[Heart transplantation in the 21st century in Netherlands: improved survival in the last decade]. / Harttransplantatie in de 21e eeuw: de overleving wordt beter.

OBJECTIVE: Over the past decades donor and recipient characteristics and medical management of heart transplantations patients have changed markedly. We studied the impact of these changes on long-term clinical outcome. DESIGN AND METHODS: Data of all consecutive heart transplant recipients in our center have been collected prospectively. Cohort A (n = 353 patients) was defined as the patients transplanted between 1984 and 1999, and was compared with cohort B (n = 227 patients) transplanted between 2000 and 2013. RESULTS: Compared to cohort A, recipients in cohort B had older donors (mean age 29 vs. 43 years, donors aged > 50 year: 2% vs. 33%, respectively). One-year survival in cohort A vs. B was 89% vs. 86% and at 10 years 53% vs. 68%, respectively (p = 0.02). Cohort B patients were treated more often with tacrolimus based immunosuppression (77% vs. 22%; p < 0.001), and early statins post-heart transplantation (88% vs. 18%; p = 0.001), while renal function was better conserved at 5 and 10 years (p = 0.001 and 0.02). Multivariate analysis showed significant reduction in 10 years mortality with tacrolimus-based immunosuppression (HR: 0.27 and 95% CI 0.17-0.42), treatment of hypertension (HR: 0.5, 95% CI 0.36-0.72) and revascularization (HR: 0.28, 95% CI 0.15-0.52). CONCLUSION: In spite of the use of much older donors, the long-term outcome after heart transplantation has improved considerably in the last decade, probably due to the introduction of newer treatment modalities.

Weaning from inotropic support and concomitant beta-blocker therapy in severely ill heart failure patients: take the time in order to improve prognosis.

AIMS: Beta-blockers improve the prognosis in heart failure (HF), but their introduction may seem impossible in patients dependent on inotropic support. However, many of these patients can be titrated on beta-blockers, but there is little evidence of successful clinical strategies. METHODS AND RESULTS: We analysed the records of inotropy-dependent patients referred for assessment for heart transplantation. Thirty-six patients (45%) could not be weaned (NW) and underwent left ventricular assist device (LVAD) implantation or transplantation, or died. However, 44 (55%) were successfully weaned (SW). Neither the aetiology (ischaemic vs. non-ischaemic) nor cardiac indexes were different in the SW as compared with the NW group (2.27±0.5 vs. 2.15±0.6 L/min/m2). The NW patients had lower LVEF (15±5% vs. 19±5%, P=0.001), higher right atrial pressure (12±6 vs. 8±6 mmHg, P=0.02), and more severe mitral regurgitation (P<0.001) than the SW patients. At discharge, 35 of 44 SW patients were receiving beta-blockers. In 29 of them, a beta-blocker could only be initiated or continued during concomitant support with i.v. enoximone for a duration of 14.1±7.2 days. Patients discharged on a beta-blocker had an LVAD/transplantation-free cumulative survival of 71% during a follow-up of 2074±201 days (confidence interval 1679­2470). CONCLUSION: It takes time to put severely ill HF patients on beta-blockers and it may require bridging with inotropes which are independent of beta-adrenergic receptors. Whether such a strategy may result in a better clinical outcome warrants further research.

Clinical implications of chronic hepatitis E virus infection in heart transplant recipients.

