Statin loading before coronary artery bypass grafting: a randomized trial.

AIMS: Evidence suggests that a high-dose statin loading before a percutaneous coronary revascularization improves outcomes in patients receiving long-term statins. This study aimed to analyse the effects of such an additional statin therapy before surgical revascularization. METHODS AND RESULTS: This investigator-initiated, randomized, double-blind, and placebo-controlled trial was conducted from November 2012 to April 2019 at 14 centres in Germany. Adult patients (n = 2635) with a long-term statin treatment (≥30 days) who were scheduled for isolated coronary artery bypass grafting (CABG) were randomly assigned to receive a statin-loading therapy or placebo at 12 and 2 h prior to surgery using a web-based system. The primary outcome of major adverse cardiac and cerebrovascular events (MACCE) was a composite consisting of all-cause mortality, myocardial infarction (MI), and a cerebrovascular event occuring within 30 days after surgery. Key secondary endpoints included a composite of cardiac death and MI, myocardial injury, and death within 12 months. Non-statistically relevant differences were found in the modified intention-to-treat analysis (2406 patients; 1203 per group) between the statin (13.9%) and placebo groups (14.9%) for the primary outcome [odds ratio (OR) 0.93, 95% confidence interval (CI) 0.74-1.18; P = 0.562] or any of its individual components. Secondary endpoints including cardiac death and MI (12.1% vs. 13.5%; OR 0.88, 95% CI 0.69-1.12; P = 0.300), the area under the troponin T-release curve (median 0.398 vs. 0.394 ng/ml, P = 0.333), and death at 12 months (3.1% vs. 2.9%; P = 0.825) were comparable between treatment arms. CONCLUSION: Additional statin loading before CABG failed to reduce the rate of MACCE occuring within 30 days of surgery.

Effect of High-Dose Selenium on Postoperative Organ Dysfunction and Mortality in Cardiac Surgery Patients: The SUSTAIN CSX Randomized Clinical Trial.

Importance: Selenium contributes to antioxidative, anti-inflammatory, and immunomodulatory pathways, which may improve outcomes in patients at high risk of organ dysfunctions after cardiac surgery. Objective: To assess the ability of high-dose intravenous sodium selenite treatment to reduce postoperative organ dysfunction and mortality in cardiac surgery patients. Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled trial took place at 23 sites in Germany and Canada from January 2015 to January 2021. Adult cardiac surgery patients with a European System for Cardiac Operative Risk Evaluation II score-predicted mortality of 5% or more or planned combined surgical procedures were randomized. Interventions: Patients were randomly assigned (1:1) by a web-based system to receive either perioperative intravenous high-dose selenium supplementation of 2000 µg/L of sodium selenite prior to cardiopulmonary bypass, 2000 µg/L immediately postoperatively, and 1000 µg/L each day in intensive care for a maximum of 10 days or placebo. Main Outcomes and Measures: The primary end point was a composite of the numbers of days alive and free from organ dysfunction during the first 30 days following cardiac surgery. Results: A total of 1416 adult cardiac surgery patients were analyzed (mean [SD] age, 68.2 [10.4] years; 1043 [74.8%] male). The median (IQR) predicted 30-day mortality by European System for Cardiac Operative Risk Evaluation II score was 8.7% (5.6%-14.9%), and most patients had combined coronary revascularization and valvular procedures. Selenium did not increase the number of persistent organ dysfunction-free and alive days over the first 30 postoperative days (median [IQR], 29 [28-30] vs 29 [28-30]; P = .45). The 30-day mortality rates were 4.2% in the selenium and 5.0% in the placebo group (odds ratio, 0.82; 95% CI, 0.50-1.36; P = .44). Safety outcomes did not differ between the groups. Conclusions and Relevance: In high-risk cardiac surgery patients, perioperative administration of high-dose intravenous sodium selenite did not reduce morbidity or mortality. The present data do not support the routine perioperative use of selenium for patients undergoing cardiac surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT02002247.

Combining Minimally Invasive Surgery With Ultra-Fast-Track Anesthesia in HeartMate 3 Patients: A Pilot Study.

