Enzymatic activity of extracellular circulating proteasome in the CSF of patients with malignant Intrinsic and metastatic brain tumors: proof of concept.

BACKGROUND: Malignant intrinsic brain tumors are a hazardous disease with limited life expectancy despite intensive research in new targeted treatment options. Lately, proteasome inhibitors have been identified as potent agents causing death in glioma cell lines. It is the aim of the present study to identify proteasomal activity in the CSF of patients suffering from malignant brain tumors. METHODS: A total of 24 patients with histological confirmed brain tumors (12 malignant gliomas, 12 metastases) were included and CSF probes preoperatively analyzed for concentration and enzymatic activity of free circulating proteasome. Tumor volumina were assessed using the preoperative MRI and correlated with the CSF findings. Statistical analyses were performed using SPSS (18.0.3; SPSS Inc., Chicago, IL, USA). RESULTS: Extracellular proteasomes were found in all CSF samples showing enzymatic activity. Proteasome concentrations (28 ng/mL and 23 ng/mL, resp.) were elevated compared to a historical control group. Proteasomal enzymatic chymotrypsin-like activity was significantly raised in patients with gliomas (mean 31 fkat/ mL) compared to controls (P<0.049), whereas the enzymatic activity was not significantly elevated in metastases (P=0.109). In gliomas, neither concentration nor enzymatic activity correlated with the preoperative assessed tumor volume. CONCLUSIONS: This pilot study clearly showed that the proteasomal activity in the CSF is significantly elevated in patients with intrinsic brain tumors. Further studies need to identify the proteasomal concentration and enzymatic activity as a potential biomarker for the effectiveness of any treatment and for the early diagnosis of a possible recurrence of the disease.

Validation of days alive and out of hospital as a new patient-centered outcome to quantify life impact after heart transplantation.

The number of patients waiting for heart transplantation (HTX) is increasing. Thus, identification of outcome-relevant factors is crucial. This study aimed to identify perioperative factors associated with days alive and out of hospital (DAOH)-a patient-centered outcome to quantify life impact-after HTX. This retrospective cohort study screened 187 patients who underwent HTX at university hospital Duesseldorf, Germany from September 2010 to December 2020. The primary endpoint was DAOH at 1 year. Risk factors for mortality after HTX were assessed in univariate analysis. Variables with significant association were entered into multivariable quantile regression. In total, 175 patients were included into analysis. Median DAOH at 1 year was 295 (223-322) days. In univariate analysis the following variables were associated with reduced DAOH: recipient or donor diabetes pre-HTX, renal replacement therapy (RRT), VA-ECMO therapy, recipient body mass index, recipient estimated glomerular filtration rate (eGFR) and postoperative duration of mechanical ventilation. After adjustment, mechanical ventilation, RRT, eGFR and recipient diabetes showed significant independent association with DAOH. This study identified risk factors associated with reduced DAOH at 1-year after HTX. These findings might complement existing data for outcome of patients undergoing HTX.

Impact of Cardiopulmonary Resuscitation of Donors on Days Alive and Out of Hospital after Orthotopic Heart Transplantation.

BACKGROUND: The number of patients waiting for heart transplantation (HTX) is increasing. Optimizing the use of all available donor hearts is crucial. While mortality seems not to be affected by donor cardiopulmonary resuscitation (CPR), the impact of donor CPR on days alive and out of hospital (DAOH) is unclear. METHODS: This retrospective study included adults who underwent HTX at the University Hospital Duesseldorf, Germany from 2010-2020. Main exposure was donor-CPR. Secondary exposure was the length of CPR. The primary endpoint was DAOH at one year. RESULTS: A total of 187 patients were screened and 171 patients remained for statistical analysis. One-year mortality was 18.7%. The median DAOH at one year was 295 days (interquartile range 206-322 days). Forty-two patients (24.6%) received donor-CPR hearts. The median length of CPR was 15 (9-21) minutes. There was no significant difference in DAOH between patients with donor-CPR hearts versus patients with no-CPR hearts (CPR: 291 days (211-318 days) vs. no-CPR: 295 days (215-324 days); p = 0.619). Multivariate linear regression revealed that there was no association between length of CPR and DAOH (unstandardized coefficients B: -0.06, standard error: 0.81, 95% CI -1.65-1.53, p = 0.943). CONCLUSIONS: Donor CPR status and length of CPR are not associated with reduced DAOH at one year after HTX.

