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Background: Cardiac graft denervation causes inadequate sinus tachycardia in patients after heart transplantation (HTX) which is associated with reduced survival. This study investigated the 5-year results of heart rate control with ivabradine or metoprolol succinate in patients after HTX., Methods: This registry study analyzed 104 patients receiving either ivabradine (n = 50) or metoprolol succinate (n = 54) within 5 years after HTX. Analysis included patient characteristics, medication, echocardiographic features, cardiac catheterization data, cardiac biomarkers, heart rates, and post-transplant survival including causes of death., Results: Demographics and post-transplant medication revealed no significant differences except for ivabradine and metoprolol succinate use. At 5-year follow-up, patients with ivabradine had a significantly lower heart rate (73.3 bpm) compared to baseline (88.6 bpm; P < 0.01) and to metoprolol succinate (80.4 bpm; P < 0.01), a reduced left ventricular mass (154.8 g) compared to baseline (179.5 g; P < 0.01) and to metoprolol succinate (177.3 g; P < 0.01), a lower left ventricular end-diastolic pressure (LVEDP; 12.0 mmHg) compared to baseline (15.5 mmHg; P < 0.01) and to metoprolol succinate (17.1 mmHg; P < 0.01), and a reduced NT-proBNP level (525.4 pg/ml) compared to baseline (3826.3 pg/ml; P < 0.01) and to metoprolol succinate (1038.9 pg/ml; P < 0.01). Five-year post-transplant survival was significantly better in patients with ivabradine (90.0%) versus metoprolol succinate (68.5%; P < 0.01)., Conclusion: Patients receiving ivabradine showed a superior heart rate reduction and a better left ventricular diastolic function along with an improved 5-year survival after HTX., (© 2020. The Author(s).)

Aims: Heart transplantation may represent a particular risk factor for severe coronavirus infectious disease 2019 (COVID-19) due to chronic immunosuppression and frequent comorbidities. We conducted a nation-wide survey of all heart transplant centers in Germany presenting the clinical characteristics of heart transplant recipients with COVID-19 during the first months of the pandemic in Germany., Methods and Results: A multicenter survey of all heart transplant centers in Germany evaluating the current status of COVID-19 among adult heart transplant recipients was performed. A total of 21 heart transplant patients with COVID-19 was reported to the transplant centers during the first months of the pandemic in Germany. Mean patient age was 58.6 ± 12.3 years and 81.0% were male. Comorbidities included arterial hypertension (71.4%), dyslipidemia (71.4%), diabetes mellitus (33.3%), chronic kidney failure requiring dialysis (28.6%) and chronic-obstructive lung disease/asthma (19.0%). Most patients received an immunosuppressive drug regimen consisting of a calcineurin inhibitor (71.4%), mycophenolate mofetil (85.7%) and steroids (71.4%). Eight of 21 patients (38.1%) displayed a severe course needing invasive mechanical ventilation. Those patients showed a high mortality (87.5%) which was associated with right ventricular dysfunction (62.5% vs. 7.7%; p = 0.014), arrhythmias (50.0% vs. none; p = 0.012), and thromboembolic events (50.0% vs. none; p = 0.012). Elevated high-sensitivity cardiac troponin T- and N-terminal prohormone of brain natriuretic peptide were significantly associated with the severe form of COVID-19 (p = 0.017 and p < 0.001, respectively)., Conclusion: Severe course of COVID-19 was frequent in heart transplanted patients. High mortality was associated with right ventricular dysfunction, arrhythmias, thromboembolic events, and markedly elevated cardiac biomarkers.

Aims: Amiodarone and digitalis are frequently used drugs in patients with heart failure. Both have separately been linked to reduced post-transplant survival, but their combined impact on mortality after HTX remains uncertain. This study investigated the effects of combined amiodarone and digitalis use before HTX on post-transplant outcomes., Methods and Results: This registry study analysed 600 patients receiving HTX at Heidelberg Heart Center between 1989 and 2016. Patients were stratified by amiodarone and digitalis use before HTX. Analysis included patient characteristics, medication, echocardiographic features, heart rates, permanent pacemaker implantation, atrial fibrillation, and post-transplant survival including causes of death. One hundred eighteen patients received amiodarone before HTX (19.7%), hereof 67 patients with digitalis (56.8%) and 51 patients without digitalis before HTX (43.2%). Patients with and without amiodarone before HTX showed a similar 1 year post-transplant survival (72.0% vs. 78.4%, P = 0.11), but patients with combined amiodarone and digitalis before HTX had a worse 1 year post-transplant survival (64.2%, P = 0.01), along with a higher percentage of death due to transplant failure (P = 0.03). Echocardiographic analysis of these patients showed a higher percentage of an enlarged right ventricle (P = 0.02), left atrium (P = 0.02), left ventricle (P = 0.03), and a higher rate of reduced left ventricular ejection fraction (P = 0.03). Multivariate analysis indicated combined amiodarone and digitalis use before HTX as a significant risk factor for 1 year mortality after HTX (hazard ratio: 1.69; 95% confidence interval: 1.02-2.77; P = 0.04)., Conclusions: Combined pre-transplant amiodarone and digitalis therapy is associated with increased post-transplant mortality., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Cardiac sarcoidosis is a chronic inflammatory disease with a large spectrum of symptoms that can mimic diseases such as dilated, hypertrophic, or arrhythmogenic cardiomyopathies. It can be asymptomatic but can also present with ventricular arrhythmias, conduction disease, and heart failure (HF) or even sudden cardiac death (SCD). We present here the case of a patient transplanted due to end-stage arrhythmogenic right ventricular cardiomyopathy (ARVC), fulfilling the task force criteria. A few years after successful heart transplantation (HTX), the patient developed similar symptoms and morphofunctional changes of the heart, which led to critical re-evaluation of his primary diagnosis., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: Severely elevated pre-transplant pulmonary vascular resistance (PVR) has been linked to adverse effects after heart transplantation (HTX). The impact of a moderately increased PVR before HTX on post-transplant outcomes remains uncertain. The aim of this study was to investigate the effects of an elevated pre-transplant PVR ≥ 300 dyn·s·cm -5 (≥3.75 Wood units) on outcomes after HTX., Methods and Results: This observational retrospective single-centre study included 561 patients receiving HTX at Heidelberg Heart Center between 1989 and 2015. Patients were stratified by degree of pre-transplant PVR. Analyses covered demographics, post-transplant medication, mortality and causes of death after HTX, early post-transplant atrial fibrillation (AF), and length of the initial hospital stay after HTX. Ninety-four patients (16.8%) had a PVR ≥ 300 dyn·s·cm -5 (≥3.75 Wood units). These patients had a higher rate of early post-transplant AF [20.2 vs. 10.7%, difference: 9.5%, 95% confidence interval (CI): 0.9-18.1%, P = 0.01] and an increased 30 day post-transplant mortality (25.5 vs. 6.4%, hazard ratio: 4.4, 95% CI: 2.6-7.6, P < 0.01), along with a higher percentage of death due to transplant failure (21.2 vs. 4.1%, difference: 17.1%, 95% CI: 8.7-25.5%, P < 0.01). Multivariate analysis revealed a PVR ≥ 300 dyn·s·cm -5 (≥3.75 Wood units) as a significant risk factor for increased 30 day mortality after HTX (hazard ratio: 4.4, 95% CI: 2.5-7.6, P < 0.01). Kaplan-Meier estimator showed a lower 2 year survival after HTX (P < 0.01) in patients with a PVR ≥ 300 dyn·s·cm -5 (≥3.75 Wood units)., Conclusions: Elevated pre-transplant PVR ≥ 300 dyn·s·cm -5 (≥3.75 Wood units) is associated with early post-transplant AF and increased mortality after HTX., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aim: With an increasing prevalence of heart failure (HF), more patients with advanced disease have to be treated in cardiology units by sophisticated medical and interventional strategies. We therefore developed a dedicated advanced heart failure unit (AHFU) to target the specific needs of the many patients with advanced HF. We here present our concept and its impact on outcome in high-risk high-urgency (HU) heart transplant candidates., Methods and Results: The eight-bed unit was established as an extension of the cardiologic intensive care and coronary care units in an intermediate care setting. Each bed was equipped with 24 h haemodynamic, respiratory, and arrhythmia monitoring. The unit is served 24/7 by five residents in cardiology, one staff cardiologist specializing in medical and interventional HF care, and 10 intensive care nurses. The cardiology team is supported by colleagues from cardiac surgery, sports medicine, psychosomatics, and the internal medicine departments. As an example of the intensified care on the AHFU, data from the cohorts of patients undergoing heart transplantation from HU status before (pre-AHFU 2008-11) and after establishment of the AHFU (AHFU 2012-15) were analysed. Interestingly, mortality on HU waiting list and post-heart transplant survival was comparable in both cohorts, despite significant increase in morbidity and co-morbidity as assessed by the Index for Mortality Prediction After Cardiac Transplantation model in the AHFU group., Conclusions: Our AHFU provides a unique and novel setting for the integration of modern pharmacological, interventional, surgical, and supportive HF therapy embedded in an academic heart centre. This may be a major step forward in the care of critical patients with advanced HF., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: Functional mitral regurgitation is complicating end-stage heart failure and potential heart transplantation by increasing pulmonary artery pressures. The aim of the present study was to investigate feasibility and haemodynamic effects of percutaneous mitral valve edge-to-edge repair using the MitraClip™ device in patients with end-stage heart failure awaiting heart transplantation., Methods and Results: In this retrospective study, we identified nine patients suffering from end-stage heart failure listed for heart transplantation in whom moderate-severe or severe functional mitral regurgitation was recognized and treated with percutaneous mitral valve edge-to-edge repair. Twenty-two patients listed for heart transplantation and presenting with moderate-severe or severe functional mitral regurgitation treated in the pre-MitraClip™ era served as controls. Patients were analysed at two separate time points: MitraClip™ group: pre-procedure and post-procedure (follow-up: 215 ± 53 days) and control group: study entry with recognition of moderate-severe or severe functional mitral regurgitation (follow-up: 197 ± 47 days). Percutaneous mitral valve edge-to-edge repair with the MitraClip™ was feasible and safe in our high-risk end-stage heart failure population. The intervention resulted in significant reduction of mitral regurgitation (grade 3.0 [0.5] to 1.5 [0.5]; P = 0.009), left atrial diameter (51 mm [16] to 49 mm [4]; follow-up MitraClip™ vs. control group P = 0.0497), pulmonary artery pressures (sPA 50 mmHg [15] to 45 mmHg [10]; P = 0.02; mPA 34 mmHg [8] to 30 mmHg [10]; P = 0.02), and New York Heart Association class (3.5 [1.0] to 3.0 [0.5]; P = 0.01) and improved mixed-venous oxygen saturation (57% [11] to 55% [7]; follow-up MitraClip™ vs. control group P = 0.02). No changes in the control group were observed., Conclusions: MitraClip™ implantation as 'bridge-to-transplant' strategy in patients with end-stage heart failure and severe functional mitral regurgitation awaiting heart transplantation is feasible and appears to result in favourable haemodynamic effects., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Cardiac amyloidosis, caused most commonly by deposition of light chain (AL) or transthyretin (ATTR) type fibrils, has an extremely poor prognosis. In this retrospective single-center study, we evaluated temporal trends in survival after heart transplantation for cardiac amyloidosis., Methods: We analyzed 48 patients with cardiac amyloidosis (AL, n = 32; familial ATTR, n = 16) who underwent heart transplantation from May 2002 to March 2017. Patients were analysed in 2 periods, Era 1 (2002- 2007) and Era 2 (2008- 2017), separated by altered patient selection in both, AL and ATTR amyloidosis, and changed chemotherapy regimens for AL amyloidosis., Results: The modern era was characterized by a lower number of extracardiac organ involvement for AL (94% isolated cardiac amyloidosis in Era 2 vs 56% in Era 1; p = 0.0221), and more frequent treatment for AL with the proteasome inhibitor bortezomib (94% in Era 2 vs 6% in Era 1; p < 0.0001). AL patients had significantly lower survival than patients with non-amyloid cardiomyopathy after heart transplantation in Era 1, and ATTR patients had numerically lower survival. However, survival in the modern era was comparable to non-amyloid transplants in both cohorts, possibly reflecting a shift in chemotherapy strategies and patient selection, respectively., Conclusions: In the current era, use of enhanced chemotherapy regimens for isolated advanced AL cardiac amyloidosis was associated with outcomes comparable to non-amyloid cardiomyopathy. We conclude that heart transplantation in highly selected patients with isolated non-systemic advanced cardiac amyloidosis may be a feasible approach., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Patients after heart transplantation (HTX) present with sinus tachycardia due to graft denervation. As elevated heart rates negatively affect survival, the aim of this study was to analyze the effects of ivabradine vs metoprolol succinate on heart rate, left ventricular (LV) mass and survival following HTX., Methods: This observational retrospective single-center study assessed 84 patients continuously receiving either ivabradine (n = 40) or metoprolol succinate (n = 44) within 2 years after HTX. Patients with dual therapy (ivabradine and metoprolol succinate), other beta blockers, amiodarone, or digitalis were excluded. Patient characteristics, post-transplant medication, heart rates, LV mass, and survival were investigated., Results: Analysis of patient characteristics, immunosuppressive drug regimen, and post-transplant medication showed no significant differences between groups except for ivabradine and metoprolol succinate. Baseline heart rates differed not significantly between patients treated with ivabradine [87.0 beats per minute (bpm)] and metoprolol succinate (86.2 bpm; P = 0.6395). At 2-year follow-up, patients with ivabradine (76.7 bpm) had a significantly lower heart rate compared to baseline (P < 0.0001) and to metoprolol succinate (82.0 bpm; P = 0.0283). LV mass in patients receiving ivabradine was lower at 2-year follow-up compared to baseline (P = 0.0067) and patients receiving metoprolol succinate (P = 0.0179). Patients with ivabradine had a superior 2-year survival after HTX (P = 0.0049)., Conclusion: Treatment with ivabradine in patients within 2 years after HTX significantly reduced post-transplant heart rate and LV mass and was associated with a superior survival in comparison with patients receiving metoprolol succinate.

