Sunitinib malate induces cell death in adult human cardiac progenitor cells.

Sunitinib malate is known to cause cardiotoxicity in a sub-population of patients, with heart failure seen in more severe cases. Cardiac progenitor cells (CPCs) have been identified in adult human myocardium and contribute to overall tissue maintenance, with previous work identifying negative impacts of sunitinib on these cells. This study aimed to characterise the toxic effects of sunitinib in human CPCs, applying sunitinib concentrations equivalent to clinical plasma levels to these cells in vitro. Cell viability was reduced by 26.5 ± 6.6 % by 2 µM sunitinib for 24 h (p < 0.01); this concentration also induced fold-change increases in gene expression of: calpain (3.1 ± 0.73, p < 0.05), FAS (2.3 ± 0.8, p < 0.05) and BAX (1.9 ± 0.2, p < 0.05), and a decrease in BCL-2 (3.5 ± 0.0, p < 0.001), vs. control (1.0 ± 0.0). This was affirmed by sunitinib inducing fold changes in protein expression of: calpain-1 (2.5 ± 0.5, p < 0.05); FAS receptor (2.1 ± 0.2, p < 0.05) and BAX (2.1 ± 0.2, p < 0.05) vs. control (1.0 ± 0.0). These results indicated that sunitinib induced apoptosis in CPCs, but negative annexin V staining and lack of protection by caspase inhibitors indicated this was not the cell death pathway activated. Further investigation found sunitinib was concentrated in the lysosomes and autophagosomes within CPCs, but did not induce accumulation of acidic organelles. In conclusion, these data confirm that cell death is caused by sunitinib in CPCs at concentrations equivalent to clinical plasma levels, inducing cell death pathway signals that lead to non-apoptotic cell death.

Association Between Type 2 Diabetes and Changes in Myocardial Structure, Contractile Function, Energetics, and Blood Flow Before and After Aortic Valve Replacement in Patients With Severe Aortic Stenosis.

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of left ventricular dysfunction after aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Persistent impairments in myocardial energetics and myocardial blood flow (MBF) may underpin this observation. Using phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance, this study tested the hypothesis that patients with severe AS and T2D (AS-T2D) would have impaired myocardial energetics as reflected by the phosphocreatine to ATP ratio (PCr/ATP) and vasodilator stress MBF compared with patients with AS without T2D (AS-noT2D), and that these differences would persist after AVR. METHODS: Ninety-five patients with severe AS without coronary artery disease awaiting AVR (30 AS-T2D and 65 AS-noT2D) were recruited (mean, 71 years of age [95% CI, 69, 73]; 34 [37%] women). Thirty demographically matched healthy volunteers (HVs) and 30 patients with T2D without AS (T2D controls) were controls. One month before and 6 months after AVR, cardiac PCr/ATP, adenosine stress MBF, global longitudinal strain, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and 6-minute walk distance were assessed in patients with AS. T2D controls underwent identical assessments at baseline and 6-month follow-up. HVs were assessed once and did not undergo 6-minute walk testing. RESULTS: Compared with HVs, patients with AS (AS-T2D and AS-noT2D combined) showed impairment in PCr/ATP (mean [95% CI]; HVs, 2.15 [1.89, 2.34]; AS, 1.66 [1.56, 1.75]; P<0.0001) and vasodilator stress MBF (HVs, 2.11 mL min g [1.89, 2.34]; AS, 1.54 mL min g [1.41, 1.66]; P<0.0001) before AVR. Before AVR, within the AS group, patients with AS-T2D had worse PCr/ATP (AS-noT2D, 1.74 [1.62, 1.86]; AS-T2D, 1.44 [1.32, 1.56]; P=0.002) and vasodilator stress MBF (AS-noT2D, 1.67 mL min g [1.5, 1.84]; AS-T2D, 1.25 mL min g [1.22, 1.38]; P=0.001) compared with patients with AS-noT2D. Before AVR, patients with AS-T2D also had worse PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.66 [1.56, 1.75]; P=0.04) and vasodilator stress MBF (AS-T2D, 1.25 mL min g [1.10, 1.41]; T2D controls, 1.54 mL min g [1.41, 1.66]; P=0.001) compared with T2D controls at baseline. After AVR, PCr/ATP normalized in patients with AS-noT2D, whereas patients with AS-T2D showed no improvements (AS-noT2D, 2.11 [1.79, 2.43]; AS-T2D, 1.30 [1.07, 1.53]; P=0.0006). Vasodilator stress MBF improved in both AS groups after AVR, but this remained lower in patients with AS-T2D (AS-noT2D, 1.80 mL min g [1.59, 2.0]; AS-T2D, 1.48 mL min g [1.29, 1.66]; P=0.03). There were no longer differences in PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.51 [1.34, 1.53]; P=0.12) or vasodilator stress MBF (AS-T2D, 1.48 mL min g [1.29, 1.66]; T2D controls, 1.60 mL min g [1.34, 1.86]; P=0.82) between patients with AS-T2D after AVR and T2D controls at follow-up. Whereas global longitudinal strain, 6-minute walk distance, and NT-proBNP all improved after AVR in patients with AS-noT2D, no improvement in these assessments was observed in patients with AS-T2D. CONCLUSIONS: Among patients with severe AS, those with T2D demonstrate persistent abnormalities in myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function after AVR; AVR effectively normalizes myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function in patients without T2D.

