Renal function in heart transplant patients after switch to combined mammalian target of rapamycin inhibitor and calcineurin inhibitor therapy

Matthias Helmschrott,1 Rasmus Rivinius,1 Thomas Bruckner,2 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, Angiology, Pneumology, 2Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany 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. Keywords: heart transplantation, cyclosporine A, tacrolimus, risk factor

Chronic digitalis therapy in patients before heart transplantation is an independent risk factor for increased posttransplant mortality

Rasmus Rivinius,1 Matthias Helmschrott,1 Arjang Ruhparwar,2 Ann-Kathrin Rahm,1,3 Fabrice F Darche,1 Dierk Thomas,1 Tom Bruckner,4 Philipp Ehlermann,1 Hugo A Katus,1 Andreas O Doesch1,5 1Department of Cardiology, Angiology and Pneumology, Heidelberg University Hospital, Heidelberg, 2Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, 3Faculty of Medicine, University of Heidelberg, Heidelberg, 4Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, 5Asklepios Klinik Bad Salzungen GmbH, Department of Pneumology and Oncology, Bad Salzungen, Germany Objectives: Digitalis therapy (digoxin or digitoxin) in patients with heart failure is subject to an ongoing debate. Recent data suggest an increased mortality in patients receiving digitalis. This study investigated the effects of chronic digitalis therapy prior to heart transplantation (HTX) on posttransplant outcomes.Patients and methods: This was a retrospective, observational, single-center study. It comprised 530 adult patients who were heart-transplanted at Heidelberg University Hospital between 1989 and 2012. Patients with digitalis prior to HTX (≥3 months) were compared to those without (no or <3 months of digitalis). Patients with digitalis were further subdivided into patients receiving digoxin or digitoxin. Primary outcomes were early posttransplant atrial fibrillation and mortality.Results: A total of 347 patients (65.5%) had digitalis before HTX. Of these, 180 received digoxin (51.9%) and 167 received digitoxin (48.1%). Patients with digitalis before HTX had a significantly lower 30-day (P=0.0148) and 2-year (P=0.0473) survival. There was no significant difference between digoxin and digitoxin in 30-day (P=0.9466) or 2-year (P=0.0723) survival. Multivariate analysis for posttransplant 30-day mortality showed pretransplant digitalis therapy as an independent risk factor (hazard ratio =2.097, CI: 1.036–4.248, P=0.0397). Regarding atrial fibrillation in the early posttransplant period, there was neither a statistically significant difference between patients with and without digitalis (P=0.1327) nor between patients with digoxin or digitoxin (P=0.5867).Conclusion: Digitalis in patients before HTX is an independent risk factor for increased posttransplant mortality. Keywords: atrial fibrillation, digitalis, heart transplantation, mortalit

The influence of surgical technique on early posttransplant atrial fibrillation — comparison of biatrial, bicaval, and total orthotopic heart transplantation

Rasmus Rivinius,1 Matthias Helmschrott,1 Arjang Ruhparwar,2 Christian Erbel,1 Christian A Gleissner,1 Fabrice F Darche,1 Dierk Thomas,1 Tom Bruckner,3 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, Angiology and Pneumology, 2Department of Cardiac Surgery, Heidelberg University Hospital, 3Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany Purpose: Early posttransplant atrial fibrillation (AF) has been associated with worse clinical outcomes after heart transplantation (HTX). The type of surgical technique may constitute a relevant risk factor for AF. Patients and methods: This retrospective single-center study included 530 adult patients. Patients were stratified by surgical technique (biatrial, bicaval, or total orthotopic HTX) and early posttransplant heart rhythm (AF or sinus rhythm). Univariate and multivariate analyses were performed to evaluate risk factors for AF. Results: A total of 161 patients received biatrial HTX (30.4%), 115 bicaval HTX (21.7%), and 254 total orthotopic HTX (47.9%). Sixty-one of 530 patients developed early posttransplant AF (11.5%). Patients with AF showed a statistically inferior 5-year survival compared to those with sinus rhythm (P<0.0001). Total orthotopic HTX had the lowest rate of AF (total orthotopic HTX [6.3%], bicaval HTX [14.8%], biatrial HTX [17.4%], P=0.0012). Multivariate analysis showed pretransplant valvular heart disease (P=0.0372), posttransplant enlarged left atrium (P=0.0066), posttransplant mitral regurgitation (P=0.0370), and non-total orthotopic HTX (P=0.0112) as risk factors for AF. Conclusion: Early posttransplant AF was associated with increased mortality (P<0.0001). Total orthotopic HTX showed the lowest rate of AF compared to biatrial or bicaval HTX (P=0.0012). Keywords: atrial fibrillation, biatrial heart transplantation, bicaval heart transplantation, mortality, surgical technique, total orthotopic heart transplantatio

Heart rate reduction for 36 months with ivabradine reduces left ventricular mass in cardiac allograft recipients: a long-term follow-up study

Andreas O Doesch,1 Susanne Mueller,1 Christian Erbel,1 Christian A Gleissner,1 Lutz Frankenstein,1 Stefan Hardt,1 Arjang Ruhparwar,2 Philipp Ehlermann,1 Thomas Dengler,3 Hugo A Katus1 1Department of Cardiology, 2Department of Cardiovascular Surgery, University of Heidelberg, Heidelberg, 3SLK Plattenwald Hospital, Bad Friedrichshall, Germany 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. Keywords: heart transplantation, heart rate control, ivabradine, left ventricular mas

