Stephan von Haehling




  • Lisa Steinbeck · Nicole Ebner · Miroslava Valentova · Tarek Bekfani · Sebastian Elsner · Pius Dahinden · Stefan Hettwer · Nadja Scherbakov · Jörg C Schefold · Anja Sandek · Jochen Springer · Wolfram Doehner · Stefan D Anker · Stephan von Haehling
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    ABSTRACT: Aims: Skeletal muscle wasting affects 20% of patients with chronic heart failure and has serious implications for their activities of daily living. Assessment of muscle wasting is technically challenging. C-terminal agrin-fragment (CAF), a breakdown product of the synaptically located protein agrin, has shown early promise as biomarker of muscle wasting. We sought to investigate the diagnostic properties of CAF in muscle wasting among patients with heart failure. Methods and results: We assessed serum CAF levels in 196 patients who participated in the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF). Muscle wasting was identified using dual-energy X-ray absorptiometry (DEXA) in 38 patients (19.4%). Patients with muscle wasting demonstrated higher CAF values than those without (125.1 ± 59.5 pmol/L vs. 103.8 ± 42.9 pmol/L, P = 0.01). Using receiver operating characteristics (ROC), we calculated the optimal CAF value to identify patients with muscle wasting as >87.5 pmol/L, which had a sensitivity of 78.9% and a specificity of 43.7%. The area under the ROC curve was 0.63 (95% confidence interval 0.56-0.70). Using simple regression, we found that serum CAF was associated with handgrip (R = - 0.17, P = 0.03) and quadriceps strength (R = - 0.31, P < 0.0001), peak oxygen consumption (R = - 0.5, P < 0.0001), 6-min walk distance (R = - 0.32, P < 0.0001), and gait speed (R = - 0.2, P = 0.001), as well as with parameters of kidney and liver function, iron metabolism and storage. Conclusion: CAF shows good sensitivity for the detection of skeletal muscle wasting in patients with heart failure. Its assessment may be useful to identify patients who should undergo additional testing, such as detailed body composition analysis. As no other biomarker is currently available, further investigation is warranted.
    European Journal of Heart Failure 10/2015; DOI:10.1002/ejhf.400 · 6.53 Impact Factor
  • Mitja Lainscak · Stephan von Haehling · Stefan D Anker
    International journal of cardiology 10/2015; 202:446-447. DOI:10.1016/j.ijcard.2015.09.121 · 4.04 Impact Factor
  • Stephan von Haehling · Stefan D Anker
    Journal of Cachexia, Sarcopenia and Muscle 09/2015; 6(3):193-6. DOI:10.1002/jcsm.12064 · 7.32 Impact Factor
  • Wolfram Doehner · Stephan von Haehling · Stefan D Anker
    European Heart Journal 09/2015; DOI:10.1093/eurheartj/ehv414 · 15.20 Impact Factor
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    ABSTRACT: Insulin resistance (IR) is a characteristic feature of heart failure (HF) pathophysiology that affects symptoms and mortality. Differences in the pathophysiological profile of IR in HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are not characterized in detail. The aim of this study was to evaluate features of IR in HFpEF vs. HFrEF. We included 18 patients with HFrEF (EF 30 ± 11%, body mass index (BMI) 26.5 ± 3.3 kg/m(2) ), 22 HFpEF patients (EF 63 ± 7%, BMI 28.6 ± 4.8 kg/m(2) ), and 20 healthy controls of similar age, all without diabetes mellitus. Patients were in stable ambulatory condition and on stable medical regimens for HF. IR was assessed at fasting steady state by the homeostasis model assessment (HOMA) index and within the physiological range of insulin-glucose interactions by the short insulin sensitivity test (SIST). Fasting-state IR was observed in HFpEF and in HFrEF in comparison with controls (HOMA 1.9, interquartile range (IQR) 1.5-3.6 vs. HOMA 3.1, IQR 1.4-3.7 vs. controls 1.2, IQR 1.8-0.9, respectively; analysis of variance P < 0.001), but no statistical difference was observed between HFpEF and HFrEF. The dynamic test over the physiological range of insulin-glucose interactions revealed a more severe IR in HFrEF as compared with HFpEF. Thus, glucose levels remained the highest in HFrEF (76 (64-89) mg/dL) at the end of the SIST compared with HFpEF and controls (68 (58-79) and 56 (44-66) mg/dL, respectively, P < 0.001). IR is present in non-diabetic patients with HFpEF and HFrEF. However, distinct differences in the insulin sensitivity characteristics in HFpEF and HFrEF become apparent by more advanced testing. Patients with HFrEF showed more severe IR. © 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.
