Impaired Intracellular Calcium Buffering Contributes to the Arrhythmogenic Substrate in Atrial Myocytes From Patients With Atrial Fibrillation.

BACKGROUND: Alterations in the buffering of intracellular Ca2+, for which myofilament proteins play a key role, have been shown to promote cardiac arrhythmia. It is interesting that although studies report atrial myofibrillar degradation in patients with persistent atrial fibrillation (persAF), the intracellular Ca2+ buffering profile in persAF remains obscure. Therefore, we aim to investigate the intracellular buffering of calcium and its potential arrhythmogenic role in persAF. METHODS: Simultaneous transmembrane fluxes (patch-clamp) and intracellular Ca2+ signaling (fluo-3-acetoxymethyl ester) were recorded in myocytes from right atrial biopsies of sinus rhythm (control) and patients with persAF, alongside human atrial subtype induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). Protein levels were quantified by immunoblotting of human atrial tissue and induced pluripotent stem cell-derived cardiac myocytes. Mouse whole heart and atrial electrophysiology was measured on a Langendorff system. RESULTS: Cytosolic Ca2+ buffering was decreased in atrial myocytes of patients with persAF because of a depleted amount of Ca2+ buffers. In agreement, protein levels of selected Ca2+ binding myofilament proteins, including cTnC (cardiac troponin C), a major cytosolic Ca2+ buffer, were significantly lower in patients with persAF. Small interfering RNA (siRNA)-mediated knockdown of cTnC in induced pluripotent stem cell-derived cardiac myocytes (si-cTnC) phenocopied the reduced cytosolic Ca2+ buffering observed in persAF. Si-cTnC induced pluripotent stem cell-derived cardiac myocytes exhibited a higher predisposition to spontaneous Ca2+ release events and developed action potential alternans at low stimulation frequencies. Last, indirect reduction of cytosolic Ca2+ buffering using blebbistatin in an ex vivo mouse whole heart model increased vulnerability to tachypacing-induced atrial arrhythmia, validating the direct mechanistic link between impaired cytosolic Ca2+ buffering and atrial arrhythmogenesis. CONCLUSIONS: Our findings suggest that loss of myofilament proteins, particularly reduced cTnC protein levels, causes diminished cytosolic Ca2+ buffering in persAF, thereby potentiating the occurrence of spontaneous Ca2+ release events and AF susceptibility. Strategies targeting intracellular buffering may represent a promising therapeutic lead in AF management.

Oral Anticoagulation Use and Left Atrial Appendage Occlusion in LAAOS III.

BACKGROUND: LAAOS III (Left Atrial Appendage Occlusion Study III) showed that left atrial appendage (LAA) occlusion reduces the risk of ischemic stroke or systemic embolism in patients with atrial fibrillation undergoing cardiac surgery. This article examines the effect of LAA occlusion on stroke reduction according to variation in the use of oral anticoagulant (OAC) therapy. METHODS: Information regarding OAC use was collected at every follow-up visit. Adjusted proportional hazards modeling, including using landmarks of hospital discharge, 1 and 2 years after randomization, evaluated the effect of LAA occlusion on the risk of ischemic stroke or systemic embolism, according to OAC use. Adjusted proportional hazard modeling, with OAC use as a time-dependent covariate, was also performed to assess the effect of LAA occlusion, according to OAC use throughout the study. RESULTS: At hospital discharge, 3027 patients (63.5%) were receiving a vitamin K antagonist, and 879 (18.5%) were receiving a non-vitamin K antagonist oral anticoagulant (direct OAC), with no difference in OAC use between treatment arms. There were 2887 (60.5%) patients who received OACs at all follow-up visits, 1401 (29.4%) who received OAC at some visits, and 472 (9.9%) who never received OACs. The effect of LAA occlusion on the risk of ischemic stroke or systemic embolism was consistent after discharge across all 3 groups: hazard ratios of 0.70 (95% CI, 0.51-0.96), 0.63 (95% CI, 0.43-0.94), and 0.76 (95% CI, 0.32-1.79), respectively. An adjusted proportional hazards model with OAC use as a time-dependent covariate showed that the reduction in stroke or systemic embolism with LAA occlusion was similar whether patients were receiving OACs or not. CONCLUSIONS: The benefit of LAA occlusion was consistent whether patients were receiving OACs or not. LAA occlusion provides thromboembolism reduction in patients independent of OAC use.

