Conversion to sirolimus with calcineurin inhibitor elimination vs. dose minimization and renal outcome in heart and lung transplant recipients.

Sirolimus (SRL) has been used as an alternative immunosuppressant strategy to allow either dose minimization or complete withdrawal of calcineurin inhibitors (CNI) therapy to improve renal outcome. One hundred thirty-one heart and 55 lung transplant patients were converted from a CNI to SRL based immunosuppression, with CNI elimination in 25 patients, and dose reduction in 161 patients. Fifty-six (28%) patients died and 65 (33%) patients had a 25% or more decline in estimated glomerular filtration rate (eGFR) during a median follow-up of 18 months. The three groups (SRL only group n = 25; SRL + tacrolimus n = 94; SRL + cyclosporine n = 67) had an initial improvement in estimated glomerular filtration rate (p = 0.05), with subsequent similar slow decline in mean eGFR (repeated measures ANOVA, p = 0.96). After controlling for important potential confounding variables, the three groups had similar renal outcome (p = 0.40) and overall survival (p = 0.45). In conclusion, the benefits of CNI withdrawal vs. minimization as part of SRL-based regimens are similar with regard to renal outcomes and patient survival.

Attrition from heart transplant waiting list for patients on ventricular assist devices is not affected by desensitization strategies.

BACKGROUND: Ventricular assist device (VAD) patients, who are commonly sensitized, can be successfully transplanted using strategies aimed at diminishing antibody burden. However, the impact of these therapies on outcomes for VAD patients on the waiting list is ill-defined. The following study was conducted to ascertain the relationship between desensitization therapies and attrition rate from the waiting list for VAD patients. METHODS: The VAD patients listed between July 1996 and June 2002 were used for this report. Transplant and inpatient pharmacy databases were queried for demographics, date of transplantation, degree of allosensitization, use of desensitization therapy, immunosuppressive strategies, and specific causes of death. RESULTS: Among 232 patients listed for heart transplantation who required bridging to transplantation with a VAD, 79 (34%) died while on the waiting list. Common causes of death included multisystem organ failure in 32 (40.5%), sepsis in 19 (24.0%), and stroke in 10 (12.6%) patients. While nearly 50% of these patients were sensitized at listing, only 5 (6.3%) patients received desensitization therapy following VAD implantation. Therapies included mycophenolate mofetil in 3 (3.7%) and IVIG in 2 (2.5%) patients. Not a single patient underwent plasmapheresis or OKT3 therapy. CONCLUSION: For patients bridged to heart transplantation with a VAD, attrition from the waiting list was associated with factors other than desensitization or induction regimens.

Exercise intolerance in chronic heart failure is not associated with impaired recovery of muscle function or submaximal exercise performance.

OBJECTIVES: This study investigated whether recovery of skeletal muscle function is impaired in patients with heart failure and whether impaired recovery is associated with abnormal submaximal systemic exercise tolerance during repeated testing. BACKGROUND: Patients with heart failure experience fatigue during daily activities. Because abnormalities of skeletal muscle play a role in their exercise intolerance, these symptoms may reflect a delay in muscle recovery and a resulting limitation in submaximal exercise tolerance. METHODS: Two protocols were used. In protocol 1, knee extensor strength and endurance, and their recovery after fatiguing exercise, were evaluated in 11 patients (mean [+/- SEM] age 62 +/- 5 years, New York Heart Association functional class 2.3 +/- 0.2, ejection fraction 24 +/- 5%) and in 10 age-matched sedentary control subjects. Protocol 2 examined the recovery of knee extensor endurance and submaximal exercise tolerance, as quantified on a self-powered treadmill, over 24 h in 18 patients (mean age 65 +/- 3 years, functional class 2.4 +/- 0.2, ejection fraction 23 +/- 3%) and in 10 control subjects. RESULTS: Peak oxygen consumption was reduced in both heart failure groups (15.4 +/- 1.4 and 15.6 +/- 1.0 ml/kg per min) compared with that in the respective control groups (23.1 +/- 2.9 and 25.6 +/- 1.0 ml/kg per min, both p < 0.05), as was muscle endurance but not muscle strength. In protocol 1, knee extensor endurance recovered more slowly in the patients than in control subjects (to 62 +/- 4% and 87 +/- 7% of the baseline value after 5 min, respectively, p < 0.05). In protocol 2, submaximal exercise tolerance was lower in the patients with heart failure than in control subjects (1,075 +/- 116 vs. 1,390 +/- 110 m), but knee extensor endurance and walking distance recovered fully by 10 and 30 min, respectively. CONCLUSIONS: Although these findings confirm earlier studies that demonstrated impaired muscle endurance in patients with heart failure, the results provide no evidence that recovery of either muscle function or submaximal exercise tolerance is delayed beyond the initial 5 to 10 min after exercise.

