Andreas Goetzenich

Selenium and Its Supplementation in Cardiovascular Disease—What do We Know?

The trace element selenium is of high importance for many of the body’s regulatory and metabolic functions. Balanced selenium levels are essential, whereas dysregulation can cause harm. A rapidly increasing number of studies characterizes the wide range of selenium dependent functions in the human body and elucidates the complex and multiple physiological and pathophysiological interactions of selenium and selenoproteins. For the majority of selenium dependent enzymes, several biological functions have already been identified, like regulation of the inflammatory response, antioxidant properties and the proliferation/differentiation of immune cells. Although the potential role of selenium in the development and progression of cardiovascular disease has been investigated for decades, both observational and interventional studies of selenium supplementation remain inconclusive and are considered in this review. This review covers current knowledge of the role of selenium and selenoproteins in the human body and its functional role in the cardiovascular system. The relationships between selenium intake/status and various health outcomes, in particular cardiomyopathy, myocardial ischemia/infarction and reperfusion injury are reviewed. We describe, in depth, selenium as a biomarker in coronary heart disease and highlight the significance of selenium supplementation for patients undergoing cardiac surgery.

Alteration of matrix metalloproteinases in selective left ventricular adriamycin-induced cardiomyopathy in the pig.

INTRODUCTION Anthracyclines are widely used in oncogenic therapy. Owing to their cardiotoxic side effects, their application is subdued to dose limitations. Many cardioprotective approaches have failed. This study examined the role of matrix metalloproteinases (MMP) in the remodeling process of extracellular matrix after treatment with doxorubicin (Adriamycin) as a toehold for a new therapeutic approach, for example, treatment with MMP inhibitors. METHODS Severe heart failure was induced in 6 pigs by the repetitive intracoronary application of Adriamycin. Degree of dilatation and insufficiency were measured by echocardiography and hemodynamics. Before and after treatment, MMP activity (fluorogenic assay: MMP-1, MMP-2) and gene expression (reverse transcription-polymerase chain reaction [RT-PCR]: MMP-1, -2, -9; membrane type-1 matrix metalloproteinase, [MT1MMP]; tissue inhibitor of metalloproteinase 1 [TIMP-1]) were measured. Spatial distribution of MMP-1, MMP-2, and collagen were visualized in antibody-stained frozen sections. One-way analysis of variance was used for data analysis. RESULTS Severe myocardial insufficiency (ejection fractions < 50% of baseline values) developed in all animals. No severe side effects were encountered. We found a strong activation of MMP-1 and MMP-2 in fluorogenic and PCR assays. RT-PCR revealed a significant activation of MMP-9 and MT1-MMP and a weaker induction of TIMP-1. Histology showed typical signs of myocardial fibrosis, with myocardial cell loss, collagen disorder, and vacuoles. CONCLUSION We showed a strong transcriptional activation for several specific MMPs in Adriamycin-induced cardiac remodeling. Contrary to published data on myocardial infarction, early inhibitory therapy before myocardial injury is possible in Adriamycin-treated patients. Local application by our catheter-based system would additionally help to avoid systemic side effects.

Interaction of MIF Family Proteins in Myocardial Ischemia/Reperfusion Damage and Their Influence on Clinical Outcome of Cardiac Surgery Patients.