Bacterial Spectrum and Infective Foci in Patients Operated for Infective Endocarditis: Time to Rethink Strategies?

OBJECTIVE: The rising incidence of infective endocarditis (IE) accompanied by the de-escalation of antibiotic prophylaxis and the complexity of surgical treatment makes IE a daunting foe. We reviewed all patients who underwent cardiac surgery for IE at our institution with a focus on causative organisms and infective foci. METHODS: A review of 3,952 consecutive patients who underwent cardiac surgery at our institution between January 2013 and December 2017 revealed 160 patients (4%) who were operated for IE. RESULTS: The predominantly affected valves were the aortic (30%) and mitral valve (26.9%) as well as a combination of both (8.8%). A total of 28.8% of patients suffered from prosthetic valve endocarditis (PVE). The most frequently identified causative organisms were Staphylococcus (45.7%), Streptococcus (27.5%), and Enterococcus species (16.7%), which was predominantly associated with PVE (p = 0.050). In 13.1% of patients, a causative organism has not been detected. The most frequent infective foci were dental (15%), soft-tissue infections (15%), spondylodiscitis (10%), and infected intravascular implants (8.8%). Relevant predisposing factors were immunosuppression (9.4%) and intravenous drug abuse (4.4%). Septic cerebral infarctions were diagnosed in 28.8% of patients. Postoperative mortality was 22.5%. CONCLUSIONS: As the bacterial spectrum and the infective foci are still the "old acquaintances," and with regard to the increasing incidence of IE, current risk-benefit evaluations concerning antibiotic prophylaxis may need to be revisited.

Randomized trial of ticagrelor vs. aspirin in patients after coronary artery bypass grafting: the TiCAB trial.

AIMS: The antiplatelet treatment strategy providing optimal balance between thrombotic and bleeding risks in patients undergoing coronary artery bypass grafting (CABG) is unclear. We prospectively compared the efficacy of ticagrelor and aspirin after CABG. METHODS AND RESULTS: We randomly assigned in double-blind fashion patients scheduled for CABG to either ticagrelor 90 mg twice daily or 100 mg aspirin (1:1) once daily. The primary outcome was the composite of cardiovascular death, myocardial infarction (MI), repeat revascularization, and stroke 12 months after CABG. The main safety endpoint was based on the Bleeding Academic Research Consortium classification, defined as BARC ≥4 for periprocedural and hospital stay-related bleedings and BARC ≥3 for post-discharge bleedings. The study was prematurely halted after recruitment of 1859 out of 3850 planned patients. Twelve months after CABG, the primary endpoint occurred in 86 out of 931 patients (9.7%) in the ticagrelor group and in 73 out of 928 patients (8.2%) in the aspirin group [hazard ratio 1.19; 95% confidence interval (CI) 0.87-1.62; P = 0.28]. All-cause mortality (ticagrelor 2.5% vs. aspirin 2.6%, hazard ratio 0.96, CI 0.53-1.72; P = 0.89), cardiovascular death (ticagrelor 1.2% vs. aspirin 1.4%, hazard ratio 0.85, CI 0.38-1.89; P = 0.68), MI (ticagrelor 2.1% vs. aspirin 3.4%, hazard ratio 0.63, CI 0.36-1.12, P = 0.12), and stroke (ticagrelor 3.1% vs. 2.6%, hazard ratio 1.21, CI 0.70-2.08; P = 0.49), showed no significant difference between the ticagrelor and aspirin group. The main safety endpoint was also not significantly different (ticagrelor 3.7% vs. aspirin 3.2%, hazard ratio 1.17, CI 0.71-1.92; P = 0.53). CONCLUSION: In this prematurely terminated and thus underpowered randomized trial of ticagrelor vs. aspirin in patients after CABG no significant differences in major cardiovascular events or major bleeding could be demonstrated. CLINICALTRIALS.GOV IDENTIFIER: NCT01755520.

Re-exploration Early after Cardiac Surgery in Adults: The Importance of Bleeding-Related Complications.

