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Vemurafenib and cobimetinib are extremely effective in treating V600E-mutated metastatic melanoma, but their use is associated with toxic cardiac effects. Vemurafenib-induced prolonged QTc interval may be associated with ventricular fibrillation and sudden cardiac death. Cobimetinib-induced myocardial damage may lead to severely reduced heart function and lethal heart failure. Few data are available about the time course of recovery after these side effects. We provide the first description of cardiac recovery after potentially fatal cardiac side effects due to vemurafenib and cobimetinib administration. A 51-year-old woman was admitted to our hospital with diarrhea, vomiting, and asthenia. At admission, her left ventricular ejection fraction (LVEF) was severely reduced and QTc interval was extremely elongated (normal range QTc ≤ 440 ms). Blood levels of troponin I (normal values below 0.07 ng/mL) and brain natriuretic peptide (brain natriuretic peptide (BNP), normal range l 100 pg/mL) were elevated. During hospitalization, she developed recurrent runs of torsades de pointes degenerating into ventricular fibrillation, requiring direct current electric shock (DC shocks). Vemurafenib and cobimetinib were discontinued. Three weeks later, QTc was still higher than 500 ms and LVEF lower than 30%: an implantable cardioverter-defibrillator (ICD) was implanted. Myocardial function improved within 1 month, and QTc intervals became 500 ms 1 week later. After 6 months, a normal ejection fraction (> 55%) was observed, and the QTc interval was 455 ms. The patient died rather from metastatic melanoma recurrence 8 months later. This case report highlights the time-course of recovery after combined vemurafenib-cobimetinib-induced severe myocardial damage. Further research is warranted to assess whether and how antineoplastic therapy may be resumed after QT normalization and heart function recovery. .

The development of solid-phase assays for antibody detection has aided in the frequent detection of human leukocyte antigen (HLA) antibodies in nonalloimmunized males. Some scientists have reported that these HLA antibodies are produced to pathogens or allergens and the reactivity with HLA coated beads is the result of cross-reactive epitopes. These antibodies may also be directed toward cryptic epitopes exposed on the denatured beads. In this report, we describe the case of a heart transplanted patient who exhibited anti-HLA-A*02:01 donor-specific antibodies detected with a bead-based assay (Luminex) and undetected with the complement-dependent cytotoxicity (CDC) test. Posttransplant monitoring, carried out with CDC and with Luminex on sera from this patient collected at the 2nd, 4th, 8th, and 12th posttransplant weeks and at 1 year confirmed the presence of anti-HLA-A*02:01 in all serum samples. Additional tests carried out with denatured and intact HLA molecules using single antigen beads demonstrated that the antibody was directed toward a cryptic epitope. One year after transplantation the patient is doing well. No sign of antibody-mediated rejection was observed throughout the follow-up. A comprehensive evaluation of the anamnesis and of antibodies is critical to avoid needless exclusion of organ donors.

Management of aggressive, usually late-occurring, post-transplant lymphoproliferative disorders (PTLDs), a life-threatening complication after solid organ transplants, remains controversial. Four children affected by aggressive CD20+ PTLDs received a chemo-immunotherapy regimen for remission induction based on fludarabine, cyclophosphamide, doxorubicin, and rituximab, associated with a rapid discontinuation of immunosuppression (IS). Subsequent consolidation chemotherapy consisted of Berlin-Frankfurt-Munster-modified blocks. All patients achieved a complete remission, which persisted for 25, 68+, 80+, and 103+ months after diagnosis. Therapy was well tolerated. No patients developed allograft rejection during PTLD treatment. Our experience suggests that this chemo-immunotherapeutic approach may be an effective treatment strategy while allowing for a concomitant discontinuation of IS. Pediatr Blood Cancer 2011; 57: 324–328. © 2011 Wiley-Liss, Inc.

Tessari G, Naldi L, Piaserico S, Boschiero L, Nacchia F, Forni A, Rugiu C, Faggian G, Dall’Olio E, Fortina AB, Alaibac M, Sassi F, Gotti E, Fiocchi R, Fagioli S, Girolomoni G. Incidence and clinical predictors of primary opportunistic deep cutaneous mycoses in solid organ transplant recipients: a multicenter cohort study. Clin Transplant 2010: 24: 328–333. © 2009 John Wiley & Sons A/S. Abstract: Background: Primary opportunistic deep cutaneous fungal infections may cause significant morbidity and mortality in solid organ transplant recipients (OTR), but no data exist about their incidence, timing, and clinical predictors in a long-term follow-up. Patients and methods: A series of 3293 consecutive OTR including 1991 kidney, 929 heart, and 373 liver transplant recipients were enrolled. Patients were regularly followed up since time at transplantation (mean 5.5 yr ±5.9 SD) and primary opportunistic fungal infections registered. Persons-year at risk (PYs), incidence rates (IR), incidence rate ratios (IRR), and 95% confidence intervals were computed. Results: Twenty-two cases of deep cutaneous mycoses were detected, (IR 1.2 cases per 1000 PYs) after a mean follow-up time since transplantation of 2.5 yr ± 2.0 SD (median 1.8 yr). Six patients had subsequent systemic involvement and three patients died of systemic dissemination. A higher risk for mycoses was observed in the first two yr after transplantation, (IRR 35.9, p

(+)-Furanomycin is an antibiotic that substitutes for L-isoleucine in bacterial protein translation. We propose here a new short synthesis of a useful intermediate, a 1,2-diprotected 2-aminopent-4-ene-1,3-diol, starting from the inexpensive natural amino acid L-serine, and via a Gamer-type aldehyde. The (R)-α-amino aldehyde was obtained by the construction of an oxazoline ring between the N-protected amino group and the hydroxy group that resulted from reduction of the carboxylic acid functionality of L-serine.

