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Inhaled treprostinil (Tyvaso) has been shown to be a safe and effective addition to pulmonary arterial hypertension (PAH) oral therapies; however, the respiratory-related safety profile of inhaled treprostinil required further elucidation in the setting of routine clinical care. The objectives of this study were to characterize respiratory-related adverse events (AEs) associated with current or recent treatment with inhaled treprostinil and to compare the incidence of respiratory-related AEs in PAH patients treated with inhaled treprostinil with that in patients treated with other Food and Drug Administration (FDA)-approved PAH therapies. This was a long-term, prospective, observational study. All respiratory-related AEs were recorded during the study. The number of PAH patients enrolled was 1,333, 666 treated with inhaled treprostinil and 667 controls (treated with an FDA-approved PAH therapy other than inhaled treprostinil), for a total of 958 and 1,094 patient-years of exposure, respectively. In the inhaled-treprostinil group, 1,281 respiratory-related AEs were reported in 403 patients (61%), and in the control group, 1,295 respiratory-related AEs were reported in 388 patients (58%). Cough, throat irritation, nasal discomfort, and hemoptysis were the most common respiratory-related AEs (occurring in ≥2% of patients in either treatment group) that demonstrated a higher number of events per patient-year of exposure in the inhaled-treprostinil group than in the control group (risk ratio [95% confidence interval]: 1.487 [1.172-1.887], 3.777 [2.050-6.956], 2.039 [1.072-3.879], and 1.957 [1.024-3.741], respectively). Overall, inhaled treprostinil was well tolerated by PAH patients in routine clinical care, with respiratory-related AEs consistent with the known safety profile (trial registration: clinicaltrials.gov identifier: NCT01266265).

Aspergillosis and zygomycosis are life-threatening fungal infections in immunocompromised patients. We report a heart transplant recipient with an early pulmonary invasive aspergillosis successfully treated with association of voriconazole and caspofungin. Zygomycosis sinusitis, which was diagnosed while he still was on voriconazole therapy, was successfully treated with the use of combination antifungal therapy including liposomal amphotericin plus posaconazole and conservative surgical debridement., (© 2012 John Wiley & Sons A/S.)

Background: Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the absolute refractory period intended to improve contraction. We previously tested the safety and efficacy of CCM in 428 NYHA functional class III/IV heart failure patients with EF ≤35% and narrow QRS randomized to optimal medical treatment (OMT) plus CCM (n = 215) versus OMT alone (n = 213) and found no significant effect on ventilatory anaerobic threshold (VAT), the study's primary end point. In the present analysis, we sought to identify if there was a subgroup of patients who showed a response to CCM., Methods and Results: The protocol specified that multiregression analysis would be used to determine if baseline EF, NYHA functional class, pVO(2), or etiology of heart failure influenced the impact of CCM on AT. Etiology and baseline pVO(2) did not affect efficacy. However, baseline NYHA functional class III and EF ≥25% were significant predictors of increased efficacy. In this subgroup (comprising 97 OMT and 109 CCM patients, ∼48% of the entire population) VAT increased by 0.10 ± 2.36 in CCM versus -0.54 ± 1.83 mL kg(-1) min(-1) in OMT (P = .03) and pVO(2) increased by 0.34 ± 3.11 in CCM versus -0.97 ± 2.31 (P = .001) at 24 weeks compared with baseline; 44% of CCM versus 23% of OMT subjects showed improvement of ≥1 class in NYHA functional class (P = .002), and 59% of CCM versus 42% of OMT subjects showed a ≥10-point reduction in Minnesota Living with Heart Failure Questionnaire (P = .01). All of these findings were similar to those seen at 50 weeks., Conclusions: The results of this retrospective hypothesis-generating analysis indicate that CCM significantly improves objective parameters of exercise tolerance in a subgroup of patients characterized by normal QRS duration, NYHA functional class III symptoms, and EF >25%., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Cardiac contractility modulation (CCM) delivers nonexcitatory electrical signals to the heart during the absolute refractory period intended to improve contraction., Methods: We tested CCM in 428 New York Heart Association class III or IV, narrow QRS heart failure patients with ejection fraction (EF) ≤ 35% randomized to optimal medical therapy (OMT) plus CCM (n = 215) versus OMT alone (n = 213). Efficacy was assessed by ventilatory anaerobic threshold (VAT), primary end point, peak Vo₂ (pVo₂), and Minnesota Living with Heart Failure Questionnaire (MLWFQ) at 6 months. The primary safety end point was a test of noninferiority between groups at 12 months for the composite of all-cause mortality and hospitalizations (12.5% allowable delta)., Results: The groups were comparable for age (58 ± 13 vs 59 ± 12 years), EF (26% ± 7% vs 26% ± 7%), pVo₂ (14.7 ± 2.9 vs 14.8 ± 3.2 mL kg⁻¹ min⁻¹), and other characteristics. While VAT did not improve at 6 months, CCM significantly improved pVo₂ and MLWHFQ (by 0.65 mL kg⁻¹ min⁻¹ [P = .024] and -9.7 points [P < .0001], respectively) over OMT. Forty-eight percent of OMT and 52% of CCM patients experienced a safety end point, which satisfied the noniferiority criterion (P = .03). Post hoc, hypothesis-generating analysis identified a subgroup (characterized by baseline EF ≥ 25% and New York Heart Association class III symptoms) in which all parameters were improved by CCM., Conclusions: In the overall target population, CCM did not improve VAT (the primary end point) but did improve pVo₂ and MLWHFQ. Cardiac contractility modulation did not have an adverse affect on hospitalizations or mortality within the prespecified boundaries. Further study is required to clarify the role of CCM as a treatment for medically refractory heart failure., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objectives: we sought to determine whether patients with functional mitral regurgitation (FMR) would benefit from ventricular reshaping by the Coapsys device (Myocor, Inc., Maple Grove, Minnesota)., Background: FMR occurs when ventricular remodeling impairs valve function. Coapsys is a ventricular shape change device placed without cardiopulmonary bypass to reduce FMR. It compresses the mitral annulus and reshapes the ventricle. We hypothesized that Coapsys for FMR would improve clinical outcomes compared with standard therapies., Methods: RESTOR-MV (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve) was a randomized, prospective, multicenter study of patients with FMR and coronary disease with core laboratory analysis. After enrollment, patients were stratified to the standard indicated surgery: either coronary artery bypass graft alone or coronary artery bypass graft with mitral valve repair. In each stratum, randomization was to either control (indicated surgery) or treatment (coronary artery bypass graft with Coapsys ventricular reshaping)., Results: the study was terminated when the sponsor failed to secure ongoing funding; 165 patients were randomized. Control and Coapsys both produced decreases in left ventricular (LV) end-diastolic dimension and MR at 2 years (p < 0.001); Coapsys provided a greater decrease in LV end-diastolic dimension (p = 0.021). Control had lower MR grades during follow-up (p = 0.01). Coapsys showed a survival advantage compared with control at 2 years (87% vs. 77%) (hazard ratio: 0.421; 95% confidence interval: 0.200 to 0.886; stratified log-rank test; p = 0.038). Complication-free survival (including death, stroke, myocardial infarction, and valve reoperation) was significantly greater with Coapsys at 2 years (85% vs. 71%) (hazard ratio: 0.372; 95% confidence interval: 0.185 to 0.749; adjusted log-rank test; p = 0.019)., Conclusions: analysis of RESTOR-MV indicates that patients with FMR requiring revascularization treated with ventricular reshaping rather than standard surgery had improved survival and a significant decrease in major adverse outcomes. This trial validates the concept of the ventricular reshaping strategy in this subset of patients with heart failure. (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve [RESTOR-MV]; NCT00120276)., (Published by Elsevier Inc. All rights reserved.)