BACKGROUND: Recent reports have shown that hepatitis E virus (HEV) infection can become chronic in solid-organ transplant recipients, but few studies have systematically investigated the clinical consequences of this chronic HEV infection in solid-organ transplant (SOT) recipients. METHODS: We have undertaken an in-depth study of 6 chronic HEV-infected heart transplant recipients to gain further insight into the clinical, biochemical and virologic presentation of this disorder. RESULTS: In 6 patients (2.3%) chronic HEV infection, genotype 3, was identified. Immunosuppression in these patients was tacrolimus-based, combined with either everolimus or prednisolone and/or mycophenolate mofetil. Median follow-up after case detection was 26 months (range 21 to 40 months). All chronic HEV cases had elevated liver enzyme values. IgM antibodies at presentation were positive in 2 of 6 (33%) patients. Liver histology in 4 of 6 (67%) patients showed advanced fibrosis within 2 years after infection. One patient spontaneously cleared the HEV infection: 1 after dose reduction of immunosuppressive therapy and 3 during ribavirin therapy. One patient has yet to clear the virus and remains on ribavirin therapy. CONCLUSIONS: Chronic HEV infection in heart transplant (HTx) recipients may lead to rapid fibrosis of the liver. We advise additional HEV RNA screening in solid-organ transplant recipients with elevated liver enzymes, because antibody production is often delayed, as demonstrated in these patients. Dose reduction of immunosuppressive therapy should be the first intervention strategy to achieve viral clearance in chronic HEV-infected immunocompromised patients. Ribavirin treatment should be considered in cases of chronic HEV.

Identifying patients at risk of death or hospitalisation due to worsening heart failure using decision tree analysis: evidence from the Trans-European Network-Home-Care Management System (TEN-HMS) study.

OBJECTIVES: To stratify patients recently discharged from hospital with heart failure (HF) according to their risk of death and/or hospitalisation for worsening HF (WHF), to enable timely and appropriate monitoring and intervention. METHODS: Data from the TEN-HMS study were used in this analysis. Chi-square automatic interaction detector (CHAID) decision trees were constructed using a 10-fold cross-validation to predict events at 1-year and compared with logistic regression (LR) models using ROC curve analysis. RESULTS: 284 patients were used for training and 160 patients available at 4-month for validation. Amino-terminal pro-brain natriuretic peptide (NT-proBNP) was the strongest predictor of mortality identifying groups with high (>13,492 pg/ml), medium (3127-13,492 pg/ml) and low (≤ 3127 pg/ml) risk, followed by MI, systolic blood pressure, age, heart rhythm, study randomisation group and serum sodium. NT-proBNP was also the strongest predictor for death or hospitalization for WHF identifying groups with high (>13,492 pg/ml), medium (584-13,492 pg/ml), and low (≤ 584 pg/ml), followed by MI, creatinine, heart rhythm, potassium and urea. CHAID trees tended to perform better than LR-models (prediction of the composite outcome: ROC area with 95% CI, 0.797 (0.745-0.849) for CHAID and 0.738 (0.680-0.796) for LR-model; p=0.041; prediction of mortality: 0.892 (0.853-0.931) for CHAID and 0.858 (0.813-0.904) for LR; p=0.15). CONCLUSIONS: Decision trees are an alternative classification method used to differentiate risk in patients with HF. The resultant models are concise, free of subjective variables and understood easily by clinicians. Further exploration of their potential and validation in other data-sets is justified.

Frequency of asymptomatic disease among family members with noncompaction cardiomyopathy.

Noncompaction cardiomyopathy (NCC) is a primary cardiomyopathy characterized by an excessively prominent trabecular meshwork and deep intertrabecular recesses of the left ventricular walls. Most cases are inherited, with a dominant inheritance pattern. The aim of the present study was to determine the prevalence and clinical characteristics of cardiomyopathies in the close relatives of patients with NCC. We evaluated 156, mostly first-degree, family members of 44 adult patients with NCC who agreed to familial screening. A family history of cardiac disease was reported by 16 (36%) of the 44 patients, including premature sudden death in 8 families (18%). NCC (n = 32) or dilated cardiomyopathy (n = 9) was diagnosed in 41 relatives (26%) by echocardiography (n = 25), contrast echocardiography (n = 6), or magnetic resonance imaging (n = 10). Of these family members, 13 already had known cardiac symptoms and signs, but most (28 of 41) were asymptomatic. Most subjects with NCC had mild to moderate left ventricular dysfunction (n = 29, 71%). After a median follow-up of 55 months (interquartile range 43 to 93), most remained asymptomatic. Four family members were treated with prophylactic implantable cardioverter-defibrillator placement and 23 of those with NCC were treated with drugs, including angiotensin-converting enzyme inhibitors (41%), ß blockers (34%), and anticoagulants (17%). In conclusion, there is a high prevalence, mostly asymptomatic, of cardiac disease (26%) among first- and second-degree family members of patients with NCC. This warrants screening and offers an opportunity for early intervention.

