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Rasmus Rivinius,1 Matthias Helmschrott,1 Arjang Ruhparwar,2 Bastian Schmack,2 Fabrice F Darche,1 Dierk Thomas,1 Tom Bruckner,3 Hugo A Katus,1 Philipp Ehlermann,1,* Andreas O Doesch1,4,* 1Department of Cardiology, Angiology and Pneumology, Heidelberg University Hospital, Heidelberg, Germany; 2Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany; 3Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany; 4Department of Pneumology and Oncology, Asklepios Hospital, Bad Salzungen, Germany *These authors contributed equally to this work Objectives: COPD is associated with reduced physical activity, an increased risk for pulmonary infections, and impaired survival in nontransplant patients. The aim of this study was to investigate the influence of COPD in patients after heart transplantation (HTX). Methods: We performed an observational retrospective single-center study of 259 patients receiving HTX at Heidelberg University Hospital between 2003 and 2012. Patients were stratified by the Tiffeneau index (forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC])

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

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 factors

Rasmus Rivinius,1 Matthias Helmschrott,1 Arjang Ruhparwar,2 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 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. Keywords: amiodarone, atrial fibrillation, bradycardia, heart transplantation, pacemaker, survival

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

Rasmus Rivinius,1 Matthias Helmschrott,1 Arjang Ruhparwar,2 Bastian Schmack,2 Christian Erbel,1 Christian A Gleissner,1 Mohammadreza Akhavanpoor,1 Lutz Frankenstein,1 Fabrice F Darche,1 Patrick A Schweizer,1 Dierk Thomas,1 Philipp Ehlermann,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 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

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

Rasmus Rivinius,1 Matthias Helmschrott,1 Arjang Ruhparwar,2 Bastian Schmack,2 Berthold Klein,2 Christian Erbel,1 Christian A Gleissner,1 Mohammadreza Akhavanpoor,1 Lutz Frankenstein,1 Fabrice F Darche,1 Dierk Thomas,1 Philipp Ehlermann,1 Tom Bruckner,3 Hugo A Katus,1 Andreas O Doesch11Department of Cardiology, Angiology and Pneumology, 2Department of Cardiac Surgery, 3Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, GermanyObjective: 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 (P1 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

Background: Due to its high impact on quality of life and mental health, close monitoring and often psychotherapy is recommended for patients with a ventricular assist device (VAD). This study investigates the psychological comorbidity and the corresponding psychotherapeutic treatment situation of VAD patients. Special attention is also given to the professional perspective VAD team (assistant and senior cardiologists and specialized nurses)., Methods: We conducted a cross-sectional observational study. Data from 50 VAD patients (mean age = 53.52, standard deviation = 13.82 years, 84.0% male) and their VAD team were analyzed. The presence of a psychological disorder was evaluated by structured clinical interviews for DSM-IV (SCID-I-Interviews). Patients answered a questionnaire regarding their current psychotherapeutic treatment status and their attitude towards psychotherapy. The VAD team answered a questionnaire about the patients' needs for psychotherapy and indicated whether they addressed this topic with the patient. Data were analyzed descriptively, by analysis of variance and t-test., Results: A total of 58% of VAD patients suffered from at least one significant psychological disorder, 79.3% of those were not in psychotherapy. The VAD team could not identify the patients who suffered from a psychological disorder (F = 1.90; p = 0.18). They perceived more need for psychotherapy than they addressed with their patients (T = 3.39; p < 0.001)., Conclusions: While there is a high psychological morbidity among VAD patients, only few receive psychotherapy. Psychological comorbidity is not easily detected by the VAD team. Standardized psychosocial care could be implemented by regular psychological assessments and further information of patients and their VAD teams., (© 2024 The Author(s). Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Right heart failure (RHF) following implantation of a left ventricular assist device (LVAD) is a common and potentially serious condition with a wide spectrum of clinical presentations with an unfavourable effect on patient outcomes. Clinical scores that predict the occurrence of right ventricular (RV) failure have included multiple clinical, biochemical, imaging and haemodynamic parameters. However, unless the right ventricle is overtly dysfunctional with end-organ involvement, prediction of RHF post-LVAD implantation is, in most cases, difficult and inaccurate. For these reasons optimization of RV function in every patient is a reasonable practice aiming at preparing the right ventricle for a new and challenging haemodynamic environment after LVAD implantation. To this end, the institution of diuretics, inotropes and even temporary mechanical circulatory support may improve RV function, thereby preparing it for a better adaptation post-LVAD implantation. Furthermore, meticulous management of patients during the perioperative and immediate postoperative period should facilitate identification of RV failure refractory to medication. When RHF occurs late during chronic LVAD support, this is associated with worse long-term outcomes. Careful monitoring of RV function and characterization of the origination deficit should therefore continue throughout the patient's entire follow-up. Despite the useful information provided by the echocardiogram with respect to RV function, right heart catheterization frequently offers additional support for the assessment and optimization of RV function in LVAD-supported patients. In any patient candidate for LVAD therapy, evaluation and treatment of RV function and failure should be assessed in a multidimensional and multidisciplinary manner., (© 2024 European Society of Cardiology.)

