Cardiopulmonary bypass (CPB) systems without a venous reservoir rarely are adopted clinically. The effects of a biocompatible CPB system with a venous reservoir were evaluated on the activation of the coagulation and inflammatory systems. DESIGN: A prospective, randomized controlled trial. SETTING: A university hospital (single center). PARTICIPANTS: Eighty-three coronary artery bypass graft (CABG) surgery patients were assigned to the Physio group (closed venous reservoir, phosphorylcholine coating, and no cardiotomy suction) or the Standard group (open, noncoated, and cardiotomy suction used). METHODS: Blood samples were obtained at 6 different time points before, during, and after surgery. Nuclear factor-kB (NF-κB) was evaluated before surgery and 2 and 24 hours after surgery. Myocardial damage was evaluated measuring cardiac troponin I. MEASUREMENTS AND MAIN RESULTS: Interleukin (IL)-6 (a marker of inflammation), prothrombin fragment 1-2 (PF-1.2, a marker of thrombin generation), plasmin-antiplasmin complex (PAP, a marker of fibrinolysis), and platelet factor 4 (PF4, a marker of platelet activation) were measured. The DNA binding activity of proinflammatory transcription factor NF-κB was quantified in the isolated lymphomonocyte cells. Surgery caused changes of all plasma biomarkers. This reaction was attenuated strongly in the Physio group; PF-1.2, PAP, and PF4 all were decreased significantly. In the Physio group, a significantly lower cardiac troponin I release was observed postoperatively. After surgery, NF-κB activity was reduced in the Physio group although this difference was not statistically significant. CONCLUSIONS: A multimodal strategy using a closed and phosphorylcholine-coated CPB circuit together with the avoidance of cardiotomy suction reduced activation of the coagulation and fibrinolytic systems intraoperatively, although these changes did not persist postoperatively. However, no difference in clinical outcome was appreciated on a larger scale.

Antithrombin (AT) concentrations are reduced after cardiac surgery with cardiopulmonary bypass compared with the preoperative levels. Low postoperative AT is associated with worse short- and mid-term clinical outcomes. The aim of the study is to evaluate the effects of AT administration on activation of the coagulation and fibrinolytic systems, platelet function, and the inflammatory response in patients with low postoperative AT levels. METHODS: Sixty patients with postoperative AT levels of less than 65% were randomly assigned to receive purified AT (5000 IU in three administrations) or placebo in the postoperative intensive care unit. Thirty patients with postoperative AT levels greater than 65% were observed as controls. Interleukin 6 (a marker of inflammation), prothrombin fragment 1-2 (a marker of thrombin generation), plasmin-antiplasmin complex (a marker of fibrinolysis), and platelet factor 4 (a marker of platelet activation) were measured at six different times. RESULTS: Compared with the no AT group and control patients, patients receiving AT showed significantly higher AT values until 48 hours after the last administration. Analysis of variance for repeated measures showed a significant effect of study treatment in reducing prothrombin fragment 1-2 (p = 0.009; interaction with time sample, p = 0.006) and plasmin-antiplasmin complex (p < 0.001; interaction with time sample, p < 0.001) values but not interleukin 6 (p = 0.877; interaction with time sample, p = 0.521) and platelet factor 4 (p = 0.913; interaction with time sample, p = 0.543). No difference in chest tube drainage, reopening for bleeding, and blood transfusion was observed. CONCLUSIONS: Antithrombin administration in patients with low AT activity after surgery with cardiopulmonary bypass reduces postoperative thrombin generation and fibrinolysis with no effects on platelet activation and inflammatory response.

Background/Objectives Calcific aortic valvular disease (CAVD) is an actively regulated process characterized by the activation of specific osteogenic signaling pathways and apoptosis. We evaluated the involvement in CAVD of the TNF-related apoptosis-inducing ligand (TRAIL), an apoptotic molecule which induces apoptosis by interacting with the death receptor (DR)-4 and DR5, and whose activity is modulated by the decoy receptor (DcR)-1 and DcR2. Methods Sections of calcific and normal aortic valves, obtained at surgery time, were subjected to immunohistochemistry and confocal microscopy for TRAIL immunostaining. Valvular interstitial cells (VICs) isolated from calcific (C-VICs) and normal (N-VICs) aortic valves were investigated for the gene and protein expression of TRAIL receptors. Cell viability was assayed by MTT. Von Kossa staining was performed to verify C-VIC ability to produce mineralized nodules. TRAIL serum levels were detected by ELISA. Results Higher levels of TRAIL were detected in calcific aortic valves and in sera from the same patients respect to controls. C-VICs express significantly higher mRNA and protein levels of DR4, DR5, DcR1, DcR2 and Runx2 compared to N-VICs. C-VICs and N-VICs, cultured in osteogenic medium, express significantly higher mRNA levels of DR4, Runx2 and Osteocalcin compared to baseline. C-VICs and N-VICs were sensitive to TRAIL-apoptotic effect at baseline and after osteogenic differentiation, as demonstrated by MTT assay and caspase-3 activation. TRAIL enhanced mineralized matrix nodule synthesis by C-VICs cultured in osteogenic medium. Conclusions TRAIL is characteristically present within calcific aortic valves, and mediates the calcification of aortic valve interstitial cells in culture through mechanism involving apoptosis.

