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.

An Alternative Mechanism of Subcellular Iron Uptake Deficiency in Cardiomyocytes.

BACKGROUND: Systemic defects in intestinal iron absorption, circulation, and retention cause iron deficiency in 50% of patients with heart failure. Defective subcellular iron uptake mechanisms that are independent of systemic absorption are incompletely understood. The main intracellular route for iron uptake in cardiomyocytes is clathrin-mediated endocytosis. METHODS: We investigated subcellular iron uptake mechanisms in patient-derived and CRISPR/Cas-edited induced pluripotent stem cell-derived cardiomyocytes as well as patient-derived heart tissue. We used an integrated platform of DIA-MA (mass spectrometry data-independent acquisition)-based proteomics and signaling pathway interrogation. We employed a genetic induced pluripotent stem cell model of 2 inherited mutations (TnT [troponin T]-R141W and TPM1 [tropomyosin 1]-L185F) that lead to dilated cardiomyopathy (DCM), a frequent cause of heart failure, to study the underlying molecular dysfunctions of DCM mutations. RESULTS: We identified a druggable molecular pathomechanism of impaired subcellular iron deficiency that is independent of systemic iron metabolism. Clathrin-mediated endocytosis defects as well as impaired endosome distribution and cargo transfer were identified as a basis for subcellular iron deficiency in DCM-induced pluripotent stem cell-derived cardiomyocytes. The clathrin-mediated endocytosis defects were also confirmed in the hearts of patients with DCM with end-stage heart failure. Correction of the TPM1-L185F mutation in DCM patient-derived induced pluripotent stem cells, treatment with a peptide, Rho activator II, or iron supplementation rescued the molecular disease pathway and recovered contractility. Phenocopying the effects of the TPM1-L185F mutation into WT induced pluripotent stem cell-derived cardiomyocytes could be ameliorated by iron supplementation. CONCLUSIONS: Our findings suggest that impaired endocytosis and cargo transport resulting in subcellular iron deficiency could be a relevant pathomechanism for patients with DCM carrying inherited mutations. Insight into this molecular mechanism may contribute to the development of treatment strategies and risk management in heart failure.

Preoperative Delirium Risk Screening in Patients Undergoing a Cardiac Surgery: Results from the Prospective Observational FINDERI Study.

OBJECTIVE: Postoperative delirium (POD) is a common complication of cardiac surgery that is associated with higher morbidity, longer hospital stay, cognitive decline, and mortality. Preoperative assessments may help to identify patients´ POD risk. However, a standardized screening assessment for POD risk has not been established. DESIGN: Prospective observational FINd DElirium RIsk factors (FINDERI) study. PARTICIPANTS: Patients aged ≥50 years undergoing cardiac surgery. MEASUREMENTS: The primary aim was to analyze the predictive value of the Delirium Risk Screening Questionnaire (DRSQ) prior to cardiac surgery. Secondary aims are to investigate cognitive, frailty, and geriatric assessments, and to use data-driven machine learning (ML) in predicting POD. Predictive properties were assessed using receiver operating characteristics analysis and multivariate approaches (regularized LASSO regression and decision trees). RESULTS: We analyzed a data set of 504 patients (68.3 ± 8.2 years, 21.4% women) who underwent cardiac surgery. The incidence of POD was 21%. The preoperatively administered DRSQ showed an area under the curve (AUC) of 0.68 (95% CI 0.62, 0.73), and the predictive OR was 1.25 (95% CI 1.15, 1.35, p <0.001). Using a ML approach, a three-rule decision tree prediction model including DRSQ (score>7), Trail Making Test B (time>118), and Montreal Cognitive Assessment (score ≤ 22) was identified. The AUC of the three-rule decision tree on the training set was 0.69 (95% CI 0.63, 0.75) and 0.62 (95% CI 0.51, 0.73) on the validation set. CONCLUSION: Both the DRSQ and the three-rule decision tree might be helpful in predicting POD risk before cardiac surgery.

Chromatin Accessibility of Human Mitral Valves and Functional Assessment of MVP Risk Loci.