Background: We report the results of a prospective study on the immunogenicity of a 3rd dose of BNT162b2 in thoracic organ recipients with no or minimal response following a two-dose BNT162b2 vaccination scheme., Methods: A total of 243 transplant recipients received a homologue 3rd dose. Anti-SARS-CoV2-immunoglobulins (IgGs) were monitored immediately before (T1), 4 weeks (T2) as well as 2 and 4 months after the 3rd dose. Neutralizing antibody capacity (NAC) was determined at T2. To reveal predictors for detectable humoral response, patients were divided into a positive response group (n = 129) based on the combined criteria of IgGs and NAC above the defined cut-offs at T2-and a group with negative response (n = 114), with both, IgGs and NAC beyond the cut-offs., Results: The 3rd dose induced a positive humoral response in 53% of patients at T2, 47% were still non-responsive. Sero-positivity was significantly stronger in patients who presented with weak, but detectable IgGs already prior to the booster (T1), when compared to those with no detectable response at T1. Multivariable analysis identified age > 55 years, a period since transplantation < 2 years, a reduced glomerular filtration rate, a triple immunosuppressive regimen, and the use of tacrolimus and of mycophenolate as independent risk factors for lack of humoral response., Conclusions: Our data indicate that a lack of immunogenicity is linked to the type and extent of maintenance immunosuppression. The necessity of the cumulative immunosuppressive regimen might individually be questioned and possibly be reduced to enhance the chance of an immune response following an additional booster dose., (© 2022. The Author(s).)

Cardiac K v 4.3 channels contribute to the transient outward K + current, I to , during early repolarization of the cardiac action potential. Two different isoforms of K v 4.3 are present in the human ventricle and exhibit differential remodeling in heart failure (HF). Cardioselective betablockers are a cornerstone of HF with reduced ejection fraction therapy as well as ventricular arrhythmia treatment. In this study we examined pharmacological effects of betablockers on both K v 4.3 isoforms to explore their potential for isoform-specific therapy. K v 4.3 isoforms were expressed in Xenopus laevis oocytes and incubated with the respective betablockers. Dose-dependency and biophysical characteristics were examined. HEK 293T-cells were transfected with the two K v 4.3 isoforms and analyzed with Western blots. Carvedilol (100 µM) blocked K v 4.3 L by 77 ± 2% and K v 4.3 S by 67 ± 6%, respectively. Metoprolol (100 µM) was less effective with inhibition of 37 ± 3% (K v 4.3 L) and 35 ± 4% (K v 4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in K v 4.3 protein expression. Carvedilol inhibited K v 4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on K v 4.3. Blockade of repolarizing K v 4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts.

Aims: Patients after heart transplantation (HTX) often require oral anticoagulants (OACs) due to atrial arrhythmias or thromboembolic events but little is known about the post-transplant use of direct oral anticoagulants (DOACs). We investigated the frequency, indications, and complications of DOACs and vitamin K antagonists (VKAs) after HTX., Methods: We screened all adult patients for the use of post-transplant OACs who underwent HTX at Heidelberg Heart Center between 2000 and 2021. Patients were stratified by type of OAC (DOAC or VKA) and by DOAC agents (apixaban, dabigatran, edoxaban, or rivaroxaban). Indications for OACs comprised atrial fibrillation, atrial flutter, pulmonary embolism, upper and lower extremity deep vein thrombosis, as well as intracardiac thrombus., Results: A total of 115 of 459 HTX recipients (25.1%) required OACs, including 60 patients with DOACs (52.2%) and 55 patients with VKAs (47.8%). Concerning DOACs, 28 patients were treated with rivaroxaban (46.7%), 27 patients with apixaban (45.0%), and 5 patients with edoxaban (8.3%). We found no significant differences between both groups concerning demographics, immunosuppressive drugs, concomitant medications, indications for OACs, ischemic stroke, thromboembolic events, or OAC-related death. Patients with DOACs after HTX had a significantly lower one-year rate of overall bleeding complications ( p = 0.002) and a significantly lower one-year rate of gastrointestinal hemorrhage ( p = 0.011) compared to patients with VKAs after HTX in the Kaplan-Meier estimator., Conclusions: DOACs were comparable to VKAs concerning the risk of ischemic stroke, thromboembolic events, or OAC-related death but were associated with significantly fewer bleeding complications in HTX recipients.

Background: Telemonitoring is used to monitor implantable cardioverter defibrillators (ICDs). Despite the scientifically proven effectiveness and safety of telemetric care, studies show that the offer is not used and accepted by all patients., Objectives: The aim of this study is to investigate the attitudes of ICD patients towards telemonitoring, including which aspects influence attitudes and decision-making., Methods: Data were collected using semi-structured, guideline-based individual interviews. A total of 14 patients with a subcutaneous ICD (sICD) and both primary and secondary prophylactic indications were recruited. Data analysis followed a content-structuring qualitative approach., Results: Patients with telemonitoring perceived a high benefit with low concerns about digital technology, while the opposite was observed for patients without telemonitoring. The patients' previous medical experience has a crucial impact on the acceptance of telemonitoring. All age groups reported the technical implementation and practical handling of telemonitoring to be simple and uncomplicated., Conclusion: The results suggest that the primary and secondary prophylactic indication for ICD implantation have an influence on the attitude towards telemonitoring and, thus, on acceptance. Further qualitative research regarding user acceptance of telemonitoring of other ICD systems is needed., (© 2023. The Author(s).)

