impact of Muscle Mass as a Prognostic Factor for Failed Waiting Time Prior to Heart Transplantation.

Objectives: Clinical deterioration during the waiting time impairs the prognosis of patients listed for heart transplantation. Reduced muscle mass increases the risk for mortality after cardiac surgery, but its impact on resilience against deterioration during the waiting time remains unclear. Methods: We retrospectively analyzed data from 93 patients without a VAD who were listed in Eurotransplant status "high urgent (HU)" for heart transplantation between January 2015 and October 2020. The axial muscle area of the erector spinae muscles at the level of thoracic vertebra 12 indexed to body surface area (TMESA/BSA) measured in the preoperative thoracic computed tomography scan was used to measure muscle mass. Results: Forty patients (43%) underwent emergency VAD implantation during the waiting time and four patients (4%) died during the waiting time. The risk of emergency VAD implantation/death during the waiting time decreased by 10% for every cm2/m2 increase in muscle area [OR 0.901 (95% CI: 0.808-0.996); p = 0.049]. After adjusting for gender [OR 0.318 (95% CI: 0.087-1.073); p = 0.072], mean pulmonary artery pressure [OR 1.061 (95% CI: 0.999-1.131); p = 0.060], C-reactive protein [OR 1.352 (95% CI: 0.986-2.027); p = 0.096], and hemoglobin [OR 0.862 (95% CI: 0.618-1.177); p = 0.360], TMESA/BSA [OR 0.815 (95% CI: 0.698-0.936); p = 0.006] remained an independent risk factor for emergency VAD implantation/death during the HU waiting time. Conclusion: Muscle area of the erector spinae muscle appears to be a potential, easily identifiable risk factor for emergency VAD implantation or death in patients on the HU waiting list for heart transplantation. Identifying patients at risk could help optimize the outcome and the timing of VAD support.

Plasmid-Mediated Transmission of KPC-2 Carbapenemase in Enterobacteriaceae in Critically Ill Patients.

Carbapenem-resistant Enterobacteriaceae (CRE) cause health care-associated infections worldwide, and they are of severe concern due to limited treatment options. We report an outbreak of KPC-2-producing CRE that was caused by horizontal transmission of a promiscuous plasmid across different genera of bacteria and hospitals in Germany. Eleven isolates (8 Citrobacter freundii, 2 Klebsiella oxytoca, and 1 Escherichia coli) were obtained from seven critically ill patients during the six months of the outbreak in 2016. One patient developed a CRE infection while the other six patients were CRE-colonized. Three patients died in the course of the hospital stay. Six of the seven patients carried the same C. freundii clone; one K. oxytoca clone was found in two patients, and one patient carried E. coli and C. freundii. Molecular analysis confirmed the presence of a conjugative, bla KPC-2-carrying 70 kb-IncN plasmid in C. freundii and E. coli and an 80 kb-IncN plasmid in K. oxytoca. All transconjugants harbored either the 70 or 80 kb plasmid with bla KPC-2, embedded within transposon variant Tn4401g. Whole genome sequencing and downstream bioinformatics analyses of all plasmid sequences showed an almost perfect match when compared to a bla KPC-2-carrying plasmid of a large outbreak in another German hospital two years earlier. Differences in plasmid sizes and open reading frames point to the presence of inserted mobile genetic elements. There are few outbreak reports worldwide on the transmission of bla KPC-2-carrying plasmids across different bacterial genera. Our data suggest a regional and supraregional spread of bla KPC-2-carrying IncN-plasmids harboring the Tn4401g isoform in Germany.

Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients.

