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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.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.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.Ea showed a strong impact on post-transplant mortality and RHF and should become part of the routine hemodynamic evaluation in HTx candidates.

The strong interaction of blood with the foreign surface of membrane oxygenators during ECMO therapy leads to adhesion of immune cells on the oxygenator membranes, which can be visualized in the form of image sequences using confocal laser scanning microscopy. The segmentation and quantification of these image sequences is a demanding task, but it is essential to understanding the significance of adhering cells during extracorporeal circulation. The aim of this work was to develop and test a deep learning-supported image processing tool (Deetect), suitable for the analysis of confocal image sequences of cell deposits on oxygenator membranes at certain predilection sites. Deetect was tested using confocal image sequences of stained (DAPI) blood cells that adhered to specific predilection sites (junctional warps and hollow fibers) of a phosphorylcholine-coated polymethylpentene membrane oxygenator after patient support (>24 h). Deetect comprises various functions to overcome difficulties that occur during quantification (segmentation, elimination of artifacts). To evaluate Deetects performance, images were counted and segmented manually as a reference and compared with the analysis by a traditional segmentation approach in Fiji and the newly developed tool. Deetect outperformed conventional segmentation in clustered areas. In sections where cell boundaries were difficult to distinguish visually, previously defined post-processing steps of Deetect were applied, resulting in a more objective approach for the resolution of these areas.

Background Endomyocardial biopsy (EMB) is a well-established procedure for the diagnosis of specific myocardial diseases and represents the gold standard in monitoring allografts after heart transplantation. In our study, we compared 2 different approaches for harvesting EMB in order to optimize patient safety and efficacy of the procedure. Methods As a standard approach for harvesting EMB, a venous introducer sheath was inserted percutaneously via the internal jugular vein using the Seldinger technique. Thereafter, a bioptome was repeatedly introduced throughout this sheath into the right ventricle (RV), each time passing the tricuspid valve (TV). Alternatively, a coronary sinus catheter was inserted via an introducer sheath placed in the subclavian vein and only once was introduced into RV cavity. Hence, just a unique passage of TV was required. Thereafter, a bioptome was introduced via this catheter and precisely guided to the targeted biopsy site. Results A standard approach was used with 34 patients, and a modified technique was used with 37 patients. Patient characteristics were comparable in both cohorts, and analyses of peri-procedural parameters identified only marginal differences between the groups. Interestingly, the number of harvested tissue samples per procedure was higher in the modified approach compared to the standard approach. No complications occurred. Conclusion The modified approach for EMB is a safe procedure. The facilitated bioptome-guidance and enhanced protection of TV may prevent periprocedural complications.

Background The implantation of cardiac implantable electronic devices is a globally established therapy to treat cardiac arrhythmias with low complication rates. Apart from technical problems, however, complications can arise from the implanted material. This can lead to bleeding, infections, or chronic irritation of the generator pocket, resulting in swellings, seromas, perforations, or fistulas. However, the cause of tissue changes is not always clear, and therefore, we would like to report on a rare tissue degeneration diagnosed in a patient. Case summary After a history of ventricular fibrillation, a 46-year-old patient received an implantable cardioverter-defibrillator (ICD) for secondary prevention. Six years later, the generator pocket swelled without evidence of infection. With the suspected diagnosis of a chronically irritated pocket, the device was then surgically relocated. After a 2-year symptom-free period, the patient presented again with a severely swollen but only slightly painful device pocket. Once again, there were no signs of infection, and so the pocket was revised again, assuming a chronic irritant effusion. Intraoperatively, a lipomatous structure (12 × 6 × 3 cm) emerged from the subpectoral ICD pocket. After its complete removal, the histopathological examination revealed a lipoma. A bacterial genesis could be ruled out by microbiological samples, and the wound healed cosmetically well and without further discomfort. Conclusion This case shows that the reason of chronically irritated generator pockets, in addition to the usually known tissue changes, can also be tumours. Therefore, resected tissue should be examined histopathologically and, if indicated, specific therapy initiated.

Various devices are available for endoscopic radial artery harvesting during coronary artery bypass grafting. Thermal spread and graft damage, however, are common concerns. The aim of this study was to compare the MiFusion TLS2 system (Endotrust, Nettetal Germany) with direct heat technique and the LigaSure Maryland system (Medtronic, Dublin, Ireland) using advanced bipolar technique in a prospective randomized study.One hundred consecutive patients undergoing coronary artery bypass grafting with endoscopic radial artery harvesting were prospectively included and randomized 1:1. The proximal (brachial) ends of the grafts were analyzed using fluorescence microscopy with focus on graft integrity. In addition, harvesting time, graft sealing, residual bleeding, and incidence of neurological disorders were compared.Patient age was 67 ± 8 years. Mean harvesting time was 26.5 ± 9 minutes for the TLS2 and 23.2 ± 8 minutes for the LigaSure (P = .049). Overall graft integrity was good in both groups. A significantly better graft integrity was observed in the LigaSure group (scale 0 to 3; 3 = best) with 2.5 ± 0.6 for TLS2 and 2.8 ± 0.4 for LigaSure (P = .031). LigaSure provided significantly better graft sealing (scale 0 to 2; 0 = best) with 0.6 ± 0.7 vs 1.0 ± 0.6 (TLS2) (P = .006) and less residual bleeding (scale 1 to 5; 1 = best) with 1.4 ± 0.6 vs 2.0 ± 0.9 (TLS2) (P.001). Transient sensibility disorders were less frequently observed with LigaSure (2% vs 16%, P = .015).Endoscopic radial artery harvesting can be performed with excellent results and good graft integrity using both devices. Compared with the MiFusion TLS2, the LigaSure device led to faster procedural times and resulted in better graft integrity. Along with providing a better seal, LigaSure was associated with less sensibility disorders.