RATIONALE: Mitral valve prolapse (MVP) is a common valvopathy that leads to mitral insufficiency, heart failure, and sudden death. Functional genomic studies in mitral valves are needed to better characterize MVP-associated variants and target genes. OBJECTIVE: To establish the chromatin accessibility profiles and assess functionality of variants and narrow down target genes at MVP loci. METHODS AND RESULTS: We mapped the open chromatin regions in nuclei from 11 human pathogenic and 7 nonpathogenic mitral valves by an assay for transposase-accessible chromatin with high-throughput sequencing. Open chromatin peaks were globally similar between pathogenic and nonpathogenic valves. Compared with the heart tissue and cardiac fibroblasts, we found that MV-specific assay for transposase-accessible chromatin with high-throughput sequencing peaks are enriched near genes involved in extracellular matrix organization, chondrocyte differentiation, and connective tissue development. One of the most enriched motifs in MV-specific open chromatin peaks was for the nuclear factor of activated T cells family of TFs (transcription factors) involved in valve endocardial and interstitial cell formation. We also found that MVP-associated variants were significantly enriched (P<0.05) in mitral valve open chromatin peaks. Integration of the assay for transposase-accessible chromatin with high-throughput sequencing data with risk loci, extensive functional annotation, and gene reporter assay suggest plausible causal variants for rs2641440 at the SMG6/SRR locus and rs6723013 at the IGFBP2/IGFBP5/TNS1 locus. CRISPR-Cas9 deletion of the sequence including rs6723013 in human fibroblasts correlated with increased expression only for TNS1. Circular chromatin conformation capture followed by high-throughput sequencing experiments provided evidence for several target genes, including SRR, HIC1, and DPH1 at the SMG6/SRR locus and further supported TNS1 as the most likely target gene on chromosome 2. CONCLUSIONS: Here, we describe unprecedented genome-wide open chromatin profiles from human pathogenic and nonpathogenic MVs and report specific gene regulation profiles, compared with the heart. We also report in vitro functional evidence for potential causal variants and target genes at MVP risk loci involving established and new biological mechanisms. Graphic Abstract: A graphic abstract is available for this article.

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.

Turbulence in surgical suction heads as detected by MRI.

BACKGROUND: Blood loss is common during surgical procedures, especially in open cardiac surgery. Allogenic blood transfusion is associated with increased morbidity and mortality. Blood conservation programs in cardiac surgery recommend re-transfusion of shed blood directly or after processing, as this decreases transfusion rates of allogenic blood. But aspiration of blood from the wound area is often associated with increased hemolysis, due to flow induced forces, mainly through development of turbulence. METHODS: We evaluated magnetic resonance imaging (MRI) as a qualitative tool for detection of turbulence. MRI is sensitive to flow; this study uses velocity-compensated T1-weighted 3D MRI for turbulence detection in four geometrically different cardiotomy suction heads under comparable flow conditions (0-1250 mL/min). RESULTS: Our standard control suction head Model A showed pronounced signs of turbulence at all flow rates measured, while turbulence was only detectable in our modified Models 1-3 at higher flow rates (Models 1 and 3) or not at all (Model 2). CONCLUSIONS: The comparison of flow performance of surgical suction heads with different geometries via acceleration-sensitized 3D MRI revealed significant differences in turbulence development between our standard control Model A and the modified alternatives (Models 1-3). As flow conditions during measurement have been comparable, the specific geometry of the respective suction heads must have been the main factor responsible. The underlying mechanisms and causative factors can only be speculated about, but as other investigations have shown, hemolytic activity is positively associated with degree of turbulence. The turbulence data measured in this study correlate with data from other investigations about hemolysis induced by surgical suction heads. The experimental MRI technique used showed added value for further elucidating the underlying physical phenomena causing blood damage due to non-physiological flow.

Transmural myocardial repair with engineered heart muscle in a rat model of heterotopic heart transplantation - A proof-of-concept study.