BACKGROUND: Everolimus, a novel proliferation inhibitor and immunosuppressive agent, may suppress cardiac-allograft vasculopathy. We conducted a randomized, double-blind, clinical trial comparing everolimus with azathioprine in recipients of a first heart transplant. METHODS: A total of 634 patients were randomly assigned to receive 1.5 mg of everolimus per day (209 patients), 3.0 mg of everolimus per day (211 patients), or 1.0 to 3.0 mg of azathioprine per kilogram of body weight per day (214 patients), in combination with cyclosporine, corticosteroids, and statins. The primary efficacy end point was a composite of death, graft loss or retransplantation, loss to follow-up, biopsy-proved acute rejection of grade 3A, or rejection with hemodynamic compromise. RESULTS: At six months, the percentage of patients who had reached the primary efficacy end point was significantly smaller in the group given 3.0 mg of everolimus (27.0 percent, P<0.001) and the group given 1.5 mg of everolimus (36.4 percent, P=0.03) than in the azathioprine group (46.7 percent). Intravascular ultrasonography showed that the average increase in maximal intimal thickness 12 months after transplantation was significantly smaller in the two everolimus groups than in the azathioprine group. The incidence of vasculopathy was also significantly lower in the 1.5-mg group (35.7 percent, P=0.045) and the 3.0-mg group (30.4 percent, P=0.01) than in the azathioprine group (52.8 percent). The rates of cytomegalovirus infection were significantly lower in the 1.5-mg group (7.7 percent, P<0.001) and the 3.0-mg group (7.6 percent, P<0.001) than in the azathioprine group (21.5 percent). Rates of bacterial infection were significantly higher in the 3.0-mg group than in the azathioprine group. Serum creatinine levels were also significantly higher in the two everolimus groups than in the azathioprine group. CONCLUSIONS: Everolimus was more efficacious than azathioprine in reducing the severity and incidence of cardiac-allograft vasculopathy, suggesting that everolimus therapy may alleviate this serious problem.

Salvage chemotherapy for refractory and relapsed posttransplant lymphoproliferative disorders (PTLD) after treatment with single-agent rituximab.

BACKGROUND: Single-agent rituximab has demonstrated encouraging efficacy and tolerability in posttransplant lymphoproliferative disorders (PTLDs) failing to respond to immunosuppression reduction (IR). This retrospective analysis was undertaken to determine the efficacy and safety of salvage therapy in recipients of solid organ transplants with progression of PTLD after rituximab first-line therapy. METHODS: Eleven patients who had received IR and single-agent rituximab were analyzed. Of these, 10 had received CHOP salvage chemotherapy. One patient with limited disease received tumor irradiation and further IR. Most patients (73%) had late PTLD (median onset of disease 145 months posttransplant), and most (83%) had monomorphic histology; 36% had EBV-association. RESULTS: IR and irradiation therapy re-induced complete remission (CR) and allowed long-term disease control in a patient with polymorphic PTLD relapse. CHOP therapy achieved CR in five (50%) and partial remission (PR) in two (20%) patients. Four of five (80%) patients achieving CR remained in CR at a median follow-up of 44.2 months. Of the patients achieving PR, one is currently alive, and the second died from transplant rejection after converting to CR after consolidative chemotherapy. Patients with stable disease (two) and progressive disease (one) have died from PTLD. There was one possible CHOP-associated death (acute cardiac event) and two patients had to be switched to less-toxic monotherapies. Median overall survival was 46.5 months (95% confidence interval: 23.6-49.1 months). CONCLUSIONS: CHOP salvage therapy achieved a favorable overall response rate of 70% in this setting, indicating that PTLD generally remains chemotherapy-sensitive after progression following first-line rituximab.

A lower incidence of cytomegalovirus infection in de novo heart transplant recipients randomized to everolimus.

BACKGROUND: Cytomegalovirus (CMV) infection in recipients of cardiac transplants is associated with higher rates of morbidity. A recent phase III trial showed highly significantly (P<0.001) lower CMV rates with the proliferation signal inhibitor everolimus compared to azathioprine (AZA). To better define this association, data on CMV risk factors were collected retrospectively and analyzed. METHODS: Data on CMV risk factors from a multicenter phase III trial on de novo heart transplant recipients (n=634) receiving a triple immunosuppressive regimen randomized to everolimus 1.5 mg/day (group 1), everolimus 3 mg/day (group 2), or AZA (group 3) were merged with prospectively collected CMV-related outcome data and analyzed. RESULTS: CMV-positive donors (D+) and CMV-negative recipients (R-) were evenly distributed across groups 1-3 at 36/209 (17.2%), 48/211 (22.7%), and 38/214 (17.8%), respectively. CMV prophylaxis had been given for a mean (SD) of 175 (127.8), 183 (137.1), and 177 (132.9) days, respectively. In the high-risk D+/R- subgroup with prophylaxis, the proportions of patients with CMV infection compared with group 3 (12/29 [41.4%]) were 3/25 (12.0%) in group 1 (P=0.031) and 6/36 (16.7%) in group 2 (P=0.049). In D+/R+ subgroups either with or without prophylaxis, the everolimus groups had less CMV disease (P<0.001). The incidence of CMV syndrome, organ involvement, and laboratory evidence was lower with everolimus use compared to AZA. CONCLUSIONS: Everolimus is associated with lower rates of CMV infection, syndrome, or organ involvement, suggesting an additional advantage from the use of everolimus in cardiac transplant recipients.