The muscle-specific miR-1 and miR-133a RNAs lock cardiomyocytes in a differentiated state by suppressing OSMR/FGFR signaling.

Description, The muscle-specific miR-1 and miR-133a RNAs lock cardiomyocytes in a differentiated state by suppressing OSMR/FGFR signaling., Dedifferentiation of cardiomyocytes is part of the survival program in the remodeling myocardium and may be essential for enabling cardiomyocyte proliferation. In addition to transcriptional processes, non-coding RNAs play important functions for the control of cell cycle regulation in cardiomyocytes and cardiac regeneration. Here, we demonstrate that suppression of FGFR1 and OSMR by miR-1/133a is instrumental to prevent cardiomyocyte dedifferentiation and cell cycle entry in the adult heart. Concomitant inactivation of both miR-1/133a clusters in adult cardiomyocytes activates expression of cell cycle regulators, induces a switch from fatty acid to glycolytic metabolism, and changes expression of extracellular matrix genes. Inhibition of FGFR and OSMR pathways prevents most effects of miR-1/133a inactivation. Short-term miR-1/133a depletion protects cardiomyocytes against ischemia, while extended loss of miR-1/133a causes heart failure. Our results demonstrate a crucial role of miR-1/133a–mediated suppression of Osmr and Ffgfr1 in maintaining the postmitotic differentiated state of cardiomyocytes.

Background Resection (triangular or quadrangular) is considered the gold standard for the treatment of posterior leaflet prolapse and loop implantation a more recent alternative. We aimed to compare the long-term outcomes of triangular or quadrangular resection vs loop implantation. Methods Single-centre, retrospective analysis of mitral valve (MV) surgeries conducted from January 2005 to December 2015. Propensity score matching was based on seven key baseline variables. Results Data from 721 patients were analyzed; 358 patients received loop implantation and 363 patients underwent resection. Patients had a mean age of 62 years, 33.0% were female and 50.6% had hypertension. Propensity score matching resulted in a matched group of 263 patients who received loop implantation or underwent resection, respectively. Postoperatively, the patients' mitral insufficiency was reduced from grade III/IV to either zero or trace (45.8%) or I (49.8%) and New York Heart Association class reduced from 66.9% in class III/IV preoperatively to 8.3% with no significant differences between groups. Fewer patients receiving loops had procedure-related complications. Fewer patients in the loop implantation group required permanent pacemaker implantation at 30 days (8.4% vs 2.3%; P = .002). The 10-year survival for patients in the resection (88.0%) and loop implantation (89.3%) groups had a hazard ratio of 1.224 (95% confidence interval, 0.633-2.367). Conclusion Our study showed that both loop implantation and resection were associated with comparable long-term survival in patients with posterior leaflet prolapse. Loop implantation is associated with a significantly higher rate of a successful repair, a significantly lower rate of MV replacement after repair failure, fewer procedure-related complications and better 30-day at comparable long-term outcomes.

Clinicians can feel confident about performing mitral repair/replacement in patients who have previously undergone mammoplasty. It may also have applications in performing atrial septal defect closure, Maze procedures for atrial fibrillation, and tricuspid valve surgery in patients with breast implants.

Objectives Ischemia-reperfusion injury is correlated with a substantial inflammatory response. Inflammation triggers the migration of cells through vessel endothelium and leads to serious tissue injury. Our hypothesis was that an early application of mammalian target of rapamycin inhibitors has an impact on human vessels after ischemia-reperfusion injury. Materials and methods After exposure to ischemia for 5 hours, human vessels (veins and arteries) from 20 patients were reperfused for 120 minutes in an in vitro bioreactor with heparinized human blood after oxygenation and warming to 37 °C. The vessels were treated with mammalian target of rapamycin inhibitor everolimus (5 ng/mL, n = 7) or sirolimus (10 ng/mL, n = 6). As a control group, untreated human vessels were reperfused (n = 7). During the reperfusion period, blood samples were collected continuously (after 0, 15, 30, 60, 120 minutes); vessel biopsies were performed at the end. Oxygen consumption was measured during reperfusion to determine vessel viability. Inflammatory markers (interleukin 6, tumor necrosis factor α, vascular endothelial growth factor) were analyzed in blood samples. To quantify vascular inflammation, we investigated the expression of CD11 and CD31. Results Physiological oxygen consumption and pH values verified vessel viability. After reperfusion, interleukin 6 and vascular endothelial growth factor levels were significantly increased in the control group over time, whereas everolimus and sirolimus showed no significant differences. Furthermore, tumor necrosis factor α level increased significantly in the sirolimus group, whereas the everolimus and control groups showed constant values. A significant decrease of expression of CD11b and CD31 in both mammalian target of rapamycin inhibitor cohorts compared with control cohort was investigated. Conclusions Early use of mammalian target of rapamycin inhibitors may limit an inflammatory rise of interleukin 6 and vascular endothelial growth factor after ischemia-reperfusion injury and could be associated with a restriction in vascular cell transmigration.