Background: Major concerns about the safety of pretransplant amiodarone use have been raised. As a result of its long half-life, the cardiac allograft is exposed to amiodarone posing potential risks such as bradycardia, requirement for pacemaker implantation, or increased mortality after heart transplantation (HTX)., Objective: The aim of this study is to investigate the posttransplant outcomes of patients with no, acute, or chronic amiodarone use before HTX., Methods: This retrospective single-center study included 530 adult patients who received HTX between 06/1989 and 12/2012. Patients were stratified by their amiodarone therapy before HTX: no continuous amiodarone use (≤90 days before HTX), acute amiodarone use (≤90 days before HTX), and chronic amiodarone use (>90 days before HTX). Differences between the 3 groups in demographics, posttransplant medication, echocardiographic features, heart rates including occurrences of bradycardia, permanent pacemaker implantation, atrial fibrillation (AF), and survival were analyzed., Results: A total of 412 patients (77.7%) were in the "no amiodarone" group, 23 patients (4.4%) in the "acute amiodarone" group, and 95 patients (17.9%) in the "chronic amiodarone" group. Left ventricular ejection fraction ( P =0.5819), heart rates including occurrence of bradycardia during posttransplant week 1 ( P =0.0979 and P =0.2695), week 2 ( P =0.1214 and P =0.8644), week 3 ( P =0.1033 and P =0.8894), and week 4 ( P =0.2892 and P =0.8644), permanent pacemaker implantation within 30-day ( P =0.8644), or overall follow-up after HTX ( P =0.8664) were not significant between groups. Patients with chronic pretransplant amiodarone therapy had the lowest rate of early posttransplant AF ( P =0.0065). There was no statistically significant difference between groups in 30-day ( P =0.8656), 1-year ( P =1.0000), 2-year ( P =0.8763), 5-year ( P =0.5174), or overall posttransplant follow-up mortality ( P =0.1936)., Conclusion: Administration of acute or chronic pretransplant amiodarone was not related to an increased occurrence of bradycardia, requirement for permanent pacemaker implantation, or mortality after HTX. Importantly, chronic amiodarone use effectively reduced early AF after HTX, whereas acute amiodarone use showed no such effect., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: A calcineurin inhibitor (CNI)-based immunosuppression combined with mammalian target of rapamycin inhibitors (mTORs) seems to be attractive in patients after heart transplantation (HTX) in special clinical situations, for example, in patients with adverse drug effects of prior immunosuppression. Previous studies in patients after HTX detected advantageous effects regarding renal function of a tacrolimus (TAC)-based vs cyclosporine-A (CSA)-based immunosuppression (in combination with mycophenolate mofetil). However, data regarding renal function after HTX in mTOR/CNI patients remain limited., Aim: Primary end point of the present study was to analyze renal function in HTX patients 1 year after switch to an mTOR/CNI-based immunosuppression., Methods: Data of 80 HTX patients after change to mTOR/CNI-based immunosuppression were retrospectively analyzed. Renal function was assessed by measured serum creatinine and by estimated glomerular filtration rate (eGFR) calculated from Modification of Diet in Renal Disease equation., Results: Twenty-nine patients received mTOR/CSA-based treatment and 51 patients received mTOR/TAC-based therapy. At time of switch and at 1-year follow-up, serum creatinine and eGFR did not differ significantly between both study groups (all P =not statistically significant). Analysis of variances with repeated measurements detected a similar change of renal function in both study groups., Conclusion: The present study detected no significant differences between both mTOR/CNI study groups, indicating a steady state of renal function in HTX patients after switch of immunosuppressive regimen., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objectives: This study sought to evaluate myocardial perfusion reserve index (MPRI) and diastolic strain rate, both assessed by cardiac magnetic resonance (CMR) as a noninvasive tool for the detection of microvasculopathy., Background: Long-term survival of cardiac allograft recipients is limited primarily by cancer and cardiac allograft vasculopathy (CAV). Besides epicardial CAV, diagnosed by coronary angiography, stenotic microvasculopathy was found to be an additional independent risk factor for survival after heart transplantation., Methods: Sixty-three consecutive heart transplant recipients who underwent CMR, coronary angiography, and myocardial biopsy were enrolled. Stenotic vasculopathy in microvessels was considered in myocardial biopsies by immunohistochemistry and CAV was graded during coronary angiography according to International Society of Heart and Lung Transplantation criteria. In addition, by CMR microvasculopathy was assessed by myocardial perfusion reserve during pharmacologic hyperemia with adenosine and strain-encoded magnetic resonance using a modified spatial modulation of magnetization tagging pulse sequence in all patients., Results: Decreasing MPRI and diastolic strain rates were observed in patients with decreasing microvessel luminal radius to wall thickness ratio and decreasing capillary density (r = 0.45 and r = 0.61 for MPRI and r = 0.50 and r = 0.38 for diastolic strain rate, respectively; p < 0.005 for all). Using multivariable analysis, both MPRI and diastolic strain rate were robust predictors of stenotic microvasculopathy, independent of age, organ age, and CAV by International Society of Heart and Lung Transplantation criteria (hazard ratio: 0.07, p = 0.006 for MPRI; hazard ratio: 0.91, p = 0.002 for diastolic strain rate). Patients without stenotic microvasculopathy in the presence of no or mild CAV (n = 36) exhibited significantly higher median survival free of events, compared with patients with stenotic microvasculopathy in the presence of no or mild CAV (n = 18; p = 0.04 by log rank)., Conclusions: CMR represents a valuable noninvasive diagnostic tool, which may be used for the early detection of transplant microvasculopathy before the manifestation of CAV during surveillance coronary angiographic procedures., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Amiodarone is a frequently used antiarrhythmic drug in patients with end-stage heart failure. Given its long half-life, pre-transplant use of amiodarone has been controversially discussed, with divergent results regarding morbidity and mortality after heart transplantation (HTX)., Aim: The aim of this study was to investigate the effects of long-term use of amiodarone before HTX on early post-transplant atrial fibrillation (AF) and mortality after HTX., Methods: Five hundred and thirty patients (age ≥18 years) receiving HTX between June 1989 and December 2012 were included in this retrospective single-center study. Patients with long-term use of amiodarone before HTX (≥1 year) were compared to those without long-term use (none or <1 year of amiodarone). Primary outcomes were early post-transplant AF and mortality after HTX. The Kaplan-Meier estimator using log-rank tests was applied for freedom from early post-transplant AF and survival., Results: Of the 530 patients, 74 (14.0%) received long-term amiodarone therapy, with a mean duration of 32.3±26.3 months. Mean daily dose was 223.0±75.0 mg. Indications included AF, Wolff-Parkinson-White syndrome, ventricular tachycardia, and ventricular fibrillation. Patients with long-term use of amiodarone before HTX had significantly lower rates of early post-transplant AF (P=0.0105). Further, Kaplan-Meier analysis of freedom from early post-transplant AF showed significantly lower rates of AF in this group (P=0.0123). There was no statistically significant difference between patients with and without long-term use of amiodarone prior to HTX in 1-year (P=0.8596), 2-year (P=0.8620), 5-year (P=0.2737), or overall follow-up mortality after HTX (P=0.1049). Moreover, Kaplan-Meier survival analysis showed no statistically significant difference in overall survival (P=0.1786)., Conclusion: Long-term use of amiodarone in patients before HTX significantly reduces early post-transplant AF and is not associated with increased mortality after HTX.

