Comparing everolimus-based immunosuppression with reduction or withdrawal of calcineurin inhibitor reduction from six months after heart transplantation: the randomized MANDELA study.

In the 12-month, open-label MANDELA study, patients were randomized at month 6 after heart transplantation to (i) convert to calcineurin inhibitor (CNI)-free immunosuppression with everolimus (EVR), mycophenolic acid and steroids (CNI-free, n=71), or to (ii) continue reduced-exposure CNI, with EVR and steroids (EVR/redCNI, n=74). Tacrolimus was administered in 48.8% of EVR/redCNI patients and 52.6% of CNI-free patients at radomization. Both strategies improved and stabilized renal function based on the primary endpoint (estimated GFR at month 18 post-transplant post-randomization) with superiority of the CNI-free group versus EVR/redCNI : mean 64.1mL/min/1.73m2 versus 52.9mL/min/1.73m2 ; difference +11.3mL/min/1.73m2 (p<0.001). By month 18, estimated GFR had increased by ≥10mL/min/1.732 in 31.8% and 55.2% of EVR/redCNI and CNI-free patients, respectively, and by ≥25 mL/min/1.73m2 in 4.5% and 20.9%. Rates of biopsy-proven acute rejection (BPAR) were 6.8% and 21.1%; all cases were without hemodynamic compromise. BPAR was less frequent with EVR/redCNI versus the CNI-free regimen (p=0.015); 6/15 episodes in CNI-free patients occurred with EVR concentration <5ng/mL. Rates of adverse events and associated discontinuations were comparable EVR/redCNI from month 6 achieved stable renal function with infrequent BPAR. One-year renal function can be improved by early conversion to EVR-based CNI-free therapy but requires close EVR monitoring. This article is protected by copyright. All rights reserved.

Five-year results of heart rate control with ivabradine or metoprolol succinate in patients after heart transplantation.

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.

Impact of troponin I-autoantibodies in chronic dilated and ischemic cardiomyopathy.

The aim of this study was to investigate the prognostic value of circulating troponin I (TNI)-autoantibodies in plasma of patients with chronic heart failure. Sera of 390 heart failure patients were tested for the presence of anti-TNI antibodies by enzyme-linked immunosorbent assay (ELISA), including 249 (63.8% of total) patients with dilated cardiomyopathy (DCM) and 141 (36.2% of total) patients with ischemic cardiomyopathy (ICM). A total of 72 patients (18.5% of total) were female and 318 (81.5% of total) were male. Mean patient age was 54.6 ± 11.3 years and mean follow-up time was 3.8 ± 3.2 years. TNI-autoantibodies (titer of ≥1:40) were detected in 73 out of 390 patients (18.7% of total). In TNI-autoantibody positive patients mean left ventricular ejection fraction (LVEF) was 27.6 ± 5.8%, compared to 25.8 ± 5.9% in TNI-autoantibody negative patients, P = 0.03. The combined end-point of death (n = 118, 30.3% of total) or heart transplantation (HTX) (n = 44, 11.3% of total) was reached in 162 patients (41.5% of total). Kaplan-Meier analysis demonstrated superior survival (combined end-point of death or HTX) in patients with DCM versus ICM (P = 0.0198) and TNI-autoantibody positive patients versus TNI-autoantibody negative patients (P = 0.0348). Further subgroup analysis revealed a favorable outcome in TNI-positive patients with heart failure if the patients suffered from DCM (P = 0.0334), whereas TNI-autoantibody status in patients with ICM was not associated with survival (P = 0.8486). In subsequent multivariate Weibull-analysis, a positive TNI serostatus was associated with a significantly lower all-cause mortality in DCM patients (P = 0.0492). The presence of TNI-autoantibodies in plasma is associated with an improved survival in patients with chronic DCM, but not ICM. This might possibly indicate a prophylactic effect of TNI-autoantibodies in this subgroup of patients, encouraging further studies into possible protective effects of antibodies against certain cardiac target structures.

Risk Factors, Treatment and Prognosis of Patients with Lung Cancer after Heart Transplantation.

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.

Negative pretransplant serostatus for Toxoplasma gondii is associated with impaired survival after heart transplantation.

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.

Effects of protein A immunoadsorption in patients with chronic dilated cardiomyopathy.