Background Minimally invasive mitral valve surgery is standard of care in many centres and it is commonly associated with the need for cardiopulmonary bypass. Conventional external aortic clamping (exoclamping) is not always feasible, so endoaortic clamping (endoclamping) has evolved as a viable alternative. The aim of this study is to compare endoclamping (Intraclude™, Edwards Lifesciences) with exoclamping (Chitwood) during minimally invasive mitral valve procedures. Methods This single-centre study included 822 consecutive patients undergoing minimally invasive mitral valve procedures. The endoclamp was used in 64 patients and the exoclamp in 758. Propensity-score (PS) matching was performed resulting in 63 patients per group. Outcome measures included procedural variables, length of intensive care unit (ICU) and hospital stay, major adverse cardiac and cerebrovascular events (MACCE) and repeat surgery. Results The mean age was similar in the two group (62.2 [endoclamp] vs. 63.5 [exoclamp] years; p = 0.554), as were the cardiopulmonary bypass (145 vs. 156 min; p = 0.707) and the procedure time (203 vs. 211 min; p = 0.648). The X-clamp time was significantly shorter in the endoclamp group (88 vs. 99 min; p = 0.042). Length of ICU stay (25.0 vs. 23.0 h) and length of hospital stay (10.0 vs. 9.0 days) were slightly longer in the endoclamp group, but without statistical significance. There were nominal but no statistically significant differences between the groups in the rates of stroke, vascular complications, myocardial infarction or repeat mitral valve surgery. The conversion rate to open sternotomy approach was 2.4% without difference between groups. The estimated 7-year survival rate was similar for both groups (89.9% [endoclamp]; 84.0% [exoclamp]) with a hazard ratio of 1.291 (95% CI 0.453–3.680). Conclusions Endoaortic clamping is an appropriate and reasonably safe alternative to the conventional Chitwood exoclamp for patients in which the exoclamp cannot be used because the ascending aorta cannot be safely mobilised.

Oncostatin M (OSM), a member of the interleukin-6 family, functions as a major mediator of cardiomyocyte remodeling under pathological conditions. Its involvement in a variety of human cardiac diseases such as aortic stenosis, myocardial infarction, myocarditis, cardiac sarcoidosis, and various cardiomyopathies make the OSM receptor (OSMR) signaling cascades a promising therapeutic target. However, the development of pharmacological treatment strategies is highly challenging for many reasons. In mouse models of heart disease, OSM elicits opposing effects via activation of the type II receptor complex (OSMR/gp130). Short-term activation of OSMR/gp130 protects the heart after acute injury, whereas chronic activation promotes the development of heart failure. Furthermore, OSM has the ability to integrate signals from unrelated receptors that enhance fetal remodeling (dedifferentiation) of adult cardiomyocytes. Because OSM strongly stimulates the production and secretion of extracellular proteins, it is likely to exert systemic effects, which in turn, could influence cardiac remodeling. Compared with the mouse, the complexity of OSM signaling is even greater in humans because this cytokine also activates the type I leukemia inhibitory factor receptor complex (LIFR/gp130). In this article, we provide an overview of OSM-induced cardiomyocyte remodeling and discuss the consequences of OSMR/gp130 and LIFR/gp130 activation under acute and chronic conditions.

Heart transplantation (HTx) represents the “gold standard” in end-stage heart failure therapy. Due to their severe heart failure and for prevention of sudden cardiac death, the majority of patients presenting for HTx will have a history of an implanted cardioverter-defibrillator (ICD). Usually, within the scope of HTx, all cardiac-implanted electronic device components are removed. In rare cases these efforts fail and some material remains. The abandoned lead fragments can cause serious complications. The case presented herein involves a patient with recurrent bacteremia after successful HTx originating from an abandoned and infected lead fragment. In 2016, a 64-year-old man received a donor heart transplant due to end-stage heart failure. Unfortunately, during the procedure, not all components of an ICD implanted in 2007 could be removed. An initially event-free period was followed by recurrent fever attacks and staphylococcal bacteremia was diagnosed. After an extensive search, the source of the bacteremia was identified by positron emission tomography–computed tomography (PET-CT), and percutaneous extraction of the abandoned and infected ICD lead fragment was scheduled. The fragment was extracted using a minimally invasive approach via percutaneous femoral vein access. The patient was discharged 3 days later, with no further complications. This case highlights the need for conscientious and complete removal of foreign material in the HTx setting. Difficult-to-diagnose sources of infection could be reliably identified by PET-CT. When required, extraction of the foreign body should be done using a minimally invasive approach.

Text of a paper presented at the conference "Reformation from the perspective of 500 years. History-Culture-Society" at Siedlce University in November 8, 2017.