Background: Nephrotoxicity is a serious adverse effect of calcineurin inhibitor therapy in patients after heart transplantation (HTX)., Aim: In this retrospective registry study, renal function within the first 2 years after HTX in patients receiving de novo calcineurin inhibitor treatment, that is, cyclosporine A (CSA) or tacrolimus (TAC), was analyzed. In a consecutive subgroup analysis, renal function in patients receiving conventional tacrolimus (CTAC) was compared with that of patients receiving extended-release tacrolimus (ETAC)., Methods: Data from 150 HTX patients at Heidelberg Heart Transplantation Center were retrospectively analyzed. All patients were continuously receiving the primarily applied calcineurin inhibitor during the first 2 years after HTX and received follow-up care according to center practice., Results: Within the first 2 years after HTX, serum creatinine increased significantly in patients receiving CSA (P<0.0001), whereas in patients receiving TAC, change of serum creatinine was not statistically significant (P=not statistically significant [ns]). McNemar's test detected a significant accumulation of patients with deterioration of renal function in the first half year after HTX among patients receiving CSA (P=0.0004). In patients receiving TAC, no significant accumulation of patients with deterioration of renal function during the first 2 years after HTX was detectable (all P=ns). Direct comparison of patients receiving CTAC versus those receiving ETAC detected no significant differences regarding renal function between patients primarily receiving CTAC or ETAC treatment during study period (all P=ns)., Conclusion: CSA is associated with a more pronounced deterioration of renal function, especially in the first 6 months after HTX, in comparison with patients receiving TAC as baseline immunosuppressive therapy.

Objective: The aim of this study was to analyze the distribution of malignancies in patients after heart transplantation (HTX) and to evaluate the risk factors including immunosuppressive therapy with regard to the development of malignancies and survival. Special emphasis was placed on the effects of a mammalian target of rapamycin (mTOR) containing immunosuppressive regimen., Methods: A total of 381 patients (age ≥18 years) receiving HTX were included in the present analysis. All patients were followed-up at the University of Heidelberg Heart Center, Heidelberg, Germany. Data were retrieved from the Heidelberg Registry for Heart Transplantation being collected between 1989 and 2014. According to center standard, all patients received induction therapy with anti-thymocyte globulin guided by T-cell monitoring since 1994. The initial immunosuppressive regimen consisting of cyclosporine A (CsA) and azathioprine (AZA) was replaced by CsA and mycophenolate mofetil (MMF) in 2001 and by tacrolimus (TAC) and MMF in 2006. Additionally, mTOR inhibitors (everolimus/sirolimus) were applied since 2003., Results: Mean recipient age at HTX was 51.2±10.5 years and the mean follow-up period after HTX was 9.7±5.9 years. During follow-up, 130 patients developed a neoplasm (34.1% of total). Subgroup analysis revealed 58 patients with cutaneous malignancy only (15.2%), 56 patients with noncutaneous malignancy only (14.7%), and 16 patients with both cutaneous and noncutaneous malignancy (4.2%). Statistically significant risk factors associated with an increased risk of malignancy after HTX were older age (P<0.0001), male recipients (P=0.0008), dyslipidemia (P=0.0263), diabetes mellitus (P=0.0003), renal insufficiency (P=0.0247), and >1 treated rejection episode (TRE) in the first year after HTX (P=0.0091). Administration of CsA (P=0.0195), AZA (P=0.0008), or steroids (P=0.0018) for >1 year after HTX was associated with increased development of malignancy, whereas administration of MMF (P<0.0001) or mTOR inhibitors (P<0.0001) was associated with a lower risk for development of malignancy. Additionally, 5-year follow-up of cutaneous malignancy recurrence (P=0.0065) and noncutaneous malignancy mortality (P=0.0011) was significantly lower in patients receiving an mTOR inhibitor containing therapy after the development of a malignancy., Conclusion: This study highlights the complexity of risk factors including immunosuppression with regard to the development of malignancies after HTX. mTOR-inhibitor-based immunosuppression is associated with a better outcome after HTX, particularly in cases with noncutaneous malignancy.

We sought to determine the ability of quantitative myocardial perfusion reserve index (MPRI) by cardiac magnetic resonance (CMR) and high-sensitive troponin T (hsTnT) for the prediction of cardiac allograft vasculopathy (CAV) and cardiac outcomes in heart transplant (HT) recipients. In 108 consecutive HT recipients (organ age 4.1±4.7 years, 25 [23%] with diabetes mellitus) who underwent cardiac catheterization, CAV grade by International Society for Heart & Lung Transplantation (ISHLT) criteria, MPRI, late gadolinium enhancement (LGE) and hsTnT values were obtained. Outcome data including cardiac death and urgent revascularization ("hard cardiac events") and revascularization procedures were prospectively collected. During a follow-up duration of 4.2±1.4 years, seven patients experienced hard cardiac events and 11 patients underwent elective revascularization procedures. By multivariable analysis, hsTnT and MPRI both independently predicted cardiac events, surpassing the value of LGE and CAV by ISHLT criteria. Furthermore, hsTnT and MPRI provided complementary value. Thus, patients with high hsTnT and low MPRI showed the highest rates of cardiac events (annual event rate=14.5%), while those with low hsTnT and high MPRI exhibited excellent outcomes (annual event rate=0%). In conclusion, comprehensive "bio-imaging" using hsTnT, as a marker of myocardial microinjury, and CMR, as a marker of microvascular integrity and myocardial damage by LGE, may aid personalized risk-stratification in HT recipients., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Aims: Cardiac allograft vasculopathy (CAV), which limits long-term survival after heart transplantation (HTX), is usually evaluated by coronary angiography (CA). Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) is a non-invasive technique that can detect CAV-related myocardial infarctions. We aimed to investigate the presence of LGE infarct-typical patterns in a large sample of HTX recipients and to correlate these findings with the severity of CAV assessed by CA., Methods and Results: LGE-CMR was performed in 132 HTX patients on a 1.5-T MRI scanner (Philips, Best, the Netherlands). Infarct-typical LGE areas were identified as bright lesions with subendocardial involvement. Infarct-atypical LGE was classified as follows: (i) right ventricle (RV) insertion, (ii) intramural, (iii) epicardial, and (iv) diffuse. CA was performed for the assessment of CAV (CAV0 = no lesion, CAV1 = mild lesions, CAV2 = moderate lesions, CAV3 = severe lesions, or mild/moderate lesions with allograft dysfunction). Infarct-typical LGE patterns were detected in 29 (22%) patients distributed in all groups and they were already present in nearly every fifth CAV0 patient, increasing significantly among CAV groups (CAV0 = 19%, CAV1 = 10%, CAV2 = 36%, and CAV3 = 71%; P < 0.01)., Conclusion: LGE-CMR was useful to identify myocardial scar possibly related to early CAV in a significant proportion of HTX recipients, otherwise classified as low-risk patients based on CA. Therefore, LGE-CMR could be helpful to intensify CAV monitoring, medical therapy, and clinical risk stratification., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: The use of tacrolimus (TAC) in patients after heart transplantation (HTX) has increased over the last few years., Aim: In this retrospective study, we evaluated the effects of a TAC (conventional and extended-release TAC)-based immunosuppressive therapy regarding rejection profile in comparison to a cyclosporine A (CSA)-based regimen in patients after HTX., Methods: The data of 233 patients who underwent HTX at the Heidelberg Heart Transplantation Center from May 1998 until November 2010 were retrospectively analyzed. Primary immunosuppressive therapy was changed from a CSA (n=114) to a TAC (n=119)-based regimen in February 2006 according to center routine. Follow-up period was 2 years post-HTX. Primary endpoint was time to first biopsy-proven rejection requiring therapy. In all patients, routine follow-up at the Heidelberg Heart Transplantation Center was mandatory., Results: Multivariate risk factor analysis regarding time to first rejection episode showed no statistically significant differences regarding recipient age, donor age, recipient sex, donor sex, sex mismatch, ischemic time, and diagnosis leading to HTX between the two groups (all P= not statistically significant). Time to first biopsy-proven rejection was significantly longer in the TAC group (intention-to-treat analysis, n=233, log-rank test P<0.0001; per-protocol analysis, n=150, log-rank test P=0.0003). In patients who underwent a change of primary immunosuppression (n=49), a significantly longer time to first biopsy-proven rejection was also found in the primary TAC subgroup (log-rank test P=0.0297). Further subgroup analysis in the TAC subgroups showed no statistically significant differences in time to biopsy-proven rejection under extended-release TAC compared to conventional TAC (intention-to-treat analysis, log-rank test P=0.1736)., Conclusion: Our study demonstrated that a TAC-based primary immunosuppressive therapy is superior to a CSA-based immunosuppressive regimen in patients after HTX regarding time to first biopsy-proven rejection.

