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Aims Timely referrals for transplantation and left ventricular assist device (LVAD) play a key role in favourable outcomes in patients with advanced heart failure (HF). The purpose of the Catheter Ablation for atrial fibrillation in patientS with end‐sTage heart faiLure and Eligibility for Heart Transplantation (CASTLE‐HTx) trial is to test the hypothesis that atrial fibrillation (AF) ablation has beneficial effects on mortality and morbidity during ‘waiting time’ for heart transplantation (HTx) or to prolong the time span until LVAD implantation. Methods and Results CASTLE‐HTx is a randomized evaluation of ablative treatment of AF in patients with severe left ventricular dysfunction who are candidates and eligible for HTx. The primary endpoint is the composite of all‐cause mortality, worsening of HF requiring a high urgent transplantation, or LVAD implantation. The secondary study endpoints are all‐cause mortality, cardiovascular mortality, cerebrovascular accidents, worsening of HF requiring unplanned hospitalization, AF burden reduction, unplanned hospitalization due to cardiovascular reason, all‐cause hospitalization, quality of life, number of delivered implantable cardioverter defibrillator therapies, time to first implantable cardioverter defibrillator therapy, number of device‐detected ventricular tachycardia/ventricular fibrillation episodes, left ventricular function, exercise tolerance, and percentage of right ventricular pacing. Ventricular myocardial tissue will be obtained from patients who will undergo LVAD implantation or HTx to assess the effect of catheter ablation on human HF myocardium. CASTLE‐HTx will randomize 194 patients over a minimum time period of 2 years. Conclusions CASTLE‐HTx will determine if AF ablation has beneficial effects on mortality in patients with end‐stage HF who are eligible for HTx.

Circulating graft-derived cell-free DNA (dd-cfDNA) is a new marker of cardiac allograft damage that is used for noninvasive rejection diagnostics. We performed dd-cfDNA (%) in heart transplant recipients during the first posttransplant year.In 87 patients, serial dd-cfDNA determination at predefined time-points was performed in 770 single samples. dd-cfDNA fraction (%) was measured using an established universal droplet digital polymerase chain reaction method, providing same-day turn-around. Rejection was diagnosed according to clinical parameters and biopsies.Median dd-cfDNA (%) was high (5.36%) immediately after reperfusion and decreased to a median (interquartile range) of 0.10% (0.05%-0.24%) in clinically stable patients by postoperative day 10. Compared to dd-cfDNA (%) samples in clinically stable patients, values were higher (P0.001) in biopsy-proven rejection ISHLT 1R (0.42% [0.15%-0.53%]) and 2R rejection (0.84% [0.39%-0.97%]). Moreover, dd-cfDNA (%) was already significantly increased 9-30 days before biopsy-proven rejection (0.36% [0.20%-0.61%]). An as yet unknown finding was a slightly, but significantly (P0.0001) higher dd-cfDNA (%) value in samples of stable patients with pericardial effusions (PEs) (n = 94; 0.18% [0.07%-0.30%]) compared to samples of non-PE patients (n = 132; 0.07% [0.04%-0.17%]). Using a cutoff of 0.35%, sensitivity and specificity of dd-cfDNA for cardiac rejection were 0.76 and 0.83 (area under the curve [AUC] ROC-curve: 0.81 [95% confidence interval, 0.73-0.89]). Omitting PE samples from the control group yielded an AUC of 0.86 [95% confidence interval, 0.76-0.95]. Samples drawn12 hours after endomyocardial biopsy showed high (0.40% [0.15%-1.21%]) dd-cfDNA values, also in ISHLT0R (0.36% [0.10%-0.60%]).dd-cfDNA plasma values were significantly associated with cardiac rejection. However, PE or improper sampling (eg, shortly after biopsy) should be considered as confounders for rejection diagnoses using dd-cfDNA.

Die Arbeit untersucht, inwieweit sich die zeitaufwendige und komplexe manuelle Erstellung von Trommelgalvanik-Fahrplänen mittels Methoden der gemischt-ganzzahligen Optimierung automatisieren lässt. Hierzu werden zwei reale Problemstellungen unterschiedlicher Größe und Struktur systematisch analysiert und auf das Optimierungsmodell von Steneberg abgebildet. Es wird gezeigt, dass die Eigenschaften realer Problemstellungen großteils abbildbar sind; Eigenschaften, welche dem Modell bislang noch fehlen, werden aufgedeckt und beschrieben. Bei beiden Problemstellungen stellt sich heraus, dass das Optimierungsmodell nicht innerhalb der erforderlichen Antwortzeit lösbar ist. Mit Hilfe der in dieser Arbeit entwickelten Modellvereinfachungsstrategie kann die Lösungszeit der Optimierungsmodelle deutlich reduziert werden. Obwohl bei Anwendung dieser Strategie Optimierungspotential verloren geht, ist es möglich, für das kleinere Anwendungsbeispiel innerhalb von 13 min Rechenzeit einen Fahrplan zu erstellen, welcher eine um 20 % höhere Anlagenauslastung gegenüber der bisherigen manuellen Planung ermöglicht. Für kleinere Parametersätze des größeren Anwendungsbeispiels kann die Vereinfachungsstrategie ebenfalls erfolgreich angewendet und die Rechenzeitgrenzen des Modells aufgezeigt werden.