BACKGROUND: Re-explorations soon after cardiac surgery are mostly related to bleeding or unclear hemodynamic situations possibly related to heart compression resulting from pericardial hematoma. This condition has a significant impact on mortality, morbidity, and costs. The aim of this study was to analyze indications and outcomes of re-exploration for bleeding or pericardial tamponade early after cardiac surgery in adults. METHODS: The clinical data of 4790 consecutive adult patients who underwent cardiac surgery in our institution from January 2011 to May 2016 were retrospectively analyzed. RESULTS: We identified 331 re-explorations performed in 231 patients. Sixty-seven of these patients had >1 re- exploration. In most cases (88%), repeat sternotomy was performed. Most procedures (57%) were performed within the first 48 hours. In two-thirds of re-explorations, active bleeding or pericardial hematoma was verified. In the remaining cases, neither bleeding nor significant pericardial hematoma leading to tamponade was found. Among the cases with active bleeding causes, the most bleeding sites were found to be at the coronary anastomosis and the epicardial exposure harvesting site, as well as from the side branches of bypass grafts and intercostal arteries. CONCLUSIONS: The incidence of re-exploration after cardiac surgery in adults was low (4.8%). In about two-thirds of the cases, active bleeding or significant pericardial hematoma was found. The most common bleeding causes were the easiest to treat.

Periodontal Bacterial DNA and Their Link to Human Cardiac Tissue: Findings of a Pilot Study.

BACKGROUND: The aim of this pilot study was to detect correlations of microbiological DNA, inflammatory proteins, and infection parameters in patients with periodontal disease (PD) and valvular heart disease (VHD). METHODS: A perioperative comprehensive dental examination for the investigation of periodontal status, including sampling of specific subgingival bacteria, was performed in 10 patients with indication for surgery of aortic valve stenosis with or without concomitant myocardial revascularization. Standard protocol biopsies were taken from right atrium (A), left septal myocardium (M), and aortic valve (V). Eleven periodontal pathogens DNA in oral and cardiac tissue samples (A/M/V) were analyzed using polymerase chain reaction. For cardiac tissue samples, Western blot analysis of LPS-binding protein (LBP), immunohistochemical (IHC) detection of LBP-big42, LPS-binding protein receptor (CD14), and macrophages (CD68), as well as inflammation scoring measurement were performed. RESULTS: Periodontitis was present in all patients with severe intensity in 7, moderate in 2 and mild in one patient. Same bacterial DNA was detected in A, M, and V in different distribution, and detection was more often in atrium than in myocardium or valve tissue. Morphological investigation revealed increased extracellular inflammatory cell migration. In IHC markers of LBP, CD68 and CD14 showed positive findings for all patients in atrium and myocardium. CONCLUSION: Our results demonstrate the presence of oral bacterial DNA in human cardiac tissue, as well as inflammatory markers potentially indicating connection of PD and VHD. Further investigation is necessary to confirm these preliminary data.

Optimized expression-based microdissection of formalin-fixed lung cancer tissue.

Analysis of specific DNA alterations in precision medicine of tumors is crucially important for molecular targeted treatments. Lung cancer is a prototypic example and one of the leading causes of cancer-related deaths worldwide. One major technical problem of detecting DNA alterations in tissue samples is cellular heterogeneity, that is, mixture of tumor and normal cells. Microdissection is an important tool to enrich tumor cells from heterogeneous tissue samples. However, conventional laser capture microdissection has several disadvantages like user-dependent selection of regions of interest (ROI), high costs for dissection systems and long processing times. ROI selection in expression-based microdissection (xMD) directly relies on cancer cell-specific immunostaining. Whole-slide irradiation leads to localized energy absorption at the sites of most intensive staining and melting of a membrane covering the slide, so that tumor cells can be isolated by removing the complete membrane. In this study, we optimized xMD of lung cancer tissue by enhancing staining intensity of tumor cell-specific immunostaining and processing of the stained samples. This optimized procedure did not alter DNA quality and resulted in enrichment of mutated EGFR DNA from lung adenocarcinoma specimens after xMD. We here also introduce a quality control protocol based on digital whole-slide scanning and image analysis before and after xMD to quantify selectivity and efficiency of the procedure. In summary, this study provides a workflow for xMD, adapted and tested for lung cancer tissue that can be used for lung tumor cell dissection before diagnostic or investigatory analyses.

Supra-aortic interventions for endovascular exclusion of the entire aortic arch.