Survival beyond 10 years following heart transplantation: The Cleveland Clinic Foundation experience.

BACKGROUND: Long-term survival after heart transplantation is a desirable although challenging goal. METHODS: We analyzed clinical outcomes in the cohort of 170 patients who have undergone heart transplantation at The Cleveland Clinic Foundation and survived >10 years. RESULTS: We found 10-year and 15-year survival rates of 54% and 41%, respectively, in these patients, but there was also a high incidence of complications, such as hypertension, renal dysfunction, transplant vasculopathy, and malignancy. CONCLUSIONS: Long-term survival following cardiac transplantation is possible although complications are frequent. Beyond 10 years, malignancy is a major cause of death.

Comparison of dobutamine-based and milrinone-based therapy for advanced decompensated congestive heart failure: Hemodynamic efficacy, clinical outcome, and economic impact.

BACKGROUND: The use of parenteral positive inotropic agents still remains a major component of therapy for patients with advanced decompensated congestive heart failure (CHF). However, no consensus guidelines have been developed for the appropriate selection of a first-line inotropic therapy. We sought to compare the clinical outcome and economic cost of dobutamine-based and milrinone-based therapy in patients with acute exacerbation of CHF. METHODS AND RESULTS: We retrospectively analyzed the outcome of 329 patients admitted to the heart failure unit with acute exacerbation of CHF. More patients were treated with dobutamine-based therapy (269/329, 81.7%) than with milrinone-based therapy (60/329, 18.3%). Both groups had similar baseline characteristics and similar hemodynamic profiles at baseline, with the exception of higher mean pulmonary arterial pressure in the milrinone group (47 mm Hg vs 42 mm Hg, P <.001). One hundred nine patients (40%) of the dobutamine group required parenteral nitroprusside for hemodynamic optimization compared with 11 patients (18%) in the milrinone group (P <.001). The use of parenteral nitroglycerin and dopamine was similar in both groups. There was no significant difference in the in-hospital mortality rate (dobutamine 7.8% vs milrinone 10%) or clinical outcome between the 2 groups. However, the average direct drug cost per patient was significantly reduced in the dobutamine group compared with the milrinone group ($45 +/- $10 vs $1855 +/- $350, P <.0001). CONCLUSION: Dobutamine-based therapy is an attractive approach for the treatment of decompensated advanced heart failure, achieving comparable clinical efficacy to milrinone with a significantly reduced economic cost.

The impact of routine mycophenolate mofetil drug monitoring on the treatment of cardiac allograft rejection.