Aims Some risk assessment tools have been developed to categorize mortality risk in heart transplant recipients, but it is unclear whether these tools can be used interchangeable in different transplant regions. Methods and results We performed a retrospective single‐centre study in 1049 adult German heart transplant recipients under jurisdiction of Eurotransplant. Univariable and multivariable Cox regression analysis was used to generate a risk scoring system. C‐statistics were used to compare our score with a US score and a French score regarding their ability to discriminate between 1 year survivors and non‐survivors within our study cohort. Of 38 parameters assessed, seven recipient‐specific parameters [age, height, dilated cardiomyopathy (DCM), ischaemic cardiomyopathy (ICM), total bilirubin, extracorporeal membrane oxygenation (ECMO), and biventricular assist device/total artificial heart (BVAD/TAH) implant], one donor‐specific parameter (cold ischaemic time), and one recipient‐independent and donor‐independent other parameter (late transplant era) were statistically significant in predicting 1 year mortality. The initial score was generated by using the regression coefficients from the multivariable analysis as follows: 1.70 * ln age − 4.0 * ln height − 0.9 * diagnosis (= 1 if diagnosis = DCM) − 0.67 * diagnosis (= 1 if diagnosis = ICM) + 0.33 * ln total bilirubin + 1.74 * ln cold ischaemic time + 0.98 * mechanical circulatory support (MCS) implant (= 1 if MCS implant = ECMO) + 0.47 * MCS implant (= 1 of MCS implant = BVAD/TAH) − 0.66 * transplant era (= 1 if transplant era = 2017–2018). The initial score was converted into the Bad Oeynhausen (BO) score as a positive integer variable by means of the following formula: BO score = (initial score + 8) * 3. In patients scoring 2 to

Background/Aims: We aimed to investigate the effect of a moderately high vitamin D dose on lipid parameters and biochemical markers of vascular calcification (VC) in patients with established cardiovascular disease. Methods: We included in this pre-specified secondary analysis of a randomized controlled trial 161 patients with advanced heart failure and 25-hydroxyvitamin D (25OHD) concentrations < 75 nmol/L (vitamin D group: n = 80; placebo group: n = 81), who received a daily vitamin D3 supplement of 4,000 IU for 3 years. We assessed between-group differences of the lipid parameters total-cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and triglycerides, and the VC markers fetuin-A and non-phosphorylated undercarboxylated matrix gla protein (MGP) at study termination, with adjustment for baseline values. Results: Lipid parameters, the percentage of patients with dyslipoproteinemia, and VC markers did not differ significantly between groups at study termination (p values: 0.395–0.939). Likewise, vitamin D achieved no significant treatment effect on these markers in subgroup analyses in patients with 25OHD concentrations < 30 nmol/L, nonusers of lipid-lowering drugs, or diabetic patients (p values: 0.245–0.998). Conclusion: Our data indicate that vitamin D does not improve the lipid profile and does not influence the calcification inhibitors fetuin-A and non-phosphorylated undercarboxylated MGP in patients with advanced heart failure.

Objective. 1,25-Dihydroxyvitamin D (1,25([OH]2D) is considered to be a negative endogenous regulator of the renin-angiotensin-aldosterone system (RAAS), but the effect of vitamin D supplementation on the RAAS is inconclusive. Design. In this prespecified secondary analysis of a randomized controlled trial, we assessed in 165 patients with heart failure (vitamin D group: n=83; placebo group: n=82) the effect of three years of vitamin D supplementation with 4000 IU daily on parameters of the RAAS (renin and aldosterone) and on circulating 1,25(OH)2D, plasma phosphate, and fibroblast growth factor (FGF)-23. We assessed age- and baseline-adjusted between-group differences at study termination. Results. Almost all patients were under treatment with beta-blockers, inhibitors of the RAAS, and diuretics. Initially, the frequency of concentrations above the laboratory-specific reference range (renin: >23.9 mIU/L; aldosterone: >232 ng/L) in the vitamin D and placebo group was 87.7% and 92.7%, respectively (renin), and 24.1% and 32.5%, respectively (aldosterone). Vitamin D increased adjusted 1,25(OH)2D concentrations significantly (mean treatment effect and 95% CI: 18.3 pmol/L,7.3 to 29.3 pmol/L; P<0.001) but had no significant effects on phosphate (0.18 mmol/L, −0.00 to 0.35 mmol/L; P=0.051), FGF-23 (685 RU/mL, −213 to 1585 RU/mL; P=0.134), renin (312 mIU/L, −279 to 902 ng/L; P=0.298), or aldosterone (−0.19 ng/L, −5.09 to 4.70 ng/L; P=0.938). Vitamin D supplementation was, however, associated with an increase in renin concentrations in the subgroup with baseline 25-hydroxyvitamin D below 30 nmol/L (n=67; 1365 mIU/, 343 to 2386 mIU/L; P=0.010). Conclusions. In patients with advanced heart failure treated according to evidence-based guidelines, vitamin D supplementation did not significantly influence parameters of the RAAS in the entire study cohort but was associated with an increase in plasma renin concentrations in the subgroup with low baseline 25-hydroxyvitamin D concentrations.