Post-heart transplantation bradycardic syncope and arrest could be due to preferential rejection of the conduction system. We present six heart transplant patients with this presentation, two of whom died. The autopsy of one of those patients demonstrated severe rejection of the conduction system, with only mild rejection throughout the rest of the myocardium. We postulate that aggressive therapy for rejection and pacemaker placement may result in improved survival in heart transplant recipients with this clinical presentation.

Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the cardiac absolute refractory period that enhance the strength of cardiac muscular contraction. Prior research in experimental and human heart failure has shown that CCM signals normalize phosphorylation of key proteins and expression of genes coding for proteins involved in regulation of calcium cycling and contraction. The results of prior clinical studies of CCM have supported its safety and efficacy. A large-scale clinical study, the FIX-HF-5 study, is currently underway to test the safety and efficacy of this treatment. In this article, we provide an overview of the system used to deliver CCM signals, the implant procedure, and the details and rationale of the FIX-HF-5 study design. Baseline characteristics for patients randomized in this trial are also presented.

Background: Prior investigations suggest that superimposing continuous flow on aortic flow (continuous aortic flow augmentation) produces vasodilation, cardiac unloading, and improved cardiac performance., Methods and Results: We compared percutaneous continuous aortic flow augmentation (flow

Background: Cardiac allograft vasculopathy (CAV) constitutes a primary cause of death after heart transplantation. Balloon angioplasty and bare metal stents have been used for revascularization but they are associated with a high risk of re-stenosis. Limited data have shown favorable results with drug-eluting stents (DES). This study examines the rate of re-stenosis for DES in CAV as well as predictors for its occurrence., Methods: Cardiac transplant patients who received at least one DES for a previously untreated coronary lesion were included. These patients were retrospectively followed until February 2007. Re-stenosis was defined as >or=50% lumen diameter narrowing on coronary angiography at the site of the DES., Results: During the study period, 35 patients underwent percutaneous coronary intervention (PCI) on a total of 84 de novo lesions. The mean follow-up was 22 +/- 14 months. Twenty-six (31%) lesions developed re-stenosis during follow-up. Re-stenosis rates were 18%, 21% and 26% at 6, 9 and 12 months, respectively. Predictors of re-stenosis included non-white race, ischemic etiology, intervention precipitated by symptoms and severe stenosis (>/=90% stenosis) of the target lesion., Conclusions: Use of DES has a favorable outcome when used in heart transplant patients for the treatment of CAV. An aggressive strategy for the treatment of CAV using DES may provide good long-term outcome compared with other available therapies.

Background: For patients hospitalized with heart failure (HF) who are inadequately responsive to medical therapy, the options include ventricular assist devices and cardiac transplant. In animal models and patients, continuous aortic flow augmentation using the Orqis Medical Cancion System (Orqis Medical Corporation, Lake Forest, California), a percutaneously placed arterial-to-arterial circuit (continuous flow up to 1.5 L/min) with an extracorporeal, magnetic, centrifugal pump, improves hemodynamics and renal function with benefits persisting 24 hours after discontinuation., Methods and Results: The Multi-center Trial of the Orqis Medical Cancion System for the Enhanced Treatment of Heart Failure Unresponsive to Medical Therapy is enrolling patients hospitalized with HF who are randomized to continuous aortic flow augmentation or medical therapy alone. Entry requires persistent HF, elevated pulmonary capillary wedge pressure, reduced cardiac index, and impaired renal function or substantial diuretic requirement despite intravenous inotrope or vasodilator treatment. The primary efficacy end point is a composite including the components of 72- to 96-hour pulmonary capillary wedge pressure reduction and days alive out of hospital with no mechanical support for more than 35 days. Additional end points include changes in serum creatinine, N-terminal pro-B-type natriuretic peptide, and health-related quality of life., Conclusions: The Multi-center Trial of the Orqis Medical Cancion System for the Enhanced Treatment of Heart Failure Unresponsive to Medical Therapy tests the hypothesis that continuous aortic flow augmentation improves the clinical status and outcomes in patients hospitalized with HF exacerbation who are inadequately responsive to medical therapy.

Unlabelled: The mycophenolate mofetil (MMF) trial involved 650 heart transplant patients from 28 centers who received MMF or azathioprine (AZA), both in combination with cyclosporine and corticosteroids. Baseline and 1-year intravascular ultrasound (IVUS) were performed in 196 patients (102 MMF and 94 AZA) with no differences between groups in IVUS results analyzed by morphometric analysis (average of 10 evenly spaced sites, without matching sites between studies). Baseline to first-year IVUS data can also be analyzed by site-to-site analysis (matching sites between studies), which has been reported to be more clinically relevant. Therefore, we used site-to-site analysis to reanalyze the multicenter MMF IVUS data., Results: IVUS images were reviewed and interpretable in 190 patients (99 MMF and 91 AZA) from the multicenter randomized trial. The AZA group compared to the MMF group had a larger number of patients with first-year maximal intimal thickness (MIT)>or=0.3 mm (43% vs. 23%, p=0.005), a greater decrease in the mean lumen area (p=0.02) and a decrease in the mean vessel area (the area actually increased in the MMF group, p=0.03)., Conclusion: MMF-treated heart transplant patients compared to AZA-treated patients, both concurrently on cyclosporine and corticosteroids, in this study have significantly less progression of first-year intimal thickening.