Background: Elevated pulmonary vascular resistance (PVR) is broadly accepted as an imminent risk factor for mortality after heart transplantation (HTx). However, no current HTx recipient risk score includes PVR or other hemodynamic parameters. This study examined the utility of various hemodynamic parameters for risk stratification in a contemporary HTx population., Methods: Patients from seven German HTx centers undergoing HTx between 2011 and 2015 were included retrospectively. Established risk factors and complete hemodynamic datasets before HTx were analyzed. Outcome measures were overall all-cause mortality, 12-month mortality, and right heart failure (RHF) after HTx., Results: The final analysis included 333 patients (28% female) with a median age of 54 (IQR 46-60) years. The median mean pulmonary artery pressure was 30 (IQR 23-38) mm Hg, transpulmonary gradient 8 (IQR 5-10) mm Hg, and PVR 2.1 (IQR 1.5-2.9) Wood units. Overall mortality was 35.7%, 12-month mortality was 23.7%, and the incidence of early RHF was 22.8%, which was significantly associated with overall mortality (log-rank HR 4.11, 95% CI 2.47-6.84; log-rank p < .0001). Pulmonary arterial elastance (Ea) was associated with overall mortality (HR 1.74, 95% CI 1.25-2.30; p < .001) independent of other non-hemodynamic risk factors. Ea values below a calculated cutoff represented a significantly reduced mortality risk (HR 0.38, 95% CI 0.19-0.76; p < .0001). PVR with the established cutoff of 3.0 WU was not significant. Ea was also significantly associated with 12-month mortality and RHF., Conclusions: Ea showed a strong impact on post-transplant mortality and RHF and should become part of the routine hemodynamic evaluation in HTx candidates., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Tricuspid valve regurgitation (TVR) is often observed after orthotopic heart transplantation. However, there is a scarcity of data regarding long-term outcomes of patients with TVR., Methods: Between January 2008 and December 2015, 169 patients underwent orthotopic heart transplantation at our center and were included in this study. TVR trends and associated clinical parameters were retrospectively analyzed. TVR was assessed after 30 d, 1 y, 3 y, and 5 y, and groups were defined according to changes in TVR grade: constant (group 1; n = 100), improvement (group 2; n = 26), and deterioration (group 3; n = 43). Survival, outcome with regard to operative technique, and long-term kidney and liver function during follow-up were assessed., Results: Mean follow-up time was 7.67 ± 4.17 y (median 8.62, Q1 5.06, Q3 11.16). Overall mortality was 42.0%, with differences between the groups ( P  < 0.01). Cox regression analysis revealed improvement of TVR as a significant predictor for survival (hazard ratio 0.23; 95% confidence interval, 0.08-0.63, P  < 0.01). After 1 y 2.7%, after 3 y 3.7%, and after 5 y 3.9% of the patients showed persistent severe TVR. Creatinine levels after 30 d and 1, 3, and 5 y showed significant differences between the groups ( P  = 0.02, P  < 0.01, P  < 0.01, and P  = 0.01), deterioration of TVR being associated with higher creatinine levels during follow-up., Conclusions: Deterioration of TVR is associated with higher mortality and renal dysfunction. Improvement of TVR may function as a positive predictor for long-term survival after heart transplantation. Improvement of TVR should be a therapeutic goal offering a prognostic value for long-term survival., Competing Interests: P.S. received honoraria from Bayer, Abbott, and Edwards. G.W. received honoraria from Abiomed, Biotest, and DZHK. The other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

The Berlin Heart ® EXCOR is a paracorporeal, pulsatile ventricular assist device used in patients of all age groups. However, adolescent and adult patients on EXCOR support are scarcely explored. Herein, we present a detailed description of infectious complications in this patient cohort. From 2006 to 2020, 58 patients received a biventricular assist device (BiVAD) at our institution and were included in this study. Postoperative infections were assessed after BiVAD implantation and subsequent heart transplantation (HTx). A Berlin Heart ® EXCOR BiVAD was implanted as a bridge to transplantation in 58 patients (12-64 years). Most patients were INTERMACS I, and their median age was 49 years. Wound infections (WI) specific to the ventricular assist device (VAD) occurred in 31 (53.4%) patients with a mean time of 113 ± 155 days after BiVAD implantation. HTx was performed in 30 (51.7%) patients and thereof 10 (33.3%) patients developed at least one WI post-HTx. The mean time of WI after HTx was 17 ± 14 days. In four cases, WIs were caused by the same pathogen as before HTx. According to our institutional BiVAD wound classification, the mean wound score was 3. The VAD-specific wound infections were manageable and did not increase mortality nor precluded HTx in Berlin Heart ® EXCOR patients. No specific risk factors for VAD-specific wound infections could be identified.

Aims: Atrial flutter (AFL) is a common late-onset complication after heart transplantation (HTX) and is associated with worse clinical outcomes. Methods: This study investigated the frequency, risk factors, and outcomes of late-onset post-transplant AFL. We analyzed 639 adult patients undergoing HTX at the Heidelberg Heart Center between 1989 and 2019. Patients were stratified by diagnosis and type of late-onset post-transplant AFL (>90 days after HTX). Results: A total of 55 patients (8.6%) were diagnosed with late-onset post-transplant AFL, 30 had typical AFL (54.5%) and 25 had atypical AFL (45.5%). Patients with AFL were younger at HTX (p = 0.028), received more biatrial anastomosis (p = 0.001), and presented with moderate or severe tricuspid regurgitation (56.4%). Typical AFL was associated with graft rejection (p = 0.016), whereas atypical AFL was associated with coronary artery disease (p = 0.028) and stent implantation (p = 0.042). Patients with atypical AFL showed a higher all-cause 1-year mortality (p = 0.010) along with a higher rate of graft failure after diagnosis of AFL (p = 0.023). Recurrence of AFL was high (83.6%). Patients with catheter ablation after AFL recurrence had a higher 1-year freedom from AFL (p = 0.003). Conclusions: Patients with late-onset post-transplant AFL were younger at HTX, received more biatrial anastomosis, and showed a higher rate of moderate or severe tricuspid regurgitation. Typical AFL was associated with graft rejection, whereas atypical AFL was associated with myocardial ischemia, graft failure, and mortality. Catheter ablation represents a viable option to avoid further episodes of late-onset AFL after HTX.

