Ajay Moza

The role of hypoxia-inducible factor-1α and vascular endothelial growth factor in late-phase preconditioning with xenon, isoflurane and levosimendan in rat cardiomyocytes

OBJECTIVES The protective effects of late-phase preconditioning can be triggered by several stimuli. Unfortunately, the transfer from bench to bedside still represents a challenge, as concomitant medication or diseases influence the complex signalling pathways involved. In an established model of primary neonatal rat cardiomyocytes, we analysed the cardioprotective effects of three different stimulating pharmaceuticals of clinical relevance. The effect of additional β-blocker treatment was studied as these were previously shown to negatively influence preconditioning. METHODS Twenty-four hours prior to hypoxia, cells pre-treated with or without metoprolol (0.55 µg/ml) were preconditioned with isoflurane, levosimendan or xenon. The influences of these stimuli on hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) as well as inducible and endothelial nitric synthase (iNOS/eNOS) and cyclooxygenase-2 (COX-2) were analysed by polymerase chain reaction and western blotting. The preconditioning was proved by trypan blue cell counts following 5 h of hypoxia and confirmed by fluorescence staining. RESULTS Five hours of hypoxia reduced cell survival in unpreconditioned control cells to 44 ± 4%. Surviving cell count was significantly higher in cells preconditioned either by 2 × 15 min isoflurane (70 ± 16%; P = 0.005) or by xenon (59 ± 8%; P = 0.049). Xenon-preconditioned cells showed a significantly elevated content of VEGF (0.025 ± 0.010 IDV [integrated density values when compared with GAPDH] vs 0.003 ± 0.006 IDV in controls; P = 0.0003). The protein expression of HIF-1α was increased both by levosimendan (0.563 ± 0.175 IDV vs 0.142 ± 0.042 IDV in controls; P = 0.0289) and by xenon (0.868 ± 0.222 IDV; P < 0.0001) pretreatment. A significant elevation of mRNA expression of iNOS was measureable following preconditioning by xenon but not by the other chosen stimuli. eNOS mRNA expression was found to be suppressed by β-blocker treatment for all stimuli. In our model, independently of the chosen stimulus, β-blocker treatment had no significant effect on cell survival. CONCLUSIONS We found that the stimulation of late-phase preconditioning involves several distinct pathways that are variably addressed by the different stimuli. In contrast to isoflurane treatment, xenon-induced preconditioning does not lead to an increase in COX-2 gene transcription but to a significant increase in HIF-1α and subsequently VEGF.

Evaluating outcomes used in cardiothoracic surgery interventional research: a systematic review of reviews to develop a core outcome set.

Background When planning clinical trials, it is a key element to choose appropriate outcomes that ensure the comparability of effects of interventions in ways that minimise bias. We hypothesise that outcome measures in cardiothoracic surgical trials are inconsistent and without standard. Therefore, comparing the relative effectiveness of interventions across studies is problematic. We surmise that cardiothoracic research has focused habitually on the identification of risk factors and on the reduction of adverse outcomes with less consideration of factors that contribute to well being and positive health outcomes (salutogenesis). Methods and Findings We conducted a systematic review of reviews to determine both the type and number of outcomes reported in current cardiothoracic surgery interventional research, in order to identify a list of potential outcomes for a minimum core outcome set (COS). Special focus was placed on outcomes that emphasise salutogenesis. We interpreted salutogenic outcomes as those relating to optimum and/or positive health and well being. We searched Issue 7 (July 2014) of the Cochrane Database of Systematic Reviews. Systematic reviews of randomised trials on non-minimal-invasive off- or on-pump cardiothoracic surgery (elective and emergency, excluding transplants) investigating pre-, intra- or postsurgical interventions related to the outcome of the procedure were eligible for inclusion. We excluded protocols and withdrawn systematic reviews. Two review authors extracted outcome data independently. Unique lists of salutogenically and non-salutogenically focused outcomes were established. 15 systematic reviews involving 371 randomized trials and 58,253 patients were included in this review. Applied definitions of single and composite endpoints varied significantly, and patient-centred, salutogenically focused outcomes were seldom reported. One third of included reviews did not assess patient-centred outcomes at all; all other reviews were unable to perform meta-analyses due to an absence of data or heterogeneity in outcome measures. This compares to 36 non-salutogenically focused outcome domains representing 121 individual non-salutogenically focused outcomes, whereof 50% were assessed only once. Measures of mortality, cerebrovascular complications and hospitalisation were reported most frequently. Two reviews chose a composite endpoint as primary outcome. Pooled analysis of composite endpoints was not possible, as the required data was not reported per patient in all components. Conclusion In cardiothoracic surgical trials, choice and definition of non-salutogenically focused single and composite outcomes are inconsistent. There is an absence of patient centred, salutogenically focused outcome parameters in cardiac trials. We recommend the development of a core outcome set of salutogenically focused and non-salutogenically focused outcomes for cardiothoracic surgical research.