Background: Photopheresis therapy (photo) has been advocated as a therapy to improve outcome after recalcitrant or severe rejection, but objective evidence of a beneficial effect has been elusive. This study examined the hypothesis that photo provides protection against rejection, rejection with hemodynamic compromise (HC), and death from rejection after cardiac transplantation., Methods: Between 1990 and 2003, 36 adult patients (from 343 adult transplant recipients) received at least 3 months of photo (2-day treatment every 3 to 6 weeks for a target of 18 months) after HC rejection (n = 12), recurrent/recalcitrant rejection (n = 20), or as prophylaxis in the presence of anti-donor antibodies (n = 4). Survival and risk factors were examined by analysis using multivariate hazard function modulated renewal function., Results: Patients selected for photo were at greater risk for rejection (p < 0.0001) and HC rejection (p < 0.0001) than non-photo patients. After 3 months of photo therapy, rejection risk was decreased (p = 0.04). More importantly, the hazard for subsequent HC rejection or rejection death was significantly reduced toward the risk-adjusted level of lower-risk non-photo patients (p = 0.006)., Conclusions: This study provides objective evidence that photo reduces the risk of subsequent HC rejection and/or death from rejection when initiated for patients with high rejection risk. Photopheresis is recommended as an important therapeutic modality after rejection with hemodynamic compromise, although further studies are needed to define the precise mechanism of the effect and the potential for benefit in other patient sub-sets.

Background: The relationship between post-heart transplant cachexia and obesity with subsequent morbidity and mortality has not yet been reported. Therefore, the purposes of this study were to: (1) describe change in body mass index (BMI) from before transplant through 5 years after transplant; (2) identify risk factors for increased BMI at 1 year post-transplant; and (3) determine whether post-transplant BMI is associated with post-transplant morbidity and mortality., Methods: Patients (n = 3,540) were from a non-random sample having received a heart transplant between January 1, 1996 and December 31, 2001 at 33 institutions of the Cardiac Transplant Research Database (CTRD). Patients were divided into groups using cut-offs for categories of BMI. Data were assessed according to frequencies, measures of central tendency, Pearson correlations, chi-square tests, multiple regression and stratified actuarial analyses with log-rank tests for comparisons. The level of statistical significance was set at p = 0.05., Results: The number of obese patients increased significantly from immediately before heart transplant to 5 years later (17% vs 38%) (p < 0.0001). Risk factors for increased BMI at 1 year after heart transplant (explaining 56% of variance) included increased BMI at transplant, younger age, black race, non-ischemic etiology of heart disease, Status I at time of transplant and non-use of mycophenolate mofetil. Patients who were underweight or obese at 1 year post-transplant were at greater risk for rejection over time than patients who were of normal weight or overweight (p = 0.009)., Conclusions: Both demographic and clinical factors are related to increased BMI at 1 year after heart transplantation. Post-transplant cachexia and obesity are risk factors for poor clinical outcomes after heart transplantation.

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.

Background: Induction immunosuppression utilizing lymphocytolytic agents in the early peri-operative period has a number of theoretical and practical advantages and disadvantages. However, the efficacy of cytolytic agents as induction therapy remains unproven., Methods: To assess the current impact of induction therapy in heart transplantation, we queried a multi-institutional database regarding the frequency of use, type of agent, duration of therapy and outcomes of 6,553 patients transplanted from 1990 to 2001. A study group of 5,897 patients were identified who survived the first 48 hours post-transplant and received either no induction therapy (n = 4,161) or induction with OKT3 or anti-thymocyte preparations (n = 1,736)., Results: By multivariate analysis, risk factors for rejection death were identified and then applied to a model of overall mortality. Among patients with a 1-year risk of rejection death at >5%, induction therapy provided a survival advantage, but survival with induction was decreased when the risk of rejection death was <2%. Specific patient sub-sets that received a survival benefit in the current era with induction included younger patients of black race with >/=4 HLA mismatches and long-term (>6 months) support on a ventricular assist device (VAD)., Conclusions: Use and application of induction therapy continues to be controversial in heart transplantation. At present, this approach appears to be beneficial in selected patients who are at high risk for rejection death, but likely detrimental in patients who are at low risk for rejection death. Those with a combination of longer term VAD support, of black ethnicity, and having extensive HLA mismatching are most likely to benefit from cytolytic induction therapy.

The development of an implantable haemodynamic monitor (IHM) has made possible the home monitoring of a patient's central haemodynamic trends during daily living. We have evaluated the usability and transmission success of such a system over a 3.2-year period. Patients with an IHM were able to transmit the stored data every week to a Web server, where trend plots and tables of haemodynamic variables could be viewed by the health-care staff concerned. Data transfer was examined from August 2000 to November 2003. During this period, 148 patients had an IHM implanted. Over the study period, 7791 data transmissions were performed and an average of 286 downloads per month were sent to the Web server. In all, 86% of data transmissions were successful, although 10% required more than one attempt. The study demonstrated that telemonitoring of haemodynamic data from an IHM was feasible. A patient survey showed that the technology was user-friendly and that the training material provided sufficient information for patients and their families to install and use the transmission equipment at home. It also suggested that transmission success was independent of patient age or gender.

Background: As therapeutic options evolve for advanced heart failure, the appropriate role for cardiac transplantation will require survival analyses that reflect changing trends in causes of death and patient and institutional risk profiles. Results from multi-institutional studies could be used to monitor progress in individual centers., Methods: Between 1990 and 1999, 7290 patients undergoing cardiac transplantation in 42 institutions entered a formal outcomes study. Changing survival, causes of death, and patient risk profiles were analyzed. Multivariable risk-factor equations were applied to a single institution (300 primary heart transplants) to examine differences in risk-adjusted expected versus observed actuarial outcomes over time., Results: Overall survival in the 42 institutions improved during the decade (P =.02). One- and 3-year cardiac transplant research database survival was as follows: era 1 (1990-1992), 84% and 76%, respectively; era 2 (1993-1995), 85% and 79%, respectively; and era 3 (1996-1999), 85% and 79%, respectively. Causes of death changed over time. Pretransplantation risk profiles increased over time (P =.0001), with increases in reoperations, devices, diabetes, severely ill recipients, pulmonary vascular resistance, sensitization, ischemic times, donor age, and donor inotropic support. Three-year actuarial survival in a single institution was 3% less than risk-adjusted predicted survival in era 1, 1% higher than predicted in era 2, and 7% higher than predicted in era 3., Conclusions: Survival after cardiac transplantation is gradually improving, despite increasing risk profiles. Further improvement requires periodic re-evaluation of risk profiles and causes of death to target areas of surveillance, therapy, and research. By using these methods, progress at individual institutions can be assessed in a time-related, risk-adjusted manner that also reflects changing institutional experience, expertise, or both.