Background: Patient access to medical records can improve quality of care. The phellow application (app) was developed to provide patients access to selected content of their medical record. It was tested at a heart transplantation (HTx) outpatient clinic. The aims of this study were (1) to assess usability of phellow, (2) to determine feasibility of implementation in routine care, and (3) to study the effects app use had on patients' self-management., Methods: Usability was measured quantitatively through the System Usability Scale (SUS). Furthermore, usability, feasibility, and effects on self-management were qualitatively assessed through interviews with users, non-users, and health care providers., Results: The SUS rating ( n = 31) was 79.9, indicating good usability. Twenty-three interviews were conducted. Although appreciation and willingness-to-use were high, usability problems such as incompleteness of record, technical issues, and complex registration procedures were reported. Improved technical support infrastructure, clearly defined responsibilities, and app-specific trainings were suggested for further implementation. Patients described positive effects on their self-management., Conclusions: To be feasible for implementation in routine care, usability problems should be addressed. Feedback on the effect of app use was encouraging. Accompanying research is crucial to monitor usability improvements and to further assess effects of app use on patients.

Current protocols for the differentiation of human-induced pluripotent stem cells (hiPSC) into cardiomyocytes only generate a small amount of cardiac pacemaker cells. In previous work, we reported the generation of high amounts of cardiac pacemaker cells by co-culturing hiPSC with mouse visceral endoderm-like (END2) cells. However, potential medical applications of cardiac pacemaker cells generated according to this protocol, comprise an incalculable xenogeneic risk. We thus aimed to establish novel protocols maintaining the differentiation efficiency of the END2 cell-based protocol, yet eliminating the use of END2 cells. Three protocols were based on the activation and inhibition of the Wingless/Integrated (Wnt) signaling pathway, supplemented either with retinoic acid and the Wnt activator CHIR99021 (protocol B) or with the NODAL inhibitor SB431542 (protocol C) or with a combination of all three components (protocol D). An additional fourth protocol (protocol E) was used, which was originally developed by the manufacturer STEMCELL Technologies for the differentiation of hiPSC or hESC into atrial cardiomyocytes. All protocols (B, C, D, E) were compared to the END2 cell-based protocol A, serving as reference, in terms of their ability to differentiate hiPSC into cardiac pacemaker cells. Our analysis revealed that protocol E induced upregulation of 12 out of 15 cardiac pacemaker-specific genes. For comparison, reference protocol A upregulated 11, while protocols B, C and D upregulated 9, 10 and 8 cardiac pacemaker-specific genes, respectively. Cells differentiated according to protocol E displayed intense fluorescence signals of cardiac pacemaker-specific markers and showed excellent rate responsiveness to adrenergic and cholinergic stimulation. In conclusion, we characterized four novel and END2 cell-independent protocols for the differentiation of hiPSC into cardiac pacemaker cells, of which protocol E was the most efficient.

Aims: Cardiac transplant recipients often suffer from type 2 diabetes mellitus (T2DM) but its influence on graft failure and post-transplant mortality remains unknown. The aim of this study was to investigate the long-term effects of pre-transplant T2DM in patients after heart transplantation (HTX)., Methods: This study included a total of 376 adult patients who received HTX at Heidelberg Heart Center between 01/01/2000 and 01/10/2016. HTX recipients were stratified by diagnosis of T2DM at the time of HTX. Patients with T2DM were further subdivided by hemoglobin A1c (HbA1c ≥ 7.0%). Analysis included donor and recipient data, immunosuppressive drugs, concomitant medications, post-transplant mortality, and causes of death. Five-year post-transplant mortality was further assessed by multivariate analysis (Cox regression) and Kaplan-Meier estimator., Results: About one-third of all HTX recipients had T2DM (121 of 376 [32.2%]). Patients with T2DM showed an increased 5-year post-transplant mortality (41.3% versus 29.8%; P = 0.027) and had a higher percentage of death due to graft failure (14.9% versus 7.8%; P = 0.035). Multivariate analysis showed T2DM (HR: 1.563; 95% CI: 1.053-2.319; P = 0.027) as an independent risk factor for 5-year mortality after HTX. Kaplan-Meier analysis showed a significantly better 5-year post-transplant survival of patients with T2DM and a HbA1c < 7.0% than patients with T2DM and a HbA1c ≥ 7.0% (68.7% versus 46.3%; P = 0.008) emphasizing the clinical relevance of a well-controlled T2DM in HTX recipients., Conclusion: Pre-transplant T2DM is associated with higher graft failure and increased 5-year mortality after HTX., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rivinius, Gralla, Helmschrott, Darche, Ehlermann, Bruckner, Sommer, Warnecke, Kopf, Szendroedi, Frey and Kihm.)

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).)