BACKGROUND: Minimally invasive surgery for left ventricular assist device implantation may have advantages over conventional sternotomy (CS). Additionally, ultra-fast-track anesthesia has been linked to better outcomes after cardiac surgery. This study summarizes our early experience of combining minimally invasive surgery with ultra-fast-track anesthesia (MIFTA) in patients receiving HeartMate 3 devices and compares the outcomes between MIFTA and CS. METHODS: From October 2015 to January 2019, 18 of 49 patients with Interagency Registry for Mechanically Assisted Circulatory Support profiles >1 underwent MIFTA for HeartMate 3 implantation. For bias reduction, propensity scores were calculated and used as a covariate in a regression model to analyze outcomes. Weighted parametric survival analysis was performed. RESULTS: In the MIFTA group, intensive care unit stays were shorter (mean difference, 8 days [95% CI, 4-13]; P<0.001), and the incidences of pneumonia and right heart failure were lower than those in the CS group (odds ratio, 1.36 [95% CI, 1.01-1.75]; P=0.016, respectively). At 6 and 12 hours postoperatively, MIFTA patients had a better hemodynamic performance with lower pulmonary wedge pressure (mean difference, 2.23 mm Hg [95% CI, 0.41-4.06]; P=0.028) and a higher right ventricular stroke work index (mean difference, -1.49 g·m/m2 per beat [95% CI, -2.95 to -0.02]; P=0.031). CS patients had a worse right heart failure-free survival rate (hazard ratio, 2.35 [95% CI, 0.96-5.72]; P<0.01). CONCLUSIONS: Compared with CS, MIFTA is a beneficial approach for non-Interagency Registry for Mechanically Assisted Circulatory Support 1 HeartMate 3 patients with lower adverse event incidences, better hemodynamic performance, and preserved right heart function. Future large multicentric investigations are required to verify MIFTA's effects on outcomes.

Speckle tracking ultrasonography as a new tool to assess diaphragmatic function: a feasibility study.

A reliable method of measuring diaphragmatic function at the bedside is still lacking. Widely used two-dimensional (2D) ultrasonographic measurements, such as diaphragm excursion, diaphragm thickness, and fractional thickening (FT) have failed to show clear correlations with diaphragmatic function. A reason for this is that 2D ultrasonographic measurements, like FT, are merely able to measure the deformation of muscular diaphragmatic tissue in the transverse direction, while longitudinal measurements in the direction of contracting muscle fibres are not possible. Speckle tracking ultrasonography, which is widely used in cardiac imaging, overcomes this disadvantage and allows observations of movement in the direction of the contracting muscle fibres, approximating muscle deformation and the deformation velocity. Several studies have evaluated speckle tracking as a promising method to assess diaphragm contractility in healthy subjects. This technical note demonstrates the feasibility of speckle tracking ultrasonography of the diaphragm in a group of 20 patients after an aortocoronary bypass graft procedure. The results presented herein suggest that speckle tracking ultrasonography is able to depict alterations in diaphragmatic function after surgery better than 2D ultrasonographic measurements.

High-dose supplementation of selenium in left ventricular assist device implant surgery: A double-blinded, randomized controlled pilot trial.

BACKGROUND: Systemic inflammation and oxidative stress remain the main causes of complications in patients with heart failure receiving a left ventricular assist device (LVAD). Selenoproteins are a cornerstone of antioxidant defense mechanisms for improving inflammatory conditions. METHODS: In a monocentric, double-blinded pilot trial patients scheduled for LVAD implantation were randomized to receive 300 mcg of selenium orally the evening before surgery, followed by a high-dose of intravenous selenium supplementation (3000 mcg after anesthesia induction, 1000 mcg upon intensive care unit [ICU] admission, and 1000 mcg daily in the ICU for a maximum of 14 days) or placebo. The main outcomes were feasibility and effectiveness in restoring serum selenium concentrations. RESULTS: Twenty patients were included in the analysis. The average duration of study intervention was 12.6 days (7-14), with 97.7% dose compliance. No patient received open-label selenium. The supplementation strategy was effective in compensating low serum selenium concentrations (before surgery: control, 63.5 ± 11.9 mcg/L vs intervention, 65.8 ± 16.5 mcg/L; ICU admission: control, 49.0 ± 9.8 mcg/L vs intervention, 144.2 ± 45.4 mcg/L). Serum selenium concentrations in the intervention group were significantly higher during the observation period (baseline: mean of placebo (MoP), 63.1 vs mean of selenium (MoS), 64.0; ICU admission: MoP, 49.0 vs MoS, 144.6; day 1-13: MoP, 43.6-48.5 vs MoS, 100.4-131.0). CONCLUSION: Selenium supplementation in patients receiving LVAD implantation is feasible and effective to compensate a selenium deficiency.