Pediatric heart transplantation (pHTx) represents only a small proportion of cardiac transplants. Due to these low numbers, clinical data relating to induction therapy in this special population are far less extensive than for adults. Induction is used more widely in pHTx than in adults, mainly because of early steroid withdrawal or complete steroid avoidance. Antithymocyte globulin (ATG) is the most frequent choice for induction in pHTx, and rabbit antithymocyte globulin (rATG, Thymoglobulin®) (Sanofi Genzyme) is the most widely-used ATG preparation. In the absence of large, prospective, blinded trials, we aimed to review the current literature and databases for evidence regarding the use, complications, and dosages of rATG. Analyses from registry databases suggest that, overall, ATG preparations are associated with improved graft survival compared to interleukin-2 receptor antagonists. Advantages for the use of rATG have been shown in low-risk patients given tacrolimus and mycophenolate mofetil in a steroid-free regimen, in sensitized patients with pre-formed alloantibodies and/or a positive donor-specific crossmatch, and in ABO-incompatible pHTx. Registry and clinical data have indicated no increased risk of infection or post-transplant lymphoproliferative disorder in children given rATG after pHTx. A total rATG dose in the range 3.5-7.5 mg/kg is advisable.

PDGF-AB and FGF-2 (GFs) induce smooth muscle cell (SMC) proliferation which is indispensible for arteriogenesis. While there is common agreement that GFs stimulate SMC proliferation through phosphorylation (P-) of MEK1/2 at Ser218/222, we previously demonstrated that the MEK inhibitors PD98059 and UO126 did not inhibit P-Ser218/222 as originally proposed but caused strong hyperphosphorylation. Here, we demonstrate that GFs increased phosphorylation of MEK1 at Thr292 while UO126 and PD98059 blocked this phosphorylation. This was again surprising since phosphorylation of Thr292 is regarded as a negative feedback loop. Our findings suggest that inhibition of Thr292 phosphorylation in combination with hyperphosphorylation of Ser218/222 serves as an "off" switch of SMC proliferation and potentially of arteriogenesis.

We report on a 61-year-old man with a previously unknown interruption of the inferior vena cava who was scheduled to undergo minimally invasive mitral and tricuspid valve surgery. We aimed to establish a cardiopulmonary bypass using femorofemoral cannulation under transoesophageal echocardiography. In spite of multiple attempts, the positioning of the venous wire in the right atrium was not accomplished. The intervention was subsequently performed by an open sternotomy. Further to the intervention, the patient underwent thoraco-abdominal multislice computed tomography that excluded the presence of an abdominal tumour or vena cava thrombosis but revealed atresia of the inferior vena cava.

Myocarditis is characterized by infiltration and activation of cytokine as well as chemokine receptors frequently producing heart failure. Causes are often infections triggering inflammatory and immune responses but these initial lines of defense might be finally disastrous. To identify mediators we screened various receptors by confocal microscopy and identified cardiac interleukin-7 (IL-7) receptor-α (IL-7Rα) expressing cells in patients with myocarditis. IL-7Rα+ cells were analyzed by markers for leukocytes (CD45), B cells (CD19), T cells (CD3, CD4, CD8) and macrophages (CD68, CD163, CD206). Immune cells were hardly detected in controls. In patients with myocarditis main inflammatory populations consisted of macrophages and T cells. B cells were hardly present. 90% of CD68+ macrophages but less than 20% of CD3+ T cells were IL-7Rα+. This was surprising since T and B lymphocytes are generally regarded as the major IL-7Rα+ cells. Since IL-7 acts as a chemokine, the expression of its receptor might orchestrate cardiac macrophage infiltration. In contrast, consumption of IL-7 by IL-7Rα+ cardiac macrophages might potentially prevent a certain overshooting immune reaction and sepsis by reducing proliferation and survival of lymphocytes. Our data suggest a participation of IL-7Rα+ macrophages in the development of myocarditis and heart failure.

Background Pediatric patients show an impressive capacity of cardiac regeneration. In contrast, severely deteriorated adult hearts do usually not recover. Since cardiac remodeling—involving the expression of fetal genes—is regarded as an adaptation to stress, we compared hearts of adult patients suffering from dilated cardiomyopathy (DCM) with remodeling of cultured neonatal (NRC) as well as adult (ARC) rat cardiomyocytes and the developing postnatal myocardium. Methods NRC and ARC were stimulated with serum and cardiac morphogens derived from DCM hearts. Protein synthesis (PS) as well as protein accumulation (PA) was measured, and cell survival was determined under ischemic conditions. Fetal markers were investigated by Western blot. Biomarkers of remodeling were analyzed in controls, DCM, and 2- to 6-month-old children with tetralogy of Fallot as well as in neonatal and adult rats by immunofluorescence. Results In NRC, serum and morphogens strongly stimulated PS and PA and the reestablishment of cell-cell contacts (CCC). In ARC, both stimulants increased PS and CCC, but PA was only elevated after serum stimulation. In contrast to serum, morphogen treatment resulted in the expression of fetal genes in ARC as determined by nonmuscle α-actinin-1 and α-actinin-4 expression (NM-actinins) and was associated with increased survival under ischemia. NM-actinins were present in cardiomyocytes of DCM in a cross-striated pattern reminiscent of sarcomeres as well as in extensions of the area of the intercalated disc (ID). NM-actinins are expressed in NRC and in the developing heart. Radixin staining revealed remodeling of the area of the ID in DCM almost identical to stimulated cultured ARC. Conclusions Remodeling was similar in ARC and in cardiomyocytes of DCM suggesting evolutionary conserved mechanisms of regeneration. Despite activation of fetal genes, the atrophy of ARC indicates differences in their regenerative capacity from NRC. Cardiac-derived factors induced NM-actinin expression and increased survival of ischemic ARC while circulating molecules were less effective. Identification of these cardiac-derived factors and determination of their individual capacity to heal or damage are of particular importance for a biomarker-guided therapy in adult patients.