Background: Optimal management of posttransplant lymphoproliferative disease (PTLD) remains to be defined due to heterogeneity of this condition and lack of predictors of the outcome. Here we report our experience with pediatric PTLD nonresponsive to immunosuppression (IS) withdrawal, managed after stratification into high and low risk according to the presenting features. Methods: This is a single-center retrospective review of prospectively enrolled patients. From 2001 to 2011, 17 children were diagnosed with severe B-lineage, CD20+, PTLD after a median of 37 months (range, 5-93) from liver (12), heart (4), or multiorgan (1) transplantation. Treatment was tailored on 2 risk groups: (1) standard-risk (SR) patients received IS reduction and rituximab; (2) high-risk (HR) patients received IS discontinuation, rituximab and polychemotherapy. Results: The cumulative incidence of rejection at 1 and 5 years after the diagnosis of PTLD was 35% (95% confidence interval [95% CI], 18-69%) and 53% (33-85%), respectively, whereas the disease-free survival at 1 and 5 years was 94% (95% CI, 65-99%) and 75% (45-90%), respectively. Three children died, PTLD-free, from different transplant-related complications: primary nonfunction after retransplantation (liver), cytomegalovirus disease 21 months after PTLD treatment (liver), graft dysfunction 25 months after PTLD (heart). Conclusions: Severe B-lineage PTLD after solid organ transplantation may be classified as SR or HR and treated accordingly with a tailored protocol obtaining a satisfactory long-term outcome. This approach accomplishes the control of lymphoproliferation in severe forms as well as the minimization of toxicity in milder PTLDs.

Background A single non-invasive gene expression profiling (GEP) test (AlloMap®) is often used to discriminate if a heart transplant recipient is at a low risk of acute cellular rejection at time of testing. In a randomized trial, use of the test (a GEP score from 0–40) has been shown to be non-inferior to a routine endomyocardial biopsy for surveillance after heart transplantation in selected low-risk patients with respect to clinical outcomes. Recently, it was suggested that the within-patient variability of consecutive GEP scores may be used to independently predict future clinical events; however, future studies were recommended. Here we performed an analysis of an independent patient population to determine the prognostic utility of within-patient variability of GEP scores in predicting future clinical events. Methods We defined the GEP score variability as the standard deviation of four GEP scores collected ≥315 days post-transplantation. Of the 737 patients from the Cardiac Allograft Rejection Gene Expression Observational (CARGO) II trial, 36 were assigned to the composite event group (death, re-transplantation or graft failure ≥315 days post-transplantation and within 3 years of the final GEP test) and 55 were assigned to the control group (non-event patients). In this case-controlled study, the performance of GEP score variability to predict future events was evaluated by the area under the receiver operator characteristics curve (AUC ROC). The negative predictive values (NPV) and positive predictive values (PPV) including 95 % confidence intervals (CI) of GEP score variability were calculated. Results The estimated prevalence of events was 17 %. Events occurred at a median of 391 (inter-quartile range 376) days after the final GEP test. The GEP variability AUC ROC for the prediction of a composite event was 0.72 (95 % CI 0.6-0.8). The NPV for GEP score variability of 0.6 was 97 % (95 % CI 91.4-100.0); the PPV for GEP score variability of 1.5 was 35.4 % (95 % CI 13.5-75.8). Conclusion In heart transplant recipients, a GEP score variability may be used to predict the probability that a composite event will occur within 3 years after the last GEP score. Trial registration Clinicaltrials.gov identifier NCT00761787 Electronic supplementary material The online version of this article (doi:10.1186/s12872-015-0106-1) contains supplementary material, which is available to authorized users.

Risk factors for graft coronary artery disease after heart transplant are discussed in relationship to cyclosporine dosages. Patients receiving a mean cyclosporine dose higher than 4 mg/kg/day had lower incidence of graft coronary disease than patients receiving lower dosages.

During heart surgery, cardiac troponin I (cTn-I) measurement provides a tool to evaluate different cardioprotective techniques. To investigate myocardial protection during heart transplantation (HTx), cTn-I and creatine kinase (CK)-MB release was measured in 42 patients randomized to receving either continuous retrograde warm blood reperfusion or no reperfusion after cold cardioplegia. A significant linear correlation was found between donor heart ischemic time and peaks and the area under the curve of cTn-I and CK-MB release. In patients with an ischemic time longer than 90 min, cTn-I release was significantly lower in those receiving continuous retrograde warm cardioplegia than in controls. No significant difference was observed for CK-MB, tCK, and myoglobin. Our data suggest that the measurement of postoperative cTn-I release may provide a method to evaluate ischemic cardiac damage after HTx. When the ischemic time is longer than 90 min, warm retrograde blood cardioplegia provides better myocardial protection than no reperfusion.