OBJECTIVE: Our aim was to analyze the outcomes of endovascular exclusion of the entire aortic arch (proximal landing in zone 0, distal landing in zone III or beyond, after Ishimaru) in which complete surgical debranching of the supra-aortic vessels (I), endovascular supra-aortic revascularization (chimney, fenestrated, or branched grafts) with partial surgical debranching (II), or total endovascular supra-aortic revascularization (III) was additionally performed. METHODS: Publications describing endovascular repair of the aortic arch (2000-2016) were systematically searched and reviewed. RESULTS: From a total of 53 relevant studies including 1853 patients, only 1021 patients undergoing 35 different total aortic arch procedures were found eligible for further evaluation and included in group I, II, or III (429, 190, and 402 patients, respectively). Overall early mortality was higher in group I vs groups II and III (P = .001; 1 - ß = 95.6%) but exceeded in group III (18.6%) and group II (14.0%) vs group I (8.0%; P = .044; 1 - ß = 57.4%) for diseases involving zone 0. Mortality was higher in all subgroups treated for zone 0 disease compared with corresponding subgroups treated for zone I to zone III disease. The incidence of cerebral ischemic events was increased in groups I and II vs group III (7.5% and 11% vs 1.7%; P = .0001) and correlated with early mortality (R2 = .20; P = .033). The incidence of type II endoleaks and endovascular reintervention was similar between groups and correlated with each other (R2 = .37; P = .004). Type Ia endoleak occurred more often in groups II and III than in group I (7.1% and 12.1% vs 5.8%; P = .023) and correlated with midterm mortality (R2 = .53; P = .005). Retrograde type A dissection was low in all groups, whereas aneurysm growth was higher in group III (2.6%, 4.2%, 10.7%; P = .002), correlating with midterm mortality (R2 = .311; P = .009). Surgical revision slightly correlated with surgical complications (R2 = .18; P = .044) but not with mortality (R2 = .10; P = .214). CONCLUSIONS: Because early mortality was significantly higher in patients receiving endovascular treatment for proximal aortic disease, endovascular-based approaches proved to be feasible alternatives to hybrid surgical procedures, especially when they were performed for aneurysms located in the distal aortic arch. Whereas cerebral ischemia accompanies both surgical and endovascular involvement of the supra-aortic vessels, endoleaks and aneurysm growth remain hallmarks of endovascular supra-aortic repair. Because surgical revision had no impact on mortality, complete surgical debranching may become the option of choice for patients with good life expectancy suffering from proximal aortic arch disease, whereas total endovascular procedures could be particularly advantageous in patients with short life expectancy and distal aortic arch disease.

ABCA3 Phenotype in Non-Small Cell Lung Cancer Indicates Poor Outcome.

BACKGROUND: ATP-binding cassette transport protein A3 (ABCA3) is expressed in non-small cell lung cancer (NSCLC). We hypothesize that high-level ABCA3 expression may have a negative prognostic impact in patients with NSCLC. METHODS: In 89 patients with NSCLC and curative intended surgery, we analyzed postoperative immunohistochemistry staining of primary tumors (anti-ABCA3) and clinicopathological parameters. We used a unidimensional four point score (FPS) system for intensity assessment and, furthermore, a combined bidimensional scoring of intensity and quantity resulting in the positive index (PI). RESULTS: Former or never-smokers were more likely to have intermediate or strong ABCA3 unidimensional expression (FPS) compared with current smokers (p < 0.01). Patients >65 years of age had a higher probability of intermediate/strong ABCA3 expression (FPS) than younger patients (p < 0.05). In PI measurement, there were no significant correlations between ABCA3 and clinicopathological parameters. Patients with high-level PI had a significantly worse disease-free survival as well as overall survival than patients with low-level PI (p < 0.05). CONCLUSIONS: High-level PI of ABCA3 in NSCLC showed poor disease-free and overall survival in this patient cohort, potentially indicating the relevance of ABCA3 in lung cancer. This observation needs to be validated in larger series.

Comparison of Conductive and Convective Warming in Patients Undergoing Video-Assisted Thoracic Surgery: A Prospective Randomized Clinical Trial.