Context: Little randomized evidence is available to guide the in-hospital management of patients with an acute exacerbation of chronic heart failure. Although intravenous inotropic therapy usually produces beneficial hemodynamic effects and is labeled for use in the care of such patients, the effect of such therapy on intermediate-term clinical outcomes is uncertain., Objective: To prospectively test whether a strategy that includes short-term use of milrinone in addition to standard therapy can improve clinical outcomes of patients hospitalized with an exacerbation of chronic heart failure., Design: Prospective, randomized, double-blind, placebo-controlled trial conducted from July 1997 through November 1999., Setting: Seventy-eight community and tertiary care hospitals in the United States., Participants: A total of 951 patients admitted with an exacerbation of systolic heart failure not requiring intravenous inotropic support (mean age, 65 years; 92% with baseline New York Heart Association class III or IV; mean left ventricular ejection fraction, 23%)., Intervention: Patients were randomly assigned to receive a 48-hour infusion of either milrinone, 0.5 microg/kg per minute initially (n = 477), or saline placebo (n = 472)., Main Outcome Measure: Cumulative days of hospitalization for cardiovascular cause within 60 days following randomization., Results: The median number of days hospitalized for cardiovascular causes within 60 days after randomization did not differ significantly between patients given milrinone (6 days) compared with placebo (7 days; P =.71). Sustained hypotension requiring intervention (10.7% vs 3.2%; P<.001) and new atrial arrhythmias (4.6% vs 1.5%; P =.004) occurred more frequently in patients who received milrinone. The milrinone and placebo groups did not differ significantly in in-hospital mortality (3.8% vs 2.3%; P =.19), 60-day mortality (10.3% vs 8.9%; P =.41), or the composite incidence of death or readmission (35.0% vs 35.3%; P =.92), Conclusion: These results do not support the routine use of intravenous milrinone as an adjunct to standard therapy in the treatment of patients hospitalized for an exacerbation of chronic heart failure.

Background: Adenosine may adversely affect renal function via its effects on renal arterioles and tubuloglomerular feedback, but effects of adenosine blockade in humans receiving furosemide and ACE inhibitors is unknown., Methods and Results: This was a randomized, double-blind, ascending-dose, crossover study evaluating 3 doses of BG9719 in 63 patients with congestive heart failure. Patients received placebo or 1 of 3 doses of BG9719 on 1 day and the same medication plus furosemide on a separate day. Renal function and electrolyte and water excretion were assessed. BG9719 alone caused an increase in urine output and sodium excretion (P<0.05). Although administration of furosemide alone caused a large diuresis, addition of BG9719 to furosemide increased diuresis, which was significant at the 0.75-microg/mL concentration. BG9719 alone improved glomerular filtration rate (GFR) at the 2 lower doses. Furosemide alone caused a decline in GFR. When BG9719 was added to furosemide, however, creatinine clearance remained at baseline at the 2 lower doses., Conclusions: In patients with congestive heart failure on standard therapy, including ACE inhibitors, BG9719 increased both urine output and GFR. In these same patients, furosemide increased urine output at the expense of decreased GFR. When BG9719 was given in addition to furosemide, urine volume additionally increased and there was no deterioration in GFR. A1 adenosine antagonism might preserve renal function while simultaneously promoting natriuresis during treatment for heart failure.

Background: Although the left ventricular assist device (LVAD) has been increasingly used as a bridge to transplant, its effect on post-transplant outcome is uncertain. We, therefore, designed this study using the Cardiac Transplant Research Database to compare patients supported on an LVAD before transplant with those treated with intravenous inotropic medical therapy., Methods and Results: Of the 5,880 patients transplanted between 1990 and 1997, a total of 502 received support from LVADs and 2,514 received intravenous inotropic medical therapy at the time of transplant. Kaplan-Meier analysis showed no significant difference in post-transplant survival between the LVAD and medical-therapy groups (p = 0.09). Results of a multivariate Cox regression analysis were consistent with that of the Kaplan-Meier analysis and did not identify LVAD as a significant risk factor for mortality. The percentage of patients who received LVADs as a function of total transplants increased from 2% in 1990 to 16% in 1997. Furthermore, although the number of extracorporeal LVADs remained relatively constant, the number of intracorporeal LVADs increased over time. Multivariate parametric analysis found that the risk factors for post-transplant death in the LVAD group were extracorporeal LVAD use (p = 0.0004), elevated serum creatinine (p = 0.05), older donor age (p = 0.03), increased donor ischemic time (p < 0.0001), and earlier year of transplant (p = 0.03)., Conclusions: Given a limited donor supply, the intracorporeal LVAD helps the sickest patients survive to transplant and provides post-transplant outcome similar to that of patients supported on inotropic medical therapy. Therefore, patients supported on LVADs before transplant may receive the greatest marginal benefit when compared with other transplant candidates.

Nesiritide is the generic name for recombinant human B-type natriuretic peptide. This drug represents the first of a new class of agents for the treatment of decompensated congestive heart failure. The properties of B-type natriuretic peptide include a balanced arterial and venous vasodilatation and a marked natriuresis and diuresis, making it an excellent drug for the management of heart failure. We review the physiology and pathophysiology of the natriuretic peptides and the clinical data for nesiritide. In addition, the hemodynamic effects of the drug as well as its efficacy and safety in the treatment of heart failure are critiqued. Nesiritide is a new class of therapeutic peptide for the treatment of heart failure that appears to offer unique and safe hemodynamic properties.

Background: The ability of patients to perform day-to-day tasks (e.g., medication management, dietary regulation) is an important concern of transplant teams., Methods: We studied a clinical series of 75 heart transplant candidates and 38 controls to examine the predictive validity of demographic, neuropsychologic, and cardiac function variables to a performance-based measure of instrumental activities of daily living (IADL) capacity (i.e., Everyday Problems Test, EPT)., Results: Multiple regression analyses, controlling for education and race, indicated that neuropsychologic tests accounted for between 34% and 67% of the variance across IADL domains (e.g., cooking, household chores, medication management). The IADL capacity was most consistently predicted by long-standing verbal ability (Shipley Institute of Living Scale-Vocabulary, SILS-VOC) and psychomotor speed and mental flexibility (Trail Making Test-Part B, TMT-B). Similarly, SILS-VOC and TMT-B also tended to show the best operating characteristics (i.e., sensitivity, specificity, positive predictive power, negative predictive power) for detection of dependence across IADL domains. In contrast, cardiac function measures (e.g., cardiac output, mean atrial pressure) were largely unrelated to the patient's performance on the paper-and-pencil EPT task., Conclusions: Long-standing intellectual ability, and a measure of speeded information processing and mental flexibility are the best predictors of IADL capacity.