Hepatitis E virus infection among solid organ transplant recipients, the Netherlands.

We screened 1,200 living heart, lung, liver, and kidney transplant recipients for hepatitis E virus infection by reverse transcription PCR. In 12 (1%) patients, hepatitis E virus infection was identified; in 11 patients, chronic infection developed. This immunocompromised population is at risk for hepatitis E virus infection.

Indications and outcome of implantable cardioverter-defibrillators for primary and secondary prophylaxis in patients with noncompaction cardiomyopathy.

BACKGROUND: Noncompaction cardiomyopathy (NCCM) is a rare, primary cardiomyopathy, with initial presentation of heart failure, emboli, or arrhythmias, including sudden cardiac death. Implantable cardioverter-defibrillators (ICDs) are frequently used for primary and secondary prevention in different cardiomyopathy patients, but data about ICD in NCCM are scarce. The aim of this study was, therefore, to investigate ICD indications and outcomes in NCCM patients. METHODS AND RESULTS: We collected prospective data from our NCCM cohort (n = 77 pts, mean age: 40 ± 14 years). ICD was implanted in 44 (57%) patients with NCCM according to the current ICD guidelines for nonischemic cardiomyopathies: in 12 for secondary prevention (7 × ventricular fibrillation, 5 × sustained ventricular tachycardia [VT]) and in 32 patients for primary prevention (heart failure/severe LV dysfunction). During a mean follow-up of 33 ± 24 months, 8 patients presented with appropriate ICD shocks due to sustained VT after median 6.1 [1-16] months. This included 4 of 32 (13%) patients in the primary prevention group and 4 of 12 (33%) in the secondary prevention group (P = 0.04). 9 patients presented with inappropriate ICD therapy: 6 (19%) in the primary and 3 (25%) in the secondary prevention group, at a median follow-up of 4 (2-23) months. CONCLUSIONS: In our cohort of NCCM patients, an ICD was frequently implanted for primary or secondary prevention of sudden cardiac death. At follow-up, frequent appropriate ICD therapy was observed in both groups, supporting the application of current ICD guidelines for primary and secondary prevention of sudden cardiac death in NCCM.

Management of chronic heart failure guided by individual N-terminal pro-B-type natriuretic peptide targets: results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study.

OBJECTIVES: The purpose of this study was to assess whether management of heart failure (HF) guided by an individualized N-terminal pro-B-type natriuretic peptide (NT-proBNP) target would lead to improved outcome compared with HF management guided by clinical assessment alone. BACKGROUND: Natriuretic peptides may be attractive biomarkers to guide management of heart failure (HF) and help select patients in need of more aggressive therapy. The PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study is, to our knowledge, the first large, prospective randomized study to address whether management of HF guided by an individualized target NT-proBNP level improves outcome. METHODS: A total of 345 patients hospitalized for decompensated, symptomatic HF with elevated NT-proBNP levels at admission were included. After discharge, patients were randomized to either clinically-guided outpatient management (n = 171), or management guided by an individually set NT-proBNP (n = 174) defined by the lowest level at discharge or 2 weeks thereafter. The primary end point was defined as number of days alive outside the hospital after index admission. RESULTS: HF management guided by this individualized NT-proBNP target increased the use of HF medication (p = 0.006), and 64% of HF-related events were preceded by an increase in NT-proBNP. Nevertheless, HF management guided by this individualized NT-proBNP target did not significantly improve the primary end point (685 vs. 664 days, p = 0.49), nor did it significantly improve any of the secondary end points. In the NT-proBNP-guided group mortality was lower, as 46 patients died (26.5%) versus 57 (33.3%) in the clinically-guided group, but this was not statistically significant (p = 0.206). CONCLUSIONS: Serial NT-proBNP measurement and targeting to an individual NT-proBNP value did result in advanced detection of HF-related events and importantly influenced HF-therapy, but failed to provide significant clinical improvement in terms of mortality and morbidity. (Effect of NT-proBNP Guided Treatment of Chronic Heart Failure [PRIMA]; NCT00149422).