OBJECTIVES: The objective of this study was to investigate functional effects of immunoadsorption (IA) in patients with chronic nonfamilial dilated cardiomyopathy (DCM) regarding clinical and humoral markers of heart failure. BACKGROUND: IA has been shown to induce early hemodynamic improvement in patients with nonfamilial dilated cardiomyopathy (DCM). METHODS: We performed IA using protein A agarose columns on five consecutive days in 51 patients with chronic DCM, congestive heart failure of NYHA class ≥ II, left ventricular ejection fraction ≤50%, and mean time since initial diagnosis of 5.0 ± 5.8 years. RESULTS: Immediately after IA, immunoglobulin G (IgG) decreased by 89.4% and IgG3 by 66.7% (both P < 0.0001). Median NT-pro BNP was reduced from 1230.0 ng L(-1) at baseline to 829.0 ng L(-1) after 6 months (P < 0.0001). Also mean left ventricular ejection fraction (LVEF) was significantly improved (26.3% ± 9.4% to 28.7% ± 11.4% after 6 months, P = 0.016) and LVEF improved ≥5% (absolute) in 21 of 51 (41.2%) patients. After 6 months, bicycle spiroergometry showed a significant increase in exercise capacity from 82.0 ± 30.8 Watts to 93.1 ± 34.3 Watts (P = 0.008) while VO2max rose from 15.0 ± 4.1 to 16.4 ± 4.8 mL min(-1) kg(-1) (P = 0.01). CONCLUSIONS: In this study, on heart failure patients with nonfamilial DCM, IA therapy significantly improved clinical and humoral markers of heart failure severity. These promising results may be due to the selected study population, with a shorter disease duration and the higher amount of IgG 3 reduction. Future blinded prospective multicenter studies are necessary to identify those patients that benefit most.

Elevated pre-transplant pulmonary vascular resistance is associated with early post-transplant atrial fibrillation and mortality.

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.

Combined amiodarone and digitalis therapy before heart transplantation is associated with increased post-transplant mortality.

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.

Effects of protein A immunoadsorption in patients with advanced chronic dilated cardiomyopathy.

OBJECTIVES: The objective of this study was to investigate functional effects of immunoadsorption (IA) in severely limited study patients with chronic nonfamilial dilated cardiomyopathy (DCM), and to analyze the prevalence of Troponin I (TNI) autoantibodies. BACKGROUND: Immunoadsorption (IA) has been shown to induce early hemodynamic improvement in patients with nonfamilial DCM. METHODS: We performed IA using Immunosorba columns on five consecutive days in 27 patients with chronic DCM, congestive heart failure of NYHA class >or=II, left ventricular ejection fraction below 40%, and mean time since initial diagnosis of 7.2 +/- 6.8 years. RESULTS: Immediately after IA, IgG decreased by 87.7% and IgG3 by 58.5%. Median NT-pro BNP was reduced from 1740.0 ng/L at baseline to 1504.0 ng/L after 6 months (P = 0.004). Mean left ventricular ejection fraction (LVEF) was not significantly improved overall (24.1 +/- 7.8% to 25.4 +/- 10.4% after 6 months, P = 0.38), but LVEF improved >or=5% (absolute) in 9 of 27 (33%) patients. Bicycle spiroergometry showed a significant increase in exercise capacity from 73.7 +/- 29.4 Watts to 88.8 +/- 31.1 Watts (P = 0.003) after 6 months while VO2max rose from 13.7 +/- 3.8 to 14.9 +/- 3.0 mL/min kg after 6 months (P = 0.09). Subgroup analysis revealed a higher NT-pro BNP reduction in patients with shorter disease duration (P = 0.03) and without TNI autoantibodies at baseline (P = 0.05). All 9 patients with an absolute increase of LVEF of >or=5.0% were diabetic (P = 0.0001). CONCLUSIONS: In this study, on severely limited heart failure patients with nonfamilial DCM, IA therapy moderately improved markers of heart failure severity in a limited subgroup of patients. This may be due to the selected study population with end-stage heart failure patients and the lower reduction of IgG3 compared to previous studies. Future blinded multicenter studies are necessary to identify those patients that benefit most.

Risk factors and survival of patients with permanent pacemaker implantation after heart 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.

Adventitial tertiary lymphoid organ classification in human atherosclerosis.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease of the arterial wall. Adjacent to lamina intima lesion progression, a cellular compound develops in the lamina adventitia, defined as tertiary lymphoid organs (TLO) in mice. But in human system, it remains unknown whether these adventitial cellular accumulations represent these highly organized immunological structures. PATIENTS AND METHODS: In this study, we investigated whether the adventitial cellular compounds represent TLOs in 72 human coronary artery samples by immunoenzyme staining. RESULTS: The study showed that the adventitial cellular compound partly represented TLOs in human coronary arteries affected by atherogenesis in patients suffering from ischemic heart disease (56%) or a fatal myocardial infarction (100%), but not dilated cardiomyopathy. In addition, we established a classification for human TLOs, stage I-III, and showed that all stages were present in diseased coronary arteries. The stage of TLOs highly correlated with lesion size as well as plaque instability and rupture, and all patients with a myocardial infarction had stage III. Additionally, there were cellular infiltration and destruction of the lamina media, which were restricted to TLOs next to ruptured plaques in patients with a fatal myocardial infarction. CONCLUSIONS: TLOs are present in patients with a coronary artery disease and highly correlated with lesion size, plaque instability, and rupture. Further studies are needed to investigate whether TLOs might be a specific diagnostic and drug target to modify plaque instability/rupture.