Severe Myocardial Dysfunction after Non-Ischemic Cardiac Arrest: Effectiveness of Percutaneous Assist Devices.

INTRODUCTION: Despite the improvements in standardized cardiopulmonary resuscitation, survival remains low, mainly due to initial myocardial dysfunction and hemodynamic instability. Our goal was to compare the efficacy of two left ventricular assist devices on resuscitation and hemodynamic supply in a porcine model of ventricular fibrillation (VF) cardiac arrest. METHODS: Seventeen anaesthetized pigs had 12 min of untreated VF followed by 6 min of chest compression and boluses of epinephrine. Next, a first defibrillation was attempted and pigs were randomized to any of the three groups: control (n = 5), implantation of an percutaneous left ventricular assist device (Impella, n = 5) or extracorporeal membrane oxygenation (ECMO, n = 7). Hemodynamic and myocardial functions were evaluated invasively at baseline, at return of spontaneous circulation (ROSC), after 10-30-60-120-240 min post-resuscitation. The primary endpoint was the rate of ROSC. RESULTS: Only one of 5 pigs in the control group, 5 of 5 pigs in the Impella group, and 5 of 7 pigs in the ECMO group had ROSC (p < 0.05). Left ventricular ejection fraction at 240 min post-resuscitation was 37.5 ± 6.2% in the ECMO group vs. 23 ± 3% in the Impella group (p = 0.06). No significant difference in hemodynamic parameters was observed between the two ventricular assist devices. CONCLUSION: Early mechanical circulatory support appeared to improve resuscitation rates in a shockable rhythm model of cardiac arrest. This approach appears promising and should be further evaluated.

Inhaled nitric oxide preserves ventricular function during resuscitation using a percutaneous mechanical circulatory support device in a porcine cardiac arrest model: an echocardiographic myocardial work analysis.

BACKGROUND: Resuscitation using a percutaneous mechanical circulatory support device (iCPR) improves survival after cardiac arrest (CA). We hypothesized that the addition of inhaled nitric oxide (iNO) during iCPR might prove synergistic, leading to improved myocardial performance due to lowering of right ventricular (RV) afterload, left ventricular (LV) preload, and myocardial energetics. This study aimed to characterize the changes in LV and RV function and global myocardial work indices (GWI) following iCPR, both with and without iNO, using 2-D transesophageal echocardiography (TEE) and GWI evaluation as a novel non-invasive measurement. METHODS: In 10 pigs, iCPR was initiated following electrically-induced CA and 10 min of untreated ventricular fibrillation (VF). Pigs were randomized to either 20 ppm (20 ppm, n = 5) or 0 ppm (0 ppm, n = 5) of iNO in addition to therapeutic hypothermia for 5 h following ROSC. All animals received TEE at five pre-specified time-points and invasive hemodynamic monitoring. RESULTS: LV end-diastolic volume (LVEDV) increased significantly in both groups following CA. iCPR alone led to significant LV unloading at 5 h post-ROSC with LVEDV values reaching baseline values in both groups (20 ppm: 68.2 ± 2.7 vs. 70.8 ± 6.1 mL, p = 0.486; 0 ppm: 70.8 ± 1.3 vs. 72.3 ± 4.2 mL, p = 0.813, respectively). LV global longitudinal strain (GLS) increased in both groups following CA. LV-GLS recovered significantly better in the 20 ppm group at 5 h post-ROSC (20 ppm: - 18 ± 3% vs. 0 ppm: - 13 ± 2%, p = 0.025). LV-GWI decreased in both groups after CA with no difference between the groups. Within 0 ppm group, LV-GWI decreased significantly at 5 h post-ROSC compared to baseline (1,125 ± 214 vs. 1,835 ± 305 mmHg%, p = 0.011). RV-GWI was higher in the 20 ppm group at 3 h and 5 h post-ROSC (20 ppm: 189 ± 43 vs. 0 ppm: 108 ± 22 mmHg%, p = 0.049 and 20 ppm: 261 ± 54 vs. 0 ppm: 152 ± 42 mmHg%, p = 0.041). The blood flow calculated by the Impella controller following iCPR initiation correlated well with the pulsed-wave Doppler (PWD) derived pulmonary flow (PWD vs. controller: 1.8 ± 0.2 vs. 1.9 ± 0.2L/min, r = 0.85, p = 0.012). CONCLUSIONS: iCPR after CA provided sufficient unloading and preservation of the LV systolic function by improving LV-GWI recovery. The addition of iNO to iCPR enabled better preservation of the RV-function as determined by better RV-GWI. Additionally, Impella-derived flow provided an accurate measure of total flow during iCPR.