We aimed to evaluate the prognostic value of procalcitonin (PCT) in acute heart failure (AHF) patients, especially in those without underlying infection. We enrolled patients presenting with acute dyspnea to the emergency department (ED) of Heidelberg University Hospital and studied the prognostic role of PCT on all-cause death. Of 312 patients, AHF was diagnosed in 139 patients. Of these, 125 patients had AHF without signs of infection, and 14 had AHF complicated by respiratory or other infection. The optimal prognostic PCT cutoff value for mortality prediction was calculated by a receiver operating characteristics curve. In patients with AHF, the prognostic PCT cutoff value was 0.08 ng/mL. The Kaplan-Meier survival analysis showed that AHF patients with PCT values > 0.08 ng/mL had a higher all-cause mortality at 120 days than those with PCT values ≤ 0.08 ng/mL (log-rank p = 0.0123). Similar results could be obtained after subdivision into AHF patients with and without signs of overt infection. In both cases, mortality was higher in patients with PCT levels above the prognostic PCT cutoff than in those with values ranging below this threshold. Moreover, we show that the prognostic PCT cutoff values for mortality prediction ranged below the established PCT cutoff for the guidance of antibiotic therapy. In conclusion, the data of our study revealed that low-level elevations of PCT were associated with an increased mortality in patients with AHF, irrespective of concomitant respiratory or other infection. PCT should thus be further used as a marker in the risk stratification of AHF.

Long-term survival after heart transplantation (HTX) is impacted by adverse effects of immunosuppressive pharmacotherapy, and post-transplant lung cancer is a common occurrence. This study aimed to examine the risk factors, treatment, and prognosis of patients with post-transplant lung cancer. We included 625 adult patients who received HTX at Heidelberg Heart Center between 1989 and 2018. Patients were stratified by diagnosis and staging of lung cancer after HTX. Analysis comprised donor and recipient characteristics, medications including immunosuppressive drugs, and survival after diagnosis of lung cancer. A total of 41 patients (6.6%) were diagnosed with lung cancer after HTX, 13 patients received curative care and 28 patients had palliative care. Mean time from HTX until diagnosis of lung cancer was 8.6 ± 4.0 years and 1.8 ± 2.7 years from diagnosis of lung cancer until last follow-up. Twenty-four patients (58.5%) were switched to an mTOR-inhibitor after diagnosis of lung cancer. Multivariate analysis showed recipient age (HR: 1.05; CI: 1.01-1.10; p = 0.02), COPD (HR: 3.72; CI: 1.88-7.37; p < 0.01), and history of smoking (HR: 20.39; CI: 2.73-152.13; p < 0.01) as risk factors for post-transplant lung cancer. Patients in stages I and II had a significantly better 1-year (100.0% versus 3.6%), 2-year (69.2% versus 0.0%), and 5-year survival (53.8% versus 0.0%) than patients in stages III and IV ( p < 0.01). Given the poor prognosis of late-stage post-transplant lung cancer, routine reassessment of current smoking status, providing smoking cessation support, and intensified lung cancer screening in high-risk HTX recipients are advisable.

Aims: Right bundle branch block (RBBB) after heart transplantation (HTX) is a common finding, but its impact on post-transplant survival remains uncertain. This study investigated the post-transplant outcomes of patients with complete RBBB (cRBBB) ≤ 30 days after HTX., Methods: This registry study analysed 639 patients receiving HTX at Heidelberg Heart Center between 1989 and 2019. Patients were stratified by diagnosis of cRBBB ≤ 30 days after HTX. Analysis included recipient and donor data, medication, echocardiographic features, graft rejections, atrial fibrillation, heart rates, permanent pacemaker implantation and mortality after HTX including causes of death., Results: One hundred thirty-nine patients showed cRBBB ≤ 30 days after HTX (21.8%), 20 patients with pre-existing cRBBB in the donor heart (3.2%) and 119 patients with newly acquired cRBBB (18.6%). Patients with newly acquired cRBBB had a worse 1-year post-transplant survival (36.1%, P < 0.01) compared with patients with pre-existing cRBBB (85.0%) or without cRBBB (86.4%), along with a higher percentage of death due to graft failure (P < 0.01). Multivariate analysis indicated cRBBB ≤ 30 days after HTX as significant risk factor for 1-year mortality after HTX (HR: 2.20; 95% CI: 1.68-2.87; P < 0.01). Secondary outcomes showed a higher rate of an enlarged right atrium (P = 0.01), enlarged right ventricle (P < 0.01), reduced right ventricular function (P < 0.01), 30-day atrial fibrillation (P < 0.01) and 1-year permanent pacemaker implantation (P = 0.02) in patients with cRBBB after HTX., Conclusions: Newly acquired cRBBB early after HTX is associated with increased post-transplant mortality., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Atrial fibrillation (AF) after heart transplantation (HTX) is associated with worse clinical outcomes. The current study aimed to analyse the association between AF before HTX and AF within 30 days after HTX., Methods and Results: This study included 639 adults who received HTX at Heidelberg Heart Center. Patients were subdivided into four groups depending on the status of AF before and after HTX. Analyses comprised recipient and donor data, medication, echocardiographic features, permanent pacemaker implantation, stroke, and mortality after HTX. Three hundred thirty-two patients (52.0%) had neither AF before nor after HTX, 15 patients (2.3%) had no AF before HTX but showed AF after HTX, 219 patients (34.3%) showed AF before HTX but had no AF after HTX, and 73 patients (11.4%) had AF before and after HTX. Patients with AF before and after HTX had a higher 1 year post-transplant mortality (39.7%) than patients without AF before or after HTX (18.1%, P < 0.01). Secondary outcomes showed a higher percentage of enlarged atria, ventricular dysfunction, mitral regurgitation, 1-year stroke, and 1-year permanent pacemaker implantation in patients with AF before and after HTX. Multivariate analysis revealed a six-fold elevated risk for post-transplant AF in patients with AF before HTX (hazard ratio: 6.59, confidence interval: 3.72-11.65; P < 0.01). Further risk factors for post-transplant AF were higher donor age and prolonged ischaemic time, whereas total orthotopic HTX was associated with a two-fold lower risk for post-transplant AF., Conclusions: Atrial fibrillation before HTX is a risk factor for post-transplant AF, permanent pacemaker implantation, and mortality after HTX., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Immunocompromised patients have been excluded from studies of SARS-CoV-2 messenger RNA vaccines. The immune response to vaccines against other infectious agents has been shown to be blunted in such patients. We aimed to analyse the humoral and cellular response to prime-boost vaccination with the BNT162b2 vaccine (Pfizer-BioNTech) in cardiothoracic transplant recipients., Methods and Results: A total of 50 transplant patients [1-3 years post heart (42), lung (7), or heart-lung (1) transplant, mean age 55 ± 10 years] and a control group of 50 healthy staff members were included. Blood samples were analysed 21 days after the prime and the boosting dose, respectively, to quantify anti-SARS-CoV-2 spike protein (S) immunoglobulin titres (tested by Abbott, Euroimmun and RocheElecsys Immunoassays, each) and the functional inhibitory capacity of neutralizing antibodies (Genscript). To test for a specific T-cell response, heparinized whole blood was stimulated with SARS-CoV-2 specific peptides, covering domains of the viral spike, nucleocapsid and membrane protein, and the interferon-γ release was measured (QuantiFERON Monitor ELISA, Qiagen). The vast majority of transplant patients (90%) showed neither a detectable humoral nor a T-cell response three weeks after the completed two-dose BNT162b2 vaccination; these results are in sharp contrast to the robust immunogenicity seen in the control group: 98% exhibited seroconversion after the prime dose already, with a further significant increase of IgG titres after the booster dose (average > tenfold increase), a more than 90% inhibition capability of neutralizing antibodies as well as evidence of a T-cell responsiveness., Conclusions: The findings of poor immune responses to a two-dose BNT162b2 vaccination in cardiothoracic transplant patients have a significant impact for organ transplant recipients specifically and possibly for immunocompromised patients in general. It urges for a review of future vaccine strategies in these patients., (© 2021. The Author(s).)