INTRODUCTION: Mycophenolate mofetil (MMF) is a unique immunosupressive agent that has been shown to be efficacious in the treatment of cardiac allograft rejection. The utility of therapeutic drug monitoring on rejection prophylaxis and treatment is inconclusive. This study was undertaken to evaluate the incidence of rejection in relation to MMF trough level following heart transplantation. METHODS: Between May 1998 and February 1999, we retrospectively analyzed the clinical outcome of 215 heart transplant patients who had routine monitoring of MMF trough level at the time of scheduled endomyocardial biopsy. Patients were divided into three groups according to the time interval post transplant, and were evaluated in relation to the MMF trough level. Group I, 104 patients within 6 months of transplant; Group II, 90 patients, 6-12 months post transplant; and Group III, 71 patients beyond one year of transplant. Fifty patients had samples in more than one group. Rejection was defined as Grade > or = 3A based on ISHLT criteria. Mean follow-up period was 179+/-52 days. RESULTS: A significantly decreased incidence of rejection was noted in the samples with MMF trough level > or = mg/l compared to those with less than 2 mg/l inpatients evaluated within the first year of transplant (Group I: 8.8% vs. 14.9%, Group II: 4.2% vs. 11.3%, both P=0.05). In the presence of therapeutic cyclosporine (CSA) or tacrolimus (FK) blood levels, the incidence of rejection decreased significantly when MMF trough level was > or = 2 mg/l compared to samples with MMF trough level <2 mg/l (3.6% vs. 14.4%, P=0.005). No significant difference was noted in the presence of subtherapeutic CSA or FK levels (15.4% vs. 13.9%, P=NS). CONCLUSIONS: Monitoring of MMF trough levels may play a role in the management of cardiac transplant recipients during the first year post transplant.

Relation of the nine-minute self-powered treadmill test to maximal exercise capacity and skeletal muscle function in patients with congestive heart failure.

The 9-minute self-powered treadmill test has been employed to evaluate submaximal exercise capacity in heart failure patients, but its relation to maximal exercise capacity and to indexes of skeletal muscle function has not been well defined. Two protocols were utilized. The first evaluated the relation of the peak oxygen uptake (VO2) achieved on the self-powered treadmill to that during a symptom-limited treadmill protocol, and examined the reproducibility of this test. Thirteen patients (aged 62 +/- 2 years, in New York Heart Association class I to III [2.3 +/- 0.1], ejection fraction 23 +/- 2% [means +/- SEM]) and 10 age-matched sedentary controls were studied. The second protocol, which involved 18 patients (aged 65 +/- 2 years, in New York Heart Association class I to IV [2.4 +/- 0.1], ejection fraction 23 +/- 2%) and 10 age-matched controls evaluated the relation of performance on the self-powered treadmill to maximal systemic exercise capacity on a cycle ergometer and to indexes of skeletal muscle function. In the first protocol, the test was found to be highly reproducible. The proportion of self-powered treadmill to maximal treadmill peak VO2 did not differ significantly between patients and controls (95 +/- 5% vs 87 +/- 6%). In the second protocol, patients achieved a lower peak VO2 (15.6 +/- 1.1 vs 25.6 +/- 0.9 ml/kg/min, p < 0.001), walked a shorter distance on the self-powered treadmill (367 +/- 32 vs 667 +/- 28 m, p < 0.001), and exhibited less knee extensor work capacity (1,075 +/- 116 vs 1,390 +/- 110 ft-lbs, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of tacrolimus in patients with steroid-resistant cardiac allograft cellular rejection.

BACKGROUND: Tacrolimus is an immunosuppressive agent that is gaining widespread use in solid organ transplantation. This study was undertaken to evaluate the efficacy of tacrolimus in treating steroid-resistant cellular myocardial rejection. METHODS: We retrospectively analyzed the incidence of rejection and clinical outcome of 21 heart transplant recipients who were electively converted from cyclosporine to tacrolimus for recurrent episodes of steroid-resistant cellular rejection. These were compared to a historic group of 6 hemodynamically stable patients who were treated electively with Orthoclone OKT3 (Muromonab/CD3) for recurrent rejection. RESULTS: Eighty five percent (56/66) of the episodes of rejection occurred within the first 3 months after heart transplantation. Tacrolimus was started 2. 4 +/- 2.0 months post-transplant, and the mean follow-up duration on tacrolimus was 11.0 +/- 7.0 months. After conversion, a significant decline was noted in both the number of episodes of acute rejection per patient (3.14 +/- 0.85-0.57 +/- 0.87, p < 0.0001), and the incidence of acute rejection per 100 patient-days (6.39 +/- 3.96-0. 25 +/- 0.47, p < 0.0001). In comparison, OKT3 was started 5.25 +/- 9. 20 months post-transplant. Similarly, there was a significant decrease in the incidence of acute rejection per 100 patient-days (8. 69 +/- 5.65-0.20 +/- 0.23, p < 0.0001). The average hospital charges per patient for the OKT3-treated group was $33,339 +/- $10,511. There was no significant difference in the actuarial 1-year survival between the tacrolimus and OKT3-treated groups (93% vs 80%, p = 0.5). CONCLUSIONS: Outpatient conversion to tacrolimus is safe, well tolerated, and an effective therapeutic strategy for the treatment of steroid-resistant cellular rejection in heart transplant recipients. It is more cost-effective than OKT3 in the hemodynamically stable patient and outcomes are similar.