Cardiac sarcoidosis (CS) is a poorly understood disease and is characterized by the focal accumulation of immune cells, thus leading to the formation of granulomata (GL). To identify the developmental principles of fatal GL, fluorescence microscopy and Western blot analysis of CS and control patients is presented here. CS is visualized macroscopically by positron emission tomography (PET)/ computed tomography (CT). A battery of antibodies is used to determine structural, cell cycle and inflammatory markers. GL consist of CD68+, CD163+ and CD206+ macrophages surrounded by T-cells within fibrotic areas. Cell cycle markers such as phospho-histone H3, phospho-Aurora and Ki67 were moderately present, however, the phosphorylated ERM (ezrin, radixin and moesin) and Erk1/2 proteins, strong expression of the myosin motor protein and the macrophage transcription factor PU.1 indicate highly active GL. Mild apoptosis is consistent with PI3 kinase and Akt activation. Massive amounts of the IL-1R antagonist reflect a mild activation of stress and inflammatory pathways in GL. High levels of oncostatin M and the Reg3A and Reg3γ chemokines are in accordance with macrophage accumulation in areas of remodeling cardiomyocytes. We conclude that the formation of GL occurs mainly through chemoattraction and less by proliferation of macrophages. Furthermore, activation of the oncostatin/Reg3 axis might help at first to wall-off substances but might initiate the chronic development of heart failure.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Telocytes (TCs) are a novel type of interstitial cells only recently described. This study aimed at characterizing and quantifying TCs and telopodes (Tps) in normal and diseased hearts. We have been suggested that TCs are influenced by the extracellular matrix (ECM) composition. We used transmission electron microscopy and c-kit immunolabelling to identify and quantify TCs in explanted human hearts with heart failure (HF) because of dilated, ischemic or inflammatory cardiomyopathy. LV myectomy samples from patients with aortic stenosis with preserved ejection fraction and samples from donor hearts which could not be used for transplantation served as controls. Quantitative immunoconfocal analysis revealed that 1 mm2 of the normal myocardium contains 14.9 ± 3.4 TCs and 41.6 ± 5.9 Tps. As compared with the control group, the number of TCs and Tps in HF decreased more than twofold. There were no differences between HF and control in the number of Ki67-positive TCs. In contrast, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling-positive TCs increased threefold in diseased hearts as compared to control. Significant inverse correlations were found between the amount of mature fibrillar collagen type I and the number of TCs (r = −0.84; P

Cardiac healing after myocardial ischemia depends on the recruitment and local expansion of myeloid cells, particularly macrophages. Here we identify Reg3β as an essential regulator of macrophage trafficking to the damaged heart. Using mass spectrometry-based secretome analysis, we found that dedifferentiating cardiomyocytes release Reg3β in response to the cytokine OSM, which signals through Jak1 and Stat3. Loss of Reg3β led to a large decrease in the number of macrophages in the ischemic heart, accompanied by increased ventricular dilatation and insufficient removal of neutrophils. This defect in neutrophil removal in turn caused enhanced matrix degradation, delayed collagen deposition and increased susceptibility to cardiac rupture. Our data indicate that OSM, acting through distinct intracellular pathways, regulates both cardiomyocyte dedifferentiation and cardiomyocyte-dependent regulation of macrophage trafficking. Release of OSM from infiltrating neutrophils and macrophages initiates a positive feedback loop in which OSM-induced production of Reg3β in cardiomyocytes attracts additional OSM-secreting macrophages. The activity of the feedback loop controls the degree of macrophage accumulation in the heart, which is instrumental in myocardial healing.

It is now accepted that heart failure (HF) is a complex multifunctional disease rather than simply a hemodynamic dysfunction. Despite its complexity, stressed cardiomyocytes often follow conserved patterns of structural remodelling in order to adapt, survive, and regenerate. When cardiac adaptations cannot cope with mechanical, ischemic, and metabolic loads efficiently or become chronically activated, as, for example, after infection, then the ongoing structural remodelling and dedifferentiation often lead to compromised pump function and patient death. It is, therefore, of major importance to understand key events in the progression from a compensatory left ventricular (LV) systolic dysfunction to a decompensatory LV systolic dysfunction and HF. To achieve this, various animal models in combination with an “omics” toolbox can be used. These approaches will ultimately lead to the identification of an arsenal of biomarkers and therapeutic targets which have the potential to shape the medicine of the future.