Changes in exercise capacity, ventilation, and body weight following heart transplantation.

AIMS: Peak oxygen uptake adjusted to body weight (peak VO(2)) and ventilatory efficiency (VE/VCO(2)-slope) are important prognostic parameters in chronic heart failure. Our study prospectively examined changes in these parameters over 24 months following heart transplantation (HTx) and evaluated the potentially confounding effects of weight gain. METHODS AND RESULTS: One hundred patients with chronic heart failure (16 female, mean age at HTx 53.9+/-9.6 years) underwent cardiopulmonary exercise testing before and 3, 6, 12 and/or 24 months after HTx. Twenty-five healthy individuals served as matched normals. VE/VCO(2)-slope during exercise improved significantly at 6 (-23.7%), 12 (-21.3%), and 24 months (-32.3%; all p<0.002 vs. baseline). At 6 months, VE/VCO(2)-slopes were similar to the matched normals (31.8+/-4.3), 46 of 78 patients achieved values within the 95% confidence interval of normal. Peak VO(2) increased significantly after HTx at 6 (+31.8%), 12 (+36.2%), and 24 months (+42.2%; all p<0.005). None of the patients reached values within the 95% CI of normal. Although VE/VCO(2)-slope and peak VO(2) were correlated inversely at every time point (p<0.03), reduction in VE/VCO(2)-slope did not correlate with increase in peak VO(2). Symptoms that limited exercise changed from dyspnoea before HTx to leg fatigue after HTx. CONCLUSION: Following HTX, VE/VCO(2)-slope returns to normal values in the majority of patients; however, despite improvement, peak VO(2) remains abnormal in all patients. Symptoms causing patients to stop exercising change from dyspnoea to leg fatigue.

Prevalence of CCR5Delta32 polymorphism in long-term survivors of heart transplantation.

BACKGROUND: CC chemokine receptor 5 (CCR5) contributes to the alloimmune response following solid organ transplantation. In individuals homozygous for the CCR5Delta32 mutation, the receptor is inactive and lymphocyte recruitment and leukocyte trafficking during rejection are inhibited. A significant improvement in graft survival following renal transplantation has been observed in homozygous CCR5Delta32 patients, although conflicting data exist. To determine whether CCR5Delta32 homozygous heart transplant recipients may also benefit compared to those with a normally functioning CCR receptor, the proportion of patients with CCR5Delta32 mutation was examined in a large cohort of patients surviving for a long period after heart transplantation. METHODS: The prevalence of CCR5 genotype was identified in patients who had survived >or=7 years after heart transplantation. Genotyping was performed centrally by polymerase chain reaction (PCR). RESULTS: A total of 555 patients were recruited at three heart transplant centers in Germany. Of these, 442 patients (79.6%) were homozygous for the wild-type allele, 106 (19.1%) were heterozygous for CCR5Delta32 and 7 (1.3%) were homozygous for CCR5Delta32. No statistically significantly differences were observed between the incidence of CCR5Delta32 homozygosity in the study population and the estimated incidence in the normal population. CONCLUSIONS: In the absence of a control arm, it cannot be established if homozygous carriers of the CCR5Delta32 allele experience a long-term survival benefit following heart transplantation that may be masked by underrepresentation of the CCR5Delta32 allele in recipients of a heart transplant. To answer this question, the prevalence of CCR5Delta32 homozygosity needs to be established in patients awaiting heart transplantation.

Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing.