Atrial fibrillation (AF) is associated with electrical remodeling, leading to cellular electrophysiological dysfunction and arrhythmia perpetuation. Emerging evidence suggests a key role for epigenetic mechanisms in the regulation of ion channel expression. Histone deacetylases (HDACs) control gene expression through deacetylation of histone proteins. We hypothesized that class I HDACs in complex with neuron-restrictive silencer factor (NRSF) determine atrial K + channel expression. AF was characterized by reduced atrial HDAC2 mRNA levels and upregulation of NRSF in humans and in a pig model, with regional differences between right and left atrium. In vitro studies revealed inverse regulation of Hdac2 and Nrsf in HL-1 atrial myocytes. A direct association of HDAC2 with active regulatory elements of cardiac K + channels was revealed by chromatin immunoprecipitation. Specific knock-down of Hdac2 and Nrsf induced alterations of K + channel expression. Hdac2 knock-down resulted in prolongation of action potential duration (APD) in neonatal rat cardiomyocytes, whereas inactivation of Nrsf induced APD shortening. Potential AF-related triggers were recapitulated by experimental tachypacing and mechanical stretch, respectively, and exerted differential effects on the expression of class I HDACs and K + channels in cardiomyocytes. In conclusion, HDAC2 and NRSF contribute to AF-associated remodeling of APD and K + channel expression in cardiomyocytes via direct interaction with regulatory chromatin regions. Specific modulation of these factors may provide a starting point for the development of more individualized treatment options for atrial fibrillation.

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.

Background: Mesenchymal stem cells (MSC) modified by gene transfer to express cardiac pacemaker channels such as HCN2 or HCN4 were shown to elicit pacemaker function after intracardiac transplantation in experimental animal models. Human MSC derived from adipose tissue (haMSC) differentiate into cells with pacemaker properties in vitro , but little is known about their behavior after intracardiac transplantation., Aim: To investigate whether haMSC elicit biological pacemaker function in vivo after transplantation into pig hearts., Methods: haMSC under native conditions (nhaMSC) or after pre-conditioning by medium differentiation (dhaMSC) ( n = 6 pigs each, 5 × 10 6 cells/animal) were injected into the porcine left ventricular free wall. Animals receiving PBS injection served as controls ( n = 6). Four weeks later, total atrioventricular (AV)-block was induced by radiofrequency catheter ablation, and electronic pacemaker devices were implanted for backup stimulation and heart rate monitoring. Ventricular rate and rhythm of pigs were evaluated during a follow-up of 15 d post ablation by 12-lead-ECG with heart rate assessment, 24-h continuous rate monitoring recorded by electronic pacemaker, assessment of escape recovery time, and pharmacological challenge to address catecholaminergic rate response. Finally, hearts were analyzed by histological and immunohistochemical investigations., Results: In vivo transplantation of dhaMSC into the left ventricular free wall of pigs elicited spontaneous and regular rhythms that were pace-mapped to ventricular injection sites (mean heart rate 72.2 ± 3.6 bpm; n = 6) after experimental total AV block. Ventricular rhythms were stably detected over a 15-d period and were sensitive to catecholaminergic stimulation (mean maximum heart rate 131.0 ± 6.2 bpm; n = 6; P < 0.001). Pigs, which received nhaMSC or PBS presented significantly lower ventricular rates (mean heart rates 47.2 ± 2.5 bpm and 37.4 ± 3.2 bpm, respectively; n = 6 each; P < 0.001) and exhibited little sensitivity towards catecholaminergic stimulation (mean maximum heart rates 76.4 ± 3.1 bpm and 60.5 ± 3.1 bpm, respectively; n = 6 each; P < 0.05). Histological and immunohistochemical evaluation of hearts treated with dhaMSC revealed local clusters of transplanted cells at the injection sites that lacked macrophage or lymphocyte infiltrations or tumor formation. Intense fluorescence signals at these sites indicated membrane expression of HCN4 and other pacemaker-specific proteins involved in cardiac automaticity and impulse propagation., Conclusion: dhaMSC transplanted into pig left ventricles sustainably induced rate-responsive ventricular pacemaker activity after in vivo engraftment for four weeks. The data suggest that pre-conditioned MSC may further differentiate along a pacemaker-related lineage after myocardial integration and may establish superior pacemaker properties in vivo ., Competing Interests: Conflict-of-interest statement: All authors have no any conflicts of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