Donor-specific antibodies (DSA) are integral to the development of antibody-mediated rejection (AMR). Chronic AMR is associated with high mortality and an increased risk for cardiac allograft vasculopathy (CAV). Anti-donor HLA antibodies are present in 3-11% of patients at the time of heart transplantation (HTx), with de novo DSA (predominantly anti-HLA class II) developing post-transplant in 10-30% of patients. DSA are associated with lower graft and patient survival after HTx, with one study suggesting a three-fold increase in mortality in patients who develop de novo DSA (dnDSA). DSA against anti-HLA class II, notably DQ, are at particularly high risk for graft loss. Although detection of DSA is not a criterion for pathologic diagnosis of AMR, circulating DSA are found in almost all cases of AMR. MFI thresholds of ~5000 for DSA against class I antibodies, 2000 against class II antibodies, or an overall cut-off of 5-6000 for any DSA, have been suggested as being predictive for AMR. There is no firm consensus on pre-transplant strategies to treat HLA antibodies, or for the elimination of antibodies after diagnosis of AMR. Minimizing the risk of dnDSA is rational but data on risk factors in HTx are limited. The effect of different immunosuppressive regimens is largely unexplored in HTx, but studies in kidney transplantation emphasize the importance of adherence and maintaining adequate immunosuppression. One study has suggested a reduced risk for dnDSA with rabbit antithymocyte globulin induction. Management of DSA pre- and post-HTx varies but typically most centers rely on a plasmapheresis or immunoadsorption, with or without rituximab and/or intravenous immunoglobulin. Based on the literature and a multi-center survey, an algorithm for a suggested surveillance and therapeutic strategy is provided.

BACKGROUND: Decision-making when offered a donor heart for transplantation is complex, and supportive data describing outcomes according to acceptance or non-acceptance choices are sparse. Our aim was to analyze donor heart acceptance decisions and associated outcomes at a single center, and after subsequent acceptance elsewhere.METHODS: This investigation was a retrospective analysis of data obtained from the University of Vienna Medical Center and Eurotransplant centers for the period 2001 to 2015RESULTS: Our center accepted 31.8% (699 of 2,199) of donor hearts offered. Unlike other centers, the acceptance rate, with or without transplantation, did not increase over time. Of the donor hearts rejected by our center, 38.1% (572 of 1,500) were later accepted elsewhere. Acceptance rates were twice as high for donor hearts initially rejected for non-quality reasons (339 of 601, 56.4%) compared with initial rejection for quality reasons (233 of 899, 25.9%). Three-year patient survival rate was 79% at Vienna; for donor hearts initially rejected by Vienna for non-quality reasons or quality reasons, it was 73% and 63%, respectively (p CONCLUSIONS: A less restrictive policy for accepting donor hearts at our center, particularly regarding rejection for non-quality reasons or for positive virology, high catecholamine levels, longer ischemic time, or low ejection fraction, could expand our donor pool while maintaining good outcomes. (C) 2018 International Society for Heart and Lung Transplantation. All rights reserved.

Dilated cardiomyopathy (DCM) is an important cause of heart failure. Single gene mutations in at least 50 genes have been proposed to account for 25–50% of DCM cases and up to 25% of inherited DCM has been attributed to truncating mutations in the sarcomeric structural protein titin (TTNtv). Whilst the primary molecular mechanism of some DCM-associated mutations in the contractile apparatus has been studied in vitro and in transgenic mice, the contractile defect in human heart muscle has not been studied. In this study we isolated cardiac myofibrils from 3 TTNtv mutants, and 3 with contractile protein mutations (TNNI3 K36Q, TNNC1 G159D and MYH7 E1426K) and measured their contractility and passive stiffness in comparison with donor heart muscle as a control. We found that the three contractile protein mutations but not the TTNtv mutations had faster relaxation kinetics. Passive stiffness was reduced about 38% in all the DCM mutant samples. However, there was no change in maximum force or the titin N2BA/N2B isoform ratio and there was no titin haploinsufficiency. The decrease in myofibril passive stiffness was a common feature in all hearts with DCM-associated mutations and may be causative of DCM.

Cardiac surgery with extracorporeal circulation is characterized by different degrees of myocardial ischemia/reperfusion, which is often associated with postoperative atrial fibrillation (POAF). We have previously shown that a novel preventive therapy based on the reinforcement of the antioxidant system using omega-3 fatty acids plus antioxidant vitamin supplementation applied to patients undergoing cardiac surgery reduces POAF occurrence. We hypothesized that oxidative stress and nitrosative stress are involved in the development of an arrhythmogenic substrate by their effect on connexins (Cx40, Cx43 and Cx45) abundance and distribution pattern. Therefore, we have assessed the effect of redox status on atrial tissue in patients undergoing cardiac surgery. Placebo/POAF and supplemented/POAF patients showed 276 and 170% higher reactive oxygen species (ROS) levels and 223 and 96% higher nitrotyrosine residues levels, respectively, compared to sinus rhythm (SR). In POAF tissue, antioxidant supplementation prevented Cx40 and Cx43 lateralization on cardiomyocyte sarcolemma, keeping them at the intercalated disks. POAF samples showed Cx40 heterogeneous distribution pattern, presenting tissue areas lacking this protein (49 and 55% lower levels in placebo/POAF and supplemented/POAF groups, respectively, compared to SR). Of note, Cx45 overexpression occurred in POAF, being 211 and 167% higher in placebo/POAF and supplemented/POAF groups, respectively, compared to SR. It is concluded that treatment with omega-3 fatty acids and antioxidant vitamins reduces oxidative and nitrosative stress and prevents Cx40/Cx43 lateralization in atrial tissue likely contributing to POAF prevention. However, it failed to fully prevent POAF occurrence because these compounds have no effects on the normalization of Cx40 down-regulation and Cx45 up-regulation, which may promote POAF.