    European Journal of Heart Failure 07/2015; 17. DOI:10.1002/ejhf.317 · 6.53 Impact Factor
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    ABSTRACT: Iron deficiency affects up to one-third of the world's population, and is particularly common in elderly individuals and those with certain chronic diseases. Iron excess can be detrimental in cardiovascular illness, and research has now also brought anaemia and iron deficiency into the focus of cardiovascular medicine. Data indicate that iron deficiency has detrimental effects in patients with coronary artery disease, heart failure (HF), and pulmonary hypertension, and possibly in patients undergoing cardiac surgery. Around one-third of all patients with HF, and more than one-half of patients with pulmonary hypertension, are affected by iron deficiency. Patients with HF and iron deficiency have shown symptomatic improvements from intravenous iron administration, and some evidence suggests that these improvements occur irrespective of the presence of anaemia. Improved exercise capacity has been demonstrated after iron administration in patients with pulmonary hypertension. However, to avoid iron overload and T-cell activation, it seems that recipients of cardiac transplantations should not be treated with intravenous iron preparations.
    Nature Reviews Cardiology 07/2015; DOI:10.1038/nrcardio.2015.109 · 9.18 Impact Factor
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    ABSTRACT: To elucidate the prognostic role of procalcitonin (PCT) in patients with acute decompensated heart failure (ADHF) without clinical signs of infection at admission. Serial measurements of PCT and NT-proBNP were performed in 168 patients, aged 68 ± 10 years with ADHF followed by 3-month outcome evaluation. Cox regression analysis demonstrated significant predictive value of baseline PCT for all-cause death/hospitalization (area under the curve: 0.67; p = 0.013) at 90th day. The patients with persistently elevated PCT or with an increase during the first 72 h of hospitalization had the worst prognosis (p = 0.0002). Baseline and serial in-hospital measurements of PCT have significant prognostic properties for 3-month all-cause mortality/hospitalization in patients with ADHF without clinical signs of infection at admission.
    Biomarkers in Medicine 07/2015; 9(7):651-9. DOI:10.2217/bmm.15.29 · 2.65 Impact Factor
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    ABSTRACT: Physical frailty (PF) and sarcopenia are two common and largely overlapping geriatric conditions upstream of the disabling cascade. The lack of a unique operational definition for PF and sarcopenia and the complex underlying pathophysiology make the development of biomarkers for these conditions extremely challenging. Indeed, the current definitional ambiguities of PF and sarcopenia, together with their heterogeneous clinical manifestations, impact the accuracy, specificity and sensitivity of individual biomarkers proposed so far. In this review, the current state of the art in the development of biomarkers for PF and sarcopenia is presented. A novel approach for biomarker identification and validation is also introduced that moves from the “one fits all” paradigm to a multivariate methodology.