OBIETTIVI La mortalità nei pazienti affetti da endocardite infettiva (EI) è tutt’oggi ancora elevata (20%), essendo le cause di morte non solo strettamente cardiache, ma anche dovute frequentemente allo stato settico ed all’interessamento multi-organo per i possibili fenomeni embolici associati. Quest’ultima evenienza in letteratura supera il 40%. Peraltro le attuali linee guida inoltre non forniscono raccomandazioni per uno screening sistematico di embolia settica. Inoltre la frequente embolizzazione a livello della milza, con evoluzione in infarto semplice o in ascesso splenico, mentre comporta terapia conservativa nel primo caso, prevede la splenectomia nella forma ascessuale a causa dell’alta incidenza in questi casi di rottura della milza e di setticemia diffusa. La diagnosi differenziale delle due forme rimane tuttavia ancora oggi difficile. Scopo principale dello studio è stato quello di individuare l'incidenza di embolizzazione splenica nella EI; ulteriori obiettivi sono stati quello di differenziare l'infarto dall'ascesso splenico con le più attuali tecniche diagnostiche, ed infine determinare momento e condotta ottimali della terapia chirurgica combinata. METODI Sono stati studiati 55 pazienti operati consecutivamente nel nostro centro per EI dal gennaio 2011 al marzo 2014. E’ stata eseguita in tutti i casi TAC total-body che dimostrava embolizzazione splenica in 22 pazienti; questi ultimi sono stati sottoposti ad eco-contrastografia ad alta definizione della milza. Tale esame evidenziava la presenza di ascesso in 15 pazienti nei quali è stata eseguita la splenectomia, mentre nei restanti 7, nei quali l’esame dimostrava infarto semplice, la milza non è stata rimossa. La splenectomia è stata eseguita sempre nella stessa seduta operatoria, subito dopo l'intervento cardiochirurgico. Nello studio sono stati considerati due gruppi: 1°) pazienti sottoposti a chirurgia cardiaca isolata (40 pazienti), e 2°) pazienti sottoposti ad intervento combinato cardiaco e splenectomia (15 pazienti). E' stato eseguito follow-up telefonico. RISULTATI L'esecuzione sistematica da noi adottata della TAC total-body ha documentato un'incidenza di embolia della milza (39%) sovrapponibile a quella presente in letteratura. Peraltro, l'uso sistematico della contrasto-ecografia ad alta definizione in pazienti con embolizzazione splenica ha documentato un'incidenza di ascesso splenico molto più alta nel nostro studio (27,3%), rispetto a quella riscontrata in letteratura (5%). Le caratteristiche pre-, peri- e post-operatorie sono state sovrapponibili a quelle della letteratura. Mortalità ospedaliera, degenza in terapia intensiva e degenza totale del soggiorno in ospedale non hanno mostrato differenze significative tra i due gruppi. La degenza non ha mai superato i 30 giorni. Abbiamo riscontrato tre decessi nel follow-up. CONCLUSIONI L'alta incidenza di embolizzazione in corso di EI rende obbligatoria una ricerca sistematica di questa eventualità mediante TAC total-body. In caso di embolizzazione splenica l’eco-contrastografia ad alta definizione è molto utile per la diagnosi differenziale tra infarto ed ascesso splenico e quindi per porre in tal caso indicazione alla rimozione della milza. La simultaneità delle due procedure, cardiochirurgica e splenectomia, non comporta differenze significative nella mortalità e morbilità rispetto all'intervento isolato di chirurgia cardiaca.