Elevated circulating CD14++CD16+ intermediate monocytes are independently associated with extracardiac complications after cardiac surgery.

Elective cardiac surgery has low procedural complications. However, about 40% of patients develop extracardiac complications including delirium and acute kidney injury. We hypothesized that inflammatory processes and immune cell activation might be associated with these complications. We therefore prospectively included 104 patients undergoing cardiac surgery in our study. We assessed peripheral blood leukocyte populations by flow cytometry and circulating cytokines before operation, after surgery and at days one and four post-operatively. Patients undergoing cardiac surgery showed significantly elevated leukocytes and neutrophils after surgery. On the contrary, monocytes decreased after surgery and significantly increased at days 1 and 4, particularly classical (Mon1,CD14++CD16-) and intermediate (Mon2,CD14++CD16+) monocytes. While peripheral leukocyte subsets were unaltered in patients with infectious (n = 15) or cardiac complications (n = 31), post-operative leukocytes (p = 0.0016), neutrophils (p = 0.0061) and Mon2 (p = 0.0007) were clearly raised in patients developing extracardiac complications (n = 35). Using multiple logistic regression analyses, patient's age, ICU days, number of blood transfusions and elevated post-surgery Mon2 independently predicted extracardiac complications. Our findings demonstrate that elevated Mon2 after cardiac surgery are associated with an increased risk for extracardiac complications. These findings might improve the risk estimation after cardiac operations and the role of Mon2 for inflammation in cardiac surgery.

Elevated expression of the metalloproteinase ADAM8 associates with vascular diseases in mice and humans.

BACKGROUND AND AIMS: Members of the family of a disintegrin and metalloproteinases (ADAMs) and their substrates have been previously shown to modulate the inflammatory response in cardiac diseases, but studies investigating the relevance of ADAM8 are still rare. Our aim is to provide evidence for the inflammatory dysregulation of ADAM8 in vascular diseases and its association with disease severity. METHODS: Western-type diet fed Apoe-/- and Ldlr-/- mice and artery ligation served as murine model for atherosclerosis and myocardial infarction, respectively. Human bypass grafts were used to study the association with coronary artery disease (CAD), with the simplified acute physiology score II (SAPS II) as a measure of postoperative organ dysfunction. Human primary vascular and blood cells were analyzed under basal and inflammatory conditions. mRNA levels were determined by RT-qPCR, ADAM8 protein levels by ELISA, immunohistochemistry or flow cytometry. RESULTS: ADAM8/ADAM8 expression is associated with atherosclerosis and CAD such as myocardial infarction in both mice and humans, especially in endothelial cells and leukocytes. We observed a strong in vivo and in vitro correlation of ADAM8 with the vascular disease markers VCAM-1, ICAM-1, TNF, IL-6, and CCL-2. Serum analysis revealed a significant elevation of soluble ADAM8 serum levels correlating with soluble CXCL16 levels and SAPS II. CONCLUSIONS: We demonstrate a general association of ADAM8 with cardiovascular diseases in mice and humans predominantly acting in endothelial cells and leukocytes. The correlation with postoperative organ dysfunctions in CAD patients highlights the value of further studies investigating the specific function of ADAM8 in cardiovascular diseases.

In vitro head-to-head comparison of anticoagulation properties of two heparin brands in a human blood miniature mock loop.