Background. Solid organ transplant patients undergoing long-term immunosuppression have high risk of developing lymphomas. The pathogenesis of the late-occurring posttransplantation lymphoproliferative disorders (PTLD) have not yet been extensively investigated. Methods. We studied 15 patients who developed PTLD after a median of 79 months (range 22–156 months) after organ transplant. Clonality, presence of Epstein-Barr virus (EBV) genome, and genetic lesions were evaluated by Southern blot analysis or polymerase chain reaction. Results. All monomorphic PTLD and two of three polymorphic PTLD showed a monoclonal pattern. Overall, 44% of samples demonstrated the presence of the EBV genome. Within monomorphic PTLD, the EBV-positive lymphomas were even lower (31%). A c-myc gene rearrangement was found in two cases (13%), whereas none of the 15 samples so far investigated showed bcl-1, bcl-2, or bcl-6 rearrangement. The modulation of immunosuppression was ineffective in all patients with monomorphic PTLD independent of the presence of the EBV genome. The clinical outcome after chemotherapy was poor because of infectious complications and resistant disease. With a median follow-up of 4 months, the median survival time of these patients was 7 months. Conclusions. Late occurring lymphomas could be considered an entity distinct from PTLD, occurring within 1 year of transplant, because they show a histological and clinical presentation similar to lymphomas of immunocompetent subjects, are frequently negative for the EBV genome, are invariably clonal, and may rearrange the c-myc oncogene. New therapeutic strategies are required to reduce the mortality rate, and new modalities of long-lasting immunosuppression are called for.

Background: Coronary artery disease (CAD) of allografted hearts is the main cause of late mortality after cardiac transplant, but its etiology is still undetermined. Hypothesis: This study was undertaken to evaluate the relevance of several risk factors, including cyclosporine (CsA) dose and blood CsA levels, to the incidence of CAD.Methods: In 163 heart transplants performed between November 1985 and August 1994 at our Institution, CAD was diagnosed by coronary angiography or at postmortem examination. Patients in whom postmortem examination or coronary angiography was not performed, as well as those 4 mg/kg/day, the 8.9 year probability of their remaining CAD free was 69% [confidence interval (CI) 50-87%] in comparison with 31% (CI 0-65%) in patients receiving a CsA dose(w) < 4 mg/kg/day.Conclusion: In our experience, a low CsA maintenance dose is the main risk factor for CAD, irrespective of blood CsA levels.

A case of human immunodeficiency virus (HIV) infection following heart transplantation is reported. The patient acquired HIV infection at surgery after receiving blood transfusions from an HIV seronegative donor who subsequently seroconverted. The patient was followed for 84 months following transplantation. He was immunosuppressed with cyclosporine and prednisone and his CD4+ lymphocyte count remained less than 200 cells/mm 3 . Before death, a progressive worsening of cardiac function was observed without any evidence of acute or chronic rejection. Death due to end-stage cardiomyopathy in the presence of opportunistic infections occurred suddenly. Cardiomyopathy might have been related to either antiretroviral treatment or HIV infection or both. The patient had a long-term survival, in spite of chronic immunosuppression, early development of low CD4+ count and early onset of an acquired immunodeficiency syndrome (AIDS)-defining illness. The possibility of a synergistic antiretroviral activity of cyclosporine in combination with zidovudine is discussed. Reported cases of HIV infection acquired after heart transplantation are reviewed.

CHL type is the least common major form of EBV-related PTLD but rarely occurs in pediatric recipients; development of CHL subsequent to other PTLD subtypes in the same transplant recipient is even more unusual. Because of its rarity, indications on the best treatment strategy are limited. Patients have been mostly treated with standard HL chemotherapy/radiotherapy, and prognosis seems more favorable than other monomorphic PTLDs. Herein, we describe a pediatric case of EBV-associated, stage IV-B, CHL arising in a heart allograft recipient eight yr after diagnosis of B-cell polymorphic PTLD. The patient was successfully treated with adjusted-dose HL chemotherapy and autologous EBV-specific CTL, without discontinuation of maintenance immunosuppression. At two yr from therapy completion, the patient is in CR with stable organ function. With this strategy, it may be possible to reproduce the good prognostic data reported for CHL-type PTLD, with decreased risk of organ toxicity or rejection.

Objective To compare the long-term risk of primary nonmelanoma skin cancer (NMSC) and the risk of subsequent NMSC in kidney and heart transplant recipients. Design Partially retrospective cohort study. Setting Two Italian transplantation centers. Patients The study included 1934 patients: 1476 renal transplant recipients and 458 heart transplant recipients. Main Outcome Measures Cumulative incidences and risk factors of the first and subsequent NMSCs. Results Two hundred patients developed a first NMSC after a median follow-up of 6.8 years after transplantation. The 3-year risk of the primary NMSC was 2.1%. Of the 200 patients with a primary NMSC, 91 (45.5%) had a second NMSC after a median follow-up after the first NMSC of 1.4 years (range, 3 months to 10 years). The 3-year risk of a second NMSC was 32.2%, and it was 49 times higher than that in patients with no previous NMSC. In a Cox proportional hazards regression model, age older than 50 years at the time of transplantation and male sex were significantly related to the first NMSC. Occurrence of the subsequent NMSC was not related to any risk factor considered, including sex, age at transplantation, type of transplanted organ, type of immunosuppressive therapy, histologic type of the first NMSC, and time since diagnosis of the first NMSC. Histologic type of the first NMSC strongly predicted the type of the subsequent NMSC. Conclusions Development of a first NMSC confers a high risk of a subsequent NMSC in transplant recipients. Intensive long-term dermatologic follow-up of these patients is advisable.