Fluorescence spectroscopy of endomyocardial tissue post-human heart transplantation: does it correlate with histopathology?

BACKGROUND: A significant correlation between autofluorescence spectroscopy and heart allograft rejection has been described in the rat heterotropic allograft model. However, the use of this technique in human heart transplants has not been validate. METHODS: We obtained fluorescence and reflectance spectra on 37 human endomyocardial biopsy specimens and correlated the spectra with International Society Heart and Lung Transplantation grade for histologic rejection. RESULTS: Using different excitation wavelengths (ultraviolet, lambda = 337 nm; blue, lambda = 440 nm, and green, lambda = 486 nm), we found no significant difference in the fluorescence spectra among the different grades of rejection. CONCLUSIONS: Fluorescence spectroscopy is not a sensitive method for detecting rejection in human heart transplant recipients.

Cellular rejection and rate of progression of transplant vasculopathy: a 3-year serial intravascular ultrasound study.

Intravascular ultrasound (IVUS) is established as the optimal method for early detection of transplant vasculopathy. The association between cellular rejection and development of transplant vasculopathy remains controversial. This study attempts to determine the rate of progression of transplant vasculopathy lesions and its relationship with cellular rejection in a long-term (> 1 year) IVUS serial follow-up.A study cohort of 47 patients undergoing heart transplantation from 1993 to 1995 was evaluated. Intravascular ultrasound was performed at baseline (within 8 weeks) and annually for a period of 3 years to determine maximum intimal thickness and maximum plaque area in each coronary segment. Significant allograft vasculopathy was defined as a site with intimal thickness > 0.5 mm not present at baseline. Biopsy results were scored by assigning a numerical weight to each ISHLT grade during the first year. Donor lesions ranged from 0.86 to 1.1 mm, showing no evidence of progression at serial follow-up. De novo lesions were identified in 30 patients. These lesions appeared yearly but progressed slowly. The average biopsy score in the entire cohort was 1.1 +/- 0.8. Average biopsy score was > 1.0 in 35 patients with significant linear correlation between the rate of intimal progression and biopsy score (r = 0.42, p = 0.01). Multivariate analysis demonstrated that only the biopsy score correlated with the rate of progression. Lesions of donor atherosclerosis do not change significantly after transplantation. However, de novo lesions continue to develop every year. In patients with evidence of rejection, the rate of progression of transplant vasculopathy correlates with the severity of rejection.

Hypogammaglobulinemia following cardiac transplantation: a link between rejection and infection.