    Journal of Cachexia, Sarcopenia and Muscle 07/2015; DOI:10.1002/jcsm.12051 · 7.32 Impact Factor
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    ABSTRACT: Myocardial infarction (MI) is a major condition causing heart failure (HF). After MI, the renin angiotensin system (RAS) and its signalling octapeptide angiotensin II (Ang II) interferes with cardiac injury/repair via the AT1 and AT2 receptors (AT1R, AT2R). Our study aimed at deciphering the mechanisms underlying the link between RAS and cellular components of the immune response relying on a rodent model of HF as well as HF patients. Flow cytometric analyses showed an increase in the expression of CD4(+) AT2R(+) cells in the rat heart and spleen post-infarction, but a reduction in the peripheral blood. The latter was also observed in HF patients. The frequency of rat CD4(+) AT2R(+) T cells in circulating blood, post-infarcted heart and spleen represented 3.8 ± 0.4%, 23.2 ± 2.7% and 22.6 ± 2.6% of the CD4(+) cells. CD4(+) AT2R(+) T cells within blood CD4(+) T cells were reduced from 2.6 ± 0.2% in healthy controls to 1.7 ± 0.4% in patients. Moreover, we characterized CD4(+) AT2R(+) T cells which expressed regulatory FoxP3, secreted interleukin-10 and other inflammatory-related cytokines. Furthermore, intramyocardial injection of MI-induced splenic CD4(+) AT2R(+) T cells into recipient rats with MI led to reduced infarct size and improved cardiac performance. We defined CD4(+) AT2R(+) cells as a T cell subset improving heart function post-MI corresponding with reduced infarction size in a rat MI-model. Our results indicate CD4(+) AT2R(+) cells as a promising population for regenerative therapy, via myocardial transplantation, pharmacological AT2R activation or a combination thereof. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
    Journal of Cellular and Molecular Medicine 05/2015; 19(8). DOI:10.1111/jcmm.12574 · 4.01 Impact Factor
  • Masaaki Konishi · Nicole Ebner · Stephan von Haehling · Stefan D Anker · Jochen Springer
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    ABSTRACT: Introduction: Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. Systemic inflammation plays a central role in its pathophysiology. As millions of patients are in a cachectic state of chronic disease, cachexia is one of the major causes of death worldwide. Difficulties in the recruitment and follow-up of clinical trials mean that well-characterized animal models are of great importance in developing cachexia therapies. However, some of the widely used animal models have limitations in procedural reproducibility or in recapitulating in the cachectic phenotype, which has warranted the development of novel models for cachexia. Areas covered: This review focuses on some of the currently developing rodent models designed to mimic each co-morbidity in cachexia. Expert opinion: Through developing cancer models, researchers have been seeking more targets for intervention. In cardiac cachexia, technical issues have been overcome by transgenic models. Furthermore, the development of new animal models has enabled the elucidation of the roles of inflammation, anabolism/catabolism in muscle/fat tissue and anorexia on cachexia. As metabolic and inflammatory pathways in cachexia may compromise cardiac muscle, the analysis of cardiac function/tissue in non-cardiac cachexia may be a useful component of cachexia assessment common to different underlying diseases and pave the way for novel drug discovery.
    Expert Opinion on Drug Discovery 04/2015; 10(7):1-10. DOI:10.1517/17460441.2015.1041914 · 3.54 Impact Factor
  • Journal of the American College of Cardiology 04/2015; 65(13):1381-2. DOI:10.1016/j.jacc.2014.12.055 · 16.50 Impact Factor
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    ABSTRACT: Background Activity of xanthine oxidase is induced in cancer cachexia, and its inhibition by allopurinol or oxypurinol improves survival and reduces wasting in the Yoshida hepatoma cancer cachexia model. Here, we tested the effects of the second-generation xanthine oxidase inhibitor febuxostat compared with placebo in the same model as used previously by our group.Methods Wistar rats (~200 g) were treated daily with febuxostat at 5 mg/kg/day or placebo via gavage for a maximum of 17 days. Weight change, quality of life, and body composition were analysed. After sacrifice, proteasome activity in the gastrocnemius muscle was measured. Muscle-specific proteins involved in metabolism were analysed by western blotting.ResultsTreatment of the tumour-bearing rats with febuxostat led to a significantly improved survival compared with placebo (hazard ratio: 0.45, 95% confidence interval: 0.22-0.93, P = 0.03). Loss of body weight was reduced (−26.3 ± 12.4 g) compared with placebo (−50.2 ± 2.1 g, P < 0.01). Wasting of lean mass was attenuated (−12.7 ± 10.8 g) vs. placebo (−31.9 ± 2.1 g, P < 0.05). While we did not see an effect of febuxostat on proteasome activity at the end of the study, the pAkt/Akt ratio was improved by febuxostat (0.94 ± 0.09) vs. placebo (0.41 ± 0.05, P < 0.01), suggesting an increase in protein synthesis.Conclusions Febuxostat attenuated cachexia progression and improved survival of tumour-bearing rats.