BACKGROUND: Primary pulmonary hypertension (PPH) is a life-threatening disease. Prognostic assessment is an important factor in determining medical treatment and lung transplantation. Whether cardiopulmonary exercise testing data predict survival has not been reported previously. METHODS AND RESULTS: We studied 86 patients with PPH (58 female, age 46+/-2 years, median NYHA class III) between 1996 and 2001 who were followed up in a tertiary referral center. Right heart catheterization was performed and serum uric acid levels were measured in all patients. Seventy patients were able to undergo exercise testing. At the start of the study, the average pulmonary artery pressure was 60+/-2 mm Hg, average pulmonary vascular resistance was 1664+/-81 dyne x s x cm(-5), average serum uric acid level was 7.5+/-0.35 mg/dL, and average peak oxygen uptake during exercise (peak VO(2) was 11.2+/-0.5 mL x kg(-1) x min(-1). During follow-up (mean: 567+/-48 days), 28 patients died and 16 underwent lung transplantation (1-year cumulative event-free survival: 68%; 95% CI 58 to 78). The strongest predictors of impaired survival were low peak VO(2) (P<0.0001) and low systolic blood pressure at peak exercise (peak SBP; P<0.0001). In a multivariable analysis, serum uric acid levels (all P<0.005) and diastolic blood pressure at peak exercise independently predicted survival (P<0.05). Patients with peak VO(2) < or =10.4 mL x kg(-1) x min(-1) and peak SBP < or =120 mm Hg (ie, 2 risk factors) had poor survival rates at 12 months (23%), whereas patients with 1 or none of these risk factors had better survival rates (79% and 97%, respectively). CONCLUSIONS: Peak VO(2) and peak SBP are independent and strong predictors of survival in PPH patients. Hemodynamic parameters, although also accurate predictors, provide no independent prognostic information.

Recommendations for use of Certican (everolimus) after heart transplantation: results from a German and Austrian Consensus Conference.

The Certican Consensus Conference has produced guidelines to help physicians apply Certican (everolimus) clinical trial data in clinical practice. Everolimus is indicated in combination with cyclosporine microemulsion (CsA; Neoral) and corticosteroids for prophylaxis of acute rejection after heart transplantation. It has also shown efficacy for prevention of cardiac allograft vasculopathy. Further indications for use pertain to patients with chronic renal failure, to allow reduced calcineurin inhibitor (CNI) exposure; reduce the risk of cytomegalovirus to disease; second transplantation; heart/lung transplantation after occurrence of bronchiolitis obliterans; and in patients with malignancies under immunosuppression. Contraindications include intolerance, severe leukocytopenia and severe thrombocytopenia. The everolimus dose is 0.75 or 1.5 mg twice daily, adjusted according to trough blood levels. Target blood levels are 3 to 8 ng/ml, with 6 to 8 ng/ml considered the optimal range for most patients. Recommended CsA trough blood levels in patients receiving everolimus are 150 to 175 ng/ml for Months 1 to 3 post-transplant, around 135 ng/ml for Months 3 to 6, and <100 ng/ml after Month 6. It may be possible to discontinue steroids in patients receiving long-term everolimus and CsA. Early cytomegalovirus prophylaxis is recommended for patients with a high-risk mismatch, and trimethoprim-sulfamethoxazole should be given to prevent Pneumocystis carinii. Everolimus dose should be reduced by about 50% if administered in conjunction with azoles or erythromycin, and increased 100% to 200% if given with rifampicin. All heart transplant recipients should receive statins unless contraindicated.

Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients.

BACKGROUND: This study reports the 36-month results of a randomized, double-blind, active-controlled trial of mycophenolate mofetil (MMF) vs azathioprine (AZA) in heart transplant patients. METHODS: Patients were randomized at the time of transplant to receive MMF (1,500 mg twice a day, N = 327) or AZA (1.5 to 3 mg/kg in 4 daily doses, N = 323) in addition to cyclosporine and corticosteroids; 289 patients in each group received study drug. Data were analyzed in all randomized patients (enrolled) and in patients who received study medications (treated). Clinical and graft assessments continued for 36 months. RESULTS: For the co-primary end-point, 53 of 289 (18.3%) AZA-treated patients either died or received another transplant compared with 34 of 289 (11.8%) MMF-treated patients (p < 0.01). Time to re-transplantation or patient death was significantly shorter for AZA- than MMF-treated patients (p = 0.029). In patients undergoing intravascular ultrasound, the change in mean maximal intimal thickness was less for the MMF group than for the AZA group (0.06 +/- 0.03 mm vs 0.13 +/- 0.03 mm, respectively; p = 0.056). No significant differences between treatments were observed in quantitative coronary angiographic measurements of transplant coronary vasculopathy. Congestive heart failure, atrial arrhythmia and leukopenia were more common in the AZA group, whereas diarrhea, esophagitis, Herpes simplex, Herpes zoster and cytomegalovirus (CMV) tissue invasion were more common in MMF-treated patients. CONCLUSION: MMF reduces mortality and graft loss up to 36 months after transplantation.