Staphylococcus aureus increases platelet reactivity in patients with infective endocarditis.

Thromboembolism is frequent in infective endocarditis (IE). However, the optimal antithrombotic regimen in IE is unknown. Staphylococcus aureus (SA) is the leading cause of IE. First studies emphasize increased platelet reactivity by SA. In this pilot study, we hypothesized that platelet reactivity is increased in patients with SA- IE, which could be abrogated by antiplatelet medication. We conducted a prospective, observatory, single-center cohort study in 114 patients with IE, with four cohorts: (1) SA coagulase positive IE without aspirin (ASA) medication, (2) coagulase negative IE without ASA, (3) SA coagulase positive IE with ASA, (4) coagulase negative IE with ASA. Platelet function was measured by Multiplate electrode aggregometry, blood clotting by ROTEM thromboelastometry. Bleeding events were assessed according to TIMI classification. In ASA-naïve patients, aggregation with ADP was increased with coag. pos. IE (coagulase negative: 39.47 ± 4.13 AUC vs. coagulase positive: 59.46 ± 8.19 AUC, p = 0.0219). This was abrogated with ASA medication (coagulase negative: 42.4 ± 4.67 AUC vs. coagulase positive: 45.11 ± 6.063 AUC p = 0.7824). Aspirin did not increase bleeding in SA positive patients. However, in SA negative patients with aspirin, red blood cell transfusions were enhanced. SA coagulase positive IE is associated with increased platelet reactivity. This could be abrogated by aspirin without increased bleeding risk. The results of this pilot study suggest that ASA might be beneficial in SA coagulase positive IE. This needs to be confirmed in clinical trials.

Days alive and out of hospital after left ventricular assist device implantation.

AIMS: Implantation of left ventricular assist devices (LVADs) as a bridge to transplant or as destination therapy is increasing. The selection of suitable patients and outcome assessment belong to the key challenges. Mortality has traditionally been a focus of research in this field, but literature on quality of life is very limited. This study aimed to identify perioperative factors influencing patients' life as measured by days alive and out of hospital (DAOH) in the first year after LVAD implantation. METHODS AND RESULTS: This retrospective single-centre cohort study screened 227 patients who underwent LVAD implantation at the University Hospital Duesseldorf, Germany, between 2010 and 2020. First, the influence of 10 prespecified variables on DAOH was investigated by univariate analysis. Second, multivariate quantile regression was conducted including all factors with significant influence on DAOH in the univariate model. Additionally, the impact of all variables on 1 year mortality was investigated using Kaplan-Meier curves to oppose DAOH and mortality. In total, 221 patients were included into analysis. As pre-operative factors, chronic kidney disease (CKD), pre-operative mechanical circulatory support (pMCS), and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) stadium < 3 were associated with lower DAOH at 1 year [CKD: 280 (155-322) vs. 230 (0-219), P = 0.0286; pMCS: 294 (155-325) vs. 243 (0-293), P = 0.0004; INTERMACS 1: 218 (0-293) vs. INTERMACS 2: 264 (6-320) vs. INTERMACS 3: 299 (228-325) vs. INTERMACS 4: 313 (247-332), P ≤ 0.0001]. Intra-operative additional implantation of a right ventricular assist device (RVAD) was also associated with lower DAOH [RVAD: 290 (160-325) vs. 174 (0-277), P ≤ 0.0001]. As post-operative values that were associated with lower DAOH, dialysis and tracheotomy could be identified [dialysis: 300 (252-326) vs. 186 (0-300), P ≤ 0.0001; tracheotomy: 292 (139-325) vs. 168 (0-269), P ≤ 0.0001]. Multivariate analysis revealed that all of these factors besides pMCS were independently associated with DAOH. According to Kaplan-Meier analysis, only post-operative dialysis was significantly associated with increased mortality at 1 year (survival: no dialysis 89.4% vs. dialysis 70.1%, hazard ratio: 0.56, 95% confidence interval: 0.33-0.94; P = 0.031). CONCLUSIONS: The results of this study indicate that there can be a clear discrepancy between hard endpoints such as mortality and more patient-centred outcomes reflecting life impact. DAOH may relevantly contribute to a more comprehensive selection process and outcome assessment in LVAD patients.