    Journal of Cachexia, Sarcopenia and Muscle 04/2015; 6(2). DOI:10.1002/jcsm.12017 · 7.32 Impact Factor
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    ABSTRACT: BackgroundA higher serum phosphate level is associated with worse outcome. Energy-demanding intracellular transport of phosphate is needed to secure anion bioavailability. In heart failure (HF), energy starvation may modify intracellular and serum levels of phosphate. We analysed determinants of serum phosphates in HF and assessed if catabolic/anabolic balance (CAB) was associated with elevation of serum phosphate.Methods We retrospectively reviewed data from 1029 stable patients with HF and have calculated negative (loss) and positive (gain) components of weight change from the onset of HF till index date. The algebraic sum of these components was taken as CAB. The univariate and multivariable predictors of serum phosphorus were calculated. In quintiles of CAB, we have estimated odds ratios for serum phosphorus above levels previously identified to increase risk of mortality. As a reference, we have selected a CAB quintile with similar loss and gain.ResultsApart from sex, age, and kidney function, we identified serum sodium, N-terminal fragment of pro-brain-type natriuretic peptide, and CAB as independent predictors of serum phosphorus. The odds for serum phosphorus above thresholds found in literature to increase risk were highest in more catabolic patients. In most catabolic quintile relative to neutral balance, the odds across selected phosphorus thresholds rose, gradually peaking at 1.30 mmol/L with a value of 3.29 (95% confidence interval: 2.00-5.40, P < 0.0001) in an unadjusted analysis and 2.55 (95% confidence interval: 1.38-2.72, P = 0.002) in a fully adjusted model.Conclusions Metabolic status is an independent determinant of serum phosphorus in HF. Higher catabolism is associated with serum phosphorus above mortality risk-increasing thresholds.
    Journal of Cachexia, Sarcopenia and Muscle 04/2015; DOI:10.1002/jcsm.12026 · 7.32 Impact Factor
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    ABSTRACT: Background Chronic heart failure (CHF) is associated with insulin resistance, indicating impairment in the control of energy metabolism. Insulin resistance in CHF relates to symptomatic status and independently predicts poor prognosis. We sought to determine whether insulin sensitivity is related to skeletal muscle strength in patients with CHF, taking into account muscle size and perfusion.Methods Quadriceps muscle size (square centimetre cross-sectional area at mid-femur level, computed tomography), isometric quadriceps muscle strength [absolute (in N) and strength per unit muscle area (N/cm2)], resting-leg blood flow (plethysmography) and maximal oxygen consumption (treadmill exercise test) were measured in 33 patients with CHF (left ventricular ejection fraction 28 ± 3.2%, mean ± Standard Error of the mean (SEM)) and 20 healthy controls. Insulin sensitivity was assessed by intravenous glucose tolerance tests and minimal modelling analysis.ResultsRight quadriceps strength (−27.0%, P < 0.0001), strength per muscle area (−18.0%, P < 0.003) and insulin sensitivity (−64.2%, P < 0.001) were lower in patients with CHF. The correlation between insulin sensitivity and absolute muscle strength was significant in the CHF group (r = 0.54, P = 0.001) and borderline in controls (r = 0.47, P = 0.06). This association remained significant between insulin sensitivity and strength per muscle area (CHF: r = 0.52, P < 0.01; controls: r = 0.62, P < 0.05). In stepwise regression analyses in CHF, only insulin sensitivity emerged as a predictor of strength per unit area of muscle [standardized coefficient (SC) = 0.45, P = 0.006; diuretic dose, SC = −0.31, P = 0.051; R2 = 0.37, P = 0.001], while age, left ventricular ejection fraction, maximal oxygen consumption, fasting glucose and insulin and blood flow were excluded. In controls, only insulin sensitivity remained in the final regression model (SC = 0.62, P = 0.004; R2 = 0.39, P = 0.004).Conclusions The myofibril contractile function of the quadriceps, i.e. functional quality of skeletal muscle, is strongly related to insulin sensitivity in patients with CHF and in healthy controls, independently of muscle size. Therapies aimed at improving insulin sensitivity in patients with CHF may clarify whether this relationship is causal.