Primary opportunistic deep cutaneous fungal infections may cause significant morbidity and mortality in solid organ transplant recipients (OTR), but no data exist about their incidence, timing, and clinical predictors in a long-term follow-up. Patients and methods: A series of 3293 consecutive OTR including 1991 kidney, 929 heart, and 373 liver transplant recipients were enrolled. Patients were regularly followed up since time at transplantation (mean 5.5 yr ±5.9 SD) and primary opportunistic fungal infections registered. Persons-year at risk (PYs), incidence rates (IR), incidence rate ratios (IRR), and 95% confidence intervals were computed. Results: Twenty-two cases of deep cutaneous mycoses were detected, (IR 1.2 cases per 1000 PYs) after a mean follow-up time since transplantation of 2.5 yr ± 2.0 SD (median 1.8 yr). Six patients had subsequent systemic involvement and three patients died of systemic dissemination. A higher risk for mycoses was observed in the first two yr after transplantation, (IRR 35.9, p < 0.0001), in renal transplant recipients (IRR 5.1 p = 0.030), and in patients transplanted after the age of 50 (IRR 11.5 p = 0.020). Conclusions: Primary deep cutaneous opportunistic mycoses in OTR occur mainly in the first two yr after transplantation, in renal transplant recipients, and in older patients.

Introduction. Therapeutic doses of colchicine in patients with renal compromise and cyclosporine therapy may result in increased plasma concentrations of colchicine and colchicine toxicity. Case Report. A 60-year-old heart transplant patient with chronic renal failure and cyclosporine-induced immunosuppression was started on colchicine for suspected gout. Four days later, he developed multi-organ failure with rhabdomyolysis, liver damage, polyneuropathy, and cardiotoxicity. Colchicine intoxication was suspected and plasma levels were 7 ng/mL 36 hours after the sixth dose. Neutropenia with an absolute neutrophil count of 700 cells/mm3 was observed five days after colchicine discontinuation. Drug discontinuation, supportive care, antibiotic therapy for a concurrent infection, and G-CSF administration resulted in recovery and he was discharged from the hospital 3 weeks later. Discussion. Cyclosporine co-administration increases colchicine toxicity by a dual mechanism: cyclosporine inhibits P-glycoprotein resulting in increased intracellular colchicine concentrations and decreased hepatic and renal excretion of the drug and cyclosporine interacts with CYP3A4 to decreases the hepatic elimination of colchicine. On the other hand, colchicine may increase cyclosporine neurotoxicity by an addictive mechanism. Conclusions. Shortterm administration of therapeutic colchicine doses may cause life-threatening side effects in cyclosporine-treated patients with renal failure.

Background: Natriuretic peptides are useful markers for risk stratification of patients with heart disease. However, conflicting results have been reported about circulating atrial natriuretic peptide (ANP) concentration in heart transplant recipients. Methods: To ascertain the effects of diabetes and acute insulin administration on plasma ANP concentrations in a model of heart denervation, we studied 12 diabetic (D-OHT) and 6 nondiabetic heart-transplanted (OHT) patients using the euglycemic-hyperinsulinemic clamp and oral glucose tolerance tests. Five patients with type 2 diabetes without heart transplantation (D) and 9 healthy subjects (NOR) matched for anthropometric features served as the controls. Results: Means baseline plasma ANP concentration was higher in D-OHT (82 ± 15 pg/mL) than in OHT or NOR (27 ± 4 or 30 ± 5; P < .01), but was not different than D (69 ± 12; P = .82). During the clamp plasma ANP showed similar increases in all groups (49 ± 4, 39 ± 3, 59 ± 4, and 49 ± 3% in D-OHT, OHT, D, and NOR; P < .02 vs basal, P = NS among groups). Plasma osmolarity and catecholamines were also not different among groups and did not increase during the clamp. Fasting plasma ANP concentrations correlated with plasma glucose concentrations measured 120 minutes after oral glucose tolerance testing. Conclusions: Among heart transplantation recipients fasting plasma ANP concentrations were not different at 5 to 6 years after the surgical procedure than in nondiabetic controls. Increased ANP concentrations were observed among recipients with diabetes and among nontransplanted diabetic patients. Although the insulin-induced increment in ANP concentrations was not different among groups, circulating ANP was strongly associated with glucose tolerance status. © 2007 Elsevier Inc. All rights reserved

Objectives: Therapeutic monitoring of everolimus with chromatographic methods (HPLC) enabled effective immunosuppression while limiting the incidence of drug-related adverse events. A fluorescence polarization immunoassay (FPIA) has been recently developed for the assessment of everolimus levels. The present study was designed to evaluate FPIA performance and to compare it to HPLC. Design and methods: The performance of HPLC and FPIA was initially tested using drug-free whole blood spiked with different amount of everolimus concentrations and, subsequently, by analyzing 113 trough blood samples from heart transplant recipients chronically given everolimus as part of their immunosuppressive regimen. Results: Inaccuracy and imprecision of both methods were below 15%. The correlation between everolimus concentrations and measured FPIA and HPLC was good, with a Pearson coefficient of 0.9118. The FPIA gave a mean overestimation of 24.3% as compared with HPLC. As additional analysis, cross-reactivity ranging from 85.4% to 138.0% was found with sirolimus, an immunosuppressant with a chemical structure close to everolimus. Conclusion: The FPIA demonstrated acceptable performance for therapeutic drug monitoring of everolimus, and is a viable alternative to HPLC-based methods.