Life impact of VA-ECMO due to primary graft dysfunction in patients after orthotopic heart transplantation.

AIMS: Primary graft dysfunction (PGD) is a feared complication after heart transplantation (HTX). HTX patients frequently receive veno-arterial extracorporeal membrane oxygenation (VA-ECMO) until graft recovery. Long-term mortality of patients weaned from VA-ECMO after HTX is comparable with non-ECMO patients. However, impact on quality of life is unknown. This study investigated days alive and out of hospital (DAOH) as patient-centred outcome in HTX patients at 1 year after surgery. METHODS AND RESULTS: This retrospective single-centre cohort study included patients who underwent HTX at the University Hospital Düsseldorf, Germany, from 2010 to 2020. Main exposure was VA-ECMO due to PGD. VA-ECMO and non-VA-ECMO patients were compared regarding the primary endpoint DAOH at 1 year after HTX. Subgroup analysis for patients weaned from VA-ECMO was performed. In total, 144 patients were included into analysis; 1 year mortality was significantly lower in non-ECMO patients [non-ECMO 14.3% (14/98) vs. VA-ECMO 34.8% (16/46), adjusted hazard ratio: 0.32, 95% confidence interval: 0.15-0.74; P = 0.002]. Mortality did not differ significantly between patients weaned from VA-ECMO and non-ECMO patients [non-ECMO 14.3% (14/98) vs. VA-ECMO (weaned) 18.9% (7/37), adjusted hazard ratio: 0.72, 95% confidence interval: 0.27-1.90; P = 0.48]. DAOH were significantly higher in non-ECMO patients compared with VA-ECMO patients and patients weaned from VA-ECMO [non-ECMO vs. VA-ECMO: median 310 (inter-quartile range 277-327) days vs. 243 (0-288) days; P < 0.0001; non-ECMO vs. VA-ECMO (weaned): 310 (277-327) days vs. 253 (208-299) days; P < 0.0001]. These results were still significant after multivariable adjustment with forced entry of predefined covariables. CONCLUSIONS: Despite similar survival rates, VA-ECMO due to PGD has a relevant life impact as defined by DAOH in the first year after HTX. As a more patient-centred endpoint, DAOH may contribute to a more comprehensive assessment of outcome in HTX patients.

Risk Factors for Acute Kidney Injury Requiring Renal Replacement Therapy after Orthotopic Heart Transplantation in Patients with Preserved Renal Function.

Acute kidney injury (AKI), requiring renal replacement therapy (RRT). is a serious complication after orthotopic heart transplantation (HTX). In patients with preexisting impaired renal function, postoperative AKI is unsurprising. However, even in patients with preserved renal function, AKI requiring RRT is frequent. Therefore, this study aimed to identify risk factors associated with postoperative AKI requiring RRT after HTX in this sub-cohort. This retrospective cohort study included patients ≥ 18 years of age with preserved renal function (defined as preoperative glomerular filtration rate ≥ 60 mL/min) who underwent HTX between 2010 and 2021. In total, 107 patients were included in the analysis (mean age 52 ± 12 years, 78.5% male, 45.8% AKI requiring RRT). Based on univariate logistic regression, use of extracorporeal membrane oxygenation, postoperative infection, levosimendan therapy, duration of norepinephrine (NE) therapy and maximum daily increase in tacrolimus plasma levels were chosen to be included into multivariate analysis. Duration of NE therapy and maximum daily increase in tacrolimus plasma levels remained as independent significant risk factors (NE: OR 1.01, 95%CI: 1.00-1.02, p = 0.005; increase in tacrolimus plasma level: OR 1.18, 95%CI: 1.01-1.37, p = 0.036). In conclusion, this study identified long NE therapy and maximum daily increase in tacrolimus plasma levels as risk factors for AKI requiring RRT in HTX patients with preserved renal function.

