Successful support of biventricular heart failure patients by new EXCOR® Adult pumps with bileaflet valves: a prospective study.

AIMS: The Berlin Heart EXCOR® Adult biventricular assist device (BiVAD) is an approved mechanical circulatory support for patients with end-stage biventricular heart failure. In this prospective post-market clinical follow-up study, we present the first clinical experience of the new EXCOR® Adult pump with bileaflet (BL) valves in Europe. METHODS AND RESULTS: After CE-mark approval in August 2014, a total of 12 patients were enrolled with a mean age of 44 years ± 11 (range 21-58 years). The majority of patients (n = 11) were in INTERMACS level 1 or 2. Eight patients had a median pre-operative extracorporeal life support (ECLS) of 6 days (range 1-37 days). Primary end point was survival, either to heart transplantation (HTx), recovery or alive at 12 months on device, whichever occurred first. Secondary end point was the number of adverse events throughout EXCOR® BiVAD support. Median support time up to last follow-up on EXCOR® BiVAD device was 248 days (range 57-381 days) and patient survival at 1 year was 92%. Half of the EXCOR® BiVAD patients (n = 6) were transplanted and five patients were still on support at 1 year post-implantation. Complications during EXCOR® BiVAD support were thoracic bleeding, exit site infection and ischemic cerebrovascular incidents in three cases, respectively. CONCLUSION: The new EXCOR® Adult pump with BL provides pulsatile high cardiac output with excellent outcome and successful bridging to HTx, particularly in critically ill patients with INTERMACS level 1 or 2 at the time of implantation.

Closing the gap in paediatric ventricular assist device therapy with the Berlin Heart EXCOR® 15-ml pump.

OBJECTIVES: The Berlin Heart EXCOR ® (EXCOR) paediatric ventricular assist device is used worldwide for mechanical support of infants and small children with end-stage heart failure. A clinically important gap between the smallest EXCOR blood pump (10 ml) and the next larger size (25 ml) limited the choice of pump size in patients with a body surface area (BSA) between 0.33 and 0.5 m 2 . We present the first clinical experience from the early product surveillance (EPS) of the new EXCOR 15-ml blood pump. METHODS: After CE and U.S. Food and Drug Administration approval in January 2013, 20 patients with a mean age of 1.6 years (range 0.5-3.5 years) and a mean BSA of 0.45 m 2 (range 0.33-0.59 m 2 ) were enrolled in the EPS. The main diagnosis was idiopathic cardiomyopathy in 13 patients; the majority ( n = 16) of children were in INTERMACS level 1 or 2. Data from high-volume paediatric transplant centres were collected prospectively for a defined follow-up period of 60 days after device implantation. RESULTS: Mean time on the EXCOR 15-ml blood pump was 43 days; the survival rate was 100% at the end of the EPS period. Seven patients underwent a heart transplant from the device; 2 children were weaned; and 11 patients remained on support. Infection of cannula exit sites occurred in 3 patients. Two patients had minor thromboembolic strokes but made a complete neurological recovery. CONCLUSIONS: The new EXCOR 15-ml blood pump demonstrated optimal ventricular assist device support of children with a BSA of 0.33-0.5 m 2 .

Clinical Durability of the CARMEDA BioActive Surface in EXCOR Ventricular Assist Device Pumps.

The durability of CBAS Heparin Surface on EXCOR pumps retrieved after clinical use for varying periods of time was studied by analyzing samples for surface heparin density and bioactivity. The mean time of clinical use of the investigated 14 EXCOR pumps was 178 days (range, 15-461 days). Mean heparin density was 3.1 ± 0.6 µg/cm² (range, 2.2-4.8 µg/cm²), and the measured mean heparin bioactivity was 14 ± 5 ρmol/cm² (range: 7-27 ρmol/cm²). There was no detectable degradation or loss of function of CBAS Heparin Surface over time. Samples from the housing and the membrane of the EXCOR pump showed no significant difference in heparin bioactivity or density. The CBAS Heparin Surface stays on the surface and remains bioactive on the EXCOR pump at least up until 1 year. This is an important demonstration of coating durability and supports the mid-term and long-term clinical use as bridge-to-heart transplantation or to myocardial recovery.

Cyclin-dependent kinase 6 phosphorylates NF-κB P65 at serine 536 and contributes to the regulation of inflammatory gene expression.