Purpose GEP (AlloMap) score instability has been shown to predict of events of graft dysfunction or death in an analysis of the IMAGE data set by Deng et al. Our goal is to test this hypothesis in the independent CARGO 2 patient data set. Methods and Materials In a case-cohort design, patients with >2 serial GEP tests were studied in multivariate Cox regression models to predict future clinical events. Intra-patient GEP score instability was defined as the standard deviation of an individual’s cumulative test scores. GEP score (range 0-39), GEP score ≥34, and GEP score stability were studied. Results GEP scores tend to rise and become more stable in the whole population during the first year post-transplantation than after 1 year. After 12 months, GEP score instability (p=0.001) and GEP ≥34 (p=0.06) predict future events. [ figure 1 ]

The in vivo assessment of free radicals concentration is hampered by their instability and extremely short half-life. The Diacron Reactive Oxygen Metabolites (D-ROM) test is a recently introduced method to evaluate the peroxidation of organic compounds. Since the manual performance of the test provides excessive analytical imprecision, the aim of this study was to evaluate the automation of this test. Within- and between-run imprecision and interference were assessed according to the guidelines proposed by the NCCLS. The reactive oxygen metabolites' (ROM) stability was evaluated in different physical conditions. For within-run and between-run imprecision the coefficients of variation were consistently lower than 5%. The maximum allowable concentration was 28.2 mmol/l, 0.068 mmol/l and 171 mmol/l for triglycerides, haemoglobin and bilirubin, respectively. Serum storage at -20 degrees C provided adequate ROM stability for up to 3 months, whereas storage at 4 degrees C yielded non-reproducible results. In conclusion, our data provide evidence that the D-ROM assay has both an acceptable stability and an adequate imprecision. The automated assay may be regarded as a fast and reproducible method for the quantitative evaluation of oxidative stress. Since it is easily performed, the method is suitable for routine in clinical laboratories and may provide an accurate estimation of oxidative stress in vivo.

Epstein-Barr virus (EBV)–associated posttransplantation lymphoproliferative disorders (PTLDs) are a well-recognized complication of immunosuppression in solid organ transplant recipients. The reported therapeutic approaches are frequently complicated by rejection, toxicity, and other infectious pathologies, and overall mortality in patients with unresponsive PTLD remains high. Thus, low-toxicity treatment options or, preferably, some form of prophylactic/preemptive intervention are warranted to improve PTLD outcome in this setting. We assessed whether transfer of EBV-specific cytotoxic T lymphocytes (CTLs) generated in vitro from the peripheral blood of allograft recipients receiving immunosuppression could increase EBV-specific killing in vivo without augmenting the probability of graft rejection. Autologous EBV-specific CTLs were generated for 23 patients who were identified as being at risk of developing PTLD through the finding of elevated EBV DNA load. Of the 23 patients, 7 received 1 to 5 infusions of EBV-specific CTLs. CTL transfer was well tolerated, and none of the patients showed any evidence of rejection. An increase of the EBV-specific cytotoxicity was observed after infusion, notwithstanding continuation of immunosuppressive therapy. EBV DNA levels had a 1.5- to 3-log decrease in 5 patients, whereas in the other 2 graft recipients CTL transfer had no apparent stable effect on EBV load. Our data suggest that the infusion of autologous EBV-specific CTLs obtained from peripheral blood mononuclear cells recovered at the time of viral reactivation is able to augment virus-specific immune response and to reduce viral load in organ transplant recipients. This approach may, therefore, be safely used as prophylaxis of EBV-related lymphoproliferative disorders in these patients, following a strategy of preemptive therapy guided by EBV DNA levels.

The heart rate (HR) and O(2) uptake (VO(2)) responses to cycle ergometer exercise and the role of O(2) transport in limiting submaximal and maximal aerobic performance were assessed in 33 heart transplant recipients (HTR) [14 children (P-HTR), 11 young adults (YA-HTR) and 8 middle-age adults (A-HTR)] and in 28 age-matched control subjects (CTL). In 7 P-HTR ("responders") the HR response to the onset of exercise (on-response) was as fast as that of CTL, whereas in all other patients ("non-responders") the HR on-response was typical of the denervated heart. Compared with non-responder P-HTR, responder P-HTR were also characterized by a normal peak HR (177+/- 16 vs. 151+/- 25 beats/min), an equally slow time constant for the VO(2) on-response (tau: 54 +/- 11 vs. 62+/- 13 s) and a similar low (approximately 60% of that of CTL) peak VO(2) (28 +/- 7 vs. 26 +/- 10 ml/kg per min). On the other hand non-responder YA-HTR and A-HTR were characterized by a relatively low peak HR (151 +/- 21 and 144 +/- 29 beats/min, respectively), a slow tau for the on-response (63 +/- 12 and 70 +/- 11 s) and a low peak (28 +/- 7 and 19 +/- 6 ml/kg per min). In conclusion, a sizeable number of paediatric patients (responder P-HTR) may reacquire the normal HR response to exercise, both in terms of kinetics and maximal level. Despite the almost complete recovery of cardiovascular function, and, probably, oxygen delivery, both the kinetics of the VO(2) on-response and the maximal aerobic power of the responder P-HTR were similar to those of non-responder P-HTR. The latter finding is probably attributable to peripheral limitations, due to inborn and/or pharmacological muscle deterioration.

The plasma concentration of noradrenaline ([NA]) is higher than that of adrenaline ([A]) both in normal subjects and in heart transplant recipients (HTR). Since in both groups the myocardial density of beta1-adrenergenic receptors is much greater than that of beta2-adrenergenic receptors, the chronotropic response of a denervated heart to changes in plasma [NA] and [A] in the absence of reinnervation should be similar to that of agonist stimulation of beta1-receptors. To test this hypothesis, 17 HTR and 9 healthy subjects (CTL) performed incremental exercise on a cycle ergometer to voluntary exhaustion. Heart rate (HR) was recorded by electrocardiography. [NA] and [A] were measured by high-pressure liquid chromatography at rest and at increasing workloads (w). In both groups, HR and [NA+A] increased with w, and HR with [NA+A]. Normalized HR values, plotted against the logarithm of [NA+A], fitted significantly logistic curves. The affinity constants were different, i.e. 2599+/-350 and 487+/-37 ng.l(-1), for HTR and CTL, respectively. The chronotropic effect of changes in [NA+A] in HTR was similar to that of combined beta1- and beta2-adrenergic activation evoked by applying isoprenaline to isolated heart myocytes (Brodde OE, Pharmacol Ther 60:405-430, 1993). These findings suggest that over time sympathetic reinnervation and the modulation of beta-receptors may take place in HTR, ruling out the hypothesis of persistent heart denervation.