Background: Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) enables high-resolution myocardial tissue characterization, showing the results of different injuries, especially in the early period after heart transplantation (HTX)., Objectives: We sought to apply LGE-CMR to investigate the prevalence and patterns of infarct-atypical myocardial involvement and associated mechanisms in patients early and late after HTX., Methods: LGE-CMR was performed on a 1.5-T MRI scanner (Philips, Best, the Netherlands) in 89 patients: group 1 (48 patients) less than 2.5 years after operation (1.2 ± 0.5 years) and group 2 (41 patients) later this period (8.2 ± 4.2 years). Following LGE-CMR, the presence, distribution, patterns of infarct-atypical LGE and possible associated mechanisms were assessed., Results: 71 % of group 1 patients (34/48) showed infarctatypical LGE whereas 57 % of group 2 patients (22/41) were affected (p = 0.25). Fewer segments/patients were involved later after HTX (1.6 ± 2.0 vs. 2.9 ± 3.1 segments/ patient; p = 0.03), but only diffuse LGE-CMR pattern decreased significantly (11.5 % of affected segments in group 1 vs. 6.5 % in group 2; p\0.001). Group 2 had lower ischemic time (181 ± 53 vs. 208 ± 61 min; p = 0.03), the donors were younger (33 ± 13 vs. 41 ± 13 years; p = 0.01) and fewer donors were Toxoplasma gondii seropositive (4 vs. 22pts; p\0.001)., Conclusion: Infarct-atypical LGE was found in a significant number of patients early post-HTX, however, fewer patients and myocardial segments per patient were affected later after HTX. Many potential factors seem to be involved, but the exact mechanisms are still unclear. Future studies are necessary to test prognostic implications associated with LGE-CMR patterns.

Background: Cyclosporine A (CSA) is a narrow therapeutic index drug. Available CSA products differ in the constitution of their emulsion. To compare intra-individual differences after a conversion to a generic CSA, a retrospective single-center study was initiated., Methods: Twenty adult stable chronic (>24 months post heart transplant) recipients were included in the present retrospective study. These patients were previously switched from Sandimmune Neoral® to the generic CSA (Equoral®) according to the patients' preference during the clinical routine. Dose-normalized trough levels (DNL) and trough levels (C0) at 8 months, 4 months, and 2 weeks before the switch were retrospectively compared with the corresponding values at 2 weeks, 4 months, and 8 months after the switch to the generic CSA. Additionally, changes in the routine laboratory parameters, the number of treated rejection episodes, and the adherence to the CSA target levels were compared., Results: The mean DNL (adapted to the daily CSA dose in mg) was 0.71±0.26 (ng/mL)/mg on Neoral therapy; on Equoral it was 0.68±0.23 (ng/mL)/mg, (P=0.38). In comparison to the CSA daily dose prior to the conversion, at postconversion, no significant changes of CSA daily dose were observed (Neoral 140.67±39.81 mg versus Equoral 134.58±41.61 mg; P=0.13). No rejection episodes requiring therapy occurred prior to or postconversion (P=0.99). Additionally, no statistically significant changes of routine laboratory parameters regarding the Modification of Diet in Renal Disease or hematological parameters were seen (all P=not significant). No adverse events after the conversion were observed., Conclusion: This study in chronic and stable HTx patients demonstrated no statistically significant differences in the CSA DNL after a conversion to generic CSA (Equoral). The generic CSA was generally well-tolerated. We concluded that a conversion from Neoral to Equoral is safe and clinically feasible in this distinct patient population. However, multiple switches between different generic immunosuppressants must especially be avoided in the interest of patient safety, and close follow-up examinations must be warranted.

Background: Due to graft denervation, sinus tachycardia is a common problem after heart transplantation, underlining the importance of heart rate control without peripheral effects. However, long-term data regarding the effects of ivabradine, a novel If channel antagonist, are limited in patients after heart transplantation., Methods: In this follow-up analysis, the resting heart rate, left ventricular mass indexed to body surface area (LVMI), tolerability, and safety of ivabradine therapy were evaluated at baseline and after 36 months in 30 heart transplant recipients with symptomatic sinus tachycardia versus a matched control group., Results: During the study period, ivabradine medication was stopped in three patients (10% of total). Further analysis was based on 27 patients with 36 months of drug intake. The mean patient age was 53.3±11.3 years and mean time after heart transplantation was 5.0±4.8 years. After 36 months, the mean ivabradine dose was 12.0±3.4 mg/day. Resting heart rate was reduced from 91.0±10.7 beats per minute before initiation of ivabradine therapy (ie, baseline) to 81.2±9.8 beats per minute at follow-up (P=0.0006). After 36 months of ivabradine therapy, a statistically significant reduction of LVMI was observed (104.3±22.7 g at baseline versus 93.4±18.4 g at follow-up, P=0.002). Hematologic, renal, and liver function parameters remained stable during ivabradine therapy. Except for a lower mycophenolate mofetil dose at follow-up (P=0.02), no statistically significant changes in immunosuppressive drug dosage or blood levels were detected. No phosphenes were observed during 36 months of ivabradine intake despite active inquiry., Conclusion: In line with previously published 12-month data, heart rate reduction with ivabradine remained effective and safe in chronic stable patients after heart transplantation, and also during 36-month long-term follow-up. Further, a significant reduction of LVMI was observed only during ivabradine therapy. Therefore, ivabradine may have a sustained long-term beneficial effect with regard to left ventricular remodeling in heart transplant patients.

Background: Modified-release tacrolimus (TAC) is a new, once-daily oral formulation of the established immunosuppressive agent TAC. This study evaluated long-term patient adherence, as well as safety and efficacy, in stable patients after heart transplantation (HTx) who switched from a conventional twice daily calcineurin inhibitor-based regimen (TAC or cyclosporine A [CsA]) to a once-daily modified-release TAC regimen., Methods: Stable patients were switched from conventional TAC or CsA (twice-daily dosing) to modified-release TAC (once-daily dosing) according to manufacturer's recommendations using a pre-experimental design. Self-reported adherence was assessed at baseline and 8 months after the switch with the Basel Assessment of Adherence with Immunosuppressive Medication Scale (BAASIS). Additionally, routine laboratory values were analyzed 8 months after switch., Results: Of 76 patients (58 male, 18 female) initially included, 72 were available for statistical analysis, as modified-release TAC was discontinued due to diarrhea in one patient and gastrointestinal discomfort in three patients. Overall nonadherence at baseline for any of the four BAASIS items was 75.0% versus 40.3% after 8 months (P<0.0001). After 8 months, adherence was improved in 41 patients (56.9%), unchanged in 27 (37.5%), and reduced in four patients (5.6%). The BAASIS visual analog scale score improved significantly from 87.0% ± 13.5% to 97.5% ± 5.7% (P<0.0001). No significant changes were observed for hematological, renal, or liver function parameters after 8 months (all P=not significant)., Conclusion: To our knowledge, this is the first study in stable patients after HTx to demonstrate a significant improvement in long-term (ie, 8-month) patient adherence after the switch to modified-release TAC. Modified-release TAC was generally well tolerated. Further studies are currently underway to investigate long-term safety after HTx of various calcineurin inhibitors for prevention of rejection and occurrence of side effects.