Low vitamin D status is common in patients with heart failure and may influence bone health. A daily vitamin D dose of 4000 IU (moderately high dose) for 3 years had however no effect on parameters of bone metabolism, even in patients with very low vitamin D status.Low vitamin D status is common in patients with heart failure (HF) and has been related to disturbed bone turnover. The present study investigated the effect of a daily vitamin DIn this pre-specified secondary analysis of a randomized controlled trial, we assessed in 158 male HF patients (vitamin D group: n = 80; placebo group: n = 78) between-group differences in calciotropic hormones (25OHD, 1,25-dihydroxyvitamin D [1,25(OH)Compared with placebo, vitamin D increased 25OHD on average by 54.3 nmol/L. At study termination, 25OHD and 1,25(OH)A daily vitamin D

BACKGROUND Left ventricular assist device (LVAD) implantation may improve kidney function, but in patients awaiting heart transplantation, the long-term effects of LVAD implantation on renal function and subsequent clinical outcome are unclear. MATERIAL AND METHODS We analyzed data in patients with LVAD implants (n=139) and without LVAD implants (n=1038) who were listed for a heart transplant at our institution between 2000 and 2019. The primary endpoint was an impairment in renal function (decrease of creatinine-based estimated glomerular filtration rate [eGFR] by ≥30%) up to a maximum of 2 years after listing. Secondary endpoints were chronic kidney disease stage 4 or 5, heart transplantation, survival during listing, and 1-year survival after transplantation. RESULTS Values for eGFR increased after LVAD implantation (P=0.001) and were higher at the time of waitlisting in the LVAD group than in the non-LVAD group (P=0.002), but were similar between groups at the end of waitlisting (P=0.75). Two-year freedom from renal impairment was 50.6% and 66.7% in the LVAD and non-LVAD groups, respectively, with a multivariable-adjusted hazard ratio for the LVAD versus the non-LVAD group of 1.78 (95% confidence interval 1.19-2.68; P=0.005). Two-year freedom from chronic kidney disease stages 4-5 was similar between study groups (LVAD group: 83.5%; non-LVAD group: 80.1%; =0.50). The 2-year probability of transplantation was slightly lower in the LVAD group than in the non-LVAD group (50.0% and 55.8%, respectively, P=0.017). However, 2-year survival on the waiting list and 1-year survival after transplantation did not differ significantly between study groups (P-values >0.20). CONCLUSIONS Our data indicate a transient improvement in creatinine-based eGFR values by LVAD implantation without influencing survival.

Background Data regarding the effects of vitamin D on cardiac function are inconclusive. Methods In a post-hoc analysis of the EVITA (Effect of vitamin D on mortality in heart failure) trial, we investigated whether a daily vitamin D3 supplement of 4000 IU for three years affects echocardiography parameters like left ventricular end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), and LV ejection fraction (LVEF) in patients with advanced heart failure (HF) and 25‑hydroxyvitamin D levels Results At baseline, values of LVEDD, LVESD, and LVEF were 67.5 ± 10.5 mm, 58.9 ± 12.0 mm, and 30.47 ± 10.2%, respectively. There were no time × treatment interaction effects on LV echocardiographic parameters in the entire study cohort, neither at 12 months nor at 36 months post-randomization (P-values > 0.05). However, in the subgroup of patients aged ≥50 years, vitamin D treatment was associated with an increase in LVEF of 2.73% (95%CI: 0.14 to 5.31%) at 12 months post-randomization (n = 311). The increase was slightly attenuated to 2.60% (95%CI: −2.47 to 7.67%) at 36 months post-randomization (n = 242). Conclusion Our data indicate that vitamin D supplementation does not significantly improve cardiac function in all patients with advanced HF. However, vitamin D probably improves LV function in HF patients aged ≥50 years.

Observational studies indicate a positive association between circulating 25-hydroxyvitamin D (25OHD) and testosterone (T) concentrations. Because low 25OHD concentrations and T deficiency are considered to be a generalized phenomenon in patients with advanced heart failure (HF), we aimed to investigate whether vitamin D supplementation has beneficial effects on T indices in these patients. In a pre-specified secondary analysis of the EVITA (effect of vitamin D on mortality in heart failure) randomized controlled trial, we analyzed in male subjects with 25OHD concentrations

OBJECTIVES As waiting times for a heart transplant (HTx) increase, the decision of whether a patient should have a high urgent (HU) listing or mechanical circulatory support becomes crucial for further prognosis. The aim of this study was to determine the characteristics that predict failure of an HU listing (death/delisting due to urgent mechanical circulatory support implant or poor clinical condition), the 5-year survival rate, the 1-year post-transplant survival rate and the prognostic accuracy of the cardiac allocation score of patients on the HU list. METHODS A total of 447 patients who were on the HU list at our institution between 2005 and 2016 were analysed and stratified according to occurrence of therapy failure or reception of an HTx. RESULTS A total of 114 patients suffered from HU listing failure after a median HU time of 31.5 (15-69) days; 320 patients had a primary HTx after a median time of 51.5 (26-90) days on the HU list; 13 patients were excluded from data analysis because of an ongoing HU listing or delisting due to improvement in their haemodynamic condition. In multivariable logistic regression analysis, blood group 0 [odds ratio (OR) 2.48, 95% confidence interval (CI) 1.43-4.3; P = 0.001], INTERMACS Class 1 or 2 (OR 5.1, 95% CI 2.7-9.4; P