Imatinib Mesylate Induces Necroptotic Cell Death and Impairs Autophagic Flux in Human Cardiac Progenitor Cells.

The receptor tyrosine kinase inhibitor imatinib improves patient cancer survival but is linked to cardiotoxicity. This study investigated imatinib's effects on cell viability, apoptosis, autophagy, and necroptosis in human cardiac progenitor cells in vitro. Imatinib reduced cell viability (75.9 ± 2.7% vs. 100.0 ± 0.0%) at concentrations comparable to peak plasma levels (10 µM). Imatinib reduced cells' TMRM fluorescence (74.6 ± 6.5% vs. 100.0 ± 0.0%), consistent with mitochondrial depolarisation. Imatinib increased lysosome and autophagosome content as indicated by LAMP2 expression (2.4 ± 0.3-fold) and acridine orange fluorescence (46.0 ± 5.4% vs. 9.0 ± 3.0), respectively. Although imatinib increased expression of autophagy-associated proteins and also impaired autophagic flux, shown by proximity ligation assay staining for LAMP2 and LC3II (autophagosome marker): 48 h of imatinib treatment reduced visible puncta to 2.7 ± 0.7/cell from 11.3 ± 2.1 puncta/cell in the control. Cell viability was partially recovered by autophagosome inhibition by wortmannin, with the viability increasing 91.8 ± 8.2% after imatinib-wortmannin co-treatment (84 ± 1.5% after imatinib). Imatinib-induced necroptosis was associated with an 8.5 ± 2.5-fold increase in mixed lineage kinase domain-like pseudokinase activation. Imatinib-induced toxicity was rescued by RIP1 inhibition: 88.6 ± 3.0% vs. 100.0 ± 0.0% in the control. Imatinib applied to human cardiac progenitor cells depolarises mitochondria and induces cell death through necroptosis, recoverable by RIP1 inhibition, with a partial role for autophagy.

An unusual cause of a haemothorax following pacemaker implantation: A case report.

Background: Haemothoraces are a reported but extremely rare complication of pacemaker implantation. Haemothoraces can be a consequence of lead perforation through the right ventricle (RV) and pericardium into the pleural space, direct lung or vascular injury during access. Case summary: A 72-year-old woman presented 24 h after a pacemaker implantation with chest pain and shortness of breath. Computed tomography of the chest confirmed perforation of the RV lead into the left pleural cavity with a large left sided haemothorax. Following percutaneous drainage of the left sided haemothorax, the patient became haemodynamically unstable necessitating emergent sternotomy. During surgery, the extra-cardiac portion of the pacing lead was cut, the RV repaired and a large haematoma evacuated from the left pleural space. Despite this, the patient remained hypotensive, and further exploration showed a bleeding intercostal artery that had been lacerated by the pacing lead. This was treated by electrocautery, and the patient's haemodynamic status improved. The RV lead remnant was removed transvenously via the subclavian vein, and the patient was left with a single chamber atrial pacemaker. Discussion: Prompt recognition of RV lead perforation and its associated sequalae, often utilising multi-modality imaging, is vital to enable transfer to a centre with cardiac surgical expertise. In this case, the perforating RV lead lacerated an intercostal artery, and this was only identified at the time of surgery. In order to minimize the risk of perforation, multiple fluoroscopic views should be used, and care should be taken during helix deployment.

Surgical ergonomics. Analysis of technical skills, simulation models and assessment methods.