Engineered heart muscle (EHM) can be implanted epicardially to remuscularize the failing heart. In case of a severely scarred ventricle, excision of scar followed by transmural heart wall replacement may be a more desirable application. Accordingly, we tested the hypothesis that allograft (rat) and xenograft (human) EHM can also be administered as transmural heart wall replacement in a heterotopic, volume-loaded heart transplantation model. We first established a novel rat model model to test surgical transmural left heart wall repair. Subsequently and in continuation of our previous allograft studies, we tested outcome after implantation of contractile engineered heart muscle (EHM) and non-contractile engineered connective tissue (ECT) as well as engineered mesenchymal tissue (EMT) allografts as transmural heart wall replacement. Finally, proof-of-concept for the application of human EHM was obtained in an athymic nude rat model. Only in case of EHM implantation, remuscularization of the surgically created transmural defect was observed with palpable graft vascularization. Taken together, feasibility of transmural heart repair using bioengineered myocardial grafts could be demonstrated in a novel rat model of heterotopic heart transplantation.

Direct proteomic and high-resolution microscopy biopsy analysis identifies distinct ventricular fates in severe aortic stenosis.

The incidence of aortic valve stenosis (AS), the most common reason for aortic valve replacement (AVR), increases with population ageing. While untreated AS is associated with high mortality, different hemodynamic subtypes range from normal left-ventricular function to severe heart failure. However, the molecular nature underlying four different AS subclasses, suggesting vastly different myocardial fates, is unknown. Here, we used direct proteomic analysis of small left-ventricular biopsies to identify unique protein expression profiles and subtype-specific AS mechanisms. Left-ventricular endomyocardial biopsies were harvested from patients during transcatheter AVR, and inclusion criteria were based on echocardiographic diagnosis of severe AS and guideline-defined AS-subtype classification: 1) normal ejection fraction (EF)/high-gradient; 2) low EF/high-gradient; 3) low EF/low-gradient; and 4) paradoxical low-flow/low-gradient AS. Samples from non-failing donor hearts served as control. We analyzed 25 individual left-ventricular biopsies by data-independent acquisition mass spectrometry (DIA-MS), and 26 biopsies by histomorphology and cardiomyocytes by STimulated Emission Depletion (STED) superresolution microscopy. Notably, DIA-MS reliably detected 2273 proteins throughout each individual left-ventricular biopsy, of which 160 proteins showed significant abundance changes between AS-subtype and non-failing samples including the cardiac ryanodine receptor (RyR2). Hierarchical clustering segregated unique proteotypes that identified three hemodynamic AS-subtypes. Additionally, distinct proteotypes were linked with AS-subtype specific differences in cardiomyocyte hypertrophy. Furthermore, superresolution microscopy of immunolabeled biopsy sections showed subcellular RyR2-cluster fragmentation and disruption of the functionally important association with transverse tubules, which occurred specifically in patients with systolic dysfunction and may hence contribute to depressed left-ventricular function in AS.

Identification of risk factors for delirium, cognitive decline, and dementia after cardiac surgery (FINDERI-find delirium risk factors): a study protocol of a prospective observational study.

BACKGROUND: Postoperative delirium is a common complication of cardiac surgery associated with higher morbidity, longer hospital stay, risk of cognitive decline, dementia, and mortality. Geriatric patients, patients undergoing cardiac surgery, and intensive care patients are at a high risk of developing postoperative delirium. Gold standard assessments or biomarkers to predict risk factors for delirium, cognitive decline, and dementia in patients undergoing cardiac surgery are not yet available. METHODS: The FINDERI trial (FINd DElirium RIsk factors) is a prospective, single-center, observational study. In total, 500 patients aged ≥ 50 years undergoing cardiac surgery at the Department of Cardiovascular and Thoracic Surgery of the University of Göttingen Medical Center will be recruited. Our primary aim is to validate a delirium risk assessment in context of cardiac surgery. Our secondary aims are to identify specific preoperative and perioperative factors associated with delirium, cognitive decline, and accelerated dementia after cardiac surgery, and to identify blood-based biomarkers that predict the incidence of postoperative delirium, cognitive decline, or dementia in patients undergoing cardiac surgery. DISCUSSION: This prospective, observational study might help to identify patients at high risk for delirium prior to cardiac surgery, and to identify important biological mechanisms by which cardiac surgery is associated with delirium. The predictive value of a delirium screening questionnaire in cardiac surgery might be revealed. Finally, the identification of specific blood biomarkers might help to predict delirium, cognitive decline, and dementia in patients undergoing cardiac surgery. TRIAL REGISTRATION: Ethics approval for this study was obtained from the IRB of the University of Göttingen Medical Center. The investigators registered this study in the German Clinical Trials Register (DRKS; https://www.drks.de ) (DRKS00025095) on April 19th, 2021.