The heart-allocation simulation model: a tool for comparison of transplantation allocation policies.

BACKGROUND: Numerous studies have investigated prognostic factors for the survival of transplant candidates waiting for a donor organ, but little is known about the impact of allocation policies on waiting list outcome. Simulation models would allow a comparison of different policies for allocating donor hearts on pretransplant outcome. METHODS: A model was built for the Eurotransplant waiting list for heart transplantation. Survival and delisting distributions were estimated from the Eurotransplant transplant candidate inflow between 1995 and 2000 (n=7,142). Other characteristics were obtained directly from the transplant candidate inflow of 1999 and 2000 (n=2,097) and the donor organs of 1998 and 1999 (n=1,520). Overall and subgroup waiting list mortality were estimated for allocation policies differing by ABO blood group, border, and clinical profile rules. RESULTS: The model estimated that international organ exchange reduces waiting list mortality in the different countries by 1.9% to 12.4%. An allocation policy incorporating the initial clinical profile of the transplant candidates further reduced waiting list mortality by 1.7%. Changing ABO rules toward identical matching yielded a slightly more equitable survival for the different groups, without an overall effect on mortality. The best possible allocation policy is the policy where organs are allocated to patients that are at highest risk of dying, and withholding organs from patients that would eventually delist because of improvement. CONCLUSIONS: Patients benefit from international organ exchange and by a heart allocation scheme based on clinical profiles. Timely delisting of patients who are-temporarily-too well for transplantation is the best waiting list policy.

A prognostic model for predicting waiting-list mortality for a total national cohort of adult heart-transplant candidates.

BACKGROUND: Current trends in medical management of advanced heart failure and transplant medicine and the enactment of a national transplant law forced a change toward allocation driven by disease severity. OBJECTIVE: The aim of this study was to create a model for predicting waiting-list survival on the basis of simple clinical parameters. METHODS: The clinical profiles of all patients registered for heart transplantation in Germany in 1997 (n=889) were used as a derivation set, and the total German 1998 cohort (n=897) was used as a validation set. The model was validated by the c statistic and by comparison of risk stratified mortality rates. The validated model was fine tuned by the appropriate calibration procedures. The data were first classified into physiologic subscores: an urgency score, a left ventricular heart failure score, a right ventricular heart failure score, and a systemic heart failure score. A stepwise modeling procedure was undertaken using these subscores as factors as well as the recipient's age, ABO blood group, and body surface area. RESULTS: The urgency and the left ventricular subscore were found to be significantly associated with waiting-list mortality. A summary index termed German Transplant Society (GTS) score was then calculated on the basis of seven parameters contained in these two subscores. The GTS score was able to predict waiting-list mortality risks for the 1998 cohort: 1-year mortality before transplantation was 71%, 34%, 11% for the high, medium, and low risk groups, respectively. CONCLUSION: The use of this continuous disease severity index may improve the selection of cardiac transplant candidates.

Coronary artery calcium scoring: diagnostic accuracy of different software implementations.

PURPOSE: To compare the diagnostic power of different software implementations for the quantification of coronary artery calcium. MATERIALS AND METHODS: Electron beam computed tomography was performed in 109 heart transplant recipients at the same time as catheter coronary angiography and intracoronary ultrasound. Electron beam computed tomography images were analyzed by 3 software packages marketed for the quantification of coronary calcifications using the same software settings, and the resultant calcium scores correlated with the invasive reference methods by Bland-Altman plots and analysis of the receiver operating characteristics. RESULTS: Although all scoring systems displayed close correlations upon regression analysis (r2=0.94-0.99), their ability to detect disease as per the invasive reference method varied significantly in some instances. The area under the ROC curve varied between Az=0.78 and 0.85 for the detection of coronary artery stenosis upon coronary angiography (P=0.05-0.13), and between Az=0.75 and 0.83 for the detection of accelerated intimal proliferation (P=0.03-0.18). CONCLUSIONS: Different software implementations for the quantification of coronary artery calcium load may display diagnostically relevant differences in spite of close direct correlation.