INTRODUCTION: Over the past two centuries the surgical profession has undergone a profound evolution in terms of efficiency and outcomes. Societal concerns in relation to quality assurance, patient safety and cost reduction have highlighted the issue of training expert surgeons. The core elements of a training model build on the basic foundations of gross and fine motor skills. In this paper we provide an analysis of the ergonomic principles involved and propose relevant training techniques. We have endeavored to provide both the trainer and trainee perspectives. METHODS: This paper is structured into four sections: 1) Pre-operative preparation issues, 2) technical skills and instrument handling, 3) low fidelity simulation models and 4) discussion of current concepts in crew resource management, deliberate practice and assessment. DISCUSSION: Rehearsal, warm-up and motivation-enhancing techniques aid concentration and focus. Appropriate posture, comprehension of ergonomic principles in relation to surgical instruments and utilisation of the non-dominant hand are essential skills to master. Low fidelity models can be used to achieve significant progress through the early stages of the learning curve. Deliberate practice and innate ability are complementary to each other and may be considered useful adjuncts to surgical skills development. CONCLUSION: Safe medical care requires that complex patient interventions be performed by highly skilled operators supported by reliable teams. Surgical ergonomics lie at the heart of any training model that aims to produce professionals able to function as leaders of a patient safety oriented culture.

Surgical management of malignant pleural mesothelioma: impact of surgery on survival and quality of life-relation to chemotherapy, radiotherapy, and alternative therapies.

Introduction. Malignant pleural mesothelioma (MPM) is an aggressive cancer arising from pleural mesothelium. Surgery aims to either cure the disease or control the symptoms. Two surgical procedures exist: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). In this systematic review we assess current evidence on safety and efficacy of surgery. Methods. Five electronic databases were reviewed from January 1990 to January 2013. Studies were selected according to a predefined protocol. Primary endpoint was overall survival. Secondary endpoints included quality of life, disease-free survival, disease recurrence, morbidity, and length of hospital stay. Results. Sixteen studies were included. Median survival ranged from 8.1 to 32 months for P/D and from 6.9 to 46.9 months for EPP. Perioperative mortality was 0%-9.8% and 3.2%-12.5%, respectively. Perioperative morbidity was 5.9%-55% for P/D and 10%-82.6% for EPP. Average length of stay was 7 days for P/D and 9 days for EPP. Conclusion. Current evidence cannot definitively answer which procedure (EPP or P/D) is more beneficial in terms of survival and operative risks. This systematic review suggests that surgery in the context of trimodality therapy offers acceptable perioperative outcomes and long-term survival. Centres specialising in MPM management have better results.

Long-term survival from 801 adjunctive coronary endarterectomies in diffuse coronary artery disease.

OBJECTIVES: The role of coronary endarterectomy (CE) in modern cardiac surgery has been an extant debate as coronary artery bypass grafting (CABG) has advanced. However, as cardiac surgeons are being referred ever more complex coronary disease for surgical correction, adjunctive strategies may need re-evaluation. The long-term results of CE are largely unknown. We present the longest cohort follow-up in a single institution looking at our 20-year experience of CEs employed as an adjunct to CABG in diffuse coronary artery disease. METHODS: We performed retrospective analysis of data collected prospectively on 801 patients undergoing CEs between February 1988 and September 2010 by a single surgeon using a standard open hydrodissection technique. We looked at patient demographics, characteristics of the vessels subjected to endarterectomy and predictors of long-term survival within this surgical group using Cox's regression analysis. RESULTS: The mean age was 63.2 (±9.6) years. The mean number of coronary arteries undergoing endarterectomy was 1.16 (±0.4) per patient. Of these, 63.7% were performed on the right coronary artery (n = 558) and 32.3% on the left anterior descending artery (n = 283). The operative mortality was 2.62% (n = 21). The median survival time was 16.67 years (95% confidence interval 15.14-18.19 years). The significant predictors of survival (P < 0.05) were a lower age at surgery, a lower EuroSCORE I, the absence of peripheral vascular disease and shorter bypass times. CONCLUSION: This significant long-term survival demonstrates that CE can be an attractive adjunct to CABG in otherwise inoperable coronary artery disease.

Presentation and management of keloid scarring following median sternotomy: a case study.

INTRODUCTION: Keloid scars following median sternotomy are rare and occur more frequently in pigmented skin. Different management strategies have been described with variable success. We present a case of keloid scar formation following cardiac surgery including our management and the final aesthetic result. CASE DESCRIPTION: A 64 year old female of fair complexion underwent mitral valve replacement. The procedure and postoperative recovery were uncomplicated, however, during the following year, thick keloid scars formed over the incision sites. Initial non surgical measures failed to relieve pain and did not offer any tangible aesthetic benefit. Eventually surgical excision was attempted. She presented to our clinic for nine months follow up with significant improvement in pain and aesthetic result. DISCUSSION AND EVALUATION: Several theories have attempted to explore the pathophysiology of keloid scar formation. A number of predisposing factors have been documented however none existed in this case. A variety of invasive and non invasive approaches have been described but significant differences in success rates and methodology of investigations still precludes a standardized management protocol. CONCLUSIONS: In this case study a rare presentation of keloid scar has been presented. The variety of methods used to improve pain and aesthetic result demonstrates the propensity of keloid scars to recur and the therapeutic challenges that surgeons have to face in their quest for a satisfactory patient outcome.