Background: Recent studies emphasize a correlation of increased FGF23 with the pathogenesis of heart diseases. Although it is widely assumed that the bone and not the heart is the major source of FGF23 we previously demonstrated that oncostatin M (OSM) activated cardiomyocytes strongly secrete FGF23. This phosphatonin can be released as intact molecule (iFGF23) as well as C-terminal (cFGF23) and N-terminal (nFGF23) fragments. Since cleavage does not only inactivate iFGF23 but might also exert antagonizing activity we wanted to determine which form is secreted by cardiomyocytes. Methods: Adult cultured cardiomyocytes were stimulated with OSM or albumin as control. Supernatant and cell lysate were analyzed by Western blot (WB) and specific ELISAs against cFGF23 as well as iFGF23. Expression of FGF23 in cardiomyocytes of 6 patients with coronary heart diseases (CHD) was analyzed by confocal microscopy because OSM signaling cascades are activated after myocardial infarction. Results: WB analysis identified cFGF23 as well as nFGF23 while iFGF23 was hardly detectable in the supernatant of OSM-stimulated cardiomyocytes. Analysis of the supernatant by ELISAs revealed that less than 3% of this secreted phosphatonin was intact. In patients with CHD the number of FGF23 positive cardiomyocytes increased from 0.2% in the remote zone to 4.4% in the border zone. Conclusions: The expression and release of FGF23 by cardiomyocytes indicate local as well as systemic functions. The determination of the ratio of iFGF23/cFGF23 will be essential to understand the functional role of this growth factor in patients with cardiac diseases.

ObjectivesWe used immuhistochemistry and Western blot to study fibrillar and non-fibrillar collagens, collagen metabolism, matricellular proteins and regulatory factors of the ECM remodeling in left ventricular (LV) septum biopsies from 3 groups of patients with aortic valve stenosis (AS): (AS-1,n = 9): ejection fraction (EF) > 50%; AS-2,(n = 12): EF 30%–50%; AS-3,(n = 9): EF < 30%). Samples from 8 hearts with normal LV function served as controls.ResultsIn comparison with controls, fibrillar collagens I and III were progressively upregulated from compensated (AS-1) toward decompensated hypertrophy (AS-3). The collagenIII/collagen I ratio decreased 2-fold in the AS-2 and AS-3 groups as compared with AS-1 and controls. Non-fibrillar collagen IV was upregulated only in AS-3 patients, whereas collagen VI progressively increased from AS-1 to AS-3 group. Collagen synthesis in AS-3 was shifted to collagen I, while the maturation/degradation level was shifted to collagen III. RECK was downregulated only in AS-3 patients. Matricellular proteins tenascin and osteopontin were increased in all AS patients. However, thrombospondin 1, 4 and CTGF were increased only in AS-3. Only AS-3 patients were characterized by increased levels of TGFβ1 and downregulation of TGFβ3, TGFβ-activated kinase1 and Smad7. In contrast, Smad3 gradually increased from AS-1 toward AS-3. Similar trend of changes was observed for TNFα-R1 and TNFα-R2, whereas TNFα was diminished only in AS-2 and AS-3.ConclusionsDistinct changes in fibrillar collagen turnover, non-fibrillar collagens, matricellular proteins and the key regulatory profibrotic and anti-fibrotic factors of the myocardial ECM remodeling are involved in the transition from compensated to decompensated LV hypertrophy and HF in human patients with AS.

Fatty acids with different chain length were deoxygenated in the absence of hydrogen (caprylic acid (CA), lauric acid (LA) and stearic acid (SA)). The catalytic tests were carried over Pd-containing catalysts out in a batch reactor under inert gas for 6 h at 250d the best performing catalyst was 10% Pd/C with 63% undecane yield at 327&degC. These catalysts were used for a comparative decarboxylation of CA, LA and SA. At equal reaction conditions (300&degC, 6 h), the chain length of the fatty acid had a strong impact on the conversion, which was steadily increasing, whereas the alkane selectivity ran through a maximum. This work demonstrated the usability of Pd-containing catalysts for the decarboxylation of various fatty acids in the absence of additionally fed hydrogen with respect to the manufacture of hydrocarbons that can be used as blending components for fuels.

Mesenchymal stem cells (MSC) have been used to treat different clinical conditions although the mechanisms by which pathogenetic processes are affected are still poorly understood. We have previously analyzed the homing of bone marrow-derived MSC to diseased tissues characterized by a high degree of mononuclear cell infiltration and postulated that MSC might modulate inflammatory responses. Here, we demonstrate that MSC mitigate adverse tissue remodeling, improve organ function, and extend lifespan in a mouse model of inflammatory dilative cardiomyopathy (DCM). Furthermore, MSC attenuate Lipopolysaccharide-induced acute lung injury indicating a general role in the suppression of inflammatory processes. We found that MSC released sTNF-RI, which suppressed activation of the NFκBp65 pathway in cardiomyocytes during DCM in vivo. Substitution of MSC by recombinant soluble TNF-R partially recapitulated the beneficial effects of MSC while knockdown of TNF-R prevented MSC-mediated suppression of the NFκBp65 pathway and improvement of tissue pathology. We conclude that sTNF-RI is a major part of the paracrine machinery by which MSC effect local inflammatory reactions. Electronic supplementary material The online version of this article (doi:10.1007/s00395-016-0573-2) contains supplementary material, which is available to authorized users.