A New Evaluation Q-Factor to Be Calculated for Suction Geometries as a Basis for Smooth Suction in the Operating Field to Ensure the Highest Possible Blood Integrity for Retransfusion Systems.

Blood hemolysis caused by mechanical impact is a serious problem in medicine. In addition to the heart-lung machine (artificial surfaces, flow irritating connection points) which contributes to hemolysis, blood suction and surgical suction devices are influencing factors. Goal of our research is to develop best flow optimizing suction geometry that represents the best compromise between all influencing effects. Based on data that negative pressure and turbulence have a negative impact on blood components, 27 surgical suction tips have been examined for acoustic stress and negative pressure behavior. Furthermore, a dimensionless factor Q was introduced to assess the overall performance of the suction tips investigated.

Dynamic risk assessment to improve quality of care in patients with atrial fibrillation: the 7th AFNET/EHRA Consensus Conference.

AIMS: The risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes. METHODS AND RESULTS: This article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence. CONCLUSION: The remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy.

The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.

Patients operated for infective endocarditis (IE) are at high risk of developing an excessive systemic hyperinflammatory state, resulting in systemic inflammatory response syndrome and septic shock. Hemoadsorption (HA) by cytokine adsorbers has been successfully applied to remove inflammatory mediators. This randomized controlled trial investigates the effect of perioperative HA therapy on inflammatory parameters and hemodynamic status in patients operated for IE. A total of 20 patients were randomly assigned to either HA therapy or the control group. HA therapy was initiated intraoperatively and continued for 24 hours postoperatively. Cytokine levels (IL-6, IL-1b, TNF-α), leukocytes, C-reactive protein (CRP), and Procalcitonin (PCT) as well as catecholamine support, and volume requirement were compared between both groups. Operative procedures included aortic (n = 7), mitral (n = 6), and multiple valve surgery (n = 7). All patients survived to discharge. No significant differences concerning median cytokine levels (IL-6 and TNF-α) were observed between both groups. CRP and PCT baseline levels were significantly higher in the HA group (59.5 vs. 26.3 mg/dL, P = .029 and 0.17 vs. 0.05 µg/L, P = .015) equalizing after surgery. Patients in the HA group required significantly higher doses of vasopressors (0.093 vs. 0.025 µg/kg/min norepinephrine, P = .029) at 12 hours postoperatively as well as significantly more overall volume replacement (7217 vs. 4185 mL at 12 hours, P = .015; 12 021 vs. 4850 mL at 48 hours, P = .015). HA therapy did neither result in a reduction of inflammatory parameters nor result in an improvement of hemodynamic parameters in patients operated for IE. For a more targeted use of HA therapy, appropriate selection criteria are required.

Impact of myocardial fibrosis on left ventricular remodelling, recovery, and outcome after transcatheter aortic valve implantation in different haemodynamic subtypes of severe aortic stenosis.

AIMS: Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes. METHODS AND RESULTS: One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson's trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF-) median percentage MF (≥11% or <11%). Myocardial fibrosis burden differed significantly between AS subtypes, with highest levels in low ejection fraction (EF), low-gradient AS and lowest levels in normal EF, high-gradient AS (29.5 ± 26.4% vs. 13.5 ± 16.1%, P = 0.003). In the entire cohort, MF+ was significantly associated with poorer LV function, higher extent of pathological LV remodelling, and more pronounced clinical heart failure at BL. After TAVI, MF+ was associated with a delay in normalization of LV geometry and function but not per se with absence of reverse remodelling and clinical improvement. However, 22 patients died during follow-up (mean, 11 months), and 14 deaths were classified as cardiovascular (CV) (n = 9 arrhythmia-associated). Importantly, 13 of 14 CV deaths occurred in MF+ patients (CV mortality 26.5% in MF+ vs. 2% in MF- patients, P = 0.0003). Multivariate analysis identified MF+ as independent predictor of CV mortality [hazard ratio (HR) 27.4 (2.0-369), P = 0.01]. CONCLUSION: Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.

