Bernhard Wernly

Soluble ST2 Predicts 1‐Year Outcome in Patients Undergoing Transcatheter Aortic Valve Implantation (TAVI)

Soluble ST2 (sST2) has been introduced as a novel biomarker in patients suffering from heart failure for risk stratification. In this study, we sought to investigate whether sST2 is useful for risk stratification and prediction of mortality in patients undergoing transcatheter aortic valve implantation (TAVI).

Multibiomarker analysis in patients with acute myocardial infarction

Novel biomarkers representing different pathobiological pathways and their role in patients with acute myocardial infarction (AMI) were studied.

A comparative analysis of novel cardiovascular biomarkers in patients with chronic heart failure

BACKGROUND Heart failure (HF) with reduced ejection fraction remains a major therapeutic challenge. The aim of this study was to investigate the role of novel cardiovascular biomarkers, i.e. soluble suppression of tumorigenicity (sST2), growth-differentiation factor-15 (GDF-15), soluble urokinase plasminogen activator receptor (suPAR) and heart-type fatty acid binding protein (H-FABP) in patients with ischaemic (ICM) or dilative cardiomyopathy (DCM). MATERIALS AND METHODS A total of 200 patients were enrolled in this study: 65 were diagnosed with DCM and 59 patients suffering from ICM were included. 76 patients without coronary artery disease or signs of heart failure were included as controls. Plasma samples of all patients were analyzed by use of ELISA. RESULTS Levels of sST2, suPAR and H-FABP were significantly higher in ICM and DCM patients compared to the control group (p<0.0001). However, there were no significant differences between ICM and DCM in biomarker levels. Ejection fraction correlated inversely with cardiac biomarkers (sST2 p<0.0001, GDF-15 p=0.0394, suPAR p=0.0029, H-FABP p<0.0001). Similarly, CRP levels also showed a positive correlation with cardiac biomarkers. Renal insufficiency (p<0.0001) and diabetes (sST2 p=0.0021, GDF-15 p=0.0055, suPAR p=0.0339, H-FABP p=0.0010) were significantly associated with a rise in cardiac biomarkers. CONCLUSION Novel cardiovascular biomarkers such as ST2, GDF-15, uPAR and H-FABP could offer a great potential for more precise diagnostic in ICM and DCM patients. H-FABP was the most promising marker in our study, followed by sST2, uPAR and GDF-15. Additional prospective studies will be necessary to further evaluate the potential clinical benefits in routine treatment of HF.

Stem Cell Therapy for Myocardial Infarction 2001–2013 Revisited

Stem cell therapy for ischemic heart disease was an emerging concept in the early 2000s. First hopes were largely overshadowed by rather inconsistent results in human trials conducted in the middle of the decade. We aimed at investigating how the field of stem cell research expanded worldwide over the years using scientometric methods. We performed a PubMed inquiry and screened a total of 2609 publications dealing with stem cell therapy for myocardial infarction in the years 2001–2013. Density equalizing maps were used to visualize important centres of stem cell research worldwide. This systematic bibliometric study revealed an increasing research interest in the field of stem cell research in the context of ischemic heart disease over the last decade. Though some of the large human trials failed to show significant effects of stem cell therapy, especially basic science represents an ever growing field that evolved promising new concepts over the last couple of years. The scientific principle of protective paracrine mediators released from transplanted stem cells seems to bear great potential for future cell-free therapeutic use. However, further mechanistic insights are needed before transition from bench to bedside should be attempted, taking the lessons learned from previous studies into account.

Model for End-stage Liver Disease excluding INR (MELD-XI) score in critically ill patients: Easily available and of prognostic relevance