Background: Polyclonal anti-thymocyte globulins (ATGs) are immunosuppressive drugs widely used in induction of immunosuppression and treatment of acute rejection after solid organ transplantation. We have previously demonstrated that ATGs bind to endothelial cells in vitro, and are able to modulate ECs. The aim of this study was to investigate the binding of ATGs to endothelial cells under in vivo conditions. Material/Methods: Muscle biopsies from extremities of cynomolgus monkeys were obtained after ischemia/reperfusion at 4 degrees C. ATGs (Thymoglobulin, Sanofi-Aventis, France;1 mg/kg) were added to the blood 30 min prior to the reperfusion. Biopsies (n=10) of patients undergoing heart transplantation and preoperatively treated with ATGs (Thymoglobulin, Sanofi-Aventis, France;1.5 mg/kg) as induction therapy were also analyzed 6 hours and 7 days after induction. Binding of ATGs to ECs was analyzed with an anti-rabbit IgG antibody by means of immunohistochemistry. Results: Binding of ATGs to endothelial cells could be demonstrated in vivo in our animal experiments 4 hours after reperfusion, as well as in the clinical biopsies 6 hours after induction of immunosuppression in heart transplant patients, showing a preferred localization in post-capillary veins. No expression of ATGs on the endothelial surface could be observed after 7 days, suggesting that ATGs may be washed out from the endothelial surface in a time-dependent manner. Conclusions: Our results show that ATGs are able to bind to endothelial cells in an experimental model and in clinical practice, supporting preconditioning strategies with ATGs in solid organ transplantation.

Background: Contemporary mitral valve repair aims at correction of leaflet function and stabilization of the annulus using closed or open annuloplasty rings. Aim of this study was to compare the outcome after OA versus CA mitral valve repair. Methods: 933 patients who received mitral valve surgery between January 2005 and December 2014 were evaluated. Differences in baseline variables were adjusted using propensity score (PS) matching which included logistic regression with 41 preoperative covariates. Mitral valve pathology was degenerative 96.6% (OA) and 95.5% (CA). Results: Cross-clamp time was 82 ± 30 minute (OA) versus 86 ± 32 minute (CA), p = ns. The repair rate was 99.1% in both groups. Postoperative intensive care unit stay was one day in both groups. In hospital mortality was 3.1% (OA) versus 2.3% (CA), p= ns. Postoperative none/trace or mild mitral incompetence at transthoracic echo was diagnosed in 96.9% (OA) versus 97.2% (CA), p = ns Conclusion: Mitral valve surgery leads to good outcomes and a high repair rate using standard techniques including OA and CA. In case of potential future need for repeat intervention CA may provide a better landing zone.

Investigations of a ZSM-5 type zeolite (HS 30, manufactured by VEB CK Bitterfeld without using any template) show that by dealumination various ratios of Si/Alframework can be achieved within a rather broad scale without structural changes of the initial substance. In any case the number of strong acid Bronsted centres of the elementary unit corresponds to the number of Al atoms contained therein. Throughout all investigations the relative catalytic activity of the catalysts has been found to be in a linear relationship to the number of strong acid Bronsted centres (bridged OH groups). With the isomerisation of m-xylene the initial non-dealuminated sample already brings about a selectivity of ≈80% for the para-isomere. No influence of dealumination on p-selectivity could be observed. With the conversion of methanol reduced catalytic activity of dealuminated samples results in an increase of the selectivity of lower olefins at the expense of aromatics for both reaction temperatures. The values obtained at 580°C are in favour of an additional formation of lower olefins due to the cracking of higher olefins. Dealumination gives also rise to an essential growth of the stability (i.e. possible integral charge by CH3OH) of the catalyst. With growing dealumination of the catalyst the attainable time on stream increases and reaches a maximum falling of thereafter.

On the occasion of the presentation of the Deane B. Judd-AIC Award to the author, he gave a historical survey of how color metrics developed from its origin to its present state of an independent and fascinating science. Only the most important stages of this development could be discussed; it was difficult to confine the scope of the presentation reasonably. Therefore, it was necessary to consider only those publications and personalities far enough removed in time to allow a retrospective, fair judgment of their importance. Most of the author's living colleagues in color metrics could not be mentioned, but this does not imply any evaluation of their recent publications or research, or deny any important future progress.

Zusammenfassung Welcher Wettbewerb ist im Gesundheitswesen der richtige? Hilft es dem Patienten und der Krankenkasse, wenn eine Einzelleistung durch den Wettbewerb um 20% billiger wird, aber diese Leistung gar keinen Gesundheitsnutzen produziert oder, noch schlimmer, die Anzahl der durchgefuhrten Leistungen ohne gleichzeitigen Nutzen um 20% steigt? Die Autoren pladieren vehement fur eine Neuausrichtung der Anreize und eine Honorierung, die statt des Einzelpreises den geschaffenen Gesundheitsnutzen und damit die Ergebnisqualitat fur den Einzelnen wie fur die Versichertengemeinschaft in das Zentrum des Wettbewerbs ruckt. Eine solche Honorierung – so die Argumentation der Verfasser – benotigt regional organisierte Systemlosungen als Treiber von Effizienz und Effektivitat und Partner der Krankenkassen. Getting the Incentives Right: New Payment Schemes within the German Health Care System and the Rising Need for Well-designed Systems What kind of competition is the one to choose for health care systems? Is i...