Background Perioperative hypothermia is frequent during thoracic surgery. After approval by the local ethics committee and written informed consent from patients, we examined the efficiency of prewarming and intraoperative warming with a convective warming system and conductive warming system to prevent perioperative hypothermia during video-assisted thoracic surgery (VATS). Methods We randomized 60 patients with indication for VATS in two groups (convective warming with an underbody blanket vs. conductive warming with an underbody mattress and additional warming of the legs). All patients were prewarmed before induction of anesthesia with the corresponding system. Core temperature was measured sublingual and in the nasopharynx. Results Both groups were not significantly different in regard to clinical parameter, prewarming, and initial core temperature. The patients in conduction group had lower intraoperative core temperatures and a higher incidence of intraoperative (73.9 vs. 24%) and postoperative hypothermia (56.5 vs. 8%) compared with convective warming. Conclusions Pre- and intraoperative convective warming with an underbody blanket prevents perioperative hypothermia during VATS better than conductive warming. The inferior prevention in conductive warming group may be caused by reduced body contact to the warming mattresses in lateral position.

The combined effects of ranolazine and dronedarone on human atrial and ventricular electrophysiology.

INTRODUCTION: Pharmacological rhythm control of atrial fibrillation (AF) in patients with structural heart disease is limited. Ranolazine in combination with low dose dronedarone remarkably reduced AF-burden in the phase II HARMONY trial. We thus aimed to investigate the possible mechanisms underlying these results. METHODS AND RESULTS: Patch clamp experiments revealed that ranolazine (5µM), low-dose dronedarone (0.3µM), and the combination significantly prolonged action potential duration (APD90) in atrial myocytes from patients in sinus rhythm (prolongation by 23.5±0.1%, 31.7±0.1% and 25.6±0.1% respectively). Most importantly, in atrial myocytes from patients with AF ranolazine alone, but more the combination with dronedarone, also prolonged the typically abbreviated APD90 (prolongation by 21.6±0.1% and 31.9±0.1% respectively). It was clearly observed that neither ranolazine, dronedarone nor the combination significantly changed the APD or contractility and twitch force in ventricular myocytes or trabeculae from patients with heart failure (HF). Interestingly ranolazine, and more so the combination, but not dronedarone alone, caused hyperpolarization of the resting membrane potential in cardiomyocytes from AF. As measured by confocal microscopy (Fluo-3), ranolazine, dronedarone and the combination significantly suppressed diastolic sarcoplasmic reticulum (SR) Ca(2+) leak in myocytes from sinus rhythm (reduction by ranolazine: 89.0±30.7%, dronedarone: 75.6±27.4% and combination: 78.0±27.2%), in myocytes from AF (reduction by ranolazine: 67.6±33.7%, dronedarone: 86.5±31.7% and combination: 81.0±33.3%), as well as in myocytes from HF (reduction by ranolazine: 64.8±26.5% and dronedarone: 65.9±29.3%). CONCLUSIONS: Electrophysiological measurements during exposure to ranolazine alone or in combination with low-dose dronedarone showed APD prolongation, cellular hyperpolarization and reduced SR Ca(2+) leak in human atrial myocytes. The combined inhibitory effects on various currents, in particular Na(+) and K(+) currents, may explain the anti-AF effects observed in the HARMONY trial. Therefore, the combination of ranolazine and dronedarone, but also ranolazine alone, may be promising new treatment options for AF, especially in patients with HF, and merit further clinical investigation.

A randomized, parallel group, double-blind study of ticagrelor compared with aspirin for prevention of vascular events in patients undergoing coronary artery bypass graft operation: Rationale and design of the Ticagrelor in CABG (TiCAB) trial: An Investigator-Initiated trial.