Double intra-atrial connections in a patient late after orthotopic heart transplantation.

Atrial tachycardias occurring late after orthotopic heart transplantation are frequently caused by an ongoing atrial tachycardia in the recipient remnant atrium that is associated with intra-atrial muscle band connections between the 2 atrial compartments. The standard approach for most centers that treat these patients is to identify and disconnect these intra-atrial connections. We present a patient where double intra-atrial connections were capable of different degrees of stimulus propagation from the recipient remnant atrium to the donor atrial compartment. After the ablation of both intra-atrial connections, we also ablated the index arrhythmia in the recipient remnant atrium. This case presentation draws attention to the possibility of the presence of multiple intra-atrial connections.

Bradycardiomyopathy: the case for a causative relationship between severe sinus bradycardia and heart failure.

A 28-year-old man presented with progressive fatigue. Physical examination and ECG revealed severe sinus bradycardia. Echocardiography showed features of noncompaction cardiomyopathy and moderate aortic valve regurgitation. We hypothesized that the chronic volume overload exaggerated by prolonged diastole due to the bradycardia resulted in heart failure and noncompaction cardiomyopathy look-alike features. After implantation of an AAI pacemaker, his symptoms and signs of cardiomyopathy were fully recovered.

[Acute abdominal symptoms: consider heart failure]. / Acute buikklachten: denk ook aan hartfalen.

A large number of intra-abdominal and extra-abdominal diseases may give rise to abdominal symptoms. Two patients are discussed who presented with abdominal pain due to severe heart failure. Initially, this diagnosis was overlooked, since abdominal complaints are rarely the primary symptoms of this condition. The authors argue that heart failure, the overall prevalence of which is increasing, should be considered in the differential diagnosis of any patient who presents with abdominal pain. In addition, they propose a systematic diagnostic approach for reaching an individualised diagnosis and therapy directed at heart failure.

Inadequate immune regulatory function of CD4+CD25bright+FoxP3+ T cells in heart transplant patients who experience acute cellular rejection.

BACKGROUND: CD4CD25FoxP3 regulatory T cells are suppressors of antigen-activated immune reactivity. Here, we assessed the clinically relevant role of these cells in the control of immune responses directed to a transplanted heart. METHODS: We investigated the phenotype and function of peripheral CD4CD25FoxP3 T cells in heart transplant patients free from acute rejections (n=9) and in rejectors (n=12) before and during acute cellular rejection. RESULTS: Between rejectors and nonrejectors, the proportion of CD4CD25 T cells and of FoxP3 cells within this population was comparable. Yet, CD4CD25FoxP3 T cells of rejectors had a higher CD127 expression than those of nonrejectors (P<0.0001). Depletion of CD4CD25 T cells from peripheral blood mononuclear cells increased the antidonor proliferative response of both nonrejectors (P=0.0005) and rejectors (P=0.03). In rejectors, however, only a 2-fold increase was measured, whereas the nonrejectors' response became 14 times higher (P=0.002). Reconstitution of CD4CD25 T cells only suppressed the overall antidonor proliferative response of CD25 responder cells of nonrejectors significantly (P=0.001). Moreover, the percentage inhibition of the response was higher in nonrejectors than in rejectors (P=0.02). Analyses of pretransplant samples revealed that CD4CD25 T cells of rejectors already had a lower suppressive capacity than those of nonrejectors before transplantation (P=0.04). CONCLUSION: CD4CD25FoxP3 T cells of heart transplant patients who experience acute rejection had an up-regulated CD127 expression and an inadequate regulatory function compared with those of nonrejecting patients. Our observations suggest that the function of circulating CD4CD25FoxP3 regulatory T cells may be pivotal for the prevention of acute cellular rejection after clinical heart transplantation.