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.)

Transient outward K + current, I to , contributes to cardiac action potential generation and is primarily carried by K v 4.3 (KCND3) channels. Two K v 4.3 isoforms are expressed in human ventricle and show differential remodeling in heart failure (HF). Lidocaine and mexiletine may be applied in selected patients to suppress ventricular arrhythmias, without effects on sudden cardiac death or mortality. Isoform-dependent effects of antiarrhythmic drugs on K v 4.3 channels and potential implications for remodeling-based antiarrhythmic management have not been assessed to date. We sought to test the hypotheses that K v 4.3 channels are targeted by lidocaine and mexiletine, and that drug sensitivity is determined in isoform-specific manner. Expression of KCND3 isoforms was quantified using qRT-PCR in left ventricular samples of patients with HF due to either ischemic or dilated cardiomyopathies (ICM or DCM). Long (K v 4.3-L) and short (K v 4.3-S) isoforms were heterologously expressed in Xenopus laevis oocytes to study drug sensitivity and effects on biophysical characteristics activation, deactivation, inactivation, and recovery from inactivation. In the present HF patient cohort KCND3 isoform expression did not differ between ICM and DCM. In vitro, lidocaine (IC 50 -K v 4.3-L: 0.8 mM; IC 50 -K v 4.3-S: 1.2 mM) and mexiletine (IC 50 -K v 4.3-L: 146 μM; IC 50 -K v 4.3-S: 160 μM) inhibited K v 4.3 with different sensitivity. Biophysical analyses identified accelerated and enhanced inactivation combined with delayed recovery from inactivation as primary biophysical mechanisms underlying K v 4.3 current reduction. In conclusion, differential effects on K v 4.3 isoforms extend the electropharmacological profile of lidocaine and mexiletine. Patient-specific remodeling of K v 4.3 isoforms may determine individual drug responses and requires consideration during clinical application of compounds targeting K v 4.3., Competing Interests: Declaration of competing interest A.K.R. reports educational support from Boston Scientific and Medtronic. D.T. reports receiving lecture fees/honoraria from Bayer Vital, Boehringer Ingelheim Pharma, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Pfizer Pharma, Sanofi-Aventis, St. Jude Medical and ZOLL CMS. P.L. reports receiving lecture fees from Bayer Vital and Pfizer Pharma and educational support from Boston Scientific and Johnson & Johnson. B.S. reports personal fees for surgical proctoring services from Abbott. The remaining authors have reported that they have no relationships relevant to the content of this paper to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.)

Engraftment and functional integration of stem cells or stem cell-derived cells within cardiac tissue is an important prerequisite for cell replacement therapy aiming at the treatment of heart disease. Recently, a novel intravenous approach for application of mesenchymal stromal cells (MSCs) to cardiac sites has been established using radiofrequency catheter ablation (RFCA)-guided targeting, bypassing the need for open chest surgery or direct myocardial cell injection. However, little is known about the quantitative efficacy and longevity of this strategy. We performed selective power-controlled RFCA with eight ablation pulses (30 W, 60 s each) to induce heat-mediated lesions at the right atrial appendices (RAAs) of pigs. Different concentrations of human bone marrow-derived MSCs (10 5 to 1.6 × 10 6 cells/kg bodyweight) labeled with superparamagnetic iron oxide (SPIO) particles were infused intravenously in nine pigs one d after RFCA treatment and hearts were explanted 8 d later to quantify the number of engrafted cells. Prussian blue staining revealed high numbers of SPIO-labeled cells in areas surrounding the RFCA-induced lesions. Cell numbers were evaluated by quantitative real-time polymerase chain reaction using specific primers for human MSCs (hMSCs), which indicated that up to 10 6 hMSCs, corresponding to ∼3.9% of the systemically applied human cells, engrafted within the RAAs of RFCA-treated pigs. Of note, infused hMSCs were observed in nontargeted organs, as well, but appeared at very low concentrations. To assess long-term deposition of MSCs, RAAs of three pigs were analyzed after 6 months, which revealed few persisting hMSCs at targeted sites. RFCA-mediated targeting of MSCs provides a novel minimal invasive strategy for cardiac stem cell engraftment. Qualitative and quantitative results of our large animal experiments indicate an efficient guidance of MSCs to selected cardiac regions, although only few cells remained at targeted sites 6 mo after cell transplantation.