The analysis of left ventricular ejection fraction after minimally invasive surgery for primary mitral valve regurgitation.

BACKGROUND: Although minimally invasive mitral valve surgery (MIMVS) has become the first choice for primary mitral regurgitation (MR) in recent years, clinical evidence in this field is yet limited. The main focus of this study was the analysis of preoperative (Pre), postoperative (Post), and 1-year follow-up (Fu) data in our series of MIMVS to identify factors that have an impact on the left ventricular ejection fraction (LVEF) evolution after MIMVS. METHODS: We reviewed the perioperative and 1-year follow-up data from 436 patients with primary MR (338 isolated MIMVS und 98 MIMVS combined with tricuspid valve repair) to analyze patients' baseline characteristics, the change of LV size, the postoperative evolution of LVEF and its factors, and the clinical outcomes. RESULTS: The overall mean value of ejection fraction (EF) slightly decreased at 1-year follow-up (mean change of LVEF: -2.63 ± 9.00%). A significant correlation was observed for preoperative EF (PreEF) und EF evolution, the higher PreEF the more pronounced decreased EF evolution (in all 436 patients; r = -.54, p < .001, in isolated MIMVS; r = -.54, p < .001, in combined MIMVS; r = -.53, p < .001). Statistically significant differences for negative EF evolution were evident in patients with mild or greater tricuspid valve regurgitation (TR) (in all patients; p < .05, odds ratio [OR] = 1.64, in isolated MIMVS; p < .01, OR = 1.93, respectively). Overall clinical outcome in New York Heart Association classification at 1 year was remarkably improved. CONCLUSIONS: Our results suggest an excellent clinical outcome at 1 year, although mean LVEF slightly declined over time. TR could be a predictor of worsened follow-up LVEF in patients undergoing MIMVS.

The Impact of Intraoperative Patient Blood Management on Quality Development in Cardiac Surgery.

OBJECTIVES: Patient blood management (PBM) is increasingly introduced into clinical practice. Minimizing effects on transfusion have been proven, but relevance for clinical outcome has been sparsely examined. In regard to this, the authors analyzed the impact of introducing intraoperative PBM to cardiac surgery. DESIGN: Retrospective case-control study. SETTING: Single center. PARTICIPANTS: A total of 3,170 patients who underwent either coronary artery bypass grafting, isolated aortic valve replacement, or a combined procedure at the authors' institution between January 1, 2007, and December 31, 2015. INTERVENTION: In 2013, an intraoperative PBM service was established offering therapy recommendations on the basis of real-time laboratory monitoring. Comparisons to conventional coagulation management were adjusted for optimization of general, surgical, and perioperative care standards by interrupted time-series analysis and risk-dependent confounding by propensity- score matching. MEASUREMENTS AND MAIN RESULTS: Primary study endpoints were in-hospital mortality and morbidity. Morbidity was defined as clinically relevant prolongation of hospital stay, which was related to accumulation of postoperative complications. Transfusion requirements, bleeding, and thromboembolic complications were not treated as primary endpoints, but were also explored. The recommendations on the basis of real-time laboratory monitoring were adopted by the operative team in 72% of patients. Intraoperative PBM was associated independently with a reduction of morbidity (8.3% v 6.3%, p = 0.034), whereas in-hospitalmortality (3.0% v 2.6%, p = 0.521) remained unaffected. The need for red blood cell transfusion decreased (71.1% v 65.0%, p < 0.001), as did bleeding complications requiring surgical re-exploration (3.5% v 1.8%, p = 0.004). At the same time, stroke increased by statistical trend (1.0% v 1.9%, p = 0.038; after correction for imbalanced type of surgical procedure p = 0.085). CONCLUSIONS: Real-time laboratory recommendations achieved a high acceptance rate early after initiation. Improvement of clinical outcome by intraoperative PBM adds to the optimized surgical care. However, the corridor between hemostatic optimization and thromboembolic risk may be narrow.