EuroScore 2 for identification of patients for transapical aortic valve replacement - a single center retrospective in 206 patients

BackgroundOperative risk scoring algorithms identify patients with severe AS for transcatheter valve implantation in whom the anticipated operative mortality for conventional surgery would be considered prohibitive. We compared the three risk scores EuroScore 1 (LES), society of thoracic surgeons’ (STS) score and ACEF (age-creatinine-ejection fraction score) to the readjusted EuroScore 2 recently presented.MethodsWe reviewed all consecutive patients receiving either isolated conventional aortic valve replacement (cAVR) or transapical aortic valve implantation (TA-TAVI) in a two-year period (n = 206). 30-days mortality was considered as primary endpoint.ResultsTA-TAVI was performed in 76 patients, isolated cAVR in 130 patients. Overall mortality was 4.4% (TA-TAVI: 7.9%; cAVR: 2.3%). EuroScore 2 showed a good estimation for the entire population as well as within the subgroups: 4,02 ± 5,36% (TA-TAVI: 6.16 ± 7.14%, cAVR: 2.77 ± 3.42%). Predicted mortalities as assessed by LES were largely overestimated (TA-TAVI: 27.4 ± 20.9% cAVR: 10.6 ± 10.6%, sensitivity: 0.89, specificity: 0.71). STS predicted mortality was 6.3 ± 4.4% for TA-TAVI patients as to 3.2 ± 3.1% for cAVR patients (sens.: 0.22, spec.: 0.96) and ACEF predicted a mortality of 1.16 ± 0.36% for cAVR and 1.58 ± 0.59% for TA-TAVI patients (sens.: 0.78, spec.: 0.89).ConclusionThe newly refined EuroScore 2 showed a good correlation within the studied population. For the individual patient, new cut-offs will have to be defined to triage patients for TAVI procedure. A drawback for complex score systems such as EuroScore and STS is the lack of recalibration to smaller populations as encountered in even large single centers.

The effects of metoprolol on hypoxia- and isoflurane-induced cardiac late-phase preconditioning

Background: The detrimental effects of metoprolol on early‐phase preconditioning (pc) have been proven. The late phase of pc is mediated via gene transcription and cyclooxygenase‐2 (COX‐2) was identified as one of the key mediators. The effect of metoprolol on this is yet unknown as is its effect on cellular energy metabolism and reactive oxygen species (ROS) creation.

Successful Treatment of Novel H1N1 Influenza related Fulminant Myocarditis with Extracorporeal Life Support

The prevalence of myocardial involvement in influenza infection ranges from 0% to 12%. The 2009 pH1N1 influenza virus, formerly known as swine flu, first appeared in Mexico and the United States of America in March and April 2009 and has swept the globe with unprecedented speed. We report a case of fulminant myocarditis associated with this virus treated successfully using extra-corporal membrane oxygenator.

A core outcome set for all types of cardiac surgery effectiveness trials: a study protocol for an international eDelphi survey to achieve consensus on what to measure and the subsequent selection of measurement instruments

BackgroundCardiovascular disease (CVD) is a major contributor to the burden of disease and the number one cause of death worldwide. From 1990 until today, more people died from coronary heart disease than from any other cause. CVD is regularly treated with minimally or non-minimally invasive off- or on-pump cardiothoracic surgery and several interventions related to the outcome of the surgical procedures have been evaluated in clinical trials, but heterogeneity in outcome reporting hinders comparison of interventions across trials and limits the ability of research synthesis. This problem is encountered with the introduction of core outcome sets (COSs), which should be measured and reported, as a minimum, in all clinical trials for a specific clinical field.Methods/designThis study protocol describes the methods used to develop a COS for all types of cardiac surgery effectiveness trials. We aim to reach consensus on what to measure in an international three-round eDelphi exercise involving adult patients in need or after cardiothoracic surgery, cardiothoracic surgeons, cardiologists, anaesthesiologists, nursing staff and researchers with expertise in this particular field of medical research. Subsequently, outcome measurement instruments (how to measure) will be determined. Recommendations on COS development given by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative and the Outcome Measures in Rheumatology (OMERACT) Initiative were followed.DiscussionThe proposed COS aims to provide methodological guidance for future cardiothoracic surgical trials to ensure the comparability of effects of interventions across studies and enable research synthesis. This does not imply that primary outcomes should always and exclusively be those of the COS. However, to ensure the comparability of results across trials, the outcomes included in this COS should be considered for inclusion besides measuring trial-specific clinical endpoints.