Complex Valve Surgery in Elderly Patients: Increasingly Necessary and Surprisingly Feasible.

OBJECTIVES: The increasing proportion of elderly patients in cardiac surgery poses additional challenges for the clinical management and leads to a higher operative risk due to multiple comorbidities of these patients. We reviewed the outcome of patients who were 75 years and older and underwent complex multiple valve surgery at our institution. METHODS: A retrospective review was performed to identify patients who were 75 years and older and underwent multiple valve surgery between January 2011 and May 2016 at our institution. Patients were assigned to one out of four subgroups: combined aortic and mitral valve surgery (group AM), aortic and tricuspid valve surgery (group AT), mitral and tricuspid valve surgery (group MT), and aortic, mitral, and tricuspid valve surgery (group AMT). RESULTS: A total of 311 patients underwent multiple valve surgery, of whom 119 (38.3%) were 75 years and older (median: 78 [25th-75th quartile: 76-80]). The estimated operative mortality (EuroSCORE II) in the overall cohort was 10.7%. The observed 30-day mortality was 4.2% (7% in group AM, 0% in group AT, 2.2% in group MT, 3.8% in group AMT; p = 0.685). Main complications were reexplorative surgery in 16%, adverse cerebrovascular events in 6.7%, prolonged mechanical ventilation in 10.1%, renal replacement therapy in 15.1%, nosocomial pneumonia in 15.1%, and pacemaker implantation in 18.5%. CONCLUSIONS: This study demonstrates the feasibility of complex multiple valve surgery in elderly patients. The observed perioperative mortality was lower than predicted. However, we observed a substantial rate of adverse events; therefore, careful patient selection is required in this high-risk patient population.

Turning Things Around: The Role of Prone Positioning in the Management of Acute Respiratory Failure After Cardiac Surgery.

OBJECTIVES: The aim of this study was to determine the benefit of prone positioning (PP) in patients developing acute respiratory failure (ARF) after cardiac surgery. DESIGN: A retrospective analysis. SETTING: Review of the institutional database between October 2016 and October 2018 revealed 24 patients who underwent PP for the treatment of ARF after cardiac surgery. PARTICIPANTS: The authors found 24 patients who underwent PP for the treatment of ARF after cardiac surgery. This included 10 patients who required extracorporeal membrane oxygenation (ECMO) therapy. Among them, 6 patients with simultaneous PP and ECMO therapy. INTERVENTIONS: Data were collected at the time of PP, 6 hours after PP, at the end of PP, and 6 hours after return to supine position (SP). MEASUREMENTS AND MAIN RESULTS: The median duration of postoperative mechanical ventilation was 281 hours (183-528 hours). Prone positioning was carried out on the fourth postoperative day (POD), with a total of 5 patients undergoing PP within 24 hours following surgery. The median duration of PP before return to SP was 12 hours (12-16 hours), with the maximal duration of PP being 22 hours in this cohort. The authors observed an increase in Horowitz index (HI) at the end of PP (p < 0.001) as well as 6 hours after supine positioning. In the subgroup of patients who underwent PP on ECMO (v-a ECLS = 3, v-v ECMO = 3), a significant reduction of ECMO support was achieved from 3.0 (2.2-5.6) liters/min to 2.5 (2.0-4.6) liters/min (p = 0.023). No adverse events occurred during the positioning of the patients. CONCLUSIONS: Prone positioning can be considered for the treatment of ARF after cardiac surgery to improve short-term respiratory conditions and possibly facilitate ECMO weaning.