Cornea donation in Germany: Obtaining consent.

Tissue donation is important to reverse cornea-related blindness. Unfortunately, the willingness to make a decision concerning organ and tissue donation while still alive remains low despite all efforts. By analyzing anonymized archived data from 25 654 next-of-kin interviews from our database over a period of 5 years (2013-2018), it was found that only 20.8% of all potential cornea donors have declared their own wishes. While still alive, refusal was communicated more often than consent by potential donors. Overall consent rates were 39.2%, with parents and siblings consenting more often than other relatives and females refusing more often than male family members. Personal interviews and interviews via telephone handled by staff known to the family resulted in better consent rates (up to 75.6%) with male interviewers receiving higher consent rates in general. The gender of the approached relatives in relation to a male/female interviewer was of low importance. The results also show that it is important to allow discussion about that topic between family members-the more relatives that were involved the higher the probability of consent.

The Course of Circulating Small Extracellular Vesicles in Patients Undergoing Surgical Aortic Valve Replacement.

In the last years, increasing efforts have been devoted to investigating the role of small extracellular vesicles (sEVs) in cardiovascular diseases. These nano-sized particles (30-150 nm), secreted by different cell types, contain signalling molecules that enable participation in intercellular communication processes. In this study, we examined the course of circulating sEVs in patients undergoing surgical aortic valve replacement (SAVR) and correlated them with echocardiographic and standard blood parameters. Peripheral blood samples were collected from 135 patients undergoing SAVR preoperatively and at three follow-up points. Circulating sEVs were precipitated using Exoquick™ exosome isolation reagent and analyzed by nanoparticle tracking analysis (NTA). Our findings indicate that no more than 7 days after SAVR, there was a marked increase of circulating sEVs before returning to initial values after 3 months. Further, shear stress is not a trigger for the formation and release of circulating sEVs. Moreover, we pointed out a correlation between circulating sEVs and erythrocytes as well as LDH and creatinine levels in peripheral blood. Finally, all patients with a moderate prosthesis-patient mismatch as well as with an impaired left ventricular mass regression had lower levels of circulating sEVs 3 months after SAVR compared to their respective status before surgery. We conclude that in patients with aortic valve stenosis (AVS), sEVs may play an important part in mediating cell-cell communication and SAVR may have a crucial and lasting impact on their circulating levels. Besides, lower levels of sEVs portend to be associated with inferior recovery after major surgical interventions. The additional use of circulating sEVs beyond echocardiographic and laboratory parameters could have a prognostic value to estimate adverse outcomes in patients undergoing SAVR.

Fibrinolysis and the Influence of Tranexamic Acid Dosing in Cardiac Surgery.

OBJECTIVE: The present study aimed to determine whether underlying disease, performed surgery, and dose of tranexamic acid influence fibrinolysis measured with D-dimer levels. DESIGN: Retrospective analysis. SETTING: Single institution (Department of Cardiac Surgery and Section of Clinical Hemostaseology at the Düsseldorf University Hospital). PARTICIPANTS: The study comprised 3,152 adult patients undergoing elective cardiac surgery between February 2013 and October 2016. INTERVENTIONS: Two doses of tranexamic acid during surgery were administered. MEASUREMENTS AND MAIN RESULTS: D-dimer levels were analyzed at the start of surgery and before protamine administration. D-dimer levels at the start of surgery were compared according to disease. Intraoperative D-dimer development was analyzed according to the type of surgery and within 2 cohorts with different tranexamic acid doses. Interindividual variability was pronounced for D-dimer levels at the start of surgery, with significant differences among patients with coronary artery disease, valve disease, and aortic disease and patients undergoing heart transplantation compared with patients receiving a left ventricular assist device (p < 0.01). Aortic dissection, endocarditis, and extracorporeal life support were associated with higher D-dimer levels (p ≤ 0.01). With tranexamic acid at a fixed dose, intraoperative D-dimer levels decreased in on-pump and off-pump coronary bypass surgery, valve surgery, and left ventricular assist device surgery (p ≤ 0.02), but levels increased in aortic surgery and heart transplantations (p < 0.01). A decrease or increase in D-dimer levels during surgery was influenced significantly by a higher or lower tranexamic acid dose (p ≤ 0.01). CONCLUSIONS: D-dimer testing allows for the assessment of individual fibrinolytic activity in cardiac surgery, which is influenced by disease type, surgery type, and dose of tranexamic acid. The assessment of the fibrinolytic status may have the potential to facilitate dose-adjusted antifibrinolytic therapy in the future.