Determination of cardiac output (CO) is essential in diagnosis and management of heart failure (HF). The gold standard to obtain CO is invasive assessment via thermodilution (TD). Noninvasive pulse contour analysis (NPCA) is supposed as a new method of CO determination. However, a validation of this method in HF is pending and performed in the present study. Patients with chronic-stable HF and reduced left ventricular ejection fraction (LVEF ≤ 45%; HF-REF) underwent right heart catheterization including TD. NPCA using the CNAP Monitor (V5.2.14, CNSystems Medizintechnik AG) was performed simultaneously. Three standardized TD measurements were compared with simultaneous auto-calibrated NPCA CO measurements. In total, 84 consecutive HF-REF patients were enrolled prospectively in this study. In 4 patients (5%), TD was not successful and for 22 patients (26%, 18 with left ventricular assist device), no NPCA signal could be obtained. For the remaining 58 patients, Bland–Altman analysis revealed a mean bias of + 1.92 L/min (limits of agreement ± 2.28 L/min, percentage error 47.4%) for CO. With decreasing cardiac index, as determined by the gold standard of TD, there was an increasing gap between CO values obtained by TD and NPCA (r = − 0.75, p

Background Low 25-hydroxyvitamin D (25OHD) levels ( 0.99). There was no between-group difference in change in the Hb concentrations (− 0.04 g/dL [95%CI:-0.53 to 0.45 g/dL]; P = 0.87). Results regarding anemia risk and Hb concentrations were similar in the subgroup of patients with chronic kidney disease (vitamin D group: n = 26; placebo group: n = 23). Moreover, results did not differ substantially when data analysis was restricted to patients with deficient baseline 25OHD levels. Conclusions A daily vitamin D supplement of 4000 IU did not reduce anemia prevalence in patients with advanced HF. Data challenge the clinical relevance of vitamin D supplementation to increase Hb levels. Trial registration The study was registered at EudraCT (No. 2010–020793-42) and clinicaltrials.gov (NCT01326650). Electronic supplementary material The online version of this article (doi:10.1186/s12937-017-0270-5) contains supplementary material, which is available to authorized users.

Die orthotope Herztransplantation (HTX) ist der weltweit akzeptierte Goldstandard in der Therapie der terminalen Herzinsuffizienz. Die Hauptindikationen fur eine HTX sind die dilatative (54%) und die ischamische Kardiomyopathie (37%). In der Akutphase nach HTX liegt das Uberleben bei rund 90%. Gerade die Langzeitprognose mit einem Uberleben von 81% nach 1 Jahr und von uber 50% nach 11 Jahren ist im Vergleich zu anderen etablierten Therapieoptionen, wie z. B. den Herzunterstutzungsverfahren, exzellent. In einigen Fallen, etwa bei nichtreversiblem pulmonalen Hypertonus mit terminaler Herzinsuffizienz oder einem komplexen kongenitalen Herzfehler wie z. B. der Pulmonalatresie, ist auch heutzutage noch die kombinierte Herz-Lungen-Transplantation (HLTX) die einzige Therapieoption. Diese ist jedoch mit einem schlechteren Kurz- und Langzeituberleben vergesellschaftet. Gute Langzeitergebnisse nach HTX und HLTX sind nicht zuletzt die Folge von wirksameren Immunsuppressiva und einer intensiven Nachbetreuung der Patienten in Spezialambulanzen. Durch das Problem der Organknappheit, insbesondere fur die HTX, hat sich die Wartezeit fur hochdringliche Patienten blutgruppenabhangig verlangert und betragt zurzeit fur haufige Blutgruppen bis zu 10 Monate. Es werden daher vermehrt Herzunterstutzungssysteme als Alternative zur HTX implantiert. Diese sind jedoch aufgrund mannigfaltiger Nebenwirkungen und dem im Vergleich zur HTX schlechteren Langzeituberleben bislang keine gleichwertige Alternative und stellen insbesondere bei Patienten, die auf eine HLTX warten, keine adaquate Therapieoption dar.

Tacrolimus (TAC) retard is a new oral formulation of TAC that is given once instead of twice daily. We investigated the efficacy and safety of TAC retard in heart transplant recipients during a 36-month follow-up period. We included 11 patients receiving TAC retard (once-daily [OD] group) and 11 age- and sex-matched patients receiving TAC (twice-daily [TD] group). The primary endpoint was a composite of death, graft loss, and drug discontinuation (treatment failure). Secondary endpoints were biopsy-proven rejection, malignancy, infection, and safety parameters determined on the basis of laboratory evaluations. In the OD and TD groups, the primary endpoint was reached by 18.2% and 45.54% of patients, respectively (P = .277). In detail, 3-year survivals were 90.0% and 70.0% (P = .291) and freedom from drug discontinuation 90.9% and 77.9% (P = .533), respectively. Freedom from biopsy-proven rejection, malignancy, and infection were similar between the groups. Moreover, biochemical parameters of kidney and liver function, hematologic parameters, and C-reactive protein levels were similar. Despite a remarkably higher prescribed dose, blood trough levels of TAC were below the lower target value in several patients of the OD group at the end of the follow-up period, but in none of the patients in the TD group. In conclusion, this small 3-year follow-up study suggests efficacy and safety in patients receiving TAC retard similar to those in patients receiving TAC. Nevertheless, the required dose of TAC retard for achieving acceptable blood trough levels should be investigated in more detail.