Blood dendritic cell levels and phenotypic characteristics in relation to etiology of end-stage heart failure: implications for dilated cardiomyopathy.

BACKGROUND: Dysregulation of dendritic cell (DC) mediated immune responses towards auto-antigens, is considered an important feature in the maintenance of experimentally induced heart failure (HF). In order to evaluate the role of blood DCs in cardiomyopathies of different origins, we examined myeloid (mDC) and plasmacytoid (pDC) subset levels and maturation characteristics, according to HF severity and etiology in humans. METHODS: Absolute numbers of mDCs and pDCs in 12 New York Heart Association (NYHA) class-II, 28 NYHA class III-IV HF patients and 18 healthy controls, were studied by 4-colour whole blood flow cytometry. RESULTS: End-stage (NYHA III-IV) HF patients had comparable circulating DC subset levels to NYHA-II patients and controls. However, within the NYHA III-IV group total DC levels in patients with non-ischemic dilated cardiomyopathy (DCM) were higher (P<0.001) than in patients with coronary artery disease (CAD), hypertrophic cardiomyopathy (HCM) or other HF etiology. This was due to a significant increase of primarily mDCs (P<0.0001) and to a lesser extent of pDCs (P<0.05) in idiopathic DCM patients, independent of systolic or diastolic cardiac dysfunction. Maturation marker CD83 and lymphoid homing chemokine receptor CCR7 surface expression was enhanced only on mDCs, but not pDCs from DCM patients (P<0.05), compared to patients with CAD, HCM or other underlying cardiac pathophysiology. CONCLUSIONS: Total blood DC levels in end-stage HF are elevated in patients with DCM. Whole blood DC characterisation may lead to new insights into the pathophysiology of idiopathic DCM in humans.

Susceptibility of human mesenchymal stem cells to tacrolimus, mycophenolic acid, and rapamycin.

BACKGROUND: Mesenchymal stem cells (MSC) have multilineage differentiation and immunomodulatory capacities and are potentially useful for therapeutic applications, such as tissue regeneration and control of alloreactivity. MSC are present in most tissues including the transplantable organs. It is therefore unavoidable that MSC will be exposed to immunosuppressive drugs in a clinical transplantation setting. The molecular targets of these drugs are expressed in MSC, but the effect of their inhibition on MSC functioning is unknown. METHODS: MSC were isolated and expanded from heart tissue and the effects of the calcineurin inhibitor tacrolimus, the cell cycle inhibitor mycophenolic acid (MPA), and the mammalian target of rapamycin inhibitor on MSC survival, proliferation, differentiation, and immunosuppressive capacity were examined. RESULTS: Short-term exposure to the immunosuppressants did not induce toxicity or apoptosis in MSC, but high-dose tacrolimus induced toxicity after 7 days. MPA and rapamycin inhibited MSC proliferation at therapeutic doses. The immunosuppressants had differential effects on the differentiation capacity of MSC. Tacrolimus reduced the expression of troponin T type 2 and desmin during cardiomyogenic differentiation of MSC, whereas MPA decreased the deposition of calcified minerals during osteogenic differentiation. Rapamycin stimulated lipid production during adipogenic differentiation. Unexpectedly, MSC had adverse effects on the immunosuppressive efficacy of tacrolimus and rapamycin. There was no such effect of MSC on the function of MPA. Preincubation of MSC with tacrolimus increased the immunosuppressive capacity of MSC. DISCUSSION: This study demonstrates that therapeutic concentrations of immunosuppressive drugs affect MSC function. MSC affect the efficacy of immunosuppressive medication. These findings are important for potential clinical use of MSC in combination with immunosuppressants.

FOXP3 mRNA expression analysis in the peripheral blood and allograft of heart transplant patients.