Abstract Aims: Cardiac surgery involves myocardial ischemia/reperfusion (I/R) with potentially deleterious consequences. Macrophage migration inhibitory factor (MIF) is a stress-regulating chemokine-like cytokine that protects against I/R damage, but functional links with its homolog, d-dopachrome tautomerase (MIF-2), and the circulating soluble receptor CD74 (sCD74) are unknown. In this study, we investigate the role of MIF, MIF-2, sCD74, and MIF genotypes in patients scheduled for elective single or complex surgical procedures such as coronary artery bypass grafting or valve replacement. Results: MIF and MIF-2 levels significantly increased intraoperatively, whereas measured sCD74 decreased correspondingly. Circulating sCD74/MIF complexes were detectable in 50% of patients and enhanced MIF antioxidant activity. Intraoperative MIF levels were independently associated with a reduced risk for the development of atrial fibrillation (AF) (odds ratio 0.99 [0.98–1.00]; p=0.007). Circulating levels of MIF-2, but not MIF, were associated with an increased frequency of organ dysfunction and predicted the occurrence of AF (area under the curve [AUC]=0.663; p=0.041) and pneumonia (AUC=0.708; p=0.040). Patients with a high-expression MIF genotype exhibited a reduced incidence of organ dysfunction compared with patients with low-expression MIF genotypes (3 vs. 25; p=0.042). Innovation: The current study comprehensively highlights the kinetics and clinical relevance of MIF family proteins and the MIF genotype in cardiac surgery patients. Conclusion: Our findings suggest that increased MIF levels during cardiac surgery feature organ-protective properties during myocardial I/R, while the soluble MIF receptor, sCD74, may enhance MIF antioxidant activity. In contrast, high MIF-2 levels are predictive of the development of organ dysfunction. Importantly, we provide first evidence for a gene–phenotype relationship between variant MIF alleles and clinical outcome in cardiac surgery patients. Antioxid. Redox Signal. 00, 000–000.

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.

What Is the Significance of Perioperative Release of Macrophage Migration Inhibitory Factor in Cardiac Surgery

Cardiac surgery is associated with release of the pleiotropic cytokine macrophage migration inhibitory factor (MIF). The trigger for MIF release has not yet been elucidated. Owing to its intrinsic antioxidative activity, MIF might reduce oxidative stress and protect from myocardial ischemia and reperfusion (I/R) injury. In the present study, patients scheduled for elective cardiac surgery (n=46) were randomized to undergo coronary artery bypass grafting either conventionally with cardiopulmonary bypass and cardioplegic arrest-induced I/R (cCABG) or in an off-pump procedure (OPCAB) with minimized I/R. We report that only patients who underwent cCABG exhibited a postoperative increase of MIF (p=0.024), while both groups showed an increase in interleukin-6. MIF release appears to be primarily mediated by I/R and to a lesser extent by inflammation. Endogenous peroxidase activity (p=0.021) and serum levels of thioredoxin (p=0.003) were significantly higher in patients who underwent cCABG after surgery. Interestingly, perioperative MIF release was associated with an enhanced antioxidant capacity and a significantly reduced postoperative incidence of atrial fibrillation (p=0.018) and acute kidney injury (p=0.048). The present study highlights the role of MIF increase during cardiac surgery in response to oxidative stress. Based on current observations, we hypothesize that intraoperative MIF secretion is due to I/R and enhances the antioxidant capacity in patients during cardiac surgery.

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.

The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia

BackroundNeuroprotective strategies after cardiopulmonary resuscitation are currently the focus of experimental and clinical research. Levosimendan has been proposed as a promising drug candidate because of its cardioprotective properties, improved haemodynamic effects in vivo and reduced traumatic brain injury in vitro. The effects of levosimendan on brain metabolism during and after ischaemia/hypoxia are unknown.MethodsTransient cerebral ischaemia/hypoxia was induced in 30 male Wistar rats by bilateral common carotid artery clamping for 15 min and concomitant ventilation with 6% O2 during general anaesthesia with urethane. After 10 min of global ischaemia/hypoxia, the rats were treated with an i.v. bolus of 24 μg kg-1 levosimendan followed by a continuous infusion of 0.2 μg kg-1 min-1. The changes in the energy-related metabolites lactate, the lactate/pyruvate ratio, glucose and glutamate were monitored by microdialysis. In addition, the effects on global haemodynamics, cerebral perfusion and autoregulation, oedema and expression of proinflammatory genes in the neocortex were assessed.ResultsLevosimendan reduced blood pressure during initial reperfusion (72 ± 14 vs. 109 ± 2 mmHg, p = 0.03) and delayed flow maximum by 5 minutes (p = 0.002). Whereas no effects on time course of lactate, glucose, pyruvate and glutamate concentrations in the dialysate could be observed, the lactate/pyruvate ratio during initial reperfusion (144 ± 31 vs. 77 ± 8, p = 0.017) and the glutamate release during 90 minutes of reperfusion (75 ± 19 vs. 24 ± 28 μmol·L-1) were higher in the levosimendan group. The increased expression of IL-6, IL-1ß TNFα and ICAM-1, extend of cerebral edema and cerebral autoregulation was not influenced by levosimendan.ConclusionAlthough levosimendan has neuroprotective actions in vitro and on the spinal cord in vivo and has been shown to cross the blood–brain barrier, the present results showed that levosimendan did not reduce the initial neuronal injury after transient ischaemia/hypoxia.