Conversion to generic cyclosporine A in stable chronic patients after heart transplantation

Maximilian Kraeuter,1 Matthias Helmschrott,1 Christian Erbel,1 Christian A Gleissner,1 Lutz Frankenstein,1 Bastian Schmack,2 Arjang Ruhparwar,2 Philipp Ehlermann,1 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, 2Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany 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. Keywords: heart transplantation, immunosuppression, generic cyclosporine

Inhibition of B7-1 (CD80) by RhuDex® reduces lipopolysaccharide-mediated inflammation in human atherosclerotic lesions

Andreas O Doesch,1,* Li Zhao,1,* Christian A Gleissner,1 Mohammadreza Akhavanpoor,1 David Rohde,1 Deniz Okuyucu,1 Maani Hakimi,2 Thomas J Dengler,3 Hugo A Katus,1 Christian Erbel1 1Department of Cardiology, 2Department of Vascular Surgery, University of Heidelberg, Germany; 3Department of Cardiology, SLK Hospital Heilbronn, Bad Friedrichshall, Germany*These authors contributed equally to this articleBackground: Atherosclerosis is based on a chronic inflammatory process including the innate and adaptive immune response. Costimulatory molecules and their receptors provide decisive signals for antigen-specific cell activation. The contribution of B7-related pathways to atherosclerosis has hardly been explored. Methods: In the present study, we investigated the contribution of B7-1 to inflammation and tissue injury in the human plaque microenvironment in order to identify possible target structures of future therapeutic agents ex vivo and in vitro.Results: Carotid artery plaque stimulation with lipopolysaccharides (LPS) could be significantly inhibited by RhuDex®, a specific inhibitor of the costimulatory molecule B7-1 ex vivo (P<0.001). Coculture of antigen-presenting cells with T-cells demonstrated that the inhibitory effects of RhuDex® derived from reduced T-cell activation. In addition, incubation of monocytes/macrophages with LPS and RhuDex® resulted in an inhibitory negative feedback on antigen-presenting cells. Signaling pathways affected by RhuDex® seem to be nuclear transcription factor kappa B, activator protein-1, and extracellular signal-regulated kinase 1/2.Conclusion: The present data support B7-1 alone as an important costimulatory molecule in the context of LPS-mediated inflammation in atherosclerotic lesions. Due to its marked inhibitory effects, RhuDex® may be a useful therapy to modulate the inflammatory milieu in atherosclerosis.Keywords: B7, CD86, costimulation, atherosclerosi

CCL19 and CCL21 modulate the inflammatory milieu in atherosclerotic lesions

Mohammadreza Akhavanpoor,1,2,* Christian A Gleissner,1,2,* Stephanie Gorbatsch,1,2 Andreas O Doesch,1,2 Hamidreza Akhavanpoor,1,2 Susanne Wangler,1,2 Frederik Jahn,1,2 Felix Lasitschka,3 Hugo A Katus,1,2 Christian Erbel1,2 1Department of Cardiology, University of Heidelberg, 2DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, 3Institute of Pathology, University of Heidelberg, Germany *These authors contributed equally to this work Abstract: Despite advances in the pharmacologic and interventional treatment of coronary artery disease, atherosclerosis remains the leading cause of death worldwide. Atherosclerosis is a chronic inflammatory disease, and elevated expression of CCL19 and CCL21 has been observed in ruptured lesions of coronary arteries of patients with myocardial infarction and carotid plaques of patients with ischemic symptoms, as well as in plasma of coronary artery disease patients. However, the exact role of CCL19 and CCL21 in atherosclerosis remains unknown. In order to identify CCL19 and CCL21 as a novel therapeutic target, we performed bone marrow transplantation as an immunomodulatory treatment concept. Bone marrow of plt/plt mice (lacking CCL19 and CCL21-Ser) was transplanted into atherogenic Ldlr-/- mice. The study demonstrated a significantly increased inflammatory cellular infiltration into the lesions of plt/plt/Ldlr-/- mice versus controls. Although the level of chemoattraction was increased, messenger ribonucleic acid and protein levels in thoracic aorta and serum of several proinflammatory cytokines (TNFα, IFNγ, IL-6, IL-12, and IL-17) were significantly reduced in plt/plt/Ldlr-/- versus control mice. Increased influx, accompanied by reduced activation of leukocytes in atherosclerotic lesion, was accompanied by increased plaque stability but unchanged lesion development. In conclusion, modulation of the chemokines CCL19 and CCL21 represents a potent immunoregulatory treatment approach, and thus represents a novel therapeutic target to stabilize atherosclerotic lesions. Keywords: atherosclerosis, chemokines, immunomodulatory therapy, bone marrow trans­plantatio

Everolimus in heart transplantation: an update.

The evidence base relating to the use of everolimus in heart transplantation has expanded considerably in recent years, providing clinically relevant information regarding its use in clinical practice. Unless there are special considerations to take into

Advantageous effects of immunosuppression with tacrolimus in comparison with cyclosporine A regarding renal function in patients after heart transplantation

Matthias Helmschrott,1 Rasmus Rivinius,1 Arjang Ruhparwar,2 Bastian Schmack,2 Christian Erbel,1 Christian A Gleissner,1 Mohammadreza Akhavanpoor,1 Lutz Frankenstein,1 Philipp Ehlermann,1 Tom Bruckner,3 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, Angiology, Pneumology, 2Department of Cardiac Surgery, 3Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany 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. Keywords: heart transplantation, renal function, extended-release tacrolimu