Special Treatment and Wound Care of the Driveline Exit Site after Left Ventricular Assist Device Implantation.

OBJECTIVE Despite good results following implantation of left ventricular assist devices (LVADs), infections of the driveline and device pocket remain a major problem for patients on long-term support. We present the data from heart failure patients treated with a Thoratec HeartMate-II LVAD (Thoratec Corporation, Pleasanton, California, United States). METHODS From January 2008 to April 2011, in our institution, 40 heart failure patients (NYHA IV) were supported with a HeartMate-II LVAD. The driveline maintenance of 17 patients consisted of the use of Octenidine for the wound dressing, whereas merbromin was additionally used for local irrigation in 31 patients. The data concerning driveline infections were analyzed retrospectively. RESULTS In our study, 95% of the entire cohort was free from infections of the system. Two patients in the conventional group (11.8%) developed a driveline infection at a mean of 130.5 days during 3,416 patient-days (0.21 infection/patient-years). In the Merbromid group (Co. New FaDem SRL Farmaceutici & Chimici, Giugliano, Campania, Italy), all patients were free from any driveline infections during the observation period. In a log-rank comparison, the difference reached statistical significance (p = 0.043). CONCLUSION During our observation period, fewer infections were noted with merbromin treatment. A multicenter setting in a larger cohort should be performed to confirm these findings, although a (double-) blinded setting might be difficult to achieve.

Glomerulonephritis triggered by a chronically infected left ventricular assist device

A 55-year-old man on the waiting list for heart transplantation with severe dilated cardiomyopathy was admitted for evaluation of low-grade fever in October, 2014. He had had a left ventricular assist device (LVAD; HeartMate II) implanted as a bridge to transplant 4 years previously. Examination was unrema rkable. Investigations showed acute kidney injury (serum creatinine increased to 354 μmol/L from 124 μmol/L 2 months previously), raised C-reactive protein, and raised procalcitonin. Urinary protein excretion was 2·2 g/day and urinalysis showed microhaematuria without dysmorphic erythrocytes or casts; previous urinalyses had been unremarkable. Blood cultures were positive for Corynebacterium jeikeium so we started intravenous linezolid 600 mg twice daily. The patient’s clinical condition continued to deteriorate so after 5 days we changed the antibiotics to daptomycin (6 mg/kg intravenously every 48 h). Further workup showed low serum complement C3 concentrations, raised PR3-ANCA, and raised rheumatoid factor concentrations, but no antiMPO-ANCA. His acute kidney injury continued to worsen so we started intermittent haemodialysis. Histological examination of a renal biopsy sample (fi gure) showed 23 glomeruli, six of which were globally sclerotic and ten that were segmentally sclerotic, cellular, and fi lled Bowman’s space circumferentially. The non-sclerotic glomerular segments had foci of increased mesangial matrix and increased mesangial cells; there was no duplication of basement membranes. Immunohistology showed positive mesangial staining for IgM, C1q, and C3; IgA and IgG were negative. Some glomerular basement membranes stained for C3 without showing humps. 80% of the cortex and outer medulla had chronic tubulointerstitial damage with interstitial matrix expansion and focal interstitial infi ltrate of mononuclear cells. Congo Red reaction was negative. Electron microscopy showed mesangial regions with increased matrix and segmental subendothelial and mesangial osmiophilic deposits (fi gure). These fi ndings indicated focal mesangial proliferative glomerulonephritis with segmental necrosis and extensive scarring (focal segmental and global glomerulosclerosis) associated with severe chronic tubulointerstitial damage in 80% of the tubulointerstitium. 18F-fl uorodeoxyglucose (18F-FDG) PET-CT showed multiple foci of increased metabolic activity at the site of the LVAD driveline insertion, the ventricular assist device pocket, and the LVAD outfl ow cannula (appendix). We made a diagnosis of focal segmental necrotising immune-complex glomerulonephritis triggered by chronic LVAD infection with C jeikeium. Blood cultures remained positive for C jeikeium despite ongoing antibiotic treatment. The patient continued to deteriorate with recurrent septicaemia and circulatory instability. At last follow-up in our centre in February, 2015, the patient asked for referral to palliative care. We report a case of immune complex glomerulonephritis with acute kidney injury RIFLE-stage L caused by a chronically infected LVAD. The pathophysiology of LVAD nephritis is similar to that of cerebral ventriculoatrial shunt nephritis, fi rst described by Black and colleagues in 1965. Shunt nephritis results from circulating bacterial antigen-antibacterial complexes, which activate the classic pathway of the complement system. Similarly our patient had low-grade fever, proteinuria, haematuria, and progressive renal failure, associated with a long-standing infection with a Gram-positive organism, low C3 concentrations, and serum positivity for PR3-ANCA. The renal histology and the long interval between surgery and onset of symptoms are also characteristic of shunt nephritis or LVAD nephritis. Dependent on the nature and extent of the glomerular injury, renal failure can recover after removal of the cerebral shunt. LVAD-specifi c infections remain among the most common causes of morbidity and mortality in patients with these devices. LVAD implantation is associated with bacteraemia as well as autoimmune eff ects such as development of cytotoxic autoantibodies. The presence of an LVAD itself causes defects in the cellular and humoral immune system leading to T-cell defects and B-cell hyperreactivity. Infection can occur at the driveline exit site, in the device pocket, or on the internal surface of the device or valves. Severe cases of LVAD-associated infection with recurrent bacteraemia usually necessitate surgical removal of the device and broad-spectrum antibiotics. The most common pathogens are Gram-positive organisms, mainly Staphylococcus and Enterococcus species, Candida Glomerulonephritis triggered by a chronically infected left ventricular assist device