OBJECTIVE—This study examined the metabolic effects of heart transplantation in patients in end-stage cardiac failure. RESEARCH DESIGN AND METHODS—A total of 18 patients after heart transplantation for end-stage heart disease (age 47± 3 years; transplant age 5.5± 1.5 years; BMI 25.8± 0.8 kg/m2; cyclosporin A 4.2 ±0.6 mg/[kg·day]; azathioprine 0.87± 0.31 mg/[kg·day]), 12 patients with type 2 diabetes (D-Tx), and 6 patients without type 2 diabetes (Tx) were studied by means of 1) an oral glucose tolerance test (OGTT) to assess the β-cell secretory response, 2) a euglycemic-hyperinsulinemic (1 mU/[kg·min]) clamp combined with indirect calorimetry and a primed continuous infusion of [6,6-2H2]glucose and [1-13C]leucine to measure postabsorptive and insulin-stimulated carbohydrate and protein metabolism, and 3) 1H-NMR spectroscopy of the calf muscles to measure intramyocellular triglyceride (IMCL) content. The patients were selected from 480 transplant patients in whom there was a 6% prevalence of type 2 diabetes. Five healthy subjects matched for anthropometric parameters served as control subjects (CON). RESULTS—Tx had postabsorptive and insulin-stimulated glucose, leucine, and free fatty acid metabolism, as well as IMCL content, similar to that of CON. D-Tx were characterized by a reduced secretory response during the OGTT and peripheral insulin resistance with respect to glucose metabolism, which was paralleled by increased plasma free fatty acid concentrations and IMCL content. A defective insulin-dependent suppression of the endogenous leucine flux (index of proteolysis) was also evident during the clamp in D-Tx. CONCLUSIONS—Heart transplantation, notwithstanding the immunosuppressive therapy, was characterized by a normal postabsorptive and insulin-stimulated glucose, leucine, and free fatty acid metabolism in Tx. In contrast, insulin resistance with respect to glucose, free fatty acids, and protein metabolism was present in D-Tx regardless of whether diabetes was preexisting or consequent to heart transplantation.

Functional re-innervation of the transplanted human heart by the autonomic nervous system has not yet been demonstrated and lack of autonomic control of the transplanted allograft is reflected by an increased resting heart rate, a sluggish heart rate response to dynamical exercise and a reduced heart rate variability. Recent evidence suggests that a measure of deterministic chaos in the heartbeat interval time series, the point correlation dimension (PD2), is superior to the conventional power spectrum analysis which is based on the assumption of stochastic dynamics and limited by the requirements of stationarity in the data stream. In the PD2 analysis, dimensional changes of the system, i.e. the number of variables involved in the generation of its output (heartbeat interval time series), are determined within small “points” of time (beat-by-beat) irrespective of whether the system is stochastic or deterministic and nonstationary. PD2 was determined from heartbeat interval time series of digitized 40 min electrocardiograms (sampling rate 1200 Hz; supine posture) in 23 heart transplant recipients (HTR; 9 adults, 14 children; 0.07–7.7 yrs after transplantation) and 21 healthy control subjects (CTL; 13 adults, 8 children). PD2 (±SD) averaged 5.4±0.7 (adults) and 5.4±0.6 (children), respectively. The noninteger number of the dimensional estimate suggests that the normal heartbeat exhibits low-dimensional chaotic dynamics. In the HTR group, irrespective of age, PD2 was reduced to ∼1 early after transplantation but would not seem to attain normal control values within the time interval studied in long-term survivors (6–7 yrs). The initial breakdown of nonlinear chaotic dynamics along with the recurrence of low-dimensional deterministic dynamics with time after transplantation would suggest a recovery of cardiac control and heartbeat fluctuations that would be attributable to reorganization of the viable intrinsic cardiac nervous system or re-innervation of the extrinsic autonomic nervous system.