COPD in patients after heart transplantation is associated with a prolonged hospital stay, early posttransplant atrial fibrillation, and impaired posttransplant survival.

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]) <0.70 before HTX. The analysis included demographics, posttransplant medication, length of the initial hospital stay after HTX, early posttransplant atrial fibrillation (AF), mortality, and causes of death. RESULTS: In total, 63 (24.3%) patients had an FEV1/FVC <0.70. These patients showed a prolonged hospital stay after HTX (52.0 days vs 43.4 days, mean difference (MD) = 8.6 days, 95% CI: 0.2, 17.0 days), a higher rate of early posttransplant AF (19.0% vs 8.2%, MD = 10.8%, 95% CI: 0.4%, 21.2%), and an increased 30-day mortality (9.5% vs 2.6%, HR = 3.79, 95% CI: 1.16, 12.40). Kaplan- Meier analysis showed a significant inferior 5-year survival in patients with an FEV1/FVC <0.70, along with a higher percentage of death due to transplant failure and infection/sepsis. In addition, a multivariate analysis for mortality within 5 years after HTX indicated an FEV1/FVC <0.70 as a significant risk factor for impaired 5-year posttransplant survival (HR =4.77, 95% CI: 2.76, 8.22). CONCLUSION: COPD in patients after HTX is associated with a prolonged hospital stay, early posttransplant AF, and impaired posttransplant survival.

Control of cardiac chronotropic function in patients after heart transplantation: effects of ivabradine and metoprolol succinate on resting heart rate in the denervated heart.

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.

Systematic RNA-interference in primary human monocyte-derived macrophages: A high-throughput platform to study foam cell formation.

Macrophage-derived foam cells are key regulators of atherogenesis. They accumulate in atherosclerotic plaques and support inflammatory processes by producing cytokines and chemokines. Identifying factors that regulate macrophage lipid uptake may reveal therapeutic targets for coronary artery disease (CAD). Here, we establish a high-throughput screening workflow to systematically identify genes that impact the uptake of DiI-labeled low-density lipoprotein (LDL) into monocyte-derived primary human macrophages. For this, monocytes isolated from peripheral blood were seeded onto 384-well plates, solid-phase transfected with siRNAs, differentiated in vitro into macrophages, and LDL-uptake per cell was measured by automated microscopy and quantitative image analysis. We applied this workflow to study how silencing of 89 genes impacts LDL-uptake into cells from 16 patients with CAD and 16 age-matched controls. Silencing of four novel genes (APOC1, CMTM6, FABP4, WBP5) reduced macrophage LDL-uptake. Additionally, knockdown of the chemokine receptor CXCR4 reduced LDL-uptake, most likely through a G-protein coupled mechanism that involves the CXCR4 ligand macrophage-induced factor (MIF), but is independent of CXCL12. We introduce a high-throughput strategy to systematically study gene function directly in primary CAD-patient cells. Our results propose a function for the MIF/CXCR4 signaling pathway, as well as several novel candidate genes impacting lipid uptake into human macrophages.

Heart rate reduction after heart transplantation with beta-blocker versus the selective If channel antagonist ivabradine.

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.

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

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.

The Two Faces of Interleukin-17A in Atherosclerosis.

A complex network of different cytokines and chemokines modulates atherosclerosis, a chronic inflammatory disease. Interleukin-17A (IL-17A) is expressed by different leukocyte subsets such as CD4+IL-17+ T cells (Th17), γδ T cells, natural killer cells, natural killer T cells, and neutrophils. IL-17A plays an important role in host defense and is involved in the pathology of different autoimmune and inflammatory diseases. Recent studies demonstrate an association of IL-17A with atherosclerosis. IL-17A seems to have primarily pro-inflammatory effects in atherogenesis, although there are partially controversial results in the literature. In the murine system, several studies indicate a pro-atherogenic role of IL-17A mediated by increased migration of leukocytes (especially macrophages) into atherosclerotic lesions, increased expression of pro-inflammatory cytokines and chemokines as well as plaque destabilizing matrix-metalloproteinases using Apoe-/- and LDLr-/- mice. In contrast, three studies show atheroprotective effects of IL-17A mediated by downregulation of aortic VCAM-1 expression on endothelial cells and increased collagen production by vascular smooth muscle cells (VSMCs) in LDLr-/- mice. In humans, expression of IL-17A was associated with increased inflammation and plaque vulnerability in human atherosclerotic lesions. Moreover, IL-17A induced a pro-inflammatory, pro-thrombotic, plaque-destabilizing, and cell-attracting response of the inflammatory milieu of human plaque tissue samples. Notably, a recently published study challenged these findings by showing a worse outcome of patients with acute myocardial infarction with low serum levels of IL-17A. In the following review, we will focus on the recent progress of functional studies of IL-17A in atherosclerosis and will try to collect explanations for the controversial data.

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

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.