Background: Permanent pacemaker (PPM) implantation after heart transplantation (HTX) may be required due to severe bradycardia. The aim of this study was to investigate the risk factors, indications, perioperative outcomes and complications of PPM implantation after HTX as well as the underlying effect on post-transplant mortality including causes of death., Methods: This registry study included 621 patients receiving HTX at Heidelberg Heart Center between 1989 and 2018. Patients were stratified by PPM implantation after HTX. Data analysis of risk factors for PPM implantation included donor and recipient demographics, post-transplant medication, mortality, and causes of death., Results: Thirty-six patients (5.8%) received PPM implantation after HTX, 12 (33.3%) with early PPM and 24 (66.7%) with late PPM. Indications for PPM implantation after HTX included sinus node dysfunction (SND) (n=15; 41.7%) and atrioventricular block (AVB) (n=21; 58.3%). Multivariate analysis revealed recipient body mass index (BMI) [hazard ratio (HR): 1.10; confidence interval (CI): 1.01-1.21; P=0.03], donor age (HR: 1.07; CI: 1.03-1.10; P<0.01), and biatrial HTX (HR: 2.63; CI: 1.22-5.68; P=0.01) as significant risk factors for PPM implantation after HTX. Kaplan-Meier estimator displayed a statistically significant inferior 5-year post-transplant survival among patients with early PPM after HTX in comparison to patients with late PPM or no PPM after HTX (P<0.01) along with a higher percentage of death due to infection (P<0.01)., Conclusions: Multivariate risk factors for PPM implantation after HTX include recipient BMI, donor age, and biatrial HTX. Early PPM implantation after HTX is associated with increased 5-year post-transplant mortality due to infection., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Journal of Thoracic Disease. All rights reserved.)

Aims: Cell-based biological pacemakers aim to overcome limitations and side effects of electronic pacemaker devices. We here developed and tested different approaches to achieve nodal-type differentiation using human adipose- and bone marrow-derived mesenchymal stem cells (haMSC, hbMSC)., Main Methods: haMSC and hbMSC were differentiated using customized protocols. Quantitative RT-PCR was applied for transcriptional pacemaker-gene profiling. Protein membrane expression was analyzed by immunocytochemistry. Pacemaker current (I f ) was studied in haMSC with and without lentiviral HCN4-transduction using patch clamp recordings. Functional characteristics were evaluated by co-culturing with neonatal rat ventricular myocytes (NRVM)., Key Findings: Culture media-based differentiation for two weeks generated cells with abundant transcription of ion channel genes (Ca v 1.2, NCX1), transcription factors (TBX3, TBX18, SHOX2) and connexins (Cx31.9 and Cx45) characteristic for cardiac pacemaker tissue, but lack adequate HCN transcription. haMSC-derived cells revealed transcript levels, which were closer related to sinoatrial nodal cells than hbMSC-derived cells. To substitute for the lack of I f , we performed lentiviral HCN4-transduction of haMSC resulting in stable I f . Co-culturing with NRVM demonstrated that differentiated haMSC expressing HCN4 showed earlier onset of spontaneous contractions and higher beating regularity, synchrony and rate compared to co-cultures with non-HCN4-transduced haMSC or HCN4-transduced, non-differentiated haMSC. Confocal imaging indicated increased membrane expression of cardiac gap junctional proteins in differentiated haMSC., Significance: By differentiation haMSC, rather than hbMSC attain properties favorable for cardiac pacemaking. In combination with lentiviral HCN4-transduction, a cellular phenotype was generated that sustainably controls and stabilizes rate in co-culture with NRVM., (Copyright © 2019 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: Human induced pluripotent stem cells (hiPSC) harbor the potential to differentiate into diverse cardiac cell types. Previous experimental efforts were primarily directed at the generation of hiPSC-derived cells with ventricular cardiomyocyte characteristics. Aiming at a straightforward approach for pacemaker cell modeling and replacement, we sought to selectively differentiate cells with nodal-type properties., Methods: hiPSC were differentiated into spontaneously beating clusters by co-culturing with visceral endoderm-like cells in a serum-free medium. Subsequent culturing in a specified fetal bovine serum (FBS)-enriched cell medium produced a pacemaker-type phenotype that was studied in detail using quantitative real-time polymerase chain reaction (qRT-PCR), immunocytochemistry, and patch-clamp electrophysiology. Further investigations comprised pharmacological stimulations and co-culturing with neonatal cardiomyocytes., Results: hiPSC co-cultured in a serum-free medium with the visceral endoderm-like cell line END-2 produced spontaneously beating clusters after 10-12 days of culture. The pacemaker-specific genes HCN4, TBX3, and TBX18 were abundantly expressed at this early developmental stage, while levels of sarcomeric gene products remained low. We observed that working-type cardiomyogenic differentiation can be suppressed by transfer of early clusters into a FBS-enriched cell medium immediately after beating onset. After 6 weeks under these conditions, sinoatrial node (SAN) hallmark genes remained at high levels, while working-type myocardial transcripts (NKX2.5, TBX5) were low. Clusters were characterized by regular activity and robust beating rates (70-90 beats/min) and were triggered by spontaneous Ca 2+ transients recapitulating calcium clock properties of genuine pacemaker cells. They were responsive to adrenergic/cholinergic stimulation and able to pace neonatal rat ventricular myocytes in co-culture experiments. Action potential (AP) measurements of cells individualized from clusters exhibited nodal-type (63.4%) and atrial-type (36.6%) AP morphologies, while ventricular AP configurations were not observed., Conclusion: We provide a novel culture media-based, transgene-free approach for targeted generation of hiPSC-derived pacemaker-type cells that grow in clusters and offer the potential for disease modeling, drug testing, and individualized cell-based replacement therapy of the SAN.