RATIONALE: Functional reinnervation of the transplanted human heart by the autonomic nervous system has not been demonstrated. A lack of autonomic control of the transplanted allograft is reflected by an increased resting heart rate, a sluggish heart rate response to dynamical exercise and a reduced heart rate variability. Recent evidence suggests that a measure of deterministic chaos in the heartbeat interval series (point correlation dimension, PD2i) is superior to the conventional power spectrum or other stochastic measures in detecting changes in the mechanism underlying heartbeat generation. METHODS: The PD2i is based on the presumption that the variability is determined and patterned, whereas the stochastic measures all assume that the variability is around a stationary mean and is noise. The PD2i reconstructs the degrees of freedom (number of independent variables) in the system that generates the time series examined, and does this irrespective of whether the system is stochastic or deterministic and is stationary in time. RESULTS: PD2i was determined for heartbeat intervals (RR, ECG digitized at 1200 Hz; supine posture) of 23 heart transplant recipients (HTR: 9 adults, 14 children; 0.04-7.7 years after transplantation) and 21 healthy control subjects (CTL; 13 adults, 8 children). The PD2i (+/-SD) averaged 5.4 +/- 0.7 for the CTL adults and 5.4 +/- 0.6 for the CTL children. Mean PD2i was reduced after transplantation to 1.1 +/- 0.1 in 6 HTRs recorded within 1 year after surgery; in one HTR recorded 2 weeks after surgery the mean PD2i was 3.7. Between 1 to 2 years PD2i was found increased in 2 of 3 subjects and between 2 to 8 years it was increased in 13 of 13, but not to control levels. In normal hearts the QT subinterval of each heartbeat cycle is associated with inotropy and the RR-QT remainder with chronotropy (i.e., the dyastolic interval during which RR is primarily regulated). To examine more closely the residual and returning heartbeat dynamics of the HTR subjects, these subinterval series were examined during mild exercise (40 to 90 Watts) and its recovery. In recent HTRs, resting QT and RR-QT were moderately reduced and modulated by exercise and recovery, but with an approximate 100 beat latency. In long-term (7-8 years) HTR subjects there was a rapid and larger response to exercise/recovery, but compared to normal the range was smaller and the complexity of the subinterval trajectories in time was simpler. CONCLUSIONS: Recurrence of low-dimensional deterministic dynamics after transplantation suggests recovery of neurocardiac control attributable to 1) reorganization of the viable intrinsic cardiac nervous system, 2) reinnervation by the extrinsic autonomic nervous system, or 3) both.

Congestive heart failure is a lethal condition that affects an increasing number of patients. In recent years a great amount of data have accumulated on the pathophysiology and medical and surgical therapy of this condition. In spite of the advances in its management and the great number of patients affected, common errors are still made by internists and cardiologists in the use of drugs and therapeutic strategies. Digitalis has only recently been shown to affect hemodynamics, exercise capacity, and clinical symptoms, but the effects on survival still have to be demonstrated. Loop diuretics, eventually combined with thiazides and antialdosterone drugs in patients with clinical signs and symptoms of fluid retention, are the mainstays of therapy of congestive heart failure. In order to make diuretic therapy efficacious, moderate salt and water intake restriction is mandatory. Angiotensin-converting enzyme (ACE) inhibitors are now considered unavoidable drugs in the management of heart failure, and an attempt to reach the doses that have been shown to be efficacious for survival in the large trials has to be made in every patient with this condition. Other vasodilators, such as hydralazine and nitrates, which show a less pronounced effect on survival but more effective hemodynamic actions than ACE inhibitors, may be used to control mitral insufficiency or to improve hemodynamics in very sick patients. Hemodynamic instability refractory to increasing doses of vasodilators and diuretics is a severe condition that requires hospital admission to administer drugs parenterally. These patients are usually treated with the combination of catecholamines and phosphodiesterase inhibitors associated with intravenous diuretics until clinical stability is again achieved and oral therapy is resumed and restructured. The use of aggressive pharmacological therapy and phosphodiesterase inhibitors has reduced the need for assisted circulatory support in these patients. Beta-blockers have shown promising results when administered to patients with heart failure, although a definitive demonstration of their effects on survival is still lacking. Other additional measures that need to be considered in patients with end-stage congestive heart failure are the use of antiarrhythmic drugs and anticoagulation.

Between February 1988 and September 1993 balloon aortic valvuloplasty was attempted in 33 consecutive patients in the first year of life: 20 patients (61%) were younger than 1 month. Major associated anomalies such as mitral stenosis, coarctation, and hypoplastic left ventricle were found in 11 cases (33%). The balloon dilation of the aortic valve was accomplished through the right carotid cut-down approach in neonates and patients with body weight < 5 kg, through a percutaneous femoral approach in the others; the procedure was completed in all. The peak systolic gradient across the aortic valve measured at catheterization fell from 80 +/- 33 mmHg (range 25-165) before the dilation to 27 +/- 17 mmHg (range 0-65), afterwards (p < 0.0001). The left ventricular ejection fraction increased from 44% +/- 26% to 61% +/- 17%, 24-48 hours after the procedure (p < 0.0001). Aortic insufficiency developed in 17 cases, being moderate in 2, mild in 6, and trivial in 9. Seven patients (21%), all in the first month of life, died within 30 days from the valvuloplasty; major associated anomalies were present in six; the death was due to a procedure related complication in one. No mortality was observed among the patients undergoing valvuloplasty beyond the first month of life. On follow-up (6 months to 6 years) aortic restenosis occurred in 3 cases; 1 was treated by surgical valvotomy, 2 by repeat balloon valvatomy; in another 2 cases, a subvalvular aortic obstruction developed and was relieved by surgical resection. There was no late mortality. Thus, balloon valvuloplasty appears to be an effective palliation for critical aortic stenosis in infancy. Early mortality is mainly related to associated anomalies.

Summary Cryptococcosis and aspergillosis in immunocompromised patients are extremely difficult clinical conditions to manage and treatment with available antifungal drugs often fails. Itraconazole, R-51211, Janssen Pharmaceutica, a new orally absorbed triazole, is a possible alternative drug which is potentially effective and nontoxic. Preliminary experience with 28 patients, eight with cryptococcosis and 20 with aspergillosis, is reported. Of these patients, 16 were immunocompromised (seven with the acquired immune-deficiency syndrome (AIDS), five heart transplant recipients and four with leukaemia or lymphoma). Overall, results of treatment were good (18 in remission, four markedly improved, four moderately improved and two failed). Prevention of relapses of cryptococcosis was obtained in all patients with AIDS on long-term itraconazole monotherapy (3 mg/kg). Treatment of invasive aspergillosis required a higher dosage (about 5 mg/kg) and prolonged administration. Besides its efficacy this antifungal agent allowed outpatient management.