Nuclear factor kappa-B (NF-κB) activates multiple genes with overlapping roles in cell proliferation, inflammation and cancer. Using an unbiased approach we identified human CDK6 as a novel kinase phosphorylating NF-κB p65 at serine 536. Purified and reconstituted CDK6/cyclin complexes phosphorylated p65 in vitro and in transfected cells. The physiological role of CDK6 for basal as well as cytokine-induced p65 phosphorylation or NF-κB activation was revealed upon RNAi-mediated suppression of CDK6. Inhibition of CDK6 catalytic activity by PD332991 suppressed activation of NF-κB and TNF-induced gene expression. In complex with a constitutively active viral cyclin CDK6 stimulated NF-κB p65-mediated transcription in a target gene specific manner and this effect was partially dependent on its ability to phosphorylate p65 at serine 536. Tumor formation in thymi and spleens of v-cyclin transgenic mice correlated with increased levels of p65 Ser536 phosphorylation, increased expression of CDK6 and upregulaton of the NF-κB target cyclin D3. These results suggest that aberrant CDK6 expression or activation that is frequently observed in human tumors can contribute through NF-κB to chronic inflammation and neoplasia.

Curcumin blocks interleukin-1 (IL-1) signaling by inhibiting the recruitment of the IL-1 receptor-associated kinase IRAK in murine thymoma EL-4 cells.

Curcumin is a dietary compound with diverse anti-inflammatory and anticarcinogenic effects in several experimental models. A mechanism by which curcumin exerts these actions might be the direct modification of protein thiols, thereby altering the activity of the affected proteins. An early event in inflammatory signaling cascades is the recruitment of the interleukin-1 (IL-1) receptor-associated kinase (IRAK) to the IL-1 receptor (IL-1RI) upon stimulation with IL-1. IRAK recruitment was shown recently to be inhibited by agents that modify thiols of IRAK. We asked, therefore, whether IRAK is also a target for curcumin. Curcumin indeed blocked IRAK thiols in a murine T-cell line stably overexpressing IRAK (EL-4(IRAK)), which resulted in the inhibition of IRAK recruitment to the IL-1RI and phosphorylation of IRAK and IL-1RI-associated proteins. Inhibitory effects were not reversible by thiol-reducing agents. Thus, modification by curcumin did not occur by oxidation but rather by alkylation, as is typical for electrophilic compounds reacting as Michael addition acceptors. The block in one of the earliest events in the IL-1 signaling cascade can explain the often observed inhibition of IL-1-mediated signaling steps by curcumin further downstream. Hence, thiol modification might be a crucial step in the anti-inflammatory functions of curcumin.

Cellular trafficking of the IL-1RI-associated kinase-1 requires intact kinase activity.

Upon stimulation of cells with interleukin-1 (IL-1) the IL-1 receptor type I (IL-1RI) associated kinase-1 (IRAK-1) transiently associates to and dissociates from the IL-1RI and thereafter translocates into the nucleus. Here we show that nuclear translocation of IRAK-1 depends on its kinase activity since translocation was not observed in EL-4 cells overexpressing a kinase negative IRAK-1 mutant (EL-4(IRAK-1-K239S)). IRAK-1 itself, an endogenous substrate with an apparent molecular weight of 24kDa (p24), and exogenous substrates like histone and myelin basic protein are phosphorylated by nuclear located IRAK-1. Phosphorylation of p24 cannot be detected in EL-4(IRAK-1-K239S) cells. IL-1-dependent recruitment of IRAK-1 to the IL-1RI and subsequent phosphorylation of IRAK-1 is a prerequisite for nuclear translocation of IRAK-1. It is therefore concluded that intracellular localization of IRAK-1 depends on its kinase activity and that IRAK-1 may also function as a kinase in the nucleus as shown by a new putative endogenous substrate.

Recruitment of the interleukin-1 receptor (IL-1RI)-associated kinase IRAK to the IL-1RI is redox regulated.

Interleukin-1 signaling is initiated by recruitment of adapter proteins and kinases to the type I interleukin-1 receptor (IL-1RI). It is modulated by accompanying redox processes at various levels, such as (auto-) phosphorylation of the IL-1RI-associated kinase IRAK, the phosphorylation of IkappaB and translocation and transcriptional activity of NF-kappaB. Here we demonstrate that the thiol-modifying agents diamide, menadione, and phenylarsine oxide (PAO) block the recruitment of IRAK to the receptor without inhibiting kinase activity in the immunoprecipitated IL-1RI complex in the human epithelial cell line ECV304 and the murine T cell line EL-4. Inhibition of IRAK receptor association by menadione is reversible in a GSH-dependent manner, while the PAO effect proved to be irreversible. Phospholipid hydroperoxide glutathione peroxidase attenuates inhibition by menadione. Recruitment correlates with the presence of thiol groups in IRAK that were available for IAIT-labeling. We conclude that recruitment of IRAK to the IL-1RI is redox regulated by the glutathione system, a reduced status being a prerequisite for an appropiate IL-1 response.