Ultrasound-assisted treatment of sternocutaneous fistula in post-sternotomy cardiac surgery patients

OBJECTIVES Using an ultrasonic debridement system (low frequency, 25 kHz), we aimed to completely remove bacterial biofilms and preserve vital sternal tissue and to compare this procedure with conventional surgical therapy. METHODS In this retrospective study, we evaluated 37 consecutive patients (25 males) between April 2011 and June 2013 in whom sternocutaneous fistula (SCF) was treated with the ultrasound-assisted wound (UAW) system (Group A, n = 18) or with conventional surgical therapy (Group B, n = 19). Treatment in Group A consisted of a complete dissection of the SCF followed by a multistep UAW debridement session after an interval of 3 days. Our final step in both groups was secondary wound closure with a musculocutaneous flap. RESULTS Patients in both groups were categorized as high risk with respect to several of the known SCF risk factors. In both groups, a similar variety of bacteria were isolated: 61% were gram-positive species, 16.5% were gram-negative species and 10.5% were Candida albicans. Time to secondary wound closure following eradication was significantly shorter in Group A (10 ± 5.4 vs 15 ± 7.1 days in Group B, P = 0.012). Postoperative antibiotic treatment time (16 ± 9.3 vs 22 ± 10.7 days in Group B, P = 0.078) showed a trend in favour of Group A, but the mean hospitalization time (22 ± 12.0 vs 26 ± 14.3 days in Group B, P = 0.34) did not differ between groups. Recurrence of SCF tended to be less frequent in Group A (6 vs 21% in Group B, P = 0.46). In Group B, one infection-related death was noted. The mean follow-up time was 8 ± 2.7 (Group A) and 10 ± 5.7 (Group B) months. CONCLUSIONS Ultrasonic debridement is a promising adjunct to SCF treatment. In combination with adequate surgical and antimicrobial therapy, we documented good mid-term results in our trial group.

Prevention of sternal dehiscence with the Sternum External Fixation (Stern-E-Fix) corset – a randomized trial in 750 patients

BackgroundThe main objective of this study will be to determine the effects of a new advanced sternum external fixation (Stern-E-Fix) corset on prevention of sternal instability and mediastinitis in high-risk patients.MethodsThis prospective, randomized study (January 2009 – June 2011) comprised 750 male patients undergoing standard median sternotomy for cardiac procedures (78% CABG). Patients were divided in two randomized groups (A, n = 380: received a Stern-E-Fix corset postoperatively for 6 weeks and B, n = 370: control group received a standard elastic thorax bandage). In both groups, risk factors for sternal dehiscence and preoperative preparations were similar.ResultsWound infections occurred in n = 13 (3.42%) pts. in group A vs. n = 35 (9.46%) in group B. In group A, only 1 patient presented with sternal dehiscence vs. 22 pts. in group B. In all 22 patients, sternal rewiring followed by antibiotic therapy was needed. Mediastinitis related mortality was none in A versus two in B. Treatment failure in group B was more than five times higher than in A (p = 0.01); the mean length of stay in hospital was 12.5 ± 7.4 days (A) versus 18 ± 15.1 days (B) (p=0.002). Re-operation for sternal infection was 4 times higher in group B. Mean ventilation time was relatively longer in B (2.5 vs. 1.28 days) (p = 0.01). The mean follow-up period was 8 weeks (range 6 – 12 weeks).ConclusionsWe demonstrated that using an external supportive sternal corset (Stern-E-Fix) yields a significantly better and effective prevention against development of sternal dehiscence and secondary sternal infection in high-risk poststernotomy patients.