BACKGROUND: Hypogammaglobulinemia (HGG) has been reported after solid organ transplantation and is noted to confer an increased risk of opportunistic infections. OBJECTIVES: In this study, we sought to assess the relationship between severe HGG to infection and acute cellular rejection following heart transplantation. METHODS: Between February 1997 and January 1999, we retrospectively analyzed the clinical outcome of 111 consecutive heart transplant recipients who had immunoglobulin G (IgG) level monitoring at 3 and 6 months post-transplant and when clinically indicated. RESULTS: Eighty-one percent of patients were males, mean age 54 +/- 13 years, and the mean follow-up period was 13.8 +/- 5.7 months. Patients had normal IgG levels prior to transplant (mean 1137 +/- 353 mg/dl). Ten percent (11 of 111) of patients developed severe HGG (IgG < 350 mg/dl) post-transplant. The average time to the lowest IgG level was 196 +/- 125 days. Patients with severe HGG were at increased risk of opportunistic infections compared to patients with IgG > 350 mg/dl (55% [6 of 11] vs. 5% [5 of 100], odds ratio = 22.8, p < 0.001). Compared to patients with no rejection, patients who experienced three or more episodes of rejection had lower mean IgG (580 +/- 309 vs. 751 +/- 325, p = 0.05), and increased incidence of severe HGG (33% [7 of 21] vs. 2.8% [1 of 35], p = 0.001). The incidence of rejection episodes per patient at 1 year was higher in patients with severe HGG compared to patients with IgG >350 (2.82 +/- 1.66 vs. 1.36 +/- 1.45 episodes/patient, p = 0.02). The use of parenteral steroid pulse therapy was associated with an increased risk of severe HGG (odds ratio = 15.28, p < 0.001). CONCLUSIONS: Severe HGG after cardiac transplantation may develop as a consequence of intensification of immunosuppressive therapy for rejection and hence, confers an increased risk of opportunistic infections. IgG level may be a useful marker for identifying patients at high risk.

The influence of donor gender on allograft vasculopathy: evidence from intravascular ultrasound.

BACKGROUND: Allograft vasculopathy is a major risk factor for mortality following cardiac transplantation. Several immune and nonimmune factors have been evaluated as risk factors for the development of coronary vasculopathy. OBJECTIVE: We evaluated the influence of donor gender on the progression of coronary vasculopathy in heart transplant recipients. METHODS: Eighty-nine heart transplant recipients (67 men, 22 women of mean age: 56 +/- 12 years) underwent serial volumetric intravascular ultrasound analysis (IVUS) at baseline (within 1 month) and at 1 year after transplantation. Patients were divided into four groups in relation to the donor-recipient gender status: female-female, n=17; female-male, n=28; male-female, n=5; male-male, n=39. Ultrasound images were recorded during an automated pullback and with an equal number of slices (average=22 per coronary vessel). The measured IVUS indices for the left anterior descending artery were: change in maximal intimal thickness, average intimal area, total plaque volume, and intimal index. RESULTS: Patients were similar in baseline characteristics. At 1 year after transplantation, IVUS indices of coronary vasculopathy were significantly increased among recipients of female allografts (P <.05). CONCLUSION: Heart transplant recipients of female allografts display increased coronary vasculopathy progression.

Donor intracranial bleeding is associated with advanced transplant coronary vasculopathy: evidence from intravascular ultrasound.

OBJECTIVES: We evaluated the impact of spontaneous intracranial bleeding (ICB) in the donor on transplant coronary vasculopathy using serial intravascular ultrasound examinations. MATERIALS AND METHODS: Between January 1995 and December 2000, 72 recipients underwent cardiac transplantation from donors who had experienced spontaneous ICB (ICB group). Their findings using serial intravascular ultrasound analysis at baseline (within 1 month) and 1 year after transplantation were compared with 90 recipients who had undergone transplantation from trauma donors (trauma group). RESULTS: Compared with the Trauma group, the ICB group showed increased coronary intimal thickness (0.55 +/- 0.33 vs 0.39 +/- 0.3 mm; P = .034), plaque volume (3.84 +/- 2.5 vs 2.28 +/- 1.65 mm(3); P = .015) and plaque burden (7.4 vs 2%) at 1 year after transplantation. CONCLUSIONS: Donor spontaneous ICB is associated with significantly increased coronary vasculopathy.

Long-term medical complications of heart transplantation: information for the primary care physician.