Objectives Identifying patients at risk for impaired long-term survival after heart transplantation (HT) remains a clinical challenge. The aim of this analysis was to investigate whether the gene expression profiling test AlloMap® is related to long-term survival after HT. Methods 46 patients who underwent HT between 2006 and 2007 who were originally included into the CARGO II trial at our institution were investigated. Patients were divided in two groups according to an increase or decrease of the AlloMap® score between 6 and 9 months after HT. The primary endpoint of this study was long-term all-cause mortality. Results 23 patients showed an increase of the AlloMap® score between 6 and 9 months after HT whereas the remaining 23 patients presented with a decrease of the score. After a median follow-up time of 8.1 years (interquartile range 7.6–8.6), all-cause mortality was significantly elevated in patients with an AlloMap® increase compared with patients who showed a decrease of the score (log-rank p = 0.005). A ratio of the AlloMap® at 9 months to 6 months of 1.02 or less was associated with a negative predictive value for all-cause mortality of 100%. Conclusions Dynamic changes of the AlloMap® score between 6 and 9 months after HT were strongly related to all-cause long-term survival after HT. These results suggest that AlloMap® potentially displays a useful tool to estimate the patients' risk for long-term mortality.

Renal impairment is a risk factor for poor clinical outcome in cardiac surgical patients and low circulating levels of the vitamin D hormone 1,25-dihydroxyvitamin D (1,25[OH](2)D) may contribute to this risk.We investigated the association between glomerular filtration rate (GFR) and 1,25(OH)(2)D in 151 heart transplant recipients and 59 other cardiac surgical patients in postoperative week 1 and at postoperative month 1. GFR estimates (eGFR) were calculated from cystatin C (CysC) and serum creatinine (SCr)-based formulas.With both formulas, linear models provided a better fit between eGFR and circulating 1,25(OH)(2)D than nonlinear models. Nonetheless, the association between 1,25(OH)(2)D and eGFR in the early postoperative period was stronger with the CysC-based formula (r = 0.560; P0.001) than with the SCr-based equation (r = 0.386; P0.001). CysC-eGFR and SCr-eGFR displayed considerably lack of agreement in the early postoperative period, especially in heart transplant recipients.There is a relatively close association between CysC-eGFR and circulating 1,25(OH)(2)D in cardiac surgical patients. Data underline the importance of preserved kidney function in cardiac surgery for adequate circulating 1,25(OH)(2)D levels. The SCr-based formula is probably too imprecise for estimating GFR in the early postoperative period correctly.

The calcineurin inhibitor cyclosporine (CSA) displays nephrotoxic side effects. We switched 95 maintenance heart transplant recipients with chronic kidney disease (CKD) stages 3-4 from CSA to everolimus (EVL). The CSA dosage was reduced by 50%. Kidney function, lipid metabolism, and cardiac function investigated during a 2-year follow-up were compared with heart transplant recipients with CKD stages 2-3 who continued to receive CSA (CSA group; n = 84). Whereas 64/95 patients received reduced CSA plus EVL during the entire follow-up period (EVL continued subgroup, ECN), 31 discontinued EVL (EVL discontinued subgroup, EDS) after 4.3 months (median) because of various clinically relevant adverse events. Glomerular filtration rates (estimated using the modification of diet in renal disease formula) increased by 4.0 mL/min/1.73 m(2) in the ECN subgroup but decreased by 2.4 mL/min/1.73 m(2) and 9.0 mL/min/1.73 m(2) in the EDS subgroup and the CSA group, respectively (P.001). Triglyceride and total cholesterol concentrations increased significantly among the ECN group, but remained constant in the EDS subgroup and the CSA group. Statin use was increased by 15% in the ECN group (P.01). Mortality and cardiac rejection rates did not differ significantly among the 3 groups. In summary, EVL combined with low-dose CSA had modest beneficial effects on kidney function in heart transplant recipients with CKD stages 3-4. A significant percentage of patients had to stop EVL because of various adverse events.

We report the first documented case of a Mycobacterium tuberculosis transmission by an orthotopic heart transplantation from the donor to the recipient. Mycobacterium tuberculosis positive blood culture showed systemic prevalence of the Mycobacteria, however, prophylactic therapy was able to prevent a clinical manifestation of tuberculosis in the recipient.

Administration of the vitamin D hormone calcitriol improves survival in solid-organ transplanted experimental animals. We investigated whether lower serum calcitriol concentrations are associated with increased 1-year mortality in cardiac transplant recipients.We prospectively recruited 171 patients who underwent cardiac transplantation at out institution between May 2004 and April 2006. We assessed calciotropic hormones, inflammation markers, and renal function preoperatively and on postoperative days 6 (t1) and 21 (t2).Serum creatinine and C-reactive protein increased, whereas calcitriol decreased significantly after transplantation (P0.001). As determined by multivariable Cox regression analysis, the calcitriol level at t2 was an independent predictor of 1-year mortality. One-year mortality was 3.7 per 100 person-years in the tertile with the highest calcitriol concentrations at t2 (18 pg/mL), 13.2 per 100 person-years in the intermediate tertile (11-18 pg/mL), and 32.1 per 100 person-years in the tertile with the lowest calcitriol concentrations at t2 (11 pg/mL) (P0.001). 25-Hydroxyvitamin D deficiency (serum concentrations below 10 ng/mL), renal insufficiency (serum creatinineor = 1.6 mg/dL), and high serum concentrations of the inflammation markers C-reactive peptide and tumor necrosis factor-alpha were predictors of a serum calcitriol concentration below 11 pg/mL (P=0.037-0.001).Low postoperative calcitriol concentrations are independently associated with high 1-year mortality in cardiac transplant recipients. A causal relationship has yet to be proven by intervention trials using active vitamin D.