This report defines the cost and benefit of extended antifungal prophylaxis in ventricular assist device (VAD) patients (pts). Extended antifungal prophylaxis is defined as prophylaxis with fluconazole or nystatin that is given until pts are extubated and off antibiotics. These data are compared with that obtained from earlier VAD patients who only received anti-fungal drugs for documented fungal colonization or infection. Thirty-six patients had HeartMate (n = 15) or Thoratec (n = 21) VADs between 1989 and 1997. Cultures positive for fungus (n = 52 cultures) were obtained from 16 of 36 patients (44% of patients). Forty-three fungal cultures were in the preprophylaxis and nine in the postprophylaxis era. There was one death attributable to fungal sepsis in the preprophylaxis era and none in the postprophylaxis era. The total cost of antifungal drugs in the preprophylaxis era was $3,840 over 1,498 patient days (PD) (mean $2.56 per PD), versus $70,670 over 1,525 PD in the postprophylaxis era (mean $46.34 per PD). Extended antifungal prophylaxis was not cost effective in VAD patients at this institution. However, short-term perioperative antifungal prophylaxis was not addressed by this study. We are now using short-term antifungal prophylaxis with fluconazole and nystatin in VAD patients because of the potential for serious morbidity and mortality that is associated with fungal device infections. A future analysis will determine the usefulness of this change in strategy.

Background: Intravenous infusion of nesiritide, a brain (B-type) natriuretic peptide, has beneficial hemodynamic effects in patients with decompensated congestive heart failure. We investigated the clinical use of nesiritide in such patients., Methods: Patients hospitalized because of symptomatic congestive heart failure were enrolled in either an efficacy trial or a comparative trial. In the efficacy trial, which required the placement of a Swan-Ganz catheter, 127 patients with a pulmonary-capillary wedge pressure of 18 mm Hg or higher and a cardiac index of 2.7 liters per minute per square meter of body-surface area or less were randomly assigned to double-blind treatment with placebo or nesiritide (infused at a rate of 0.015 or 0.030 microg per kilogram of body weight per minute) for six hours. In the comparative trial, which did not require hemodynamic monitoring, 305 patients were randomly assigned to open-label therapy with standard agents or nesiritide for up to seven days., Results: In the efficacy trial, at six hours, nesiritide infusion at rates of 0.015 and 0.030 microg per kilogram per minute decreased pulmonary-capillary wedge pressure by 6.0 and 9.6 mm Hg, respectively (as compared with an increase of 2.0 mm Hg with placebo, P<0.001), resulted in improvements in global clinical status in 60 percent and 67 percent of the patients (as compared with 14 percent of those receiving placebo, P<0.001), reduced dyspnea in 57 percent and 53 percent of the patients (as compared with 12 percent of those receiving placebo, P<0.001), and reduced fatigue in 32 percent and 38 percent of the patients (as compared with 5 percent of those receiving placebo, P<0.001). In the comparative trial, the improvements in global clinical status, dyspnea, and fatigue were sustained with nesiritide therapy for up to seven days and were similar to those observed with standard intravenous therapy for heart failure. The most common side effect was dose-related hypotension, which was usually asymptomatic., Conclusions: In patients hospitalized with decompensated congestive heart failure, nesiritide improves hemodynamic function and clinical status. Nesiritide is useful for the treatment of decompensated congestive heart failure.

We present the case of a patient with a single papillary muscle that is supporting both orifices of a stenotic double orifice mitral valve. With the use of both transthoracic and transesophageal echocardiography, we were able to prospectively define this entity, which was confirmed at surgery.

Background: Pulmonary hypertension is a progressive and often fatal complication of the scleroderma spectrum of disease for which no treatment has been proven effective in a randomized trial., Objective: To determine the effect of epoprostenol on pulmonary hypertension secondary to the scleroderma spectrum of disease., Design: Randomized, open-label, controlled trial., Setting: 17 pulmonary hypertension referral centers., Patients: 111 patients with moderate to severe pulmonary hypertension., Intervention: Epoprostenol plus conventional therapy or conventional therapy alone., Measurements: The primary outcome measure was exercise capacity. Other measures were cardiopulmonary hemodynamics, signs and symptoms of pulmonary hypertension and scleroderma, and survival., Results: Exercise capacity improved with epoprostenol (median distance walked in 6 minutes, 316 m at 12 weeks compared with 270 m at baseline) but decreased with conventional therapy (192 m at 12 weeks compared with 240 m at baseline). The difference between treatment groups in the median distance walked at week 12 was 108 m (95% CI, 55.2 m to 180.0 m) (P < 0.001). Hemodynamics improved at 12 weeks with epoprostenol. The changes in mean pulmonary artery pressure for the epoprostenol and conventional therapy groups were -5.0 and 0.9 mm Hg, respectively (difference, -6.0 mm Hg [CI, -9.0 to -3.0 mm Hg), and the mean changes in pulmonary vascular resistance were -4.6 and 0.9 mm Hg/L per minute, respectively (difference, -5.5 mm Hg/L per minute [CI, -7.3 to -3.7 mm Hg/L per minute). Twenty-one patients treated with epoprostenol and no patients receiving conventional therapy showed improved New York Heart Association functional class. Borg Dyspnea Scores and Dyspnea-Fatigue Ratings improved in the epoprostenol group. Trends toward greater improvement in severity of the Raynaud phenomenon and fewer new digital ulcers were seen in the epoprostenol group. Four patients in the epoprostenol group and five in the conventional therapy group died (P value not significant). Side effects of epoprostenol therapy included jaw pain, nausea, and anorexia. Adverse events related to the epoprostenol delivery system included sepsis, cellulitis, hemorrhage, and pneumothorax (4% incidence for each condition)., Conclusions: Continuous epoprostenol therapy improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension due to the scleroderma spectrum of disease.