Previously, we demonstrated in heart transplant patients that FOXP3, a gene required for the development and function of regulatory T cells, was highly expressed in the graft during an acute cellular rejection. In this study, we analyzed whether the FOXP3 gene expression in the peripheral blood also reflects anti-donor immune responses, and therefore may provide clues for non-invasive detection of non-responsiveness or acute rejection. We examined the FOXP3 expression patterns of peripheral blood mononuclear cells (PBMC; n=69) of 19 heart transplant patients during quiescence and rejection in comparison with those of endomyocardial biopsies (EMB; n=75) of 24 heart transplant patients. While the FOXP3 mRNA levels were abundantly expressed in rejecting EMB (ISHLT rejection grade>1R) compared with EMB without histological evidence of myocardial damage (ISHLT rejection grade 0R-1R; p=0.003), no association with rejection or non-responsiveness was found for the FOXP3 mRNA levels in the peripheral blood. Thus, in contrast to intragraft FOXP3 gene expression, the peripheral FOXP3 mRNA levels lack correlation with anti-donor immune responses in the graft, and, consequently, FOXP3 does not appear to be a potential candidate gene for non-invasive diagnosis of non-responsiveness or rejection.

Predictors of cardiac events after cardiac resynchronization therapy with tissue Doppler-derived parameters.

BACKGROUND: To evaluate the prognostic value of tissue Doppler imaging (TDI)-derived parameters (E/E' ratio and Tei index) in heart failure (HF) patients who underwent cardiac resynchronization therapy (CRT). METHODS AND RESULTS: The study comprised 74 consecutive HF patients (mean age 60 +/- 11 years) who underwent CRT. Echocardiography including TDI measurements was performed in all patients at baseline and 3 months after CRT. During a median follow-up period of 720 days (range 210 to 1020 days), 21 patients (28%) had events (8 deaths, and hospitalization for HF in the remaining 13). From the baseline clinical and echocardiography data, univariable Cox-regressions analysis revealed that only diabetes (hazard ratio [HR] 3.703, P < .01), E/A ratio (HR 3.492, P < .001), and E/E' ratio (HR 1.130, P < .001) were predictors for cardiac events. From the 3-month follow-up data, the E/A ratio (HR 2.988, P < .005), E/E' ratio (HR 1.170, P < .001), left ventricular ejection fraction (HR 0.835, P < .01), deceleration time (HR 0.977, P < .05), and the Tei index (HR 15.784, P < .001) were predictors for cardiac events. After multivariable analysis, only diabetes (HR 5.544, P < .05), the 3-month E/E' ratio (HR 1.229, P < .001), and change in Tei index (HR 32.174, P < .001) were independent predictors for cardiac events. Patients with a high baseline and 3-month follow-up E/E' ratio had an 88% cardiac event rate. CONCLUSIONS: The Tei index and E/E' ratio are independent predictors of poor response and cardiac events after CRT.

Intragraft FOXP3 mRNA expression reflects antidonor immune reactivity in cardiac allograft patients.

BACKGROUND: Regulatory FOXP3+ T cells control immune responses of effector T cells. However, whether these cells regulate antidonor responses in the graft of cardiac allograft patients is unknown. Therefore, we analyzed the gene expression profiles of regulatory and effector T-cell markers during immunological quiescence and acute rejection. METHODS: Quantitative real-time polymerase chain reaction was used to analyze mRNA expression levels in time-zero specimens (n=24) and endomyocardial biopsies (EMB; n=72) of cardiac allograft patients who remained free from rejection (nonrejectors; n=12) and patients with at least one histologically proven acute rejection episode (rejectors; International Society for Heart and Lung Transplantation [ISHLT] rejection grade>2; n=12). RESULTS: For all analyzed regulatory and effector T-cell markers, mRNA expression levels were increased in biopsies taken after heart transplantation compared with those in time-zero specimens. Posttransplantation, the FOXP3 mRNA levels were higher in EMB assigned to a higher ISHLT rejection grade than the biopsies with grade 0: the highest mRNA levels were detected in the rejection biopsies (rejection grade>2; P=0.003). In addition, the mRNA levels of CD25, glucocorticoid-induced TNF receptor family-related gene, cytotoxic T lymphocyte-associated antigen 4, interleukin-2, and granzyme B were also significantly higher in rejecting EMB than in nonrejecting EMB (rejection grade

Interleukin-21: an interleukin-2 dependent player in rejection processes.