Background: Vitamin D receptor knockout mice develop typical signs of congestive heart failure (CHF). In approximately 20% of stable CHF patients, frankly low concentrations of the vitamin D hormone calcitriol are found. Aims: We investigated whether serum calcitriol concentrations predict clinical outcome in end-stage CHF. Methods and results: We collected blood samples in 383 end-stage CHF patients who were on a waiting list for cardiac transplantation. We assessed associations of calcitriol with disease severity and freedom from event (death or cardiac transplantation) during 1-year follow-up. In electively listed patients (n=325), 31% had deficient calcitriol levels (

Cell death in the inner ear tissues is an important mechanism leading to hearing impairment. Here, using microarrays and real-time RT-PCR we analyzed expression of selected apoptosis-related genes in rat's inner ear. We determined the gene expression in tissues freshly isolated from neonatal rats (3-5 days old) and compared it to that of explants cultured for 24 h under normoxic or hypoxic conditions. For the analyses, we used pooled samples of the organ of Corti (OC), modiolus (MOD) and stria vascularis (SV), respectively. We observed region-specific changes in gene expression between the fresh tissues and the normoxic culture. In the OC, expression of the proapoptotic genes caspase-2, caspase-3, caspase-6 and calpain-1 was downregulated. In the MOD, the antioxidative defense SOD-2 and SOD-3 were upregulated. In the SV, caspase-2, caspase-6, calpain-1 and SOD-3 were downregulated and SOD-2 upregulated. We speculate that these changes could reflect survival shift in transcriptome of inner ear explants tissues under in vitro conditions. With the exception of SOD-2, hypoxic culture conditions induced the same changes in gene expression as the normoxic conditions indicating that culture preparation is likely the dominating factor, which modifies the gene expression pattern. We conclude that various culture conditions induce different expression pattern of apoptosis-related genes in the organotypic cochlear cultures, as compared to fresh tissues. This transcriptional pattern may reflect the survival ability of specific tissues and could become a tempting target for a pharmacological intervention in inner ear diseases.

We have recently hypothesized that low vitamin D status may contribute to the pathogenesis of congestive heart failure (CHF). This study was aimed at evaluating, in a pilot study, whether CHF patients have indications for a low vitamin D status during earlier periods of their lives. We performed a case-controlled study in 150 CHF patients and 150 controls. Study participants had to answer a questionnaire that included several items concerning vitamin D-associated lifestyle factors during childhood, adolescence, and adulthood. A vitamin D score was constructed. This score takes into consideration that ultraviolet-B (UVB) exposure is the major vitamin D source for humans and that those lifestyle factors, which are associated with regular UVB exposure, can guarantee an adequate vitamin D status at best. The vitamin D score was significantly higher in controls than in patients (p < 0.001). Compared with the controls, more patients lived in large cities (p < 0.001), fewer patients were members of a sport club (p < 0.001), and fewer patients had summer holidays every year (p < 0.01). Patients also reported significantly less alcohol consumption during adulthood than controls (p < 0.001). Our results demonstrate that CHF patients and controls differed in several vitamin D-associated lifestyle factors and in alcohol consumption during earlier periods of their lives.

In solid organ transplantation, sensitive real-time biomarkers to assess the graft health are desirable to enable early intervention, for example, to avoid full-blown rejections. During rejection, high amounts of graft-derived cell-free DNA (GcfDNA) are shed into the blood stream. The quantification of this GcfDNA in allotransplantation is considered to fulfill this need, because it can be measured with great precision and at reasonable cost.Patients from 2 ongoing studies in kidney (KTx) and heart (HTx) transplantation were monitored blinded on a scheduled basis, by means of a published universal droplet digital polymerase chain reaction to quantify the GcfDNA.Immediately after engraftment, GcfDNA reaches high values (5% of total cfDNA), with a rapid decrease to values of 0.5% within 1 week. Living-related KTx recipients show lower initial values, reflecting the absence of preservation injury. Episodes of rejection in KTx and HTx are accompanied by a significant increase of GcfDNA (5-fold) above values in patients without complications, occurring earlier than clinical or biochemical hints to rejection. One case of rejection, which became clinically suspect after 1 year and was proven with biopsy, showed a significant 10-fold increase 3 months earlier.The quantification of GcfDNA has the potential to detect rejection episodes at early stages, when other means of diagnosis are not effective. The method's noninvasiveness enables the monitoring recipients at intervals that are desired to catch rejections at early actionable stages to prevent full-blown rejection. This biomarker will be particularly valuable in regimens to minimize immunosuppression.