The Role of Macrophage Migration Inhibitory Factor in Anesthetic-Induced Myocardial Preconditioning

Introduction Anesthetic-induced preconditioning (AIP) is known to elicit cardioprotective effects that are mediated at least in part by activation of the kinases AMPK and PKCε as well as by inhibition of JNK. Recent data demonstrated that the pleiotropic cytokine macrophage migration inhibitory factor (MIF) provides cardioprotection through activation and/or inhibition of kinases that are also known to mediate effects of AIP. Therefore, we hypothesized that MIF could play a key role in the AIP response. Methods Cardiomyocytes were isolated from rats and subjected to isoflurane preconditioning (4 h; 1.5 vol. %). Subsequently, MIF secretion and alterations in the activation levels of protective kinases were compared to a control group that was exposed to ambient air conditions. MIF secretion was quantified by ELISA and AIP-induced activation of protein kinases was assessed by Western blotting of cardiomyocyte lysates after isoflurane treatment. Results In cardiomyocytes, preconditioning with isoflurane resulted in a significantly elevated secretion of MIF that followed a biphasic behavior (30 min vs. baseline: p = 0.020; 24 h vs. baseline p = 0.000). Moreover, quantitative polymerase chain reaction demonstrated a significant increase in MIF mRNA expression 8 h after AIP. Of note, activation of AMPK and PKCε coincided with the observed peaks in MIF secretion and differed significantly from baseline. Conclusions These results suggest that the pleiotropic mediator MIF is involved in anesthetic-induced preconditioning of cardiomyocytes through stimulation of the protective kinases AMPK and PKCε.

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.

PAS-Port® clampless proximal anastomotic device for coronary bypass surgery in porcelain aorta.

OBJECTIVES The severely calcified so-called porcelain aorta is one of the most dangerous and challenging findings in patients requiring coronary bypass surgery. Several techniques and technologies have been invented to handle this potentially lethal disease. We report on our initial experience with the PAS-Port® automated proximal clampless anastomotic device (Cardica, Inc., Redwood City, CA, USA), especially focussing on these patients. METHODS PAS-Port® anastomoses (for saphenous vein grafts) were performed in 17 patients undergoing coronary artery bypass graft (CABG) surgery. Of these, eight presented with the entity of porcelain aorta. In two patients, the diagnosis was previously known, in six cases heavily calcified aortas prohibiting any clamp manoeuvre were incidentally found intra-operatively. The site of anastomosis was determined by palpation and in individual cases with epi-aortic echocardiography. Other indications for PAS-Port® were localised dissection, acute myocardial infarction and partial sternotomy. Multislice computed tomography (CT) was performed in every patient to evaluate graft and anastomoses patency and appearance. RESULTS All 25 PAS-Port® anastomoses were triggered successfully. Two patients developed neurological deficits (prolonged reversible ischaemic neurological deficits, (PRIND)), with use of cardiopulmonary bypass (CPB) being the major predisposing factor (p=0.02). Graft patency could be affirmed in all grafts by multislice CT in all patients. CONCLUSIONS PAS-Port® anastomoses can be performed quickly, easily and, above all, safely in conditions prohibiting aortic clamping. Short-term results are excellent. Clear visualisation of anastomoses using multislice CT is an important advantage of the PAS-Port® device.