Osteopontin as novel biomarker for reversibility of pressure overload induced left ventricular hypertrophy.

Aim: The aim of this study was to evaluate the prognostic value of osteopontin (OPN) as a marker for left ventricular (LV) hypertrophy and its reversibility after surgical aortic valve replacement (SAVR). Patients & methods: Echocardiographic data and OPN plasma levels of 149 consecutive patients undergoing SAVR were obtained preoperatively and 3 months postoperatively. OPN was measured by Quantikine Human OPN immunoassay. Results: There was a significant correlation between higher OPN plasma levels and lower LV-mass regression. In patients receiving SAVR combined with coronary artery bypass grafting, high OPN plasma levels were also an indicator for eccentric hypertrophy phenotype. Conclusion: OPN may be a useful indicator for LV hypertrophy phenotype and could have a prognostic value to estimate LV-mass regression after SAVR.

Impact of Ca2+-Sensitive Potassium Channels in Levosimendan-Induced Postconditioning.

PURPOSE: Small and big conductance Ca2+-sensitive potassium (KCa) channels are involved in cardioprotective measures aiming at reducing myocardial reperfusion injury. For levosimendan, infarct size-reducing effects were shown. Whether activation of these channels is involved in levosimendan-induced postconditioning is unknown. We hypothesized that levosimendan exerts a concentration-dependent cardioprotective effect and that both types of Ca2+-sensitive potassium channels are involved. METHODS: In a prospective blinded experimental laboratory investigation, hearts of male Wistar rats were randomized and placed on a Langendorff system, perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 min of global ischemia and 60 min of reperfusion. At the onset of reperfusion, hearts were perfused with various concentrations of levosimendan (0.03-1 µM) in order to determine a concentration-response relationship. To elucidate the involvement of KCa-channels for the observed cardioprotection, in the second set of experiments, 0.3 µM levosimendan was administered in combination with the subtype-specific KCa-channel inhibitors paxilline (1 µM, big KCa-channel) and NS8593 (0.1 µM, small KCa-channel) respectively. Infarct size was determined by tetrazolium chloride (TTC) staining. RESULTS: Infarct size in controls was 60 ± 7% and 59 ± 6% respectively. Levosimendan at a concentration of 0.3 µM reduced infarct size to 30 ± 5% (P < 0.0001 vs. control). Higher concentrations of levosimendan did not induce a stronger effect. Paxilline but not NS8593 completely abolished levosimendan-induced cardioprotection while both substances alone had no effect on infarct size. CONCLUSIONS: Cardioprotection by levosimendan-induced postconditioning shows a binary phenomenon, either ineffective or with maximal effect. The cardioprotective effect requires activation of big but not small KCa channels.

The age-adjusted Charlson comorbidity index in minimally invasive mitral valve surgery.

