The inflammatory responsiveness of phagocytes to exogenous and endogenous stimuli is tightly regulated. This regulation plays an important role in systemic inflammatory response syndromes (SIRSs). In SIRSs, phagocytes initially develop a hyperinflammatory response, followed by a secondary state of hyporesponsiveness, a so-called “tolerance.” This hyporesponsiveness can be induced by endotoxin stimulation of Toll-like receptor 4 (TLR4), resulting in an ameliorated response after subsequent restimulation. This modification of inflammatory response patterns has been described as innate immune memory. Interestingly, tolerance can also be triggered by endogenous TLR4 ligands, such as the alarmins myeloid-related protein 8 (MRP8, S100A8) and MRP14 (S100A9), under sterile conditions. However, signaling pathways that trigger hyporesponsiveness of phagocytes in clinically relevant diseases are only barely understood. Through our work, we have now identified 2 main signaling cascades that are activated during MRP-induced tolerance of phagocytes. We demonstrate that the phosphatidylinositol 3-kinase/AKT/GSK-3β pathway interferes with NF-κB–driven gene expression and that inhibition of GSK-3β mimics tolerance in vivo. Moreover, we identified interleukin-10–triggered activation of transcription factors STAT3 and BCL-3 as master regulators of MRP-induced tolerance. Accordingly, patients with dominant-negative STAT3 mutations show no tolerance development. In a clinically relevant condition of systemic sterile stress, cardiopulmonary bypass surgery, we confirmed the initial induction of MRP expression and the tolerance induction of monocytes associated with nuclear translocation of STAT3 and BCL-3 as relevant mechanisms. Our data indicate that the use of pharmacological JAK-STAT inhibitors may be promising targets for future therapeutic approaches to prevent complications associated with secondary hyporesponsiveness during SIRS.

This study provides early results of re-operations after the prior surgical treatment of acute type A aortic dissection (AAD) and identifies risk factors for mortality. Between May 2003 and January 2014, 117 aortic re-operations after an initial operation for AAD (a mean time from the first procedure was 3.98 years, with a range of 0.1-20.87 years) were performed in 110 patients (a mean age of 59.8 ± 12.6 years) in seven European institutions. The re-operation was indicated due to a proximal aortic pathology in ninety cases: twenty aortic root aneurysms, seventeen root re-dissections, twenty-seven aortic valve insufficiencies and twenty-six proximal anastomotic pseudoaneurysms. In fifty-eight cases, repetitive surgical treatment was subscripted because of distal aortic pathology: eighteen arch re-dissections, fifteen arch dilation and twenty-five anastomotic pseudoaneurysms. Surgical procedures comprised a total of seventy-one isolated proximals, thirty-one isolated distals and fifteen combined interventions. In-hospital mortality was 19.6 % (twenty-three patients); 11.1 % in patients with elective/urgent indication and 66.6 % in emergency cases. Mortality rates for isolated proximal, distal and combined operations regardless of the emergency setting were 14.1 % (10 pts.), 25.8 % (8 pts.) and 33.3 % (5 pts.), respectively. The causes of death were cardiac in eight, neurological in three, MOF in five, sepsis in two, bleeding in three and lung failure in two patients. A multivariate logistic regression analysis revealed that risk factors for mortality included previous distal procedure (p = 0.04), new distal procedure (p = 0.018) and emergency operation (p < 0.001). New proximal procedures were not found to be risk factors for early mortality (p = 0.15). This multicenter experience shows that the outcome of REAAD is highly dependent on the localization and extension of aortic pathology and the need for emergency treatment. Surgery in an emergency setting and distal re-do operations after previous AAD remain a surgical challenge, while proximal aortic re-operations show a lower mortality rate. Foresighted decision-making is needed in cases of AAD repair, as the results are essential preconditions for further surgical interventions.

Heparin-induced thrombocytopenia (HIT) is a rare but life-threatening side effect of heparin therapy. It is a demanding therapeutic challenge in patients undergoing left ventricular assist device (LVAD) implantation. We present our experience with LVAD implantation under extracorporeal life support (ECLS) in patients suffering from HIT. Seven patients (mean age 54.0 ± 16.7 years, 1 female, 6 male patients) suffering from acute heart failure were stabilized with ECLS. Under heparin therapy, they all showed a sudden decrease of mean platelet count (maximum 212.6 ± 41.5 tsd/μl; minimum 30.7 ± 13.1 tsd/μl). Due to the clinical suspicion of HIT anticoagulation was switched from heparin to argatroban (aPTT 70-80 s.). No improvement of cardiac function could be detected under ECLS, so LVAD implantation was indicated. We performed LVAD implantation under ECLS. During LVAD implantation under argatroban (aPTT of 50-60 s.) one patient developed massive intraventricular thrombus formations, so the device had to be removed. In 6 cases, we could successfully perform LVAD implantation under argatroban with a higher aPTT of 70-80 s and modified operative strategy. Four patients needed postoperative re-exploration because of bleeding complications. Perioperative management of LVAD patients under argatroban anticoagulation is very difficult. We were able to minimize the perioperative risk for thrombosis with a target aPTT of 70-80 s. To keep the phase of stasis within the device as short as possible we anastomosed the VAD outflow graft to the ascending aorta first before connecting the device to the apex. However, postoperative bleeding complications are frequent.

Partial upper sternotomy is a feasible access for safe aortic root replacement with valved conduits. Nevertheless, minimally invasive aortic root replacement is a challenging operative procedure.

Direct cannulation of the right axillary artery can lead to cerebral malperfusion, caused by an obstruction of the vertebral artery's orifice by the arterial cannula or a subclavian steal phenomenon due to flow reversal. The safety of direct axillary artery cannulation can be improved by a well-considered dissecting site and insertion length of the cannula.