The purpose of our study was to investigate whether the quantification of myocardial blush grade (MBG) during surveillance coronary angiography can predict long-term outcome after heart transplantation (HT). In 105 HT recipients who underwent cardiac catheterization, cardiac allograft vasculopathy (CAV) was assessed visually using the ISHLT grading scale (prospective cohort study). MBG was quantified by dividing the plateau of contrast agent gray-level intensity (G(max)) by the time-to-peak intensity (T(max)). In a subgroup (n = 72), myocardial perfusion index by cardiac magnetic resonance imaging (CMR) was assessed. During a mean follow-up duration of 2.7 (standard deviation [SD] 1.0) years, 26 patients experienced cardiac events, including 7 with cardiac death and 19 who underwent coronary revascularization. G(max)/T(max) was related to CAV by ISHLT criteria and to subsequent cardiac events. By univariate analysis, patient age, organ age, CAV, MBG and myocardial perfusion index by CMR were all predictive for cardiac events. Multivariable analysis demonstrated that G(max)/T(max) provided the most robust prediction of cardiac death (hazard ratio [HR] = 0.2, 95% confidence interval [CI] = 0.06-0.64, p < 0.01) and cardiac events (HR = 0.52, 95% CI = 0.32-0.84, p < 0.01), beyond clinical parameters and the presence of CAV. G(max)/T(max) is a valuable surrogate parameter of microvascular integrity, which is associated with cardiac death and revascularization procedures after HT., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Type 2 Diabetes mellitus (T2DM) is a common comorbidity in patients after heart transplantation (HTx) and is associated with adverse long-term outcomes., Methods: The retrospective study reported here analyzed the effects of vildagliptin therapy in stable patients post-HTx with T2DM and compared these with control patients for matched-pairs analysis. A total of 30 stable patients post-HTx with T2DM were included in the study. Fifteen patients (mean age 58.6 ± 6.0 years, mean time post-HTx 4.9 ± 5.3 years, twelve male and three female) were included in the vildagliptin group (VG) and 15 patients were included in the control group (CG) (mean age 61.2 ± 8.3 years, mean time post-HTx 7.2 ± 6.6 years, all male)., Results: Mean glycated hemoglobin (HbA1c) in the VG was 7.4% ± 0.7% before versus 6.8% ± 0.8% after 8 months of vildagliptin therapy (P = 0.002 vs baseline). In the CG, HbA1c was 7.0% ± 0.7% versus 7.3% ± 1.2% at follow-up (P = 0.21). Additionally, there was a significant reduction in mean blood glucose in the VG, from 165.0 ± 18.8 mg/dL to 147.9 ± 22.7 mg/dL (P = 0.002 vs baseline), whereas mean blood glucose increased slightly in the CG from 154.7 ± 19.7 mg/dL to 162.6 ± 35.0 mg/dL (P = 0.21). No statistically significant changes in body weight (from 83.3 ± 10.8 kg to 82.0 ± 10.9 kg, P = 0.20), total cholesterol (1.5%, P = 0.68), or triglyceride levels (8.0%, P = 0.65) were seen in the VG. No significant changes in immunosuppressive drug levels or dosages were observed in either group., Conclusion: Vildagliptin therapy significantly reduced HbA1c and mean blood glucose levels in post-HTx patients in this study with T2DM and did not have any negative effects on lipid profile or body weight. Thus, vildagliptin therapy presented an interesting therapeutic approach for this selected patient cohort.

Following heart transplantation, cardiac biomarkers remain elevated for several weeks eventually as a result of membrane leakage of the donor organ. We now test the predictive power of blood levels of troponin T (TNT) measured by the new hsTNT assay (Roche Diagnostics, Roche Diagnostics, Mannheim, Germany) early after heart transplantation. TNT was determined in 141 cardiac allograft recipients and 40 controls. Our findings demonstrate that patients who died within the first year after transplantation had significantly higher median hsTNT serum levels 6 weeks after transplantation (156 ng/l ± 203 vs. 29 ng/l ± 21, P = 0.0002). Using ROC analysis, a serum hsTNT concentration of 33.55 ng/l 6 weeks after transplantation was found to be the best cutoff to predict death at 1 year (HR 0.16, 95%CI:0.05-0.46, P = 0.001) with a sensitivity of 90.91% and a specificity of 70.97%. In addition, survival at 5 years (HR 0.15, 95% CI 0.06-0.35, P < 0.0001) was significantly better among patients below that cutoff value. In multivariate analysis, hsTNT serum level 6 weeks after transplantation emerged as an independent predictor for first-year mortality (hsTNT-HR 0.90, 95% CI: 0.81-1.00, P = 0.03). Cardiac troponin T concentrations early after transplantation as measured with a highly sensitive assay represent a strong and independent risk predictor of death after heart transplantation., (© 2012 The Authors Transplant International © 2012 European Society for Organ Transplantation. Published by Blackwell Publishing Ltd.)

Background: High-Mobility-Group Box 1 (HMGB1) has been established as an important mediator of myocardial inflammation and associated with progression of heart failure (HF). The aim of this study was to analyze the prognostic value of systemic HMGB1 levels in HF patients with ischemic and non-ischemic cardiomyopathy., Methods and Results: We conducted an analysis (median follow-up time 2.5 years) of HMGB1 plasma concentration in 154 patients with systolic HF and correlated the results with disease severity and prognosis. HMGB1 in HF patients with severe symptoms (NYHA III/IV; 5.35 ng/ml; interquartile range (IQR) = 3.48-8.42 ng/ml) was significantly elevated compared with that in patients with mild symptoms (NYHA I/II; 3.37 ng/ml, IQR = 2.31-5.22 ng/ml, p < 0.0001) and with controls (3.25 ng/ml, IQR = 3.04-3.67 ng/ml, p < 0.0001). HMGB1 levels correlated with other markers of heart failure indicating an association of HMGB1 with disease severity in HF. In a univariate cox regression model for the combined endpoint of death and heart transplantation, HMGB1 proved to be a predictor at cut-off values based on HMGB1 terciles of either 3.4 or 6.1 ng/ml (p = 0.001 and p < 0.0001, respectively). In a multivariate cox regression model, which included NT-proBNP, creatinine, age, NYHA class, white blood cell count, anemia, and age, HMGB1 remained an independent predictor of the combined endpoint (hazard ratio (HR) = 2.48, 95% confidence interval (CI) = 1.06-5.83, p = 0.037 and HR = 2.48, 95% CI = 1.31-4.71, p = 0.005, respectively)., Conclusion: Our findings demonstrate that HMGB1 plasma concentration is elevated in HF and correlates with disease severity and that is an independent predictor of the combined endpoint death and heart transplantation in HF patients.

Aims: To investigate determinants and temporal developments of treatment strategies, 5-year survival and heart transplantation rates between patients treated at secondary and tertiary hospitals., Methods and Results: Baseline characteristics, treatment and follow-up data from 2,023 patients with chronic systolic heart failure due to ischaemic or dilated cardiomyopathy enrolled between 1995 and 2005 (996 patients treated at a secondary hospital vs. 1,027 patients treated at a tertiary hospital) were prospectively compared. Patients treated at the secondary hospital setting were twice as likely to have ischaemic cardiomyopathy compared to the tertiary hospital setting as the underlying cause of heart failure (59.7% vs. 33.0%, respectively) and were almost a decade older (mean age 65.2 vs. 56.7 years, respectively). The use of guideline-recommended therapy increased in both centres over time. In direct temporal comparison, both guideline-adherent pharmacological therapy and device therapy were implemented earlier at the tertiary hospital. Survival rates were significantly lower among patients treated at the secondary hospital (log-rank test P < 0.0001). The combined endpoint of all-cause mortality and heart transplantation, however, was not significantly different after adjustment for differences in baseline characteristics (P = 0.44)., Conclusion: This study demonstrates the marked disparity between the patient cohorts with chronic systolic heart failure presenting at secondary and tertiary hospitals. Though patient characteristics-particularly age, aetiology of heart failure and the time of implementation of pharmacological and device treatment of heart failure-differed significantly, after adjustment for differences in baseline characteristics, no substantial difference in the combined endpoint of all-cause mortality and HTX was found during the 5-year follow-up period.

Background: Cytomegalovirus (CMV) infection is a serious complication following heart transplantation. This study (June 2003-January 2010) retrospectively assessed the effects of oral valganciclovir prophylaxis in adult heart transplant recipients during the first year after transplantation., Methods: In patients with normal renal function, 900 mg of oral valganciclovir was administered twice daily for 14 days after heart transplant followed by 900 mg per day for following 6 months. In the event of renal insufficiency, valganciclovir was adjusted according to the manufacturer's recommendations. Antigenemia testing for pp65 antigen and simultaneous polymerase chain reaction (PCR) were used to document exposure to CMV. From 2003 to 2010, 146 patients (74.0% men) of mean age 50.7 ± 10.3 years at the time of heart transplant were included., Results: A total of 16 patients (11.0% of total, 75.0% male) had a positive pp65 and PCR result (ie, CMV infection) during the year following heart transplant; three of these patients had discontinued valganciclovir prophylaxis within the first 6 months following transplant because of leukopenia, including one patient developed CMV colitis. Two further patients developed CMV pneumonia during prophylactic valganciclovir therapy. Eight patients had positive pp65 and PCR tests in the 6-12 months after heart transplant following cessation of routine prophylaxis. One of these patients developed CMV pneumonia and another developed CMV colitis and CMV pneumonia. Thirty-seven of the 146 (25.3%) patients were CMV donor-seropositive/recipient-seronegative, and seven (18.9% of this subgroup) had a positive CMV test. In patients who were CMV donor-seropositive/recipient-seronegative, the risk of a positive CMV test (ie, CMV infection) was significantly elevated (P = 0.023)., Conclusion: CMV prophylaxis with oral valganciclovir for 6 months following heart transplant is clinically feasible. In line with previous studies, CMV donor-seropositive/recipient-seronegative patients have a significantly elevated risk of CMV infection. In patients who prematurely discontinue valganciclovir, close monitoring of CMV antigenemia appears warranted. No significantly elevated rate of CMV infection was observed after 6 months of valganciclovir prophylaxis.