Studies in animal models and patients have suggested that 31P-magnetic resonance spectroscopy (MRS) may be useful in diagnosing transplant rejection, but such studies often are confounded by the late inclusion of patients after transplantation. The present study examined the utility of 31P-MRS in the diagnosis of acute allograft rejection during the first posttransplant month. Thirteen recent heart transplant recipients underwent 57 resting 31P-MRS studies within 24 hr of a biopsy. Subjects lay supine with a 10-cm surface coil placed over the heart. A 1-dimensionsal chemical shift imaging protocol was used to collect spectral information. Spectra from the heart were weighted for distance from the coil and summed before analysis. ANOVA and Duncan's multiple range test were used to analyze the data comparing phosphocreatine (PCr)/ATP ratios with biopsy scores. Transplant patients had significantly lower myocardial PCr/ATP ratios when compared with a normal control group (1.27 +/- 0.27 versus 1.61 +/- 0.22, p < 0.001). However, when the patient group was classified by biopsy score, the expected order of score, 0 > 1 > 2 > 3, was not obtained. Rather, the order was 2 > 0 > 1 > 3. Although the difference between scores 2 and 3 was significant (1.46 versus 1.14, alpha = 0.05 level), the lower three groups were statistically indistinguishable. In addition, the PCr/ ATP ratios were not predictive of future biopsies. Although significantly lower than normal control subjects, resting myocardial PCr/ATP ratios of transplant subjects are not useful in assessing thelevel of rejection. It is suggested that the measurement may be more predictive in mildly exercised myocardium.

Background: The optimal management of an acute exacerbation of chronic heart failure (CHF) is uncertain. There is little randomized evidence available to support the various treatment strategies for patients hospitalized with an exacerbation of CHF. Inotropic agents may produce beneficial hemodynamic effects, and although they are currently used in these patients, their effect on clinical response and impact on clinical outcome is unclear. We present a unique and simple study designed to determine whether a treatment strategy for CHF exacerbations that includes an intravenous agent with inotropic properties can reduce hospital length of stay and lead to improved patient outcome., Methods: The OPTIME CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) trial is an ongoing multicenter, randomized, placebo-controlled trial of a treatment strategy for patients with acute exacerbations of CHF. The design of this study provides a novel approach to the evaluation of treatment strategies in the care of this population. The OPTIME CHF design uses early initiation of intravenous milrinone as both an adjunct to the best the medical therapy and to facilitate optimal dosing of standard oral therapy for heart failure. Patients with known systolic heart failure requiring hospital admission for a CHF exacerbation are randomly assigned within 48 hours of admission to receive a 48-hour infusion of either intravenous milrinone or placebo. The primary end point of this design is a reduction in the total hospital days for cardiovascular events within 60 days after therapy. Enrollment of 1000 patients began July 7, 1997, at 80 US centers and is projected to conclude in late 1999.

Background: The introduction of cyclosporine has resulted in significant improvement in the survival of cardiac allograft recipients due to decreased mortality from infection and rejection. The original oil-based cyclosporine formulation exhibits variable and unpredictable bioavailability that correlates with an increased incidence of acute and chronic rejection in those patients in whom this is most pronounced. The primary objectives of this prospective, multicenter, randomized, double-blind study in cardiac transplant patients were: to compare the efficacy of cyclosporine microemulsion (CsA-NL) with oil-based cyclosporine (CsA-SM) as measured by cardiac allograft and recipient survival and the incidence and severity of acute rejection episodes; and to assess the safety and tolerability of CsA-NL compared with CsA-SM in this population. This report represents the analysis of results 6 months after transplantation., Methods: A total of 380 patients undergoing their first cardiac transplant at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial examining the safety and efficacy of CsA-NL versus CsA-SM. Rejection was diagnosed using endomyocardial biopsy and were graded according to standardized criteria of the International Society of Heart and Lung Transplantation (ISHLT). Clinical parameters were monitored during the study. Survival and freedom from were used for analysis as was Fisher's exact test for comparisons between groups., Results: At 6 months after transplantation, allograft and patient survival were the same for both groups. The frequency of ISHLT grade 3A or greater episodes in the two groups was identical. Fewer CsA-NL patients (5.9%) required antilymphocyte antibody (ATG or OKT-3) therapy for rejection compared with the CsA-SM-treated patients (14.1%, P=0.01). Females with ISHLT rejection grade > or = 3A treated with CsA-NL had a 46% lower incidence of rejection compared with the CsA-SM-treated group (31.3% vs. 57.6%, P=0.032). Fewer infections were seen in the CsA-NL. With the exception of baseline and 1 week posttransplant creatinines which were higher in the CsA-NL group, the overall creatinine was not significantly different between the two groups., Conclusions: This multicenter, randomized study of cardiac transplant recipients documented less severe rejection (in particular those requiring antibody therapy) and a lower incidence of infection in CsA-NL-treated patients. Results from the female subgroup analysis suggest that the improved bioavailability of CsA-NL might reduce the frequency of rejection episodes in female patients. The use of CsA-NL was not associated with an increased risk of adverse events.

Background: The use of inotropic agents in the therapy of patients with congestive heart failure (CHF) is controversial. One concern regarding inotropic therapy has been that drug withdrawal could be associated with a worsening of symptoms., Methods and Results: We took advantage of the discontinuation of the recent trial of vesnarinone in the therapy of CHF to assess the effects of withdrawal of the inotropic agent, vesnarinone, in patients with chronic CHF who had been randomized to receive either placebo or 30 or 60 mg of vesnarinone. Contrary to our initial hypothesis, withdrawal of vesnarinone did not impact on either morbidity or mortality over a period of 6 months., Conclusion: Although these results suggest vesnarinone withdrawal is safe, the applicability of these results to other inotropic agents remains unclear.

Background: The relationship between pre-transplant body weight and post-transplant outcome has only recently been identified using a single, indirect measure of weight (percent ideal body weight [PIBW]). The literature is equivocal regarding which index is the better indicator of body weight. The purpose of this study was to determine (1) if pre-heart transplant body weight, measured by body mass index (BMI) and PIBW, is associated with post-heart transplant morbidity and mortality and (2) if patient gender, age, and etiology of heart disease affect this association., Methods: The sample included 4,515 patients who received a heart transplant from January 1, 1990-December 31, 1995 at 38 institutions participating in the Cardiac Transplant Research Database (CTRD). Patients were divided into groups according to their BMI and PIBW. Data were described using frequencies, measures of central tendency, Pearson correlation coefficients, stratified actuarial analyses and log rank tests for comparisons, and a multivariable risk factor analysis in the hazard domain., Results: For all patients (n = 4,515), being <80% or >140% of IBW before heart transplant was a risk factor for increased mortality after heart transplant. The association between pre-heart transplant PIBW and post-heart transplant survival was affected by gender, age, and etiology of heart disease. In males, a higher PIBW was a significant risk factor for death early after transplant (p = .0003). Although not significant, there was a trend for a higher PIBW being a risk factor for death in females throughout the post transplant period (p = .07). No differences in cause of death were found for PIBW and BMI. In male and female recipients <55 years, being overweight pre-heart transplant was a risk factor for infection. In patients with pre-transplant ischemic heart disease, the greatest risk for infection was found in patients who were >140% of IBW. Pre-heart transplant BMI and PIBW were not associated with acute rejection or cardiac allograft arteriopathy after transplant., Conclusions: In conclusion, being cachectic or obese preoperatively is associated with decreased survival in all patients after heart transplantation. Being obese preoperatively is associated with increased infection after heart transplant in males and females <55 years and in patients with ischemic heart disease. Of the 2 indices of body weight used in this study, percent ideal body weight appears to be the better predictor of future morbidity and mortality following heart transplantation.