OBJECTIVES: The first aim was the development of a human blood miniature mock-loop system consisting of 2 identical extracorporeal circuits, which enable systematic head-to-head comparisons of test substances. In a second step, we evaluated the suitability of the mock-loop system, by comparing 2 different brands of heparin (ROTEXMEDICA vs B.BRAUN), which have showed different anticoagulation capacities in the clinic. METHODS: For 1 experiment (18 in total), blood of the same healthy human donor was divided into 2 portions (2 × 50 ml), heparinized with 37.5 IU⋅ml-1 of the competing test substances and diluted to a haematocrit value of 20-25%. Each mock loop was filled with 70 ml, and in vivo heparin degradation was simulated in 3 different groups by protamine application, representing 0%, 50% and 100% heparin antagonization. At baseline, 5, 60, 120, 240 and 360 min, blood samples were taken to perform thromboelastometry, flow cytometry, haemolysis and general haemostasis analysis. RESULTS: Blood pressure, blood flow and blood temperature within the loops remained stable for 6 h in all groups. After 6 h, in the 100% antagonized ROTEXMEDICA heparin group, significantly increased haemolysis (148.7 ± 80 mg⋅dl-1 vs 57.5 ± 15.8 mg⋅dl-1), activated platelets (8 ± 3.8% vs 3.3 ± 0.7%), D-dimers (7376 ± 7144 ng ml-1 vs 576.2 ± 190 ng ml-1) and fulminant blood clots were detected. CONCLUSIONS: Our in vitro system is suitable for the detection of reduced anticoagulation capacity of a test drug, which was reported in vivo previously.

Prediction of Prolonged ICU Stay in Cardiac Surgery Patients as a Useful Method to Identify Nutrition Risk in Cardiac Surgery Patients: A Post Hoc Analysis of a Prospective Observational Study.

BACKGROUND: Cardiovascular surgery patients with a prolonged intensive care unit (ICU) stay may benefit most from early nutrition support. Using established scoring systems for nutrition assessment and operative risk stratification, we aimed to develop a model to predict a prolonged ICU stay ≥5 days in order to identify patients who will benefit from early nutrition interventions. METHODS: This is a retrospective analysis of a prospective observational study of patients undergoing elective valvular, coronary artery bypass grafting, or combined cardiac surgery. The nutrition risk was assessed by well-established screening tools. Patients' preoperative EuroSCORE (European System for Cardiac Operative Risk Evaluation), primary disease, and intraoperative cardiopulmonary bypass (CPB) time were included as independent variables in a multivariate logistic regression analysis to predict a prolonged ICU stay (>4 days). RESULTS: The number of cardiac surgery patients included was 1193. Multivariate analysis revealed that for prediction of ICU stay >4 days, both Nutritional Risk Screening 2002 (area under the curve (AUC): 0.716, P = .020) and Mini Nutritional Assessment (MNA) score (AUC: 0.715, P = .037) were significant, whereas for prediction of ICU stay >5 days, only the MNA score showed significant results (AUC: 0.762, P = .011). CONCLUSION: Present data provide first evidence about the combined use of EuroSCORE, primary disease, CPB time, and nutrition risk screening tools for prediction of prolonged ICU stay in cardiac surgery patients. If prospectively evaluated in adequately designed studies, this model may help to identify patients with prolonged ICU stay to initiate early postoperative nutrition therapy and thus, facilitate an enhanced recovery.

In vitro comparison of the hemocompatibility of two centrifugal left ventricular assist devices.

OBJECTIVES: Shear stress from left ventricular assist devices induces von Willebrand factor degradation and platelet dysfunction, leading to nonsurgical bleeding. We characterized the hemostatic changes induced by 2 centrifugal left ventricular assist devices, the HeartMate 3 (Abbott Inc, Chicago, Ill) and the EVAHEART (Evaheart Inc, Houston, Tex), for comparison. METHODS: Whole blood from 8 healthy volunteers was used ex vivo. Blood from the same donor was used for 6 hours of circulation in a miniature mock-loop system consisting of 2 identical extracorporeal circuits to compare the following experimental settings: (1) optimal revolutions per minute (rpm) for the HeartMate 3 (n = 4; 5000 rpm) and the EVAHEART (n = 4; 2500 rpm) and (2) equal rpm (3000 rpm for the HeartMate 3 and EVAHEART, n = 4 vs n = 4). For both settings, blood flow was adjusted to 1 mock-loop filling volume per minute (HeartMate 3 = 82 mL/min, EVAHEART = 100 mL/min). A panel of coagulation markers was analyzed to investigate hemostatic changes. RESULTS: The free plasma hemoglobin concentration was significantly lower in the EVAHEART compared with the HeartMate 3 after 6 hours of mock-loop circulation under both settings (optimal: 37 ± 31 vs 503 ± 173 mg/dL, P < .0001; equal: 27 ± 4 vs 139 ± 135 mg/dL, P = .024). Loss of von Willebrand factor high-molecular-weight multimers occurred in both left ventricular assist devices and settings, but the von Willebrand factor:activity/von Willebrand factor:antigen ratio after 6 hours was significantly lower in optimal settings for the HeartMate 3 (P = .009). The thrombin-antithrombin complex level was significantly lower with the EVAHEART for both settings (P < .0001). CONCLUSIONS: The EVAHEART left ventricular assist device caused less hemolysis, resulted in lower coagulation activation, and provided better preservation of von Willebrand factor functional activity compared with the HeartMate 3 device. These findings prove that left ventricular assist device design plays a major role in minimizing blood damage during left ventricular assist device support.