Background: Calcineurin inhibitor (CNI)-free immunosuppression is used increasingly after heart transplantation to avoid CNI toxicity, but in the absence of a randomized trial, concerns remain over an increased rejection risk., Methods: We studied the incidence of graft rejection episodes among all cardiac graft recipients, beginning with the first introduction of CNI-free protocols. We compared events during CNI-free and CNI-containing immunosuppression among 231 transplant recipients of overall mean age 55.2 ± 11.8 years, from a mean 5.2 ± 5.4 years after transplantation through a mean follow-up of 3.1 ± 1.4 years. We considered as acute rejection episodes requiring treatment those of International Society for Heart and Lung Transplantation., Results: During the total follow-up of 685 patient years (CNI-containing, 563; CNI-free, 122), we performed 1,374 biopsies which diagnosed 78 rejection episodes. More biopsies were performed in CNI-free patients: biopsies/patient-month of CNI-containing, 0.13 versus CNI-free, 0.22 (P < .05). The incidence of rejection episodes per patient-month was significantly higher on CNI-free compared with CNI therapy, among patients switched both early and later after heart transplantation, namely, within 1 year, 0.119 versus 0.035 (P = .02); beyond 1 year, 0.011 versus 0.004 (P = .007); beyond 2 years, 0.007 versus 0.003 (P = .04); and beyond 5 years: 0.00578 versus 0.00173 (P = .04)., Conclusions: Rejection incidence during CNI-free immunosuppression protocols after heart transplantation was significantly increased in both early and later postoperative periods. Given the potentially long delay to rejection occurrence, patients should be monitored closely for several months after a switch to CNI-free immunosuppressive protocols., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Celiac disease is characterised by chronic immune-mediated malabsorption in genetically susceptible individuals induced by gluten proteins present in wheat, barley and rye. It occurs in adults and children at rates approaching 1% of the population. Cardiomyopathy associated with celiac disease is infrequent. The authors present here a first case of a severe progressive dilated cardiomyopathy that required heart transplantation in young woman with celiac disease.

Background: Modified release tacrolimus (TAC) is a new, once-daily oral formulation of the established immunosuppressive agent TAC. Simplification of regimen has been associated with better adherence. This study evaluated patient adherence, as well as safety and efficacy among chronic stable heart transplantation (HT) patients switched from a conventional twice daily calcineurin inhibitor-based regimen (TAC or cyclosporine A [CsA]) to (once daily) modified release TAC., Methods: We switched 54 chronic stable patients (41 males and 13 females) from twice daily dosing with conventional TAC or CsA to once daily dosing with modified release TAC. Self-reported adherence was assessed at baseline and at 4 months after the switch using the Basel Assessment of Adherence with Immunosuppressive Medication Scale [BAASIS]), a 4-item validated questionnaire including also a Visual Analogue Scale (VAS). Nonadherence was defined as any self-reported nonadherence on any item., Results: Modified release TAC was discontinued in 4 patients because of diarrhea (n = 1) or gastrointestinal discomfort (n = 3) leaving 50 evaluable patients. Overall nonadherence at baseline for any of the 4 items was 74% versus 38% after 4 months (P = .0001). Thereafter, adherence improved in 28 patients (56.0%), was unchanged in 18 (36.0%), and decreased in 4 subjects (8.0%). The VAS score improved from 82.3% ± 2.6% to 97.5% ± 4.8% (P < .0001). No significant changes were observed after 4 months regarding hematologic, renal, or liver function parameters (all P = NS)., Conclusions: Therapeutic regimens for transplant recipients are often complex, contributing to a high incidence of medication nonadherence. This study in chronic, stable, heart transplantation patients demonstrated a significant improvement in patient adherence after a switch to modified release TAC, which was generally well tolerated., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Proton pump inhibitors (PPIs) are often prescribed for gastrointestinal discomfort after heart transplantation. This study investigated the impact of PPI use on mycophenolic acid (MPA) pharmacokinetics in heart transplant recipients receiving mycophenolate mofetil (MMF) in combination with a calcineurin inhibitor (tacrolimus [TAC]/cyclosporine [CsA]) or mammalian target of rapamycin inhibitor (sirolimus/everolimus)., Methods: Abbreviated MPA areas under the curve (AUCs; 0, 30, and 120 minutes after morning intake) were obtained in 19 patients on a PPI (initial examination) and 1 month after PPI discontinuation (follow-up). Mean patient age was 58.2 ± 8.8 years, and mean time after transplantation was 2.3 ± 4.0 years (range, 0.2-13.0 years)., Results: At initial examination mean daily MMF dose was 2.2 ± 0.8 g. MMF dose was kept unchanged for the duration of study (P = ns). Mean predose (C0) MPA serum concentrations were insignificantly lower with PPI comedication (2.5 ± 2.2 mg/L vs 2.8 ± 1.7 mg/L; P = .15). Dose-adjusted abbreviated MPA AUCs (adjusted to morning dose) were significantly lower during PPI therapy (45.2 ± 20.3 vs 65.2 ± 38.8 mg·h/L·g [MMF]; P = .02)., Conclusions: Patients with PPI comedication during MMF therapy show significantly lower exposure to mycophenolic acid determined by dose-adjusted abbreviated MPA AUCs. Although the clinical relevance of this pharmacokinetic interaction was not determined in this study, MPA drug monitoring by limited sampling strategies might be helpful during changes in antacid comedication in patients on MMF., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The objectives of the present study were to evaluate the incidence of malignancies and to describe the effects of immunosuppression on survival and recurrence of malignancies after heart transplantation (HTX). Data were analyzed in 211 cardiac allograft recipients, in whom HTX was performed between 1989 and 2005. All of these patients survived for more than 2 years after HTX and received induction therapy with antithymocyte globulin (RATG) guided by T-cell monitoring since 1994. An immunosuppressive regimen consisting of cyclosporine A (CsA) combined with azathioprine was followed by CsA and mycophenolate mofetil (MMF) in 2001; mammalian target of rapamycin (mTOR) inhibitors (everolimus/sirolimus) were used since 2003. Mean patient age at HTX was 51.4 ± 10.5 years; mean follow-up time after HTX 9.2 ± 4.7 years. Overall incidence of neoplasias was 30.8%. Individual risk factors associated with a higher risk of malignancy after HTX were higher age at transplantation (P = .003), male gender (P = .005) and ischemic cardiomyopathy before HTX (P = .04). Administration of azathioprine (P < .0001) or a calcineurin inhibitor (CNI) (P = .02) for more than 1 year was associated with development of malignancy, whereas significantly fewer malignancies were noticed in patients receiving an mTOR-inhibitor (P < .0001). Kaplan-Meier analysis demonstrated a strong statistical trend toward an improved survival in patients with a noncutaneous neoplasia switched to a CNI-free protocol (P = .05). This study demonstrated the impact of a variety of individual risk factors and immunosuppressive drugs on development of malignancy after HTX. Markedly fewer patients with noncutaneous malignancies died after switch to a CNI-free regimen, not quite reaching statistical significance by Kaplan-Meier analysis, however., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Heart transplantation is the most effective treatment option for patients with end-stage heart failure to improve exercise tolerance and quality of life. This increase in quality of life may assume that heart transplant recipients are also able to return to their work. In general, there are no medical reasons to oppose a return to work. Despite enormous advances in medical rehabilitation after heart transplantation, the rate of working people among heart transplant recipients is very low. According to a survey at the Heidelberg Heart Transplant Center, only 37% of the heart transplant recipients return to work. This may be caused by tranplant-related problems as well as factors independent of heart transplantation. Furthermore, the psychological burden due to heart transplantation might hamper professional rehabilitation. Thus, psychotherapeutical support during transplant process appears to be appropriate. As a major issue for a return to work appears to be the patient's will, the voluntary nature of return to work step by step has to be limited. Programmes with close collaboration between physicians, health insurance companies, retirement insurance companies, employers, and especially the patients are necessary to increase the rate of professional rehabilitation and to underscore the health economic justification of heart transplant programmes.