Minimally invasive versus conventional extracorporeal circulation circuits in patients undergoing coronary artery bypass surgery: a propensity-matched analysis.

OBJECTIVES: Minimally invasive extracorporeal circulation circuits provide several advantages compared to conventional extracorporeal circulation circuits. We compared the results of a minimally invasive extracorporeal circulation system with those of conventional extracorporeal circulation system, in patients undergoing isolated coronary artery bypass grafting. METHODS: We identified 753 consecutive patients who underwent coronary artery bypass grafting at our centre between October 2014 and September 2016. These patients were divided into two groups: a minimally invasive extracorporeal circulation group (M, n = 229) and a conventional extracorporeal circulation group (C, n = 524). Baseline parameters, details of cardiac surgery as well as postoperative complications and outcomes were compared by means of a propensity-matched analysis of 180 matched pairs. RESULTS: The median EuroSCORE II was 1.3%. Transfusion requirement of packed red blood cells (p = 0.002) was lower in Group M compared to conventional extracorporeal circulation systems. There were no differences in hospital mortality or in rates of adverse events between the matched groups. Total in-hospital mortality of the cohort was 1.7%. CONCLUSION: The use of minimally invasive extracorporeal circulation is associated with a significantly lower use of blood products after isolated coronary revascularisation. There were no differences concerning duration of surgery, complication rates and mortality between the groups. Therefore, the application of minimally invasive extracorporeal circulation systems should be considered as preferred technique in isolated coronary artery bypass grafting procedures.

[The Joy of Being a Surgeon - How to Generate Enthusiasm in Undergraduate Medical Education - A Local Example: The "Göttinger Aufschneidertag"]. / Freude an der Chirurgie ­ Einblicke gewähren, Begeisterung wecken.

Offering a full-day program including practical courses and the possibility of direct exchange between medical students and university teachers, the "Göttinger Aufschneidertag" was launched to generate enthusiasm for surgery. Workshops comprising four surgical disciplines enable participants to gain insight into the craft of surgery. The program aims to create interest in surgery among medical students at an early point of their studies and to make them enjoy their profession.

bFGF-mediated pluripotency maintenance in human induced pluripotent stem cells is associated with NRAS-MAPK signaling.

BACKGROUND: Human pluripotent stem cells (PSCs) open new windows for basic research and regenerative medicine due to their remarkable properties, i.e. their ability to self-renew indefinitely and being pluripotent. There are different, conflicting data related to the role of basic fibroblast growth factor (bFGF) in intracellular signal transduction and the regulation of pluripotency of PSCs. Here, we investigated the effect of bFGF and its downstream pathways in pluripotent vs. differentiated human induced (hi) PSCs. METHODS: bFGF downstream signaling pathways were investigated in long-term culture of hiPSCs from pluripotent to differentiated state (withdrawing bFGF) using immunoblotting, immunocytochemistry and qPCR. Subcellular distribution of signaling components were investigated by simple fractionation and immunoblotting upon bFGF stimulation. Finally, RAS activity and RAS isoforms were studied using RAS assays both after short- and long-term culture in response to bFGF stimulation. RESULTS: Our results revealed that hiPSCs were differentiated into the ectoderm lineage upon withdrawing bFGF as an essential pluripotency mediator. Pluripotency markers OCT4, SOX2 and NANOG were downregulated, following a drastic decrease in MAPK pathway activity levels. Notably, a remarkable increase in phosphorylation levels of p38 and JAK/STAT3 was observed in differentiated hiPSCs, while the PI3K/AKT and JNK pathways remained active during differentiation. Our data further indicate that among the RAS paralogs, NRAS predominantly activates the MAPK pathway in hiPSCs. CONCLUSION: Collectively, the MAPK pathway appears to be the prime signaling pathway downstream of bFGF for maintaining pluripotency in hiPSCs and among the MAPK pathways, the activity of NRAS-RAF-MEK-ERK is decreased during differentiation, whereas p38 is activated and JNK remains constant.

Multimodal Imaging for In Vivo Evaluation of Induced Pluripotent Stem Cells in a Murine Model of Heart Failure.