As heart transplantation becomes much more common primary care physicians will play a key role in preventing, detecting, and treating the short-term and long-term complications of this procedure. These complications include chiefly graft rejection and accelerated coronary artery disease, but also dyslipidemia, hypertension, diabetes mellitus, kidney failure, gout, osteoporosis, and malignancy.

Stable and metastable hard-sphere crystals in fundamental measure theory.

Using fully minimized fundamental measure functionals, we investigate free energies, vacancy concentrations, and density distributions for bcc, fcc, and hcp hard-sphere crystals. Results are complemented by an approach due to Stillinger, which is based on expanding the crystal partition function in terms of the number n of free particles while the remaining particles are frozen at their ideal lattice positions. The free energies of fcc and hcp and one branch of bcc agree well with Stillinger's approach truncated at n=2. A second branch of bcc solutions features rather spread-out density distributions around lattice sites and large equilibrium vacancy concentrations and is presumably linked to the shear instability of the bcc phase. Within fundamental measure theory and the Stillinger approach (n=2), hcp is more stable than fcc by a free energy per particle of about 0.001k(B)T. In previous simulation work, the reverse situation has been found, which can be rationalized in terms of effects due to a correlated motion of at least five particles in the Stillinger picture.

Post-transplant ischemic injury is associated with up-regulated AlloMap gene expression.

BACKGROUND: The AlloMap gene expression test is used for the non-invasive detection of rejection. However, the impact of early post-transplant ischemic injury on subsequent AlloMap gene expression analysis has not been evaluated before. METHODS: Sixty seven heart transplant recipients, mean age 53 years, were evaluated at a mean 34 months post-transplant. AlloMap score was determined on the same day of heart biopsies. Nineteen patients had evidence of early post-transplant ischemic injury (Injury group). These were compared with the remaining 48 patients, Control group. RESULTS: Using multiple regression model with a backward selection method, post-transplant ischemic injury was found to be associated with significant increased AlloMap score compared with controls (31.5 +/- 4.6 vs. 26 +/- 6.2, p < 0.001). The Injury group had increased transplant vasculopathy (KM 5-year freedom from vasculopathy: 34% vs. 52%, p = 0.015), than Controls. CONCLUSIONS: Post-transplant ischemic injury is associated with up-regulated AlloMap gene expression, and hence, may provide another explanation for a high score in the absence of rejection.

Hypertension, myocardial ischemia, and sudden death.

Patients with essential hypertension are at an increased risk for sudden cardiac death. As is the case with other complications of hypertension, this increased risk reflects the interplay between a higher prevalence of coronary artery disease and the pathophysiologic consequences of left ventricular hypertrophy. The presence of coronary artery disease is the most important factor, but left ventricular hypertrophy also results in changes in the coronary circulation that predispose to myocardial ischemia, and is also associated with an increased frequency of ventricular arrhythmias. Hypertension itself is associated with changes in the autonomic nervous system that may predispose to sudden death. It is therefore likely that the mechanisms responsible for sudden death are multifactorial, but it is also clear that effective antihypertensive therapy will prevent or mitigate these predisposing factors and will reduce the incidence of this and other cardiac complications.

Hypogammaglobulinemia after heart transplantation: impact of pre-emptive use of immunoglobulin replacement (CytoGam) on infection and rejection outcomes.

Hypogammaglobulinemia (HGG) in solid organ transplant (SOT) patients confers an increased risk of opportunistic infections and poorer outcomes. Severe HGG (IgG < 350 mg/dL) after heart transplantation may follow intensification of immunosuppressive therapy and the resultant increased risk of opportunistic infections, particularly cytomegalovirus (CMV) disease. Evaluation of the effects of replacement therapy using intravenous immunoglobulin (CMV-IGIV, CytoGam) was conducted in cardiac transplant recipients and the data matched with a historical control group. Patients with severe HGG who received pre-emptive replacement therapy had significantly fewer opportunistic infections (P < 0.001) and episodes of rejection (grade > or = 3; P = 0.03 and grade > or = 2; P = 0.04) compared with the control group.