The relevance of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentration for postoperative infections and postoperative organ dysfunctions in cardiac surgery patients: The eVIDenCe study.

BACKGROUND & AIMS: Recent studies indicate that vitamin D deficiency is associated with increased morbidity and mortality in critically ill patients. Knowledge about the functional role and clinical relevance of vitamin D for patients undergoing cardiac surgery is sparse. Therefore, we investigated the clinical significance of vitamin D levels on outcome of cardiac surgery patients. METHODS: 92 patients undergoing elective cardiac surgery with cardiopulmonary arrest were included in this prospective observational pilot study. 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were measured prior to surgery, immediately postoperatively as well as 6, 12 and 24 h after surgery. We assessed postoperative organ dysfunctions, infections and death until hospital discharge. RESULTS: The serum concentration of 1,25(OH)2D significantly decreased intraoperatively by 29.3% (p < 0.001) and was significantly lower at any postoperative time point compared to baseline values, whereas 25OHD levels did not show significant changes during the observation period. Coronary artery bypass graft (CABG) patients had significant higher baseline 1,25(OH)2D values than patients with valve surgery (39.7 ± 13.9 ng/l vs. 30.1 ± 14.1 ng/l, p = 0.010) or CABG + valve surgery (39.7 ± 13.9 ng/l vs. 32.6 ± 11.8 ng/l, p = 0.044). Our data showed a significant odds ratio to develop postoperative organ dysfunction (OR 0.95; p = 0.009) and PCT levels ≥5 µg/l (OR 0.94; p = 0.046) for every ng/l increment in 1,25(OH)2D, when performing multivariable analysis and after adjusting for preoperative illness and demographics. In addition, multivariable-adjusted statistical analyses revealed that patients stayed significantly shorter on ICU (-0.21 h; p = 0.001) and in hospital (-2.6 days; p = 0.009) for every ng/l increment in 1,25(OH)2D. CONCLUSION: Our data highlight important evidence about the clinical significance of 1,25(OH)2D levels in cardiac surgery patients. Higher levels were associated with significantly less postoperative organ dysfunctions, elevated PCT levels, death and prolonged hospital stay. 1,25(OH)2D levels decreased significantly intra- and postoperatively, while serum levels of 25OHD did not. TRIAL REGISTRATION: clinicaltrials.gov (NCT02488876), registered May 1, 2015.

Oxidation-Reduction Potential in Patients undergoing Transcatheter or Surgical Aortic Valve Replacement.

BACKGROUND: Aortic valve stenosis has gained increasingly more importance due to its high prevalence in elderly people. More than two decades ago, transcatheter aortic valve replacement emerged for patients who were denied surgery, and its noninferiority has been demonstrated in numerous studies. Oxidative stress has generated great interest because of its sensitivity to cell damage and the possibility of offering early hints of clinical outcomes. The aim of the present study was to investigate whether there is a significant difference between transcatheter (TAVR) or surgical aortic valve replacement (SAVR) in terms of the changes in oxidation-reduction potential (ORP) and antioxidant capacity. Therefore, we investigated perioperative oxidative stress levels and their influence on clinical outcomes. METHODS: A total of 72 patients (50% TAVR versus 50% SAVR) were included in the present study. Static oxidation-reduction potential (sORP) and antioxidant capacity were measured using the RedoxSys™ Diagnostic System (Luoxis Diagnostics, USA) in serum samples drawn before and after surgery, as well as on the first postoperative day. In addition, clinical data were obtained to evaluate the clinical outcome of each case. RESULTS: TAVR patients had higher preoperative sORP levels compared to the SAVR patients and more severe comorbidities. Unlike the TAVR cohort, patients in the SAVR group showed a significant difference in sORP from the pre- to postoperative levels. Capacity demonstrated higher preoperative levels in the SAVR cohort and also a greater difference postoperatively compared to the TAVR cohort. Regression analysis revealed a significant correlation between pre- and postoperative capacity levels (r = -0.9931, p < 0.0001), providing a method of predicting postoperative capacity levels by knowing the preoperative levels. According to the multivariable analysis, both sORP and antioxidant capacity are dependent on time point, baseline value, and type of surgery, with the largest variations observed for time effect and surgery method. CONCLUSION: A high preoperative sORP level correlated to more severe illness in the TAVR patients. As the TAVR patients did not show significant differences in their preoperative levels, we assume that there was a smaller production of oxidative agents during TAVR due to the less invasive nature of the procedure. Baseline values and development of antioxidant capacity values strengthen this hypothesis. The significant correlation of pre- and postoperative capacity levels might allow high risk patients to be detected more easily and might provide more adequate and individualized therapy preoperatively. This trial is registered with clinicaltrials.gov, identifier: NCT 02488876.