    ESC Heart Failure 04/2015; 2(2). DOI:10.1002/ehf2.12035
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    ABSTRACT: The study aimed to identify early echocardiographic and circulating biomarkers of heart failure (HF) in hypertensive patients with normal resting echocardiography. Echocardiography at rest and during exercise, and selected biomarkers were assessed in control group, dyspnea group, and HF group. On exercise dyspnea patients had lower early diastolic (E') and systolic (S') mitral annular velocity (12.8 ± 1.0 vs 14.9 ± 3.0 cm/sec and 9.3 ± 2.0 vs 10.9 ± 2.0 cm/sec, respectively), and higher E/E' ratio compared to control group (6.7 ± 1.0 vs 5.9 ± 1.0) (p < 0.05 for all comparisons). The level of N-terminal propeptide of procollagen type III (PIIINP) was significantly higher in dyspnea group than in controls (p = 0.01). Control and dyspnea patients had lower levels of cardiotrophin-1, cystatin C, syndecan-4, and N terminal–probrain natriuretic peptide than HF patients (all p ≤ 0.01). In multivariate analysis PIIINP (unadjusted odds ratio [OR] = 8.2, 95% confidence interval [Cl] 1.7–40.6; p = 0.001; adjusted OR = 8.7; 95%CI: 1.5–48.3; p = 0.001) and E/E' ratio on exercise (unadjusted OR = 1.8, 95%CI: 0.8–4.0; p = 0.033; adjusted OR = 2.0; 95%CI: 0.8–4.8; p = 0.012) were the only factors significantly associated with the presence of dyspnea. PIIINP is the first early biomarker for the HF development in patients with HA and normal resting echocardiography. Exertional echocardiography may indicate patients with incipient HF with preserved ejection fraction.
    Scientific Reports 03/2015; 5(8916). DOI:10.1038/srep08916 · 5.58 Impact Factor
  • Journal of the American College of Cardiology 03/2015; 65(10):A854. DOI:10.1016/S0735-1097(15)60854-3 · 16.50 Impact Factor
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    Stephan von Haehling · Stefan D. Anker
    Journal of Cachexia, Sarcopenia and Muscle 03/2015; 6(1):1-1. DOI:10.1002/jcsm.12015 · 7.32 Impact Factor
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    ABSTRACT: Overactivity of the immune system may be a worthwhile therapeutic target for implementing prognostic improvements. Therefore the impact of lipopolysaccharide (LPS) desensitization on survival may help in the development of novel therapies. An understanding of the pathophysiology of the trace element selenium may complement such approaches, as recent data suggest that inflammatory responses are selenium-dependent.
    02/2015; 3(1-4):34-35. DOI:10.1016/j.pisc.2014.11.022
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    ABSTRACT: INTRODUCTION Abnormal serum calcium levels are associated with adverse cardiovascular effects. Therapy of heart failure (HF) may result in urinary calcium excretion and calcium apposition to bones, and consequently, in calcemia. OBJECTIVES The aim of the study was to assess the prevalence of abnormal calcium levels in the blood of patients receiving maximized HF therapy, to explore clinical and laboratory determinants of abnormal serum calcium levels, and to analyze the relation of abnormal calcium levels to prognosis. PATIENTS AND METHODS The study included 722 patients with HF classified as New York Heart Association (NYHA) classes III-IV at baseline (age 53 +/- 10 years, 13% of women), who underwent HF therapy optimization to maximum tolerated doses. RESULTS After therapy maximization, the NYHA class improved in 66.7% of the patients, while it did not change in 31.0% and worsened in 2.4%. Hypocalcemia occurred in 166 patients (22.9%) and was more prevalent in patients in whom the NYHA class improved. Hypercalcemia was diagnosed in 63 patients (8.7%) and was more common in patients with no functional improvement or worsening of the NYHA class. This effect was independent of age, sex, etiology of HF, body mass index, kidney function, or the use of thiazides. Hypercalcemia was associated with increased catabolism, hemodynamic compromise, more intensive inflammation, and lower bone mineral density. Lower albumin and higher phosphorus levels, were significant predictors of hypercalcemia, independently of kidney function. Hypocalcemia was associated with reduced catabolism, higher albumin and lower phosphorus levels, use of thiazides, and smoking history. Neither hypocalcemia nor hypercalcemia was associated with poor prognosis. CONCLUSIONS Our study shows that abnormal serum calcium levels are associated with a clinical response to treatment maximization in patients with HF. Mild hypocalcemia after maximization of therapy is not associated with poorer prognosis. Hypercalcemia is associated with lack of response to treatment, and its prognostic value remains unclear.
    Polskie archiwum medycyny wewnȩtrznej 01/2015; 125(1-2):54-64. · 2.12 Impact Factor

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