BACKGROUND: For patients with coronary artery disease undergoing coronary bypass surgery, acetylsalicylic acid (ASA) currently represents the gold standard of antiplatelet treatment. However, adverse cardiovascular event rates in the first year after coronary artery bypass grafting (CABG) still exceed 10%. Graft failure, which is predominantly mediated by platelet aggregation, has been identified as a major contributing factor in this context. Therefore, intensified platelet inhibition is likely to be beneficial. Ticagrelor, an oral, reversibly binding and direct-acting P2Y12 receptor antagonist, provides a rapid, competent, and consistent platelet inhibition and has shown beneficial results compared with clopidogrel in the subset of patients undergoing bypass surgery in a large previous trial. HYPOTHESIS: Ticagrelor is superior to ASA for the prevention of major cardiovascular events within 1 year after CABG. STUDY DESIGN: The TiCAB trial (NCT01755520) is a multicenter, phase III, double-blind, double-dummy, randomized trial comparing ticagrelor with ASA for the prevention of major cardiovascular events within 12 months after CABG. Patients undergoing CABG will be randomized in a 1:1 fashion to either ticagrelor 90 mg twice daily or ASA 100 mg once daily. The study medication will be started within 24 hours after surgery and maintained for 12 months. The primary end point is the composite of cardiovascular death, myocardial infarction, stroke, and repeat revascularization at 12 months after CABG. The sample size is based on an expected event rate of 13% of the primary end point within the first 12 months after randomization in the control group, a 2-sided α level of .0492 (to preserve the overall significance level of .05 after planned interim analysis), a power of 0.80%, 2-sided testing, and an expected relative risk of 0.775 in the active group compared with the control group and a dropout rate of 2%. According to power calculations based on a superiority design for ticagrelor, it is estimated that 3,850 patients should be enrolled. SUMMARY: There is clinical equipoise on the issue of optimal platelet inhibition after CABG. The TiCAB trial will provide a pivotal comparison of the efficacy and safety of ticagrelor compared with ASA after CABG.

Role of late sodium current as a potential arrhythmogenic mechanism in the progression of pressure-induced heart disease.

The aim of the study was to determine the characteristics of the late Na current (INaL) and its arrhythmogenic potential in the progression of pressure-induced heart disease. Transverse aortic constriction (TAC) was used to induce pressure overload in mice. After one week the hearts developed isolated hypertrophy with preserved systolic contractility. In patch-clamp experiments both, INaL and the action potential duration (APD90) were unchanged. In contrast, after five weeks animals developed heart failure with prolonged APDs and slowed INaL decay time which could be normalized by addition of the INaL inhibitor ranolazine (Ran) or by the Ca/calmodulin-dependent protein kinase II (CaMKII) inhibitor AIP. Accordingly the APD90 could be significantly abbreviated by Ran, tetrodotoxin and the CaMKII inhibitor AIP. Isoproterenol increased the number of delayed afterdepolarizations (DAD) in myocytes from failing but not sham hearts. Application of either Ran or AIP prevented the occurrence of DADs. Moreover, the incidence of triggered activity was significantly increased in TAC myocytes and was largely prevented by Ran and AIP. Western blot analyses indicate that increased CaMKII activity and a hyperphosphorylation of the Nav1.5 at the CaMKII phosphorylation site (Ser571) paralleled our functional observations five weeks after TAC surgery. In pressure overload-induced heart failure a CaMKII-dependent augmentation of INaL plays a crucial role in the AP prolongation and generation of cellular arrhythmogenic triggers, which cannot be found in early and still compensated hypertrophy. Inhibition of INaL and CaMKII exerts potent antiarrhythmic effects and might therefore be of potential therapeutic interest. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".

Intracellular ATP-binding cassette transporter A3 is expressed in lung cancer cells and modulates susceptibility to cisplatin and paclitaxel.

Patients with advanced-stage bronchial cancer benefit from systemic cytostatic therapy, in particular from regimens integrating cisplatin and taxanes. However, eventual disease progression leads to a fatal outcome in most cases, originating from tumor cells resisting chemotherapy. We here show that the intracellular ATP-binding cassette transporter A3 (ABCA3), previously recognized as critical for the secretion of surfactant components from type 2 pneumocytes, is expressed in non-small-cell lung cancer (NSCLC) cells. With some heterogeneity in a given specimen, expression levels detected immunohistochemically in primary cancer tissue were highest in adenocarcinomas and lowest in small cell lung cancers. Genetic silencing of ABCA3 in the NSCLC cell line models A549, NCI-H1650 and NCI-H1975 significantly increased tumor cell susceptibility to the cytostatic effects of both cisplatin (in all cell lines) and paclitaxel (in two of three cell lines). Taken together, ABCA3 emerges as a modulator of NSCLC cell susceptibility to cytostatic therapy.

Incidence of deep sternal wound infection is not reduced with autologous platelet rich plasma in high-risk cardiac surgery patients.