Objective The clinical features and outcomes of patients undergoing heart transplantation after a failed Fontan operation are still debated. The aim of this study was to retrospectively evaluate our experience in 14 patients undergoing heart transplantation after previous Fontan-type operations. Methods From 1990 to 2002, 14 patients underwent heart transplantation in our institution after a previous Fontan procedure. The mean age at the time of the Fontan operation and at transplantation was 7.3 ± 2.8 and 17.2 ± 6.3 years, respectively. The indication for transplantation was protein-losing enteropathy in 7 patients, arrhythmia with ventricular dysfunction in 5 patients, and heart failure in 2 patients. All patients received basic immunosuppressive therapy with cyclosporine (INN: ciclosporin) and azathioprine without induction therapy or maintenance steroids. Results Two hospital deaths occurred: one patient died on the fifth postoperative day of graft failure, and the second died on the 17th postoperative day after an acute neurologic event. Two patients died later, one 23 months after transplantation of acute rejection and the other after 90 months of chronic rejection and endocarditis. One patient underwent successful reintervention 2 years after heart transplantation for pulmonary vein obstruction. The 10 surviving patients are in New York Heart Association class I, with a mean follow-up of 64.5 ± 42 months. One of them was delivered of a healthy baby 5 years after transplantation. Patients with protein-losing enteropathy reached a normal protein level within a mean of 10 months (range, 6-18 months) after transplantation. Four patients required a temporary administration (3-6 months) of oral steroid therapy for recurrent rejection episodes. Currently, 7 patients are taking cyclosporine, and 3 are taking cyclosporine and azathioprine. The actuarial survival at 1, 5, and 10 years was 86% ± 9%, 77% ± 12%, and 62% ± 17%, respectively. Conclusion Heart transplantation is a good option for patients with a failing Fontan operation. We documented the reversibility of protein-losing enteropathy in all patients. No mortality caused by surgical complications was observed.

Cardiopulmonary receptors have been shown to modulate renin release in animals. However, their involvement in reflex control of renin in humans has never been unequivocally established. This report reviews data on the effects on plasma renin activity of maneuvers (lower body negative pressure and passive leg raising) that reduce and increase central venous pressure and cardiac diameter without affecting blood pressure and heart rate, thereby deactivating and stimulating cardiopulmonary receptors with little or no involvement of the arterial baroreceptors. In normotensive subjects, reduction in central venous pressure was accompanied by an increase in plasma renin activity that was similar to the increase observed during tilt that reduced central venous pressure to a similar extent. Conversely, an increase in central venous pressure was accompanied by a reduction in plasma renin activity. The increase in plasma renin activity that followed the reduction in central venous pressure was drastically attenuated in four patients who had undergone cardiac transplantation, along with other reflex effects (changes in forearm vascular resistance and plasma norepinephrine) of cardiopulmonary receptor manipulations. There was a modest reduction in the overall reflex changes in plasma renin activity in patients with mild to moderate essential hypertension compared with normotensive subjects. However, patients with essential hypertension and cardiac hypertrophy showed marked attenuation of all reflex influences of the cardiopulmonary receptors. In five subjects, therapeutic regression of this structural alteration was associated with a clear improvement in the cardiopulmonary reflex. Thus, in humans, cardiopulmonary receptors exert an important reflex control of renin release. This control (which is due in part to receptors located in the cardiac walls) is moderately affected by a mild to moderate blood pressure elevation but is markedly impaired when the elevation produces structural alterations in the heart. Preliminary evidence, however, suggests that the cardiopulmonary reflex may be improved by a reduction in cardiac hypertrophy.

Background. Posttransplant lymphoproliferative disorders (PTLDs) that occur late after solid-organ transplantation are usually a monoclonal proliferation frequently characterized by the lack of the Epstein-Barr virus genome in tumor cells. The clinical outcome and the best management for patients who present with late PTLDs still remain unclear. Patients and Methods. Thirty patients who developed PTLDs more than 12 months (range 13-156) after heart, kidney, or liver transplantation were retrospectively evaluated. Median age was 36.7 years (range 1-70). Fifty-five percent of patients presented with advanced-stage (III-IV) lymphoma, 43% of patients presented with B symptoms, and 40% of patients showed extranodal involvement. Twenty-four cases (75%) were categorized as monoclonal monomorphic PTLD. Results. Three patients died of progressive multiorgan failure before any treatment was initiated. Overall, 17 (63%) patients obtained a clinical response (14 patients had complete remission [CR] and 3 patients had partial remission [PR]). Eight (47%) patients are still alive and in CR, two (12%) patients died in CR, and seven (41%) patients relapsed. With a median follow-up of 6 months (range 0.5-42.8), the median overall survival was 6.2 months. Both clinical response and survival were significantly influenced by the treatment. Indeed, all patients treated for limited disease with surgery or radiotherapy in combination with modulation of immunosuppression obtained CR and are still alive and in CR. On the contrary, 33% of patients who received chemotherapy obtained a clinical response, whereas 15% of patients who received chemotherapy showed progressive disease and 50% of patients who received chemotherapy died of toxicity (infectious or multiorgan failure). Conclusions. We suggest that patients with late PTLDs and limited disease may benefit from local treatment. For patients who require chemotherapy, we suggest that it should be administered to minimize the risk of infection complications.