Briefing and debriefing in the cardiac operating room. Analysis of impact on theatre team attitude and patient safety.

Error in health services delivery has long been recognised as a significant cause of inpatient morbidity and mortality. Root-cause analyses have cited communication failure as one of the contributing factors in adverse events. The formalised fighter pilot mission brief and debrief formed the basis of the National Aeronautics and Space Administration (NASA) crew resource management (CRM) concept produced in 1979. This is a qualitative analysis of our experience with the briefing-debriefing process applied to cardiac theatres. We instituted a policy of formal operating room (OR) briefing and debriefing in all cardiac theatre sessions. The first 118 cases were reviewed. A trouble-free operation was noted in only 28 (23.7%) cases. We experienced multiple problems in 38 (32.2%) cases. A gap was identified in the second order problem solving in relation to instrument repair and maintenance. Theatre team members were interviewed and their comments were subjected to qualitative analysis. The collaborative feeling is that communication has improved. The health industry may benefit from embracing the briefing-debriefing technique as an adjunct to continuous improvement through reflective learning, deliberate practice and immediate feedback. This may be the initial step toward a substantive and sustainable organizational transformation.

Surgical training in the 48-h week: a novel simulation and educational tool. From amateur golfer to professional pilot.

INTRODUCTION: Compliance with the European Working Time Directive has made obvious the need for a surgical skills training system that will produce surgeons fast and reliably. We have previously proposed a model for objective assessment of surgical dexterity. In this paper we aim to place an updated version of that model into the context of a holistic approach on assessment of a trainee's progress towards becoming an independently operating surgeon. METHODS: The PAR matrix breaks down an operation into clearly defined skills that need to be successively acquired. It consists of a 3 x 6 table depicting 18 skill-goals. The y-axis is divided into six levels and the x-axis into three columns. The initials of the three skills on each level form the acronym PAR. Each skill is further graded from 1 to 3 (unsatisfactory, competent, good). The levels are: Level 1--posture, address, relaxation; Level 2--pick-up, airtime, rotation; Level 3--placing, angles, rhythm; Level 4--precision, adaptability, reproducibility; Level 5--pace, awareness, relations; Level 6--planning, announce, review/reflexion. RESULTS: The format of the PAR model is such that it allows trainer and trainee to objectively assess progress, identify deficiencies and strengths and formulate an appropriate plan of action. CONCLUSION: Ergonomics and crew resource management skills are essential for a safe operating environment. The PAR matrix may prove helpful in selection of trainees and revalidation of trainee surgeons as a competence and performance testing method, placed in the appropriate training curriculum.

Analysis of bedside entertainment services' effect on post cardiac surgery physical activity: a prospective, randomised clinical trial.

BACKGROUND: A rising number of acute hospitals in the UK have been providing patients with bedside entertainment services (BES) since 1995. However, their effect on postoperative patient mobility has not been explored. OBJECTIVES: The aim of this prospective randomised clinical trial was to compare the level of postoperative physical activity and length of in-hospital stay of patients undergoing cardiac surgery depending on whether they had access to BES or not. METHODS: One hundred patients requiring elective cardiac surgery were randomised to receive access to BES (52 patients) or not (48 patients). Pedometers were used to quantify postoperative physical activity for 5 days. To assess the significance of the effect of intervention (TV off or on) on the pedometer counts over time a mixed effect Poisson regression model is used, with the time varying aspect as random component. The potential influence of gender difference and age on pedometer counts were assessed by incorporating these two factors as covariates in the Poisson model. RESULTS: On average, patients with no access to BES walked more than those with BES access. This difference ranged between 192 and 609 steps in favour of the first group for each individual postoperative day. Patients with no access to BES were 84% more likely (risk ratio: 1.84, 95% CI: 1.29-2.63) to walk higher number of steps than patients with access to BES. On average, participants with access to BES were likely to stay longer in hospital (median of 7 days with interquartile range 6-7 days), than participants with no access to BES (median of 6 days with interquartile range 5-7 days), however the difference did not reach statistical significance. CONCLUSION: We have demonstrated that the bedside entertainment systems may have an adverse effect on post cardiac surgery patient ambulation and may contribute to an increase in hospital stay.