Increased apoptosis of cardiac progenitor cells (CPCs) has been proposed as a mechanism of myocardial damage and dysfunction. Glucagon-like peptide-1 (GLP-1) has been shown to improve heart recovery and function after ischemia and to promote cell survival. The protective effects of GLP-1 on oxidative stress-induced apoptosis were investigated in human CPCs isolated from human heart biopsies. Mesenchymal-type cells were isolated from human heart biopsies, exhibited the marker profile of CPCs, differentiated toward the myocardiocyte, adipocyte, chondrocyte, and osteocyte lineages under appropriate culture conditions, and expressed functional GLP-1 receptors. CPCs were incubated with GLP-1 with or without hydrogen peroxide (H(2)O(2)). Phospho- and total proteins were detected by immunoblotting and immunofluorescence analysis. Gene expression was evaluated by quantitative RT-PCR. The role of the canonical GLP-1 receptor was assessed by using the receptor antagonist exendin(9-39) and receptor-specific silencer small interfering RNAs. Cell apoptosis was quantified by an ELISA assay and by flow cytometry-detected Annexin V. Exposure of CPCs to H(2)O(2) induced a 2-fold increase in cell apoptosis, mediated by activation of the c-Jun N-terminal protein kinase (JNK) pathway. Preincubation of CPCs with GLP-1 avoided H(2)O(2)-triggered JNK phosphorylation and nuclear localization, and protected CPCs from apoptosis. The GLP-1 effects were markedly reduced by coincubation with the receptor antagonist exendin(9-39), small interfering RNA-mediated silencing of the GLP-1 receptor, and pretreatment with the protein kinase A inhibitor H89. In conclusion, activation of GLP-1 receptors prevents oxidative stress-mediated apoptosis in human CPCs by interfering with JNK activation and may represent an important mechanism for the cardioprotective effects of GLP-1.

Background. Anemia is a risk factor for adverse events after cardiac operations. We evaluated the incremental value of preoperative anemia over the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II to predict hospital death after cardiac operations. Methods. Data for 4,594 consecutive adults (1,548 women [33.7%]), aged 67 ± 11 years, who underwent cardiac operations from January 2011 to July 2013 were extracted from the Regional Cardiac Surgery Registry of Puglia. The last preoperative hemoglobin value was used, according to World Health Organization criteria, to classify anemia as mild (hemoglobin 11.0 to 12.9 g/dL in men and 11.0 to 11.9 g/dL in women) in 1,021 patients (22.2%) and as moderate to severe (hemoglobin <11.0 g/dL) in 593 patients (12.9%). The EuroSCORE II was used to evaluate predicted hospital death after operations. Logistic regression analysis for in-hospital death was performed including EuroSCORE II risk factors and anemia, with model discrimination quantified by C statistic and risk classification by the use of net reclassification improvement (NRI). Results. Overall expected and observed mortality rates were 4.4% and 5.9%. Anemia was significantly associated with a mortality rate of 3.4% in patients without anemia, 7.7% in mild anemia, and 15.7% in moderate to severe anemia (p < 0.001) and also at multivariate analysis correcting for EuroSCORE II (p < 0.001). When anemia was analyzed with EuroSCORE II, the model improved in discrimination (C statistic = 0.852 vs 0.860; p = 0.007) and reclassification (category free-NRI, 0.592; p < 0.001), preserving the calibration with good concordance between predicted probabilities and outcome. Conclusions. Preoperative anemia has strong association with operative death in cardiac surgical patients. Anemia provides significant incremental value over the EuroSCORE II and should be considered for assessment of cardiac surgical risk

Background ST2 is a member of the interleukin-1 receptor family that is markedly upregulated in cultured cardiomyocytes subjected to mechanical strain. Serum soluble ST2 (sST2) levels can be detected in patients with acute myocardial infarction and severe chronic heart failure. This study sought to assess for the first time the activation of the ST2 pathway in patients with severe chronic degenerative mitral regurgitation. Materials and Methods Serum sST2 levels were measured in 20 patients scheduled for mitral valve (MV) repair at baseline, at the end of the intervention, on postoperative day 1, at hospital discharge, and after 6 months. Patients also underwent measurement of N-terminal pro-brain natriuretic peptide and echocardiographic evaluation at each time point. Results At baseline, sST2 was detected in 10 (50%) patients (mean value, 60 ± 74 pg/mL; range, 0-234 pg/mL; median, 8 pg/mL). MV repair was performed successfully in all patients. Cardiac surgery with cardiopulmonary bypass was associated with a rapid and transient increase in sST2 levels. Patients with baseline higher versus lower sST2 levels (≥ 8 vs. < 8 pg/mL) had significantly higher levels of sST2 on postoperative day 1 (1,050 ± 593 vs. 440 ± 312 pg/mL; p = 0.009). At follow-up, patients with preoperative sST2 ≥ 8 pg/mL had significantly higher ejection fraction (EF) (64.7 ± 5.8 vs. 57.6 ± 5.9; p = 0.03) and lower left ventricular end-diastolic diameter (LVEDD) (50.6 ± 5.8 vs. 56 ± 4.2; p = 0.03) compared with patients with preoperative sST2 < 8 pg/mL. Conclusion Preoperative ST2 activation, evidenced by the presence of serum sST2 levels, is present in half of the patients with chronic degenerative mitral regurgitation and is associated with higher levels of EF and lower levels of LVEDD after MV repair.