Cardiac transplantation is now a well-accepted therapy for patients with advanced heart failure. In appropriately selected recipients, it has shown to significantly improve the survival and quality of life. The shortage of appropriate cardiac donor hearts, the costs of cardiac transplantation and its associated long-term medical follow-up, and the potential morbidity and mortality associated with the procedure and with life after transplantation mandates the judicious application of cardiac transplantation to appropriate recipients. A review of current indications, contraindications and evaluation of patients for cardiac transplantation is presented.

Background: Primary pulmonary hypertension results from progressive narrowing of the precapillary pulmonary vasculature. A variety of endothelial abnormalities have been identified, including a net reduction in pulmonary clearance of the vasoconstrictor and smooth muscle mitogen endothelin-1. In many patients, net pulmonary release of endothelin-1 is observed. Chronic infusions of epoprostenol (prostacyclin) improve functional capacity, survival, and hemodynamics in patients with advanced primary pulmonary hypertension. We hypothesized that the epoprostenol infusions, as compared with conventional therapy, might alter the abnormal pulmonary endothelin-1 homeostasis., Methods and Results: Using a subset of patients from a larger randomized study comparing epoprostenol plus conventional therapy (n=11 in the present study) with conventional therapy alone (n=7 in the present study), we determined the ratio of plasma endothelin-1 levels in systemic arterial blood leaving the lung to levels in mixed venous blood entering the lung both before randomization and after 88 days of continuous therapy. There were no differences between the 2 groups before therapy, but by day 88, the epoprostenol-treated group had a greater proportion of patients (82%) with an arterial/venous ratio <1 than did the conventional therapy group, in which only 29% of patients had a ratio <1 (P<0.05)., Conclusions: These results suggest that continuous epoprostenol therapy may have a beneficial effect on the balance between endothelin-1 clearance and release in many patients with primary pulmonary hypertension and may provide one explanation for the salutary effect of epoprostenol in this disease.

Background: The maximum sinus rate during exertion in humans is inversely related to age. However, the sinus rate at rest is quite variable. The intrinsic heart (IHR) following pharmacologic blockade of autonomic tone with propranolol and atropine has been proposed as a test of sinus node function and is related to age by the linear regression equation: IHR = 118.1 - (0.57 x age). Whether this relationship exists for transplanted hearts for which the donor sinus node is denervated has not been determined., Methods: The relationship between the resting heart rate and the age of the donor heart was examined in 103 patients 1 year following orthotopic cardiac transplantation in the absence of rejection or intercurrent illness. Patients receiving beta-blockers, calcium blockers, antiarrhythmic drugs, digitalis, theophylline, or with biopsy evidence of rejection or abnormal coronary arteriograms were excluded from analysis., Results: The recipient age, left ventricular ejection fraction, pulmonary capillary pressure, cardiac index, donor heart ischemic time and cardiopulmonary bypass time did not correlate with the rate of the resting donor sinus node. The resting heart rate was inversely related to age of the donor heart by the linear regression equation: HR = 112.0 - (046 x age)., Conclusion: The resting rate of the denervated sinus node is related to donor age with a regression equation that is similar, though slightly slower, than that predicted after pharmacologic autonomic blockade.

Background: Vesnarinone, an inotropic drug, was shown in a short-term placebo-controlled trial to improve survival markedly in patients with severe heart failure when given at a dose of 60 mg per day, but there was a trend toward an adverse effect on survival when the dose was 120 mg per day. In a longer-term study, we evaluated the effects of daily doses of 60 mg or 30 mg of vesnarinone, as compared with placebo, on mortality and morbidity., Methods: We enrolled 3833 patients who had symptoms of New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 30 percent or less despite optimal treatment. The mean follow-up was 286 days., Results: There were significantly fewer deaths in the placebo group (242 deaths, or 18.9 percent) than in the 60-mg vesnarinone group (292 deaths, or 22.9 percent) and longer survival (P=0.02). The increase in mortality with vesnarinone was attributed to an increase in sudden death, presumed to be due to arrhythmia. The quality of life had improved significantly more in the 60-mg vesnarinone group than in the placebo group at 8 weeks (P<0.001) and 16 weeks (P=0.003) after randomization. Trends in mortality and in measures of the quality of life in the 30-mg vesnarinone group were similar to those in the 60-mg group but not significantly different from those in the placebo group. Agranulocytosis occurred in 1.2 percent of the patients given 60 mg of vesnarinone per day and 0.2 percent of those given 30 mg of vesnarinone., Conclusions: Vesnarinone is associated with a dose-dependent increase in mortality among patients with severe heart failure, an increase that is probably related to an increase in deaths due to arrhythmia. A short-term benefit in terms of the quality of life raises issues about the appropriate therapeutic goal in treating heart failure.

Background: Impaired fibrinolytic activity has been linked to the presence and severity of allograft vasculopathy (Tx CAD). This impairment may be associated with the presence of certain fibrinolytic protein gene polymorphisms., Methods and Results: To investigate the relation between donor-specific fibrinolytic protein genotypes and Tx CAD, we identified donor plasminogen activator inhibitor-1 (PAI-1) HindIII and tissue plasminogen activator (TPA) EcoRI restriction fragment length polymorphisms-based genotypes by Southern blot analysis in 48 recipients of cardiac allografts and correlated these genotypes with the development of CAD. No association was found between donor TPA genotypes and the presence of Tx CAD. Among the 48 patients, 17% were homozygous for the 1/1 PAI-1 genotype, 51% for the 2/2 PAI-1 genotype, and 32% for the 1/2 PAI-1 genotype. The actuarial freedom from any CAD for the recipients with each respective donor PAI-1 genotype at 12 and 24 months was 100% and 100% for the 1/1 PAI-1 genotype, 92% and 92% for the 1/2 PAI-1 genotype, and 75% and 45% for the 2/2 PAI-1 genotype (P=0.03). Recipients with a diseased 2/2 PAI-1 genotyped allograft had longer ischemic times (P=0.02) than those recipients with a Tx CAD-free allograft., Conclusions: These data suggest that recipients with a 2/2 PAI-1 genotype are at a significant risk of developing Tx CAD. This genotype may serve as a useful screening tool for predicting the future development of Tx CAD.