Background: Cardiac allograft vasculopathy (CAV) progressively compromises microvascular perfusion and function in heart transplantation (HTx)-recipients. The aim of our study was to investigate the ability of quantitative myocardial blush grade (MBG) to detect CAV., Methods: In consecutive HTx-recipients (n = 72) who underwent surveillance cardiac catheterization, MBG was assessed visually and quantitatively, by analyzing the time course of contrast agent intensity rise. Hereby, the parameter G(max)/T(max) was calculated as the plateau of grey-level intensity (G(max)) divided by the time-to-peak intensity (T(max)). HTx-recipients and 18 healthy volunteers underwent cardiac magnetic resonance, to assess diastolic strain rates and myocardial perfusion reserve during pharmacologic hyperemia., Results: Significant correlations were observed between G(max)/T(max) with perfusion reserve and with mean diastolic strain rates (r(2) = 0.68 and r(2) = 0.58, P < .001 for both). Visual and quantitative MBG using a cutoff value of G(max)/T(max) = 2.7/s yielded significantly higher accuracy than stenosis severity on coronary angiograms for the detection of impaired microvascular integrity as a surrogate marker for CAV (AUC = 0.78, SE = 0.06, 95% CI = 0.66-0.87 for lumen narrowing versus AUC = 0.91, SE = 0.03, 95%CI = 0.84-0.97 for G(max)/T(max); P < .01). Furthermore, quantitative MBG provided more robust prediction of survival (chi(2)= 14.0, P < .001), compared to visually estimated blush (chi(2)= 5.4, P = .02) and to coronary lumen narrowing assessment, (chi(2)= 4.8, P = .04)., Conclusions: Quantification of MBG can be performed on coronary angiograms of HTx-recipients, and may help with the identification of early CAV in patients with impaired perfusion reserve but without angiographically evident atherosclerosis., (Copyright 2010 Mosby, Inc. All rights reserved.)

Chronic Toxoplasma gondii infection is known to trigger potentially adverse immunoregulatory changes, but limited data exist on long-term implications for heart transplant (HTX) recipients. We evaluated the risk of all cause mortality regarding T. gondii serostatus prior to HTX. Pre-HTX T. gondii serostatus was obtained in 344 recipients and 294 donors. Mean age was 52.1 +/- 10.2 years and mean follow-up time after HTX was 5.7 (+/-5.5, median 3.5) years. All seronegative patients received prophylaxis with pyrimethamine/sulfomethoxazole or cotrimoxazol for 6 months after transplantation. Multivariate survival analysis adjusted for diabetes mellitus, pre-HTX renal function, recipient age, type of primary immunosuppression (i.e. HTX before 2001), cytomegalovirus (CMV) high-risk status, ischemic time, and number of treated rejection episodes was performed. Overall, 190 recipients (55.2% of total) were seronegative and 154 (44.8% of total) were seropositive for T. gondii prior to HTX. One hundred and fifty-two recipients died during follow-up (44.2% of total). Negative recipient Toxoplasma serostatus was associated with a significantly higher risk of all-cause mortality (P = 0.0213). Recipient T. gondii serostatus did not influence the number of cellular or humoral rejection episodes. Analyses of specific causes of death showed a trend toward a higher number of infection-related deaths in the seronegative subgroup (P = 0.13). No statistically significant effects of T. gondii donor/recipient seropairing, or seroconversion were observed. Negative preoperative serostatus for T. gondii in HTX recipients appears to be an independent risk factor associated with increased all-cause mortality. The cause of impaired survival in Toxoplasma seronegative recipients is currently unclear; possible explanations include an alteration of immune-reactivity/-regulation or adverse effects of prophylactic medication.

We report on a woman presenting with fever and novel round lesion in the lung four months after heart transplantation. Microbiologic assessment of bronchial lavage and operative specimen revealed pulmonary nocardiosis. Furthermore, cerebral involvement has been observed. Antibiotic treatment according to the microbiological sensitivity test for eleven months resulted in complete remission of pulmonary and cerebral nocardiosis. Immunosuppressive treatment increases the risk for opportunistic infections early after transplantation as well as malignancies during the late course.

The aim of our study was to investigate the ability of Strain-Encoded magnetic resonance imaging (MRI) to detect cardiac allograft vasculopathy (CAV) in heart transplantation (HTx)-recipients. In consecutive subjects (n = 69), who underwent cardiac catheterization, MRI was performed for quantification of myocardial strain and perfusion reserve. Based on angiographic findings subjects were classified: group A including patients with normal vessels; group B, patients with stenosis <50%; and group C, patients with severe CAV (stenosis >or= 50%). Significant correlations were observed between myocardial perfusion reserve with peak systolic strain (r =-0.53, p < 0.001) and with mean diastolic strain rate (r = 0.82, p < 0.001). Peak systolic strain and strain rate were significantly reduced only in group C, while mean diastolic strain rate and myocardial perfusion reserve were already reduced in group B and A. Myocardial perfusion reserve and mean diastolic strain rate had higher accuracy for the detection of CAV (AUC = 0.95, 95% CI = 0.87-0.99 and AUC = 0.93, 95% CI = 0.84-0.98, respectively) and followed peak systolic strain and strain rate (AUC = 0.80, 95% CI = 0.69-0.89 and AUC = 0.78, 95% CI = 0.67-0.87, respectively). Besides the quantification of myocardial perfusion, the estimation of the diastolic strain rate is a useful parameter for CAV assessment. In combination with the clinical evaluation, these parameters may be effective tools for the routine surveillance of HTx-recipients.

Aims: The prognosis of advanced cardiac light-chain amyloidosis is poor. Heart transplantation might enable causative therapy and ultimately improve prognosis., Methods and Results: Nineteen patients with cardiac amyloidosis but no obvious involvement of other organs were scheduled for heart transplantation. Four to 6 months later, high-dose melphalan chemotherapy and autologous stem cell transplantation (HDM-ASCT) was planned in patients not in complete remission. Seven of nineteen patients died while waiting for heart transplantation. The remaining 12 patients (complete remission, n = 4) underwent surgery. Chemotherapy in patients not in complete remission consisted of HDM-ASCT (n = 5/12; subsequent complete remission, n = 2; partial remission, n = 3) or melphalan-prednisolone (partial remission, n = 1). Two of twelve patients were ineligible for any chemotherapy. Three of twelve patients died [423.5 (105-2131) days] from progressive disease, relapse, or sepsis. The 1- and 3-year survival rates were 83 and 83%, respectively, similar to those of patients undergoing heart transplantation for standard indications. Corresponding survival rates stratified by haematological response were 100 and 100% for complete remission (partial remission, 100 and 100%; progressive disease, 0 and 0%)., Conclusion: Heart transplantation in advanced cardiac amyloidosis is a promising approach to interrupting the vicious circle of ineligibility for potential curative chemotherapeutic treatment and extremely poor prognosis of cardiac amyloidosis without chemotherapy. Highly urgent heart transplantation combined with subsequent HDM-ASCT appears to offer a successful treatment option to improve the poor outcome of cardiac amyloidosis. However, it should be restricted to highly selected patients in specialized centres.

Background: Graft denervation in heart transplant recipients causes sinus tachycardia, occasionally requiring pharmacologic heart rate reduction. Currently, no 12-month data regarding effects of the novel I(f) channel antagonist ivabradine on heart rate control, effects on left ventricular mass, tolerability, and safety are available in patients after heart transplantation (HTX)., Methods: Mean heart rate, left ventricular mass indexed (LVMI) to body surface area, tolerability, and safety of ivabradine therapy were evaluated at baseline and after 12 months in 30 HTX recipients with marked sinus tachycardia., Results: In three patients (10.0% of total), ivabradine medication was discontinued. Further analysis was based on 27 patients with 12-month drug exposure. Mean patient age was 53.3+/-11.3 years, and mean time after HTX was 5.0+/-4.8 years. Mean ivabradine dose was 12.5 mg/day (+/-3.3 mg). Mean heart rate was reduced from 96.2+/-8.6 beats per minute (bpm) at baseline to 80.9+/-8.1 bpm at follow-up (P<0.0001). A statistically significant effect of heart rate reduction on LVMI was observed (104.3+/-22.7 g at baseline vs. 95.9+/-18.5 g at follow-up, P=0.04). No statistically significant changes in immunosuppressive drug dosage or blood levels were observed, except from a lower mycophenolate mofetil dose at follow-up (P=0.01). Safety laboratory values were unchanged. No phosphenes were observed., Conclusions: Heart rate reduction with ivabradine is effective and safe in heart transplant recipients. After 12 months, significant effects on LVMI were observed. Therefore, ivabradine may offer a beneficial effect on left ventricular remodelling in HTX patients.

Background: This study evaluates the objective rate of return to work after heart transplantation (HTX) in comparison with the patients' subjective rating of their work ability and identifies predictors for return to work in a German heart transplant center., Methods: A questionnaire covering demographics, clinical data, and professional aspects was sent to 200 heart transplant recipients at least 12 months after HTX. Participation was strictly anonymous enabling reliable results concerning subjective work ability., Results: Response rate was 150 of 200 (75%). During the time after HTX, 45 of 150 (30.0%) patients had ever been in a job. Thirty-five of 95 (36.8%) patients of formal working age (<65 years) were employed after 12.6+/-1.9 months: 18 of 95 (18.9%) in full-time work, 9 of 95 (9.5%) in part-time work, and 6 of 95 (6.3%) in casual employment. Two of 95 (2.1%) patients worked as handicapped employees; only 1 of 95 (1.1%) patients was currently seeking work. Patients obtained financial benefits from their illness (n=54; 36%) or age-related annuity (n=8; 5.3%). Forty-two of 95 (44.2%) patients did not feel capable of working, three patients did not answer, and 50 of 95 patients (52.6%) felt fit for employment. Employment after HTX depended on age, duration of unemployment, diabetes mellitus, and financial need for paid employment. Financially independent patients (n=66) more often felt unable to work by subjective judgement (n=34/67; 50.7%) than patients who depended on paid employment (8/28; 28.6%; P<0.05)., Conclusions: The rate of employment after HTX in Germany is significantly lower than the subjective perception of the individual ability to work; underscoring the importance of sociodemographic and psychologic aspects during rehabilitation of HTX recipients.