BACKGROUND: Interleukin (IL)-21 is the most recently described cytokine that signals via the common cytokine receptor (gammac), is produced by activated CD4+ T-cells, and regulates expansion and effector function of CD8+ T-cells. MATERIALS: To explore the actions of IL-21 with other gammac-dependent cytokines in alloreactivity, mRNA expression of IL-21, IL-21R alpha-chain, and IL-2 proliferation and cytotoxicity was measured after stimulation in mixed lymphocyte reactions. Additionally, IL-21 and IL-21R alpha-chain expression was studied in biopsies of heart transplant patients. RESULTS: Analysis of mRNA expression levels of allostimulated T-cells showed a 10-fold induction of IL-21 and IL-21R alpha-chain. Interestingly, induction of IL-21 was highly dependent on IL-2 (as in the presence of anti-IL-2, anti-IL-2R alpha-chain, and the immunosuppressive drugs cyclosporine A, tacrolimus, and rapamycin) the transcription of IL-21 was almost completely inhibited, whereas in the presence of exogenous IL-2 the mRNA expression of IL-21 was even more upregulated. IL-21 functioned as a costimulator for IL-2 to augment proliferation and cytotoxic responses, while blockade of the IL-2 route abrogated these functions of IL-21. Blockade of the IL-21 route by anti-IL-21R alpha-chain monoclonal antibodies inhibited the proliferation of alloactivated T-cells. Also, in vivo alloreactivity was associated with IL-21/IL-21R alpha-chain expression. After heart transplantation, the highest intragraft IL-21, IL-21R alpha-chain, and IL-2 mRNA expression levels were measured during acute rejection (P<0.001, P=0.01, P=0.03). CONCLUSION: IL-21 is a critical cytokine for IL-2 dependent immune processes. Blockade of the IL-21 pathway may provide a new perspective for the treatment of allogeneic responses in patients after transplantation.

Type D personality is associated with impaired health-related quality of life 7 years following heart transplantation.

OBJECTIVE: Health-related quality of life (HRQoL) following transplantation is gaining importance as an endpoint, but little is known about the role of normal personality traits as a determinant of HRQoL in this patient group. We investigated whether Type D personality (tendency to experience increased negative emotions paired with the nonexpression of these emotions) was associated with impaired HRQoL in heart transplant recipients. METHODS: Data were collected from all surviving heart transplant recipients >or=21 years of age (n=186) with a mean (S.D.) of 7 (5) years following transplantation. Patients completed the Short-Form Health Survey 36 (SF-36) and the Type D Scale (DS14). Clinical data were obtained from the medical records. RESULTS: Of the 186 patients, 18% had a Type D personality. Type D patients had significantly worse scores on the Physical Component scale (PCS) (P=.04) and the Mental Component scale (MCS) (P<.001) of the SF-36 and all the SF-36 subdomains (all P<.01) compared with non-Type D patients, except for Bodily Pain. Type D personality remained an independent determinant of impaired PCS [odds ratio (OR), 3.62; 95% confidence interval (CI), 1.25-10.45] and MCS (OR, 6.13; 95% CI, 2.23-16.83) and six of the eight subscales of the SF-36, adjusting for demographic and clinical characteristics. CONCLUSIONS: Type D personality was associated with more than a three- to six-fold increased risk of impaired HRQoL in heart transplant recipients, showing that the Type D personality construct also has value in heart transplant recipients. The adoption of a personality approach may lead to improved risk stratification in research and clinical practice in this patient group.