Purpose MELD-XI, an adapted version of Model for End-stage Liver Disease (MELD) score excluding INR, was reported to predict outcomes e.g. in patients with acute heart failure. We aimed to evaluate MELD-XI in critically ill patients admitted to an intensive care unit (ICU) for prognostic relevance. Methods A total of 4381 medical patients (66±14 years, 2862 male) admitted to a German ICU between 2004 and 2009 were included and retrospectively investigated. Admission diagnoses were e.g. myocardial infarction (n = 2034), sepsis (n = 694) and heart failure (n = 688). We divided our patients in two cohorts basing on their MELD-XI score and evaluated the MELD-XI score for its prognostic relevance regarding short-term and long-term survival. Optimal cut-offs were calculated by means of the Youden-Index. Results Patients with a MELD-XI score >12 had pronounced laboratory signs of organ failure and more comorbidities. MELD-XI >12 was associated with an increase in short-term (27% vs 6%; HR 4.82, 95%CI 3.93–5.93; p<0.001) and long-term (HR 3.69, 95%CI 3.20–4.25; p<0.001) mortality. In a univariate Cox regression analysis for all patients MELD-XI was associated with increased long-term mortality (changes per score point: HR 1.06, 95%CI 1.05–1.07; p<0.001) and remained to be associated with increased mortality after correction in a multivariate regression analysis for renal failure, liver failure, lactate concentration, blood glucose concentration, oxygenation and white blood count (HR 1.04, 95%CI 1.03–1.06; p<0.001). Optimal cut-off for the overall cohort was 11 and varied remarkably depending on the admission diagnosis: myocardial infarction (9), pulmonary embolism (9), cardiopulmonary resuscitation (17) and pneumonia (17). We performed ROC-analysis and compared the AUC: SAPS2 (0.78, 95%CI 0.76–0.80; p<0.0001) and APACHE (0.76, 95%CI 0.74–0.78; p<0.003) score were superior to MELD-XI (0.71, 95%CI 0.68–0.73) for prediction of mortality. Conclusions The easily calculable MELD-XI score is a robust and reliable tool to predict both intra-ICU and long-term mortality in critically ill medical patients admitted to an ICU. Optimal cut-off values for MELD-XI scores seem to depend on the primary disease and need to be validated in future prospective studies. Compared to SAPS2 and APACHE score, MELD-XI lacks precision but might have comparable and even additive value, as it is easily available and independent of subjective values.

Differential Impact of Hyperglycemia in Critically Ill Patients: Significance in Acute Myocardial Infarction but Not in Sepsis?

Hyperglycemia is a common condition in critically ill patients admitted to an intensive care unit (ICU). These patients represent an inhomogeneous collective and hyperglycemia might need different evaluation depending on the underlying disorder. To elucidate this, we investigated and compared associations of severe hyperglycemia (>200 mg/dL) and mortality in patients admitted to an ICU for acute myocardial infarction (AMI) or sepsis as the two most frequent admission diagnoses. From 2006 to 2009, 2551 patients 69 (58–77) years; 1544 male; 337 patients suffering from type 2 diabetes (T2DM)) who were admitted because of either AMI or sepsis to an ICU in a tertiary care hospital were investigated retrospectively. Follow-up of patients was performed between May 2013 and November 2013. In a Cox regression analysis, maximum glucose concentration at the day of admission was associated with mortality in the overall cohort (HR = 1.006, 95% CI: 1.004–1.009; p < 0.001) and in patients suffering from myocardial infarction (HR = 1.101, 95% CI: 1.075–1.127; p < 0.001) but only in trend in patients admitted to an ICU for sepsis (HR = 1.030, 95% CI: 0.998–1.062; p = 0.07). Severe hyperglycemia was associated with adverse intra-ICU mortality in the overall cohort (23% vs. 13%; p < 0.001) and patients admitted for AMI (15% vs. 5%; p < 0.001) but not for septic patients (39% vs. 40%; p = 0.48). A medical history of type 2 diabetes (n = 337; 13%) was not associated with increased intra-ICU mortality (15% vs. 15%; p = 0.93) but in patients with severe hyperglycemia and/or a known medical history of type 2 diabetes considered in combination, an increased mortality in AMI patients (intra-ICU 5% vs. 13%; p < 0.001) but not in septic patients (intra-ICU 38% vs. 41%; p = 0.53) could be evidenced. The presence of hyperglycemia in critically ill patients has differential impact within the different etiological groups. Hyperglycemia in AMI patients might identify a sicker patient collective suffering from pre-diabetes or undiagnosed diabetes with its’ known adverse consequences, especially in the long-term. Hyperglycemia in sepsis might be considered as adaptive survival mechanism to hypo-perfusion and consecutive lack of glucose in peripheral cells. AMI patients with hyperglycemic derailment during an ICU-stay should be closely followed-up and extensively screened for diabetes to improve patients’ outcome.