BACKGROUND: Deep sternal wound infections (DSWI) remain a devastating complication in cardiac surgery applying full sternotomy. As the risk profile in cardiac surgery changed toward an older and sicker population, the incidence of DSWI increases. Platelet rich plasma (PRP) holds promise in tissue regeneration with respect to bone regeneration, reduction of bleeding, and accelerated wound healing. The effect of PRP on DSWI was investigated in high-risk patients undergoing cardiac surgery with full sternotomy. METHODS: 196 consecutive patients at risk of DSWI were randomized to application of autologous PRP before sternal wiring (n = 97) or control (n = 99). All patients underwent cardiac surgery on cardiopulmonary bypass with cardioplegic cardiac arrest. Endpoint was occurrence of DSWI requiring revision surgery. RESULTS: Demographic, intraoperative, and perioperative variables as well as risk factors were comparable between groups. Incidence of DSWI was not different between the PRP-group and the control-group (6/97 (6.2%) vs. 3/99 (3.0%); n.s.). CONCLUSIONS: Local application of autologous PRP in cardiac surgery patients with full sternotomy at high risk for sternal complications did not reduce the incidence of DSWI.

Expression and prognostic impact of DNA-PK in human lung cancer.

Among all cancer patient's lung cancer is the leading cause of death. Prognostic biomarkers continue to be investigated for the detection and stratification of lung cancer for clinical use. The DNA-dependent protein kinase is involved in mechanisms of DNA damage repair. Deregulation and overexpression of DNA-dependent protein kinase is associated with poor prognosis in various tumor entities. In this study, we investigated the expression of DNA-dependent protein kinase in relation to clinicopathological features and overall survival in patients with lung cancer. By immunohistochemistry, expression of DNA-dependent protein kinase was analyzed in 205 cases of lung cancer; 95 cases of adenocarcinoma, 83 cases of squamous cell lung carcinoma and 27 cases of small cell lung cancer and correlated with clinicopathological characteristics as well as patient's overall survival. In patients with adenocarcinoma, a significant correlation between strong expression of DNA-dependent protein kinase and worse overall survival was found. No significant association was observed in patients with squamous cell lung carcinoma and small cell lung cancer. Strong detection of DNA-dependent protein kinase expression was most evident in small cell lung cancer (81.48 %), followed by squamous cell lung carcinoma (62.65 %) and adenocarcinoma (61.05 %). In our study, expression of DNA-dependent protein kinase was associated with poor overall survival in patients with adenocarcinoma. DNA-dependent protein kinase could serve as a new prognostic biomarker.

Oral Drug Absorption and Drug Disposition in Critically Ill Cardiac Patients.

(1) Background: In critically ill cardiac patients, parenteral and enteral food and drug administration routes may be used. However, it is not well known how drug absorption and metabolism are altered in this group of adult patients. Here, we analyze drug absorption and metabolism in patients after cardiogenic shock using the pharmacokinetics of therapeutically indicated esomeprazole. (2) Methods: The pharmacokinetics of esomeprazole were analyzed in a consecutive series of patients with cardiogenic shock and controls before and after elective cardiac surgery. Esomeprazole was administered orally or with a nasogastric tube and once as an intravenous infusion. (3) Results: The maximum plasma concentration and AUC of esomeprazole were, on average, only half in critically ill patients compared with controls (p < 0.005) and remained lower even seven days later. Interestingly, esomeprazole absorption was also markedly compromised on day 1 after elective surgery. The metabolites of esomeprazole showed a high variability between patients. The esomeprazole sulfone/esomeprazole ratio reflecting CYP3A4 activity was significantly lower in critically ill patients even up to day 7, and this ratio was negatively correlated with CRP values (p = 0.002). The 5'-OH-esomeprazole and 5-O-desmethyl-esomeprazol ratios reflecting CYP2C19 activity did not differ significantly between critically ill and control patients. (4) Conclusions: Gastrointestinal drug absorption can be significantly reduced in critically ill cardiac patients compared with elective patients with stable cardiovascular disease. The decrease in bioavailability indicates that, under these conditions, any vital medication should be administered intravenously to maintain high levels of medications. After shock, hepatic metabolism via the CYP3A4 enzyme may be reduced.

Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma.