Evaluation of the cardioprotective potential of extracellular vesicles - a systematic review and meta-analysis.

Cardiovascular diseases are the main cause of death worldwide, demanding new treatments and interventions. Recently, extracellular vesicles (EVs) came in focus as important carriers of protective molecules such as miRNAs and proteins which might contribute to e.g. improved cardiac function after myocardial infarction. EVs can be secreted from almost every cell type in the human body and can be transferred via the bloodstream in almost every compartment. To provide an all-encompassing overview of studies investigating these beneficial properties of EVs we performed a systematic review/meta-analysis of studies investigating the cardioprotective characteristics of EVs. Forty-three studies were investigated and catalogued according to the EV source. We provide an in-depth analysis of the purification method, size of the EVs, the conducted experiments to investigate the beneficial properties of EVs as well as the major effector molecule encapsulated in EVs mediating protection. This study provides evidence that EVs from different cell types and body fluids provide cardioprotection in different in vivo and in vitro studies. A meta-analysis was performed to estimate the underlying effect size. In conclusion, we demonstrated that EVs from different sources might serve as a promising tool for treating cardiovascular diseases in the future.

Synchronous or Staged Carotid Endarterectomy and Coronary Artery Bypass Grafting? Propensity score matched study.

BACKGROUND: The optimal treatment strategy in patients presenting with hemodynamically significant carotid artery disease who are to undergo cardiac surgery, remains controversial. In this study, we retrospectively analyzed the outcome data of patients receiving synchronous or staged coronary artery bypass graft (CABG) surgery and carotid endarterectomy (CEA). METHODS: Between 2011 and 2016, 3173 patients underwent CABG surgery in our institution, of whom 323 received CABG and CEA either as synchronous (N = 307) or as staged (N = 16) procedures. Patients´ characteristics, peri- and postoperative data were collected from our digital medical database. Propensity score matching was used to match each patient from the staged group to two appropriate patients (1:2 matching) from the synchronous group (synchronousmatched). RESULTS: The overall incidence of ischemic stroke (IS) and transitory ischemic attack (TIA) was 4.9% and 5.6%, respectively. No hemorrhagic stroke was noted in both groups. Incidence of IS did not differ significantly between matched groups (P = 1.000). Significantly higher rates of postoperative neurological complications, such as TIA and delirium, were found in the synchronousmatched group (P = .041 and P = .043, respectively) compared with the staged group. Additionally, there were more postoperative respiratory insufficiencies in the synchronousmatched group (P = .043). Thirty days mortality did not differ significantly between the matched groups. CONCLUSION: In this experience combined with the data given in literature, our findings suggest a possible superiority of the staged CABG/CEA approach. Large, randomized studies are required to verify our findings and to establish applicable guidelines.

Sildenafil Reduces the Risk of Thromboembolic Events in HeartMate II Patients with Low-Level Hemolysis and Significantly Improves the Pulmonary Circulation.