Donor-transmitted coronary atherosclerosis.

BACKGROUND: Autopsies show that coronary atherosclerosis is present frequently in the young and healthy. However, according to our former guideline, we performed pre-transplant evaluation without coronary angiogram in donors <60 years. The purpose of this study is to evaluate to what extent native coronary atherosclerosis is transmitted through heart transplantation. METHODS: Between April 1986 and December 2000, a total of 1253 patients underwent heart transplantation at our institution. If coronary evaluation with coronary angiogram or autopsy had been performed within 6 months after transplantation, we regarded focal and non-circumferential atherosclerosis with >or=50% stenosis in proximal segments of at least 1 coronary vessel of the donor heart as transmitted, native coronary atherosclerosis, rather than newly developed transplant vasculopathy. RESULTS: We excluded 85 of 1253 (6.8%) cases because coronary evaluation was not performed within 6 months (n = 45) or because hearts underwent angiography during pre-transplant evaluation (n = 40). Of these, 2 patients with significant coronary atherosclerosis underwent transplantation and concurrent coronary artery bypass grafting. The prevalence of significant (stenosis >or=50%) and inadvertently transmitted coronary atherosclerosis was 7.0% (82/1168). CONCLUSION: The prevalence of coronary atherosclerosis in patients who underwent angiography within 6 months after transplantation was 5.2% (49/950). Among subjects who had autopsies within the first 6 months after heart transplantation, we found significant coronary atherosclerosis (stenosis >or=50%) 15.1% (33/218), and among those with early graft failure (<10 days after transplantation), the prevalence was 22.8% (26/114). The prevalence of coronary atherosclerosis in the donor pool is high, and donor screening without coronary angiogram overlooks significant coronary atherosclerotic lesions (stenosis >or=50%) in a considerable number of cases (7.0%). Because donor-transmitted coronary atherosclerosis is a risk factor in short-term (early graft failure) survival after heart transplantation, we have now changed our policy to include coronary angiography as a standard in screening donors >or=40 years. However, to what extent donor coronary atherosclerosis is accepted undoubtedly must be made arbitrarily until an evidence-based algorithm becomes available.

Early detection of left ventricular dysfunction related to transplant coronary artery disease.

BACKGROUND: Transplant coronary artery disease (TxCAD) is a major limitation to the long-term success of cardiac transplantation. We assessed left ventricular (LV) function in relation to severity of coronary lesions to improve both early diagnosis of TxCAD and evaluation of the severity of myocardial damage. METHODS: Echocardiographic evaluation of LV function, including pulsed-wave tissue Doppler imaging (PW-TDI) wall motion analysis, was performed in 304 heart recipients before each of their follow-up cardiac catheterizations. LV systolic and diastolic parameters obtained both invasively and non-invasively were tested for their relation to angiographic and intravascular ultrasound (IVUS) findings. RESULTS: LV end-diastolic pressure and most of the PW-TDI parameters differed significantly (p < 0.001) between patients with and without TxCAD. In comparison to patients without the disease, even those with moderate, angiographically non-visible TxCAD showed significant differences for all systolic PW-TDI parameters. Wall motion alterations during angiographic TxCAD were almost always global and related mainly to diffuse Type B lesions. Systolic PW-TDI parameter changes showed highly predictive values for TxCAD. At systolic wall motion peak velocity (Sm) values constantly <10 cm/sec, we found a 97.37% likelihood of TxCAD (angiographically and/or IVUS-visible), whereas Sm values of > or =11 cm/sec excluded angiographic TxCAD with 90.41% probability. CONCLUSIONS: Among all parameters investigated for the evaluation of allograft LV function, PW-TDI systolic parameters were of the greatest diagnostic value. Wall motion assessment allows early detection of myocardial dysfunction and provides information on both local and global LV dysfunction linked to TxCAD, with potential usefulness for both timing of cardiac catheterizations and prognostic evaluation.