Myocardial stem cell therapy in heart failure is strongly dependent on successful cellular transfer, engraftment, and survival. Moreover, massive cell loss directly after intramyocardial injection is commonly observed, generating the need for efficient longitudinal monitoring of transplanted cells in order to develop more efficient transplantation techniques. Therefore, the aim of the present study was to assess viability and cardiac retention of induced pluripotent stem cells after intramyocardial delivery using in vivo bioluminescence analysis (BLI) and magnetic resonance imaging (MRI). Murine induced pluripotent stem cells (iPSCs) were transfected for luciferase reporter gene expression and labeled intracellularly with supraparamagnetic iron oxide particles. Consequently, 5 × 105 cells were transplanted intramyocardially following left anterior descending coronary artery ligation in mice. Cardiac iPSCs were detected using BLI and serial T2* sequences by MRI in a 14-day follow-up. Additionally, infarct extension and left ventricular (LV) function were assessed by MRI. Controls received the same surgical procedure without cell injection. MRI sequences showed a strong MRI signal of labeled iPSCs correlating with myocardial late enhancement, demonstrating engraftment in the infarcted area. Mean iPSC volumes were 4.2 ± 0.4 mm3 at Day 0; 3.1 ± 0.4 mm3 at Day 7; and 5.1 ± 0.8 mm3 after 2 weeks. Thoracic BLI radiance decreased directly after injection from 1.0 × 106 ± 4.2 × 104 (p/s/cm2 /sr) to 1.0 × 105 ± 4.9 × 103 (p/s/cm2 /sr) on Day 1. Afterward, BLI radiance increased to 1.1 × 106 ± 4.2 × 104 (p/s/cm2 /sr) 2 weeks after injection. Cardiac graft localization was confirmed by ex vivo BLI analysis and histology. Left ventricular ejection fraction was higher in the iPSC group (30.9 ± 0.9%) compared to infarct controls (24.0 ± 2.1%; P < 0.05). The combination of MRI and BLI assesses stem cell fate in vivo, enabling cardiac graft localization with evaluation of LV function in myocardial infarction.

Perioperative Hemodynamic Instability and Fluid Overload are Associated with Increasing Acute Kidney Injury Severity and Worse Outcome after Cardiac Surgery.

PURPOSE: The study aimed to investigate patients' characteristics, fluid and hemodynamic management, and outcomes according to the severity of cardiac surgery-associated acute kidney injury (CSA-AKI). METHODS: In a single-center, prospective cohort study, we enrolled 282 adult cardiac surgical patients. In a secondary analysis, we assessed preoperative patients' characteristics, physiological variables, and medication for intra- and postoperative fluid and hemodynamic management and outcomes according to CSA-AKI stages by the Renal risk, Injury, Failure, Loss, End-stage renal disease (RIFLE) classification. Variables of fluid and hemodynamic management were further assessed with regard to the need for postoperative renal replacement therapy (RRT) and in-hospital mortality by the area under the curve for the receiver operating characteristic (AUC-ROC) and multivariate regression analysis. RESULTS: Patients with worsening RIFLE stage, were significantly older, had lower estimated glomerular filtration rate and higher body mass index, more peripheral vascular and chronic obstructive pulmonary disease, atrial fibrillation, and prolonged duration of cardiopulmonary bypass (all p < 0.01). Patients with more severe AKI stage stayed longer in the intensive care and hospital, had higher in-hospital mortality, and requirement for RRT (all p < 0.001). Also, with worsening RIFLE stage, patients had lower intraoperative mean arterial pressure (MAP); p = 0.047, despite higher doses of norepinephrine (p < 0.001). The intraoperative MAP showed the best discriminatory ability (AUC-ROC: >0.8) for and was independently associated with RRT and in-hospital mortality. Moreover, with increasing AKI severity, patients received significantly more fluid infusion, and required higher dose of furosemide; nonetheless, they had increased postoperative fluid balance. CONCLUSIONS: In this cohort, reduced MAP and increased fluid balance were independently associated with increased mortality and need for RRT after cardiac surgery.