OBJECTIVES: Mitral valve repair is the preferred method used to address mitral valve regurgitation, whereas transcatheter mitral valve repair is recommended for high-risk patients. We evaluated the risk-predictive value of the age-adjusted Charlson comorbidity index (aa-CCI) in the setting of minimally invasive mitral valve surgery. METHODS: The perioperative course and 1-year follow-up of 537 patients who underwent isolated or combined minimally invasive mitral valve surgery were evaluated for 1-year mortality as the primary end point and other adverse events. The predictive values of the EuroSCORE II and STS score were compared to that of the aa-CCI by a comparative analysis of receiver operating characteristic curves. Restricted cubic splines were applied to find optimal aa-CCI cut-off values for the increased likelihood of experiencing the predefined adverse end points. Consequently, the perioperative course and postoperative outcome of the aa-CCI ≥8 patients and the remainder of the sample were analysed. RESULTS: The predictive value of the aa-CCI does not significantly differ from those of the EuroSCORE II or STS score. Patients with an aa-CCI ≥8 were identified as a subgroup with a significant increase of mortality and other adverse events. CONCLUSIONS: The aa-CCI displays a suitable predictive ability for patients undergoing minimally invasive mitral valve surgery. In particular, multimorbid or frail patients may benefit from the extension of the objectively assessed parameters, in addition to the STS score or EuroSCORE II. Patients with an aa-CCI ≥8 have a very high surgical risk and should receive very careful attention.

Preconditioning by Levosimendan is Mediated by Activation of Mitochondrial Ca2+-Sensitive Potassium (mBKCa) Channels.

PURPOSE: Activation of mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa)-channels is a crucial step for cardioprotection by preconditioning. Whether activation of these channels is involved in levosimendan-induced preconditioning is unknown. We investigated if cardioprotection by levosimendan requires activation of mBKCa-channels in the rat heart in vitro. METHODS: In a prospective blinded experimental laboratory investigation, hearts of male Wistar rats were randomized and placed on a Langendorff system, perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 min of global ischemia and 60 min of reperfusion. Before ischemia, hearts were perfused with different concentrations of levosimendan (0.03-1 µM) for determination of a dose-effect curve. In a second set of experiments, 0.3 µM levosimendan was administered in combination with the mBKCa-channel inhibitor paxilline (1 µM). Infarct size was determined by TTC staining. RESULTS: In control, animal's infarct size was 58 ± 7%. Levosimendan at a concentration of 0.3 µM reduced infarct size to 30 ± 7% (P < 0.05 vs. control). Higher concentrations with 1 µM levosimendan did not confer stronger protection. Paxilline completely blocked levosimendan-induced cardioprotection while paxilline alone had no effect on infarct size. CONCLUSIONS: This study shows that activation of mBKCa-channels plays a pivotal role in levosimendan-induced preconditioning.

A role for very low-dose recombinant activated factor VII in refractory bleeding after cardiac surgery: Lessons from an observational study.

OBJECTIVES: Although off-label use of recombinant activated factor VII against refractory bleeding is incorporated in current guideline recommendations, safety concerns persist predominantly with respect to thromboembolic complications. We analyzed the safety and efficacy of recombinant activated factor VII at a very low dose in cardiosurgical patients with refractory bleeding. METHODS: This prospective study includes 1180 cardiosurgical patients at risk of bleeding. Goal-directed substitution was based on real-time laboratory testing and clinical scoring of the bleeding intensity. All patients who fulfilled the criteria for enhanced risk of bleeding (n = 281) were consequently included in the present analysis. Patients in whom refractory bleeding developed despite substitution with specific hemostatic compounds (n = 167) received a single shot of very low-dose recombinant activated factor VII (≤20 µg/kg). Mortality and risk of thromboembolic complications, and freedom from stroke and acute myocardial infarction in particular, were analyzed (vs patients without recombinant activated factor VII) by multivariable logistic and Cox regression analyses, as well as Kaplan-Meier estimates. RESULTS: There was no increase in rates of mortality (30-day mortality 4.2% vs 7.0% with P = .418; follow-up survival 85.6% at 13.0 [interquartile range, 8.4-15.7] months vs 80.7% at 10.2 [interquartile range, 7.2-16.1] months with P = .151), thromboembolic complications (6.6% vs 9.6% with P = .637), renal insufficiency, need for percutaneous coronary intervention, duration of ventilation, duration of hospital stay, or rehospitalization in patients receiving very low-dose recombinant activated factor VII compared with patients not receiving recombinant activated factor VII. Complete hemostasis without any need for further hemostatic treatment was achieved after very low-dose recombinant activated factor VII administration in the majority of patients (up to 88.6% vs 0% with P < .001). The key results were confirmed after adjustment by propensity score-based analyses. CONCLUSIONS: When combined with early and specific restoration of hemostatic reserves after cardiac surgery, very low-dose recombinant activated factor VII treatment of refractory bleeding is effective and not associated with any apparent increase in adverse events.