Low-level hemolysis (LLH) after left ventricular assist device implantation contributes to thromboembolic events (TE). Free plasma hemoglobin (fHb) scavenges nitric oxide (NO), which causes endothelial dysfunction and activates platelets. fHb also interacts with von Willebrand factor (vWF). We hypothesized that improved hemodynamic and enhanced NO signaling in HeartMate II (HMII) patients with LLH taking the phosphodiesterase-5 inhibitor sildenafil may reduce the risk of TE.From 2011 to 2015, 83 patients underwent HMII implantation. Patients with LLH as defined by elevated lactate dehydrogenase (400 < LDH ≤ 700 U/L) at hospital discharge were identified. Patients were categorized into 4 groups: 1) LLH + sildenafil, 2) LLH no sildenafil, 3) no LLH + sildenafil, and 4) no LLH no sildenafil. Adverse event-free survival was compared between the groups.Thirty-four patients (40.9%) were discharged with LLH and 22 (64.7%) of them took sildenafil. LDH and fHb remained significantly elevated in both LLH groups compared to the no LLH patients (P < 0.0001). Overall incidence of pump thrombosis (PT) was 4.8% and of ischemic stroke (IS) was 8.4%. HMII patients with LLH not on sildenafil had higher risk of TE (hazard ratio (HR): 14.4, 95%-CI: 1.8-117.1, P = 0.001). vWF activity and bleeding incidence did not differ between the LLH and no LLH patients. Mean pulmonary artery pressure and pulmonary vascular resistance decreased significantly in HMII taking sildenafil (P < 0.0001) while cardiac index increased (P < 0.0001).Sildenafil treatment among HMII patients with LLH reduced the risk of thromboembolic events and significantly improved and decompressed the pulmonary circulation during HMII support.

Soluble CD74 Reroutes MIF/CXCR4/AKT-Mediated Survival of Cardiac Myofibroblasts to Necroptosis.

Background Although macrophage migration inhibitory factor ( MIF ) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD 74, the function of the soluble CD 74 receptor ectodomain ( sCD 74) and its interaction with circulating MIF have not been explored in cardiac disease. Methods and Results Cardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co-treatment with recombinant MIF and sCD 74 induced cell death ( P<0.001), which was mediated by receptor-interacting serine/threonine-protein kinase ( RIP) 1/ RIP 3-dependent necroptosis ( P=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and RT - qPCR technology revealed a 4-fold upregulation of several interferon-induced genes upon co-treatment of myofibroblasts with sCD 74 and MIF (Ifi44: P=0.011; Irg1: P=0.022; Clec4e: P=0.011). Furthermore, Western blot analysis confirmed the role of sCD 74 as a modulator of MIF signaling by diminishing MIF -mediated protein kinase B ( AKT) activation ( P=0.0197) and triggering p38 activation ( P=0.0641). We obtained evidence that sCD 74 inhibits MIF -mediated survival pathway through the C-X-C chemokine receptor 4/ AKT axis, enabling the induction of CD 74-dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD 74/ MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244). Conclusions These findings suggest that treatment of cardiac myofibroblasts with sCD 74 and MIF induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the sCD 74/ MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.

Reduced post-operative DPP4 activity associated with worse patient outcome after cardiac surgery.

Cardiac surgery with cardiopulmonary bypass (CPB) triggers myocardial ischemia/reperfusion injury contributing to organ dysfunction. Preclinical studies revealed that dipeptidyl peptidase (DPP4) inhibition is protective during myocardial infarction. Here, we assessed for the first time the relation of peri-operative DPP4-activity in serum of 46 patients undergoing cardiac surgery with patients' post-operative organ dysfunction during intensive care unit (ICU) stay. Whereas a prior myocardial infarction significantly reduced pre-operative DDP4-activity, patients with preserved left ventricular function showed an intra-operative decrease of DPP4-activity. The latter correlated with aortic cross clamping time, indicative for the duration of surgery-induced myocardial ischemia. As underlying mechanism, mass-spectrometry revealed increased DPP4 oxidation by cardiac surgery, with DPP4 oxidation reducing DPP4-activity in vitro. Further, post-operative DPP4-activity was negatively correlated with the extent of post-operative organ injury as measured by SAPS II and SOFA scoring, circulating levels of creatinine and lactate, as well as patients' stay on the ICU. In conclusion, cardiac surgery reduces DPP4-activity through oxidation, with low post-operative DPP4-activity being associated with organ dysfunction and worse outcome of patients during the post-operative ICU stay. This likely reflects the severity of myocardial ischemia/reperfusion injury and may suggest potential beneficial effects of anti-oxidative treatments during cardiac surgery.