Background Heart transplantation (HTx) is still considered the therapeutic gold standard in end-stage heart failure. Methods In “high urgent” (HU)-listed patients for HTx (n ¼ 274) and patients receiving left ventricular assist device (LVAD) implants (n ¼ 332), we compared 1-year overall survival (primary endpoint) and 1-year probability of HTx and therapy failure (the need for LVAD implantation in HU-listed patients or the need for HU listing in LVAD patients) (secondary endpoints). Results In the HU and LVAD group, 1-year survival was 86.8 and 64.7%, respectively (p < 0.001). The propensity score (PS)-adjusted hazard ratio of mortality did not differ between the groups and for the LVAD group (reference ¼ HU group) was ¼ 1.36 (95% confidence interval [CI]: 0.85–2.19; p ¼ 0.198). The PS-adjusted hazard ratio for the failure to receive HTx for the LVAD group (reference ¼ HU group) was ¼ 9.77 (95% CI: 6.00–15.89;p < 0.001).The correspondinghazardratiofor therapyfailurefor theLVAD group was ¼ 0.16, 95% CI: 0.10–0.27; p < 0.001). Conclusion Despite considerable differences in the probability of HTx and therapy failure, 1-year overall survival was similar in HU and LVAD patients.

Der Transkriptionsfaktor HIF-1 („hypoxia-inducible factor-1“) reguliert unter Ischamie/Hypoxie die Expression von Genen fur Glukoseversorgung, Wachstum, Stoffwechsel, Redoxreaktionen und Durchblutung. Im Hinblick auf Tinnitus und Schwerhorigkeit wurden HIF-1-Aktivitat und Expression von HIF-1-abhangigen Genen in der Kochlea unter Ischamie/Hypoxie untersucht. HIF-1 wurde in einer Einzelzellkultur der Regionen Corti-Organ (OC), Stria vascularis (SV) und Modiolus (MOD), die mRNA-Expression in der organotypischen Kultur mittels Microarray-Technik (RN U34-Chip, Affymetrix) bestimmt. Ischamie (Hypoxie + Glukosemangel) fuhrt zu einer ahnlichen HIF-1-Aktivierung wie reine Hypoxie mit dem hochsten Anstieg im MOD und OC. Der HIF-1α-mRNA-Gehalt ist in der SV hoher als im OC und MOD. Wahrend der Kultivierung werden HIF-1α-mRNA und zahlreiche HIF-1-abhangige Gene wie Gapdh/“Glyceraldehyde-3-phosphate dehydrogenase“, Slc2a1/“Solute carrier family 2 (facilitated glucose transporter), member 1“, Tf/Transferrin und Tfrc/Transferrin Rezeptor in allen 3 Regionen hochreguliert. In SV, MOD und OC erfolgt eine besonders hohe Zunahme der Expression von Hmox1/Hamoxygenase 1, Nos2/induzierbare Stickstoffmonoxid-Synthase und Tfrc. Hypoxie (5 h) fuhrt zu einer Erhohung der Expression von Igf2/“insulin-like growth factor 2“. Die Daten unterstreichen die Bedeutung radikalbildender Prozesse fur die Innenohrschadigung. Die organotypische Kultur geht moglicherweise mit einer Hypoxie einher.

Tacrolimus (TAC) is a calcineurin inhibitor that is used for cardiac allograft rejection. Efficacy and safety data of a combined TAC/mycophenolate mofetil (MMF) therapy in comparison with a TAC/cortisone therapy in heart recipients are lacking. We analysed the clinical outcome of 41 patients who received TAC in combination with MMF (TMF group) and of 41 patients who received TAC in combination with cortisone (TCO group). Outcomes were serum creatinine levels, cardiac rejections, cytomegalovirus infections, graft vasculopathy, malignancy rates and two-yr survival. Baseline characteristics were comparable in the two study groups. During follow-up, serum creatinine levels decreased slightly in the TMF group (p=0.039) but not in the TCO group. Compared with the TMF group, more clinically proven cardiac rejections which needed a cortisone bolus and more severe rejections that needed lymphoablative therapy with OKT occurred in the TCO group (p=0.001 and 0.04, respectively). In contrast, significantly more cytomegalovirus (CMV) infections occurred in the TMF group compared with the TCO group (p=0.01). The number of patients with graft vasculopathy as well as malignancy rates and overall survival did not differ significantly between the two study groups. The introduction of MMF was associated with an improvement of renal function and a more efficient immunosuppressive therapy. However, this treatment strategy also had led to a higher CMV infection rate compared with cortisone. Consequently, no general recommendation can be given at present whether TAC should be combined with MMF or with cortisone in heart transplant recipients.