Endomyocardial biopsy (EMB) remains the mainstay for the diagnosis of acute cellular rejection in cardiac transplant patients. A noninvasive alternative that would supplant or reduce the number of EMBs would be a highly desirable and cost-effective tool. To evaluate one potential alternative, a pacemaker with high resolution telemetry capabilities and two fractally coated epimyocardial leads were implanted in 30 patients at five transplant centers during the heart transplant procedure. Ventricular electrograms were recorded during intrinsic and paced activity and digitized to a laptop-based data acquisition device. Electrograms were recorded at frequent intervals and systematically on days when EMBs were performed. The electrogram data were then transferred via the Internet to a central data processing site. Clinical patient management was blinded to the electrogram results and varied considerably among the five centers. Using EMB together with clinical assessment of the transplant revealed 18 cases of clinically significant rejection beyond postoperative day 27 that required antirejection therapy. The normalized parameter values extracted from the electrogram recordings during pacing (the ventricular evoked response) that were associated with significant rejection were statistically lower (86% +/- 16% versus 96% +/- 22%, P < 0.005). The application of a single-threshold diagnosis model to the parameter values allowed detection of significant rejection with a negative predictive value of 98%. This analysis also showed that as many as 55% of the routine surveillance EMBs could have been eliminated had the pacemaker monitoring technique been used as a screening tool prior to EMB. A prospective study should further define the role of this technique in the detection and management of cardiac transplant patients.

Background: After heart transplantation, 1-year and 5-year survival rates are 79% and 63%, respectively, with rejection, infection, and allograft coronary artery disease accounting for the majority of deaths. Mycophenolate mofetil (MMF), an inhibitor of the de novo pathway for purine biosynthesis, decreases rejection in animals and in human renal transplantation., Methods: In a double-blind, active-controlled trial, 28 centers randomized 650 patients undergoing their first heart transplant to receive MMF (3000 mg/day) or azathioprine (1.5-3 mg/kg/day), in addition to cyclosporine and corticosteroids. Rejection and survival data were obtained for 6 and 12 months, respectively. Because 11% of the patients withdrew before receiving study drug, data were analyzed on all randomized patients (enrolled patients) and on patients who received study medications (treated patients)., Results: Survival and rejection were similar in enrolled patients (MMF, n=327; azathioprine, n=323). In treated patients (MMF, n=289; azathioprine, n=289), the MMF group compared with the azathioprine group was associated with significant reduction in mortality at 1 year (18 [6.2%] versus 33 deaths [11.4%]; P=0.031) and a significant reduction in the requirement for rejection treatment (65.7% versus 73.7%; P=0.026). There was a trend for fewer MMF patients to have > or = grade 3A rejection (45.0% versus 52.9%; P=0.055) or require the murine monoclonal anti-CD3 antibody or antithymocyte globulin (15.2% versus 21.1%; P=0.061). Opportunistic infections, mostly herpes simplex, were more common in the MMF group (53.3% versus 43.6%; P=0.025)., Conclusions: Substitution of MMF for azathioprine may reduce mortality and rejection in the first year after cardiac transplantation.

Background: Controversy exists regarding donor and recipient factors that promote the development and progression of coronary artery disease after heart transplantation and the likelihood of coronary artery disease causing death or retransplantation., Methods: To investigate this issue in a large cohort of patients, we analyzed 5963 postoperative angiograms performed in 2609 of the 3837 patients undergoing heart transplantation at 39 institutions between January 1990 and December 1994. Coronary artery disease was classified as mild, moderate, or severe on the basis of left main involvement, primary vessel stenoses, and branch stenoses. Coronary artery disease was considered severe if left main stenosis was > 70% or 2 or more primary vessels stenoses were > 70% or branch stenoses were > 70% in all 3 systems., Results: By the end of 5 years after heart transplantation, coronary artery disease was present in 42% of the patients, mild in 27%, moderate in 8%, and severe in 7%. Coronary artery disease-related events (death or retransplantation) had an actuarial incidence of 7% at 5 years and occurred in 2 of 3 of the patients with development of angiographically severe coronary artery disease. By multivariable logistic analysis, risk factors for donor coronary artery disease included older donor age (P < .0001) and donor hypertension (P=.0002). By multivariable analysis in the hazard function domain, risk factors identified for the earlier onset of allograft coronary artery disease included older donor age (P < .0001 ), donor male sex (P=.0006), donor hypertension (P=.07), recipient male sex (P=.02), and recipient black race (P=.01). The actuarial incidence of severe coronary artery disease was 9% at 5 years., Conclusions: Angiographic coronary artery disease is very common after heart transplantation, occurring in approximately 42% of the patients by 5 years. Older donor age, donor hypertension, and male donor or recipient predict earlier onset of angiographic allograft coronary artery disease. Although severe angiographic allograft coronary artery disease occurs in only 7% of the patients at 5 years, its presence is highly predictive of subsequent coronary artery disease-related events or retransplantation.

We undertook a study to determine the efficacy of stents in reducing restenosis in cardiac allograft vasculopathy. The result shows that coronary stenting significantly reduces restenosis in cardiac allograft vasculopathy compared with balloon angioplasty alone.

Continuous intravenous infusion of epoprostenol sodium in selected patients with primary pulmonary hypertension improves symptoms and survival. This report describes two patients with primary pulmonary hypertension treated with epoprostenol in whom intrapulmonary shunting and severe hypoxemia occurred. Intrapulmonary shunting was confirmed by contrast echocardiography showing delayed appearance of bubbles in the left cardiac chambers after peripheral venous injection of agitated saline solution.

Pilots who have received a heart transplant may subsequently want to resume flying. This study was undertaken to determine whether a group of heart transplant recipients who had a particularly low risk of sudden unexpected death could be identified from clinical data. An event, "rapid-onset death," was defined incorporating a number of possible causes of death that could result in a heart transplant recipient-pilot losing control of an airplane. The survival of 3676 patients undergoing a first heart transplantation was 85% and 73% at 1 and 5 years, respectively, the hazard function having a high early phase of risk. When time zero was moved to the beginning of the second year after transplantation, the freedom from "rapid-onset death" at posttransplantation year 2 and posttransplantation year 5 was 96.8% and 88%, respectively. For patients who had both a "normal" coronary angiogram and no episodes of acute heart rejection during the first year transplantation, the probability of "rapid onset death" during the second posttransplantation year was 1.4%, and given the same circumstances, during the third posttransplantation year the risk of "rapid-onset death" was 1.6%. This information is potentially useful to the Federal Aviation Administration for policy decisions regarding this issue.