OBJECTIVES: The occurrence of intra-abdominal hypertension (IAH), as well as its promoting factors in cardiac surgery, has been poorly explored. The aim of the present study was to characterize intra-abdominal pressure (IAP) variations in patients undergoing cardiac surgical procedures, and to identify the risk factors for IAH in this setting. METHODS: All consecutive adult patients requiring postoperative intensive care unit admission for >24 h were enrolled. Demographic data, pre-existing comorbidities, type and duration of surgery, cardiopulmonary bypass (CPB) use and duration, perioperative IAP, organ function and fluid balance were recorded. IAH was defined as a sustained increase in IAP >12 mmHg. Multivariate logistic regression and stepwise analyses identified the baseline and perioperative variables associated with IAH. RESULTS: Of 69 patients, 22 (31.8%) developed IAH. In the logistic model, baseline IAP, high central venous pressure, vasoactive drugs administration, positive fluid balance, AKI, CPB, total sequential organ failure assessment score and age were all promoting factors for IAH (Hosmer-Lemeshow ÷2 = 7.23; P = 0.843). Baseline IAP, high central venous pressure and positive fluid balance were independent risk factors for IAH in the stepwise analysis. The ROC curve analysis, obtained by plotting the occurrence of IAH vs the IAP baseline value, showed an AUC of 0.75 (SE 0.064; 99% CI 0.62-0.87; P < 0.0001). The best IAP cut-off value was at 8 mmHg (sensitivity 63% and specificity 76%). Considering on- and off-pump surgery groups, fluid balance and vasoactive drugs use were significantly higher in the on-pump group. Linear regression analysis showed a positive correlation (P = 0.0001) between IAP changes and fluid balance only in the on-pump group. CONCLUSIONS: IAH develops in one-third of cardiac surgery patients and is strongly associated with higher baseline IAP values, higher central venous pressure, positive fluid balance, extracorporeal circulation, use of vasoactive drugs and AKI. Determinants of IAH should be accurately assessed before and after surgery, and patients presenting risk factors must be monitored properly during the perioperative period. In this context, the baseline value of IAP may be a valuable and early warning parameter for IAH occurrence. © 2013 The Author. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Objectives: A systematic review of the European System for Cardiac Operative Risk Evaluation (euroSCORE) II performance for prediction of operative mortality after cardiac surgery has not been performed. We conducted a meta-analysis of studies based on the predictive accuracy of the euroSCORE II. Methods: We searched the Embase and PubMed databases for all English-only articles reporting performance characteristics of the euroSCORE II. The area under the receiver operating characteristic curve, the observed/ expected mortality ratio, and observed-expected mortality difference with their 95% confidence intervals were analyzed. Results: Twenty-two articles were selected, including 145,592 procedures. Operative mortality occurred in 4293 (2.95%), whereas the expected events according to euroSCORE II were 4802 (3.30%). Meta-analysis of these studies provided an area under the receiver operating characteristic curve of 0.792 (95% confidence interval, 0.773-0.811), an estimated observed/expected ratio of 1.019 (95% confidence interval, 0.899-1.139), and observed-expected difference of 0.125 (95% confidence interval, 0.269 to 0.519). Statistical heterogeneity was detected among retrospective studies including less recent procedures. Subgroups analysis confirmed the robustness of combined estimates for isolated valve procedures and those combined with revascularization surgery. A significant overestimation of the euroSCORE II with an observed/expected ratio of 0.829 (95% confidence interval, 0.677-0.982) was observed in isolated coronary artery bypass grafting and a slight underestimation of predictions in high-risk patients (observed/expected ratio 1.253 and observed-expected difference 1.859). Conclusions: Despite the heterogeneity, the results from this meta-analysis show a good overall performance of the euroSCORE II in terms of discrimination and accuracy of model predictions for operative mortality. Validation of the euroSCORE II in prospective populations needs to be further studied for a continuous improvement of patients' risk stratification before cardiac surgery.