Development of Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is a serious complication following heart transplantation (HTX). This study investigates EBV DNA load in adult heart transplant recipients, its association with immunosuppression, and its potential as a marker for development of PTLD. EBV DNA load was measured prospectively by quantitative real-time polymerase chain reaction (PCR) in 172 stable HTX patients. Sixty-seven patients (39.0% of total) had a positive EBV PCR at initial examination [median 4.9 (range 1.1-16.9) years post-HTX]. In follow-up testing of 67 positive patients 6 months later, 36 patients continued to have a positive EBV PCR. Overall incidence of EBV DNA was significantly associated with calcineurin inihibitors, azathioprine medication, and with the absence of mycophenolate mofetil (MMF) treatment. In patients with positive EBV DNA levels at initial examination and negative levels at retesting, cyclosporine A levels were found to be significantly higher at initial examination (148.4 +/- 70.2 vs. 119.6 +/- 53.5 ng/ml, P < 0.05). Three patients (1.7%, 3/172) were diagnosed with PTLD during the course of the study (mean follow up 4.0 years). EBV DNA viral load determination does not appear to be useful for risk prediction or early diagnosis of PTLD in adults after HTX, but an association of EBV DNA load with qualitative and quantitative immunosuppression is demonstrated.

Objectives: Transplant coronary artery disease (TCAD) limits long-term survival after heart transplantation (HTX). We hypothesized that contrast-enhanced magnetic resonance imaging (CE-MRI) detects chronic TCAD-related myocardial infarctions (MIs), even in patients with angiographically classified mild TCAD., Background: Coronary angiography underestimates the TCAD-degree, subsequently missing occluded small coronary arteries and resulting MI. CE-MRI as a noninvasive imaging technique identifies infarct-typical MI and myocardial fibrosis., Methods: CE-MRI (gadolinium: 0.2 mmol/kg/bw) was performed in 53 HTX patients on a 1.5-T MRI scanner (Philips, Best, the Netherlands). Infarct-typical CE-MRI areas were classified as: I=or=75%. Infarct-atypical forms were divided into diffuse, spotted, intramural, and infero-septal. Coronary angiography results were reviewed qualitatively with the TCAD score (TCAD I=mild evidence; II=30% to 75%, III=>or=75% stenosis). Groups were compared with analysis of variance (statistically significant p values

We investigated tolerability and efficacy of ezetimibe treatment (10 mg/d) in 25 heart allograft recipients already on stable statin therapy. Total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C), triglycerides (TG), immunosuppressant drug levels, laboratory and clinical parameters were assessed before, four months and one yr after initiation of ezetimibe treatment. Mean equivalent statin dose was 53.5 +/- 12.3 mg of pravastatin, remaining unchanged throughout the study period. Ezetimibe was generally well tolerated, only two patients (8%) discontinued ezetimibe due to stomach pain or headache. Mean TC decreased from 231.8 +/- 6.4 mg/dL before therapy to 202.2 +/- 8.8 mg/dL after four months and 192.9 +/- 7.0 mg/dL after one yr (p < 0.001). Mean LDL-C decreased from 143.1 +/- 5.4 mg/dL to 121.4 +/- 7.9 mg/dL (month 4; p < 0.05) and 107.1 +/- 5.6 mg/dL (one yr; p < 0.001). TG decreased from 182 +/- 14.3 mg/dL to 173.3 +/- 17.5 mg/dL after one yr (p < 0.05), whereas HDL-C was unchanged. Initial LDL-C and cardiac diagnosis before transplantation were identified as predictors of absolute LDL-C reduction. Immunosuppressant drug doses and blood concentrations were unchanged as well as other laboratory and clinical parameters. Ezetimibe appears safe and effective for further reduction of TC and LDL-C in heart allograft recipients already on stable statin therapy. Extent of pre-treatment LDL-C and cardiac disorder prior to transplantation appear to correlate with the efficacy of ezetimibe therapy.

Background: Hyperlipidemia is an important complication after organ transplantation and may contribute to the development of posttransplant-accelerated coronary artery disease. Immunosuppressive therapy, especially mammalian target of rapamycin inhibitors, induces a considerable increase in cholesterol and triglyceride plasma levels. Omega-3 fatty acids (FAs) exert cardioprotective effects supporting a therapeutic role in cardiovascular conditions., Methods: An observational study of omega-3 FAs 4 g/day was performed in 15 heart transplant recipients with hypertriglyceridemia. Six patients received rapamycin, and nine received everolimus. Apart from one patient the immunosuppressive therapy was combined with mycophenolate mofetil, only one patient received steroids; two patients presented with diabetes., Results: Mean triglyceride levels before heart transplantation (HTx) were 137+/-54 mg/dL. After HTx, before sirolimus or everolimus treatment triglyceride level had increased to 188+/-67 mg/dL (P<0.05). Treatment with sirolimus or everolimus induced an increase in triglycerides to 354+/-107 mg/dL (P<0.001). Subsequent treatment with omega-3 FAs for 4 months resulted in a marked decrease in triglycerides to 226+/-74 mg/dL (P<0.001). All patients (100%) showed a reduction in triglyceride by more than 20% (responders). In 10 of 15 patients available 12-month data confirmed the long-term efficacy of omega-3 FAs treatment. There were no adverse events or any discontinuations; no changes in immunosuppression were required., Conclusions: Treatment with mammalian target of rapamycin inhibitors after HTx induces marked increase in serum levels of triglycerides. Omega-3 FAs significantly lower triglyceride levels and seem to be effective, safe, and well-tolerated in sirolimus- or everolimus-treated heart transplant recipients.

Recently, we established a pharmacodynamic assay to monitor immunosuppressive effectiveness of cyclosporine A (CsA) in patients on standard CsA regimen. The aim of the present study was to extend this correlation to reduced CsA regimen and to compare pharmacodynamic and kinetic parameters to allow prediction of rejections and infections. In 53 heart allograft recipients, nuclear factor of activated T cells (NFAT)-regulated gene expression was quantified at trough (C0) and 2-h post-CsA dose (C2). Gene expression at C2 was calculated relative to C0 (residual gene expression, RGE) or relative to a healthy reference group (absolute gene expression, AGE). RGE correlated with CsA C2-levels in bimodal fashion: above 575 ng/ml correlation was seen with flat regression gradient. Below 575 ng/ml, correlation was excellent with markedly steeper gradient. At C0 in the low-C2 group (<575 ng/ml), AGE remained unchanged, whereas in the high-C2 group (>575 ng/ml) AGE was markedly reduced. In both groups, AGE at C2 was strongly inhibited. In patients contracting infection during follow-up, RGE was lower than in those without infections independent of CsA levels. CsA-monitoring by quantitation of NFAT-regulated gene expression is feasible with standard and reduced CsA regimens. It correlates better with the incidence of infections than measurement of CsA concentrations and might help in avoiding over-immunosuppression.

Background: Graft denervation in heart transplant recipients causes sinus tachycardia, occasionally requiring pharmacologic heart rate reduction. The If channel antagonist ivabradine has not been compared to beta-blocker after heart transplantation. Heart rate control, tolerability, short-term safety, and effects on exercise capacity were studied consecutively with an established heart rate-reducing drug (metoprolol succinate) compared to a novel agent (ivabradine) in heart transplant recipients., Methods: In 25 heart transplant recipients, heart rate, exercise capacity, and patient preference were assessed under no medication (baseline) and after consecutive 8-week treatment periods under metoprolol and ivabradine., Results: Drug discontinuation following side effects occurred in 5 patients (metoprolol: 4, ivabradine: 1); per-protocol analysis was performed on 20 patients completing both consecutive treatment periods. Mean heart rate was reduced from baseline (96.5+/-7.0 bpm) to 84.4+/-8.8 bpm on beta-blocker (P=0.0004 vs. baseline) and to 76.2+/-8.9 bpm with ivabradine (P=0.0001 vs. baseline and P=0.003 vs. beta-blocker). Exercise capacity by spiroergometry was not altered by either drug. Relevant pharmacokinetic interaction with immunosuppressants was not seen under ivabradine; safety laboratory values were unchanged. Mild adverse effects were noted in 45% of patients during beta-blocker and 20% during ivabradine treatment. Questionnaire analysis demonstrated patient preference for heart rate reduction with ivabradine., Conclusions: Heart rate reduction with ivabradine is effective and potentially better tolerated than beta-blocker therapy in heart transplant recipients. Although the prognostic role of heart rate after HTX is unknown, ivabradine may offer relevant symptomatic benefit, especially in cases of beta-blocker intolerance.

Patient monitoring following heart transplantation aims to detect complications (eg, acute graft rejection, vasculopathy, infection) early and contributes to risk prognostication. Numerous biomarkers of different biologic pathways have been evaluated as ancillary diagnostic and prognostic tools to reduce the need for invasive and expensive technical investigations. With the possible exception of cardiac troponins and N-type natriuretic peptides, no biomarkers have become established firmly in posttransplant patient surveillance. This article aims to show that the identification of a single biomarker that meets all needs (noninvasive diagnosis of rejection, prediction of transplant vasculopathy, survival prognostication) is unlikely. Rather, multiple marker strategies, including gene-based tests, are likely to enhance future monitoring quality and enable individualized risk-adapted patient management.