Activating KRAS mutations occur in about 30% of pulmonary adenocarcinoma (AC) cases and the discovery of specific inhibitors of G12C-mutated KRAS has considerably improved the prognosis for a subgroup of about 14% of non-small cell lung cancer (NSCLC) patients. However, even in patients with a KRAS G12C mutation, the overall response rate only reaches about 40% and mutations other than G12C still cannot be targeted. Despite the fact that one-carbon metabolism (1CM) and epigenetic regulation are known to be dysregulated by aberrant KRAS activity, we still lack evidence that co-treatment with drugs that regulate these factors might ameliorate response rates and patient prognosis. In this study, we show a direct dependency of Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and Enhancer of Zeste Homolog 2 (EZH2) expression on mutationally activated KRAS and their prognostic relevance in KRAS-mutated AC. We show that aberrant KRAS activity generates a vulnerability of AC cancer cell lines to both MTHFD2 and EZH2 inhibitors. Importantly, co-inhibition of both factors was synergistically effective and comparable to KRASG12C inhibition alone, paving the way for their use in a therapeutic approach for NSCLC cancer patients.

Expression and prognostic impact of CD49b in human lung cancer.

ABSTRACT: Lung cancer remains the worldwide leading cause of cancer-related death. Currently, prognostic biomarkers for the detection and stratification of lung cancer are being investigated for clinical use. The surface protein cluster of differentiation 49b (CD49b) plays an important role in promoting cell proliferation and invasion in different tumor entities and blocking CD49b improved the tumor immune response. Overexpression of CD49b has been associated with unfavorable survival rates in several malignant tumor entities, such as prostate cancer, gastric cancer and colon cancer. Therefore, we aimed to analyze the protein expression of CD49b in patients with different types of lung cancer and additionally to identify the influence of CD49b on clinicopathological characteristics and overall survival.Expression levels of CD49b were retrospective analyzed by immunohistochemistry in 92 cases of pulmonary adenocarcinoma (AC), 85 cases of squamous cell lung carcinoma (SQCLC) and 32 cases of small cell lung cancer (SCLC) and correlated with clinicopathological characteristics and patients' overall survival.A strong expression of CD49b was most seen in SQCLC (78%), followed by AC (48%) and SCLC (9%). All patients combined, strong expression of CD49b correlated significantly with poorer overall survival. However, an increased expression of CD49b correlated significantly with a poorer survival rate only in SQCLC. In AC and SCLC, no significant correlation could be demonstrated in this regard.In our study, CD49b expression was associated with poor overall survival in patients with SQCLC. Accordingly, CD49b could serve as a new prognostic biomarker and, moreover, be a potential new drug target in SQCLC.

Impact of observer experience on multi-detector computed tomography aortic valve morphology assessment and valve size selection for transcatheter aortic valve replacement.

Transcatheter aortic valve replacement (TAVR) has become the standard treatment for aortic stenosis in older patients. It increasingly relies on accurate pre-procedural planning using multidetector computed tomography (MDCT). Since little is known about the required competence levels for MDCT analyses, we comprehensively assessed MDCT TAVR planning reproducibility and accuracy with regard to valve selection in various healthcare workers. 20 randomly selected MDCT of TAVR patients were analyzed using dedicated software by healthcare professionals with varying backgrounds and experience (two structural interventionalists, one imaging specialist, one cardiac surgeon, one general physician, and one medical student). Following the analysis, the most appropriate Edwards SAPIEN 3™ and Medtronic CoreValve valve size was selected. Intra- and inter-observer variability were assessed. The first structural interventionalist was considered as reference standard for inter-observer comparison. Excellent intra- and inter-observer variability was found for the entire group in regard to the MDCT measurements. The best intra-observer agreement and reproducibility were found for the structural interventionalist, while the medical student had the lowest reproducibility. The highest inter-observer agreement was between both structural interventionalists, followed by the imaging specialist. As to valve size selection, the structural interventionalist showed the highest intra-observer reproducibility, independent of the brand of valve used. Compared to the reference structural interventionalist, the second structural interventionalist showed the highest inter-observer agreement for valve size selection [ICC 0.984, 95% CI 0.969-0.991] followed by the cardiac surgeon [ICC 0.947, 95%CI 0.900-0.972]. The lowest inter-observer agreement was found for the medical student [ICC 0.507, 95%CI 0.067-0.739]. While current state-of-the-art MDCT analysis software provides excellent reproducibility for anatomical measurements, the highest levels of confidence in terms of valve size selection were achieved by the performing interventional physicians. This was most likely attributable to observer experience.