Objective: Cardiac surgery and cardiopulmonary bypass (CPB) induce an acute inflammatory response contributing to postoperative morbidity. The use of steroids as anti-inflammatory agents in surgery using CPB has been tested in many trials and has been shown to have good anti-inflammatory effects but no clear clinical advantages for the lack of an adequately powered sample size. The aim of this study was to evaluate the effects of steroid treatment on mortality and morbidity after cardiac surgery. Design: A systematic meta-analysis of randomized double-blind trials (RDBs). Setting: A university hospital. Participants: Adult patients who underwent cardiac surgery. Measurements and Main Results: A trial search was performed through PubMed and Cochrane databases from 1966 to January 2009. Among 104 clinical trials reviewed, 31 RDB trials (1,974 patients) were considered suitable to be analyzed. A quality assessment of the trials was performed using the Jadad score. The types of steroid used in these trials were methylprednisolone (51.4%), dexamethasone (34.3%), hydrocortisone (5.7%), prednisolone (2.9%), or a combination of methylprednisolone and dexamethasone (5.7%). Steroid prophylaxis provided a protective effect preventing postoperative atrial fibrillation (odds ratio = 0.56; confidence interval [CI] 0.44-0.72, p < 0.0001), reducing postoperative blood loss (mean difference = -204.2 mL; CI from -287.4 to -121 mL; p < 0.0001), and reducing intensive care unit (mean difference = -6.6 hours; CI from -10.5 to -2.7 hours, p = 0.0007) and overall hospital stay (mean difference = -0.8 days; CI from -1.4 to -0.2 days, p = 0.01). Steroid prophylaxis had no effect on postoperative mortality, mechanical ventilation duration, re-exploration for bleeding, and postoperative infection. Conclusions: A systematic review of RDB trials reveals that steroid prophylaxis may reduce morbidity after cardiac surgery and does not increase the risk of postoperative infections.

Cell saving systems are commonly used during cardiac operations to improve hemoglobin levels and to reduce blood product requirements. We analyzed the effects of residual pump blood salvage through a cell saver on coagulation and fibrinolysis activation and on postoperative hemoglobin levels. Thirty-four elective coronary artery bypass graft (CABG) patients were randomized. In 17 patients, residual cardiopulmonary bypass (CPB) circuit blood was transfused after the cell saving procedure (cell salvage group). In the other 17 patients, residual CPB circuit blood was discarded (control group). Activation of the coagulative, fibrinolytic and inflammatory systems was evaluated pre-operatively (Pre), 2 hours after the termination of CPB (T0) and 24 hours postoperatively (T1), measuring prothrombin fragment 1.2 (PF 1.2), plasmin-anti-plasmin (PAP), plasminogen activator inhibitor-1 (PAI-1) and interleukin-6 (IL-6). The cell salvage group of patients had a significant improvement in hemoglobin levels after processed blood infusion (2.7 ± 1.7 g/dL vs 1.2 ± 1.1 g/dL; p=0.003). PF1.2 levels were significantly higher after infusion (T0: 1175 ± 770 pmol/L vs 730 ± 237 pmol/L; p=0.037; T1: 331 ± 235 pmol/L vs 174 ± 134 pmol/L; p=0.026). Also, PAP levels were higher in the cell salvage group, although not significantly (T0: 253 ± 251 ng/mL vs 168 ± 96 ng/mL; p: NS; T1: 95 ± 60 ng/mL vs 53 ± 32 ng/mL; p: NS). No differences were found for PAI-1, IL-6, heparin levels or for red blood cell (RBC) transfusions. The cell salvage group of patients had increased chest tube drainage (749 ± 320 vs 592 ± 264; p: NS) and fresh frozen plasma transfusion rate (5 (29%) pts vs 0 pts; p&lt;0.04). Pump blood salvage with a cell saving system improved postoperative hemoglobin levels, but induced a strong thrombin generation, fibrinolysis activation and lower fibrinolysis inhibition. These conditions could generate a consumption coagulopathy.

Calcific aortic valve disease (CAVD) represents a slowly progressive pathologic process associated with major morbidity and mortality. The process is characterized by multiple steps: inflammation, fibrosis, and calcification. Numerous studies focalised on its physiopathology highlighting different “actors” for the multiple “acts”. This review focuses on the role of the tumor necrosis factor superfamily (TNFSF) members in the pathogenesis of CAVD. In particular we discuss on clinical and experimental studies providing evidence of the involvement of tumor necrosis factor alpha (TNF-α), receptor activator of nuclear factor kappa-B (NF-kB) ligand (RANKL), its membrane receptor RANK and its decoy receptor osteoprotegerin (OPG), and TNF-related apoptosis-inducing ligand (TRAIL) in valvular calcification.