Specifics of fetuin-A levels in distinct types of chronic heart failure

Fetuin‐A has been described to correlate inversely with vascular calcification both in animal models but also in patients with heart and renal disease. In this current study, we sought to investigate whether fetuin‐A might be a useful marker for the discrimination of ischemic (ICM) from dilated cardiomyopathy (DCM).

Influences of Ivabradine treatment on serum levels of cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in patients with chronic heart failure

Chronic heart failure (CHF) represents a major cause of hospitalization and death. Recent evidence shows that novel biomarkers such as soluble suppression of tumorigenicity (sST2), growth-differentiation factor-15 (GDF-15), soluble urokinase plasminogen activator receptor (suPAR) and heart-type fatty acid binding protein (H-FABP) are correlated with inflammatory and ischemic responses in CHF patients. In this study we examined the effects of Ivabradine that inhibited the hyperpolarization-activated cyclic nucleotide-gated channel (HCN channel, also called funny current If), thereby leading to selective heart rate reduction and improved myocardial oxygen supply on the cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in 50 CHF patients at the University Hospital of Jena. Patients were divided into three groups based on the etiology of CHF: dilated cardiomyopathy (DCM, n=20), ischemic cardiomyopathy (ICM, n=20) and hypertensive cardiomyopathy (HCM, n=10). The patients were administered Ivabradine (5 mg, bid for 3 months, and 7.5 mg bid for further 3 months). Analyses of cardiovascular biomarkers were performed at baseline as well as at 3- and 6-month follow-ups. At 6-month follow-up, GDF-15 levels were significantly reduced compared to baseline levels (P=0.0215), indicating a reduction in the progress of cardiac remodeling. H-FABP concentration was significantly lower in DCM patients compared to ICM (1.89 vs 3.24 μg/mL) and HCM patients (1.89 vs 3.80 μg/mL), and decreased over the 6-month follow-up (P=0.0151). suPAR median levels remained elevated, implying major ongoing inflammatory processes. As shown by significant decreases in GDF-15 and H-FABP levels, a reduction in ventricular remodeling and sub-clinical ischemia could be assumed. However, markers of hemodynamic stress (sST2) and inflammation (suPAR) showed no change or progression after 6 months of Ivabradine treatment in CHF patients. Further studies are necessary to validate the clinical applicability of these novel cardiovascular biomarkers.

Acute effects of moderate altitude on biomarkers of cardiovascular inflammation and endothelial function and their differential modulation by dual endothelin receptor blockade

BACKGROUND Endothelial dysfunction is accompanied by the release of microparticles (MP). OBJECTIVE We sought to investigate the effect of moderate hypoxia on circulatory levels of microparticles, biomarkers of cardiovascular function and inflammation and on echocardiographic parameters in healthy volunteers staying at an altitude of 2978 m. METHODS Eighteen healthy volunteers were subjected to moderate hypoxia by staying at 2978 m above sea level for three days. Blood samples were evaluated for MP using flow cytometry. ELISA analysis was performed for sST2, H-FABP, suPAR and GDF-15. Moreover, the effect of dual endothelin-receptor blockade was investigated. RESULTS Oxygen saturation decreased to 93%. A significant decrease of endothelial and platelet MP levels was found. These results were corroborated by a similar response in sST2 and suPAR plasma concentration. Endothelin-receptor blockade by macitentan only had a marginal influence on MP, sST2, H-FABP, suPAR and GDF-15 levels, though it led to a significant amelioration of echocardiographic parameters of right heart function. CONCLUSIONS These experimental results show that moderate hypoxia due to altitude exposition led to a reduction in parameters of endothelial dysfunction as shown by a decrease in endothelial and platelet MP, sST2 and suPAR levels. A slight increase in pulmonary pressure at moderate altitude was decreased by dual endothelin receptor blockade.

Effect of endothelin‐1 and endothelin receptor blockade on the release of microparticles

Increased levels of endothelial cell microparticles (EMP) are known to reflect endothelial dysfunction (ED). In diabetes mellitus type 2 (T2DM), the expression of endothelin (ET)‐1 is increased. As treatment with an ET‐1 antagonist significantly inhibited atherosclerosis in animal models, we sought to investigate whether treatment with ET‐1 antagonists affects EMP levels in vitro and in vivo in patients with T2DM.