Previous Sternotomy as a Risk Factor in Minimally Invasive Mitral Valve Surgery.

BACKGROUND: Cardiac redo surgery, especially after a full sternotomy, is considered a high-risk procedure. Minimally invasive mitral valve surgery (MIMVS) is a potential therapeutic approach. However, current developments in interventional cardiology necessitate additional discussion regarding the therapy of choice in high-risk patients. In this context, it is necessary to clarify the perioperative and postoperative risks induced by the factor previous sternotomy in the setting of MIMVS. Thus, we present a comparative study analyzing the outcome of MIMVS after previous sternotomy vs. primary operation. METHODS: We identified 19 patients who received isolated or combined mitral valve (MV) surgery via the MIMVS approach after previous full sternotomy (PS group) and compared the results to those of a group of 357 patients who received primary MIMVS (non-PS group). After a propensity score analysis, groups of n = 15 and n = 131, respectively, were subjected to a comparative evaluation. A 1-year follow-up analysis of functional cardiac parameters and clinical symptoms was performed, accompanied by a Kaplan-Meier analysis. RESULTS: Except for the rate of realized MV reconstructions (PS group: 53.8% vs. non-PS group: 85.5%; p = 0.011), no significant differences were to be noted within the intraoperative and early postoperative course. However, patients in the PS group experienced an increased intensive care unit stay length (PS group: 2 days, 95% CI, 1-8 vs. non-PS group: 1 day, 95% CI, 1-2; p = 0.072). The follow-up examinations revealed excellent functional and clinical outcomes for both groups. The Kaplan-Meier analysis displayed no significant difference regarding the postoperative mortality (p = 0.929) related to the patients at risk. CONCLUSION: A previous sternotomy remains a risk factor for MIMVS and demands special attention in the early postoperative period. Nevertheless, the early- and late-term results concerning the functional and clinical outcomes suggest that the MIMVS procedure is satisfactory, even after a full sternotomy.

Continuous Procedural Full-Lung Ventilation During Minimally Invasive Coronary Bypass Grafting.

BACKGROUND: In the past, minimally invasive cardiac surgery (MICS)- coronary artery bypass graft surgery (CABG) alternatives have been introduced that dramatically reduce the invasiveness of standard operative procedures while still showing excellent clinical outcomes. However, in patients with high morbidity, reduced lung function impeding single-lung ventilation is one of the major concerns for MICS-CABG procedures, although those patients might reap the largest benefit from a procedure of reduced invasiveness. METHODS: Here, we describe a simple surgical technique-the fan technique-that allows for continuous full-lung ventilation with unimpeded surgical view during common MICS-CABG procedures. To evaluate the procedural feasibility of this technique, we analyzed intraoperative ventilation measurements of 22 consecutive MICS-CABG patients in whom the fan technique was used. RESULTS: This study demonstrates a significant improvement of standard respiratory measurements during procedural full-lung ventilation using the fan technique as compared with conventional single-lung ventilation (ventilation pressure 21.4 ± 3.2 versus 26.6 ± 3 mbar, p < 0.001; respiratory rate 13.1 ± 1.4 versus 14.4 ± 2.2 breaths per minute, p < 0.001; minute volume 7.4 ± 1.1 versus 6.2 ± 1 L/min, p < 0.0001; Pao2 during ventilation 294.9 ± 74.6 versus 153.2 ± 71 mm Hg, p < 0.0001). CONCLUSIONS: The presented technique may not only enable us to perform MICS-CABG procedures in patients not suitable for single-lung ventilation owing to reduced pulmonary function, but also may soon also become a standard procedure for MICS-CABG surgery, especially with regard to procedures involving complex and time-consuming multivessel revascularizations. However, further studies are strongly warranted to assess whether the fan technique may also decrease postoperative pulmonary complications and benefit clinical outcome indicators.