It is suggested that the vacuum technique is a promising new method for the therapy of mediastinitis, but reliable investigations are currently almost completely lacking. We therefore compared clinical outcome of patients whose sternal infection was managed with the vacuum-assisted closure system or with the conventional procedure of open packing.We performed a retrospective analysis in 68 cases of sternal wound infection that were identified at our Heart Center between September 1998 and September 2003. Thirty-five patients could be allocated to the vacuum group and 33 patients to the conventional group. We compared the time interval from sternal infection until freedom of microbiological cultures, in-hospital stay, the status at discharge (rewired or open sternum), the time interval until wound healing was achieved, and survival rates. Moreover, we compared serum levels of C-reactive protein and blood leukocyte counts on admission, at diagnosis of sternal infection, and at different points of time until discharge.Baseline characteristics and blood factors did not differ between the two study groups at diagnosis of sternal infection. Moreover, the number of prescribed antibiotics was similar, and the C-reactive protein level and blood leukocyte counts at discharge were comparable in both groups. However, freedom from mediastinal microbiological cultures was achieved earlier (p0.01), C-reactive protein levels declined more rapidly (p0.025), in-hospital stay was shorter (p0.01), rewiring was earlier (p0.01), and survival tended to be higher (p0.15) in the vacuum group compared to the conventional group.This retrospective analysis could demonstrate that the vacuum technique improves the medical outcome of patients with mediastinitis compared with the conventional technique of open packing.

Background Heart transplant recipients are at increased risk of developing malignant neoplasms. Administration of the calcineurin inhibitors cyclosporine A (CSA) or tacrolimus (TAC) may contribute to this risk. Material and methods We compared tumor incidence in heart transplant recipients receiving either CSA (n=25) or TAC (n=120) as maintenance immunosuppressive therapy. Exclusion criteria were therapy with mammalian target of rapamycin-inhibitors, death within the first postoperative year, re-transplantation, and age less than 18 years. Results The 2 study groups were comparable with respect to sex, primary and concomitant diagnoses, and mean follow-up (60.7 ± 19.3 months in the CSA group vs. 59.8 ± 18.1 months in the TAC group; P=0.81). The CSA group was, however, significantly older compared with the TAC group (58.8 ± 11.4 years vs. 49.1 ± 13.0 years, P=0.001), as was the donor age of the CSA group (43.2 ± 11.2 years vs. 37.0 ± 11.7 years, P=0.02). In the CSA group, 5 patients (20%) developed malignant neoplasms compared with 10 patients (8.3%) in the TAC group (P=0.14). Covariate-adjusted 5-year tumor-free survival was comparable between groups (relative risk for the CSA group =1.162 [95% CI: 0.378-3.572; P=0.794]). Moreover, covariate-adjusted 5-year overall survival did not differ between the 2 groups (relative risk for the CSA group =1.95 [95% CI: 0.53-7.19; P=0.36). The incidence of infection, acute rejection, graft vasculopathy, renal failure, and neurological complications was also comparable between the 2 groups. Conclusions Our data indicate that tumor incidence does not significantly differ in patients receiving CSA or TAC as maintenance therapy.

The mTOR inhibitor everolimus (EVL) can be used for calcineurin inhibitor-sparing immunosuppression in heart transplantation (HTx). However, comparable data regarding clinical outcomes in HTx recipients receiving EVL either with dosage reduction of cyclosporine A (CSA) or with dosage reduction of tacrolimus (TAC) is scarce. In a retrospective data analysis, we compared 5-year clinical outcomes in 154 maintenance patients receiving EVL with CSA (n=106) or TAC (n=48). The primary endpoint was a composite of death, graft loss and EVL discontinuation (treatment failure). Secondary endpoints were kidney function, cardiac rejection, cytomegalovirus infection and biochemical safety parameters. In the CSA and TAC group, the primary endpoint was reached by 59.8% and 53.1%, respectively (P=0.716). Five-year mortality was 30.4% (CSA group) and 23.13% (TAC group), respectively (P=0.371), and freedom from EVL discontinuation was 53.3% and 59.6% (P=0.566) in the respective groups. Covariate-adjusted relative risk of treatment failure was in the CSA group=1.28 (95% CI: 0.70-2.34; P=0.43) compared with the TAC group. The course of covariate-adjusted estimated glomerular filtration rate and freedom from cytomegalovirus infection was similar in the two groups (P=0.502 and P=0.476), whereas covariate-adjusted freedom from rejection was lower in the CSA group compared with the TAC group (P=0.023). Lipid status and blood cell counts were comparable between groups. In conclusion, data indicate that EVL plus reduced TAC is not superior to EVL plus reduced CSA regarding treatment failure and kidney function. However, compared with EVL plus reduced CSA, EVL plus reduced TAC seems to reduce cardiac rejections.

An 18-year-old female Japanese patient who suffered from heart failure and severe pulmonary hypertension was referred to our clinic. The etiology of her cardiomyopathy was unclear. Inhaled prostacyclin therapy resulted in an improvement of pulmonary arterial pressure and allowed us to avoid lung transplantation. Heart transplantation resulted in a complete remission of her respiratory function. Autopsies of the explanted heart revealed massive endomyocardial fibroelastosis. We concluded that endomyocardial fibroelastosis has to be considered a cause of heart failure in young adults with unclear cardiomyopathy.

Everolimus has recently received approval for immunosuppressive therapy in heart transplant recipients in Austria and Germany. At our heart center we have treated 114 patients with everolimus since January 2004. Here we describe 6 cases of lingual angioedema (corresponding to 5.3% of the patients). Symptoms occurred within 2 to 41 days after initiation of therapy. In 5 out of the 6 patients, lingual angioedema disappeared with anti-allergic treatment alone. However, in one patient, two severe recurrent episodes of lingual angioedema occurred so that therapy had to be discontinued. We conclude that the potentially life-threatening condition of lingual angioedema should be considered a severe drug reaction after initiation of everolimus therapy in heart transplant recipients.