Publications

  • John E Morley, Stefan D Anker, Stephan von Haehling
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    ABSTRACT: Sarcopenia is now defined as a decline in walking speed or grip strength associated with low muscle mass. Sarcopenia leads to loss of mobility and function, falls, and mortality. Sarcopenia is a major cause of frailty, but either condition can occur without the other being present. Sarcopenia is present in about 5 to 10 % of persons over 65 years of age. It has multiple causes including disease, decreased caloric intake, poor blood flow to muscle, mitochondrial dysfunction, a decline in anabolic hormones, and an increase in proinflammatory cytokines. Basic therapy includes resistance exercise and protein and vitamin D supplementation. There is now a simple screening test available for sarcopenia-SARC-F. All persons 60 years and older should be screened for sarcopenia and treated when appropriate.
    Journal of cachexia, sarcopenia and muscle. 12/2014; 5(4):253-259.
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    ABSTRACT: We evaluated the prognostic value of mid-regional proadrenomedullin (MR-proADM) in atrial fibrillation (AF) patients undergoing radiofrequency ablation. Plasma concentrations of MR-proADM were measured at baseline and after 12months in 87 AF patients in whom radiofrequency ablation was performed. The association between MR-proADM and AF recurrence was tested by univariable and multivariable Cox models. In all 87 patients radiofrequency ablation was successfully performed. Of the total population 54% had paroxysmal AF. The mean left ventricular ejection fraction was 54% (minimum 25%). After 12months of follow-up, 71% of the patients were free of AF recurrence. At baseline, mean MR-proADM in the total population was 0.72nmol/l±0.22. Patients with AF recurrence had significantly higher baseline MR-proADM (0.89nmol/l±0.29) as compared with patients without AF recurrence (0.65nmol/l±0.14; p<0.001). After 12months, mean MR-proADM plasma concentration remained higher in patients with AF recurrence (0.81nmol/l±0.22 as compared with patients free of AF 0.54nmol/l±0.20; p<0.001). Receiver operating characteristic (ROC) curve analysis for MR-proADM yields a specificity of 98% and a sensitivity of 64% with an optimal cut-off value of 0.82nmol/l to predict recurrence of AF after catheter ablation. In the logistic regression analysis only MR-proADM remained independently predictive for AF recurrence. This is the first study revealing the association between MR-proADM elevation before ablation and poor outcomes after ablation of AF. Larger studies are needed to validate these results. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    International journal of cardiology. 11/2014; 180C:129-133.
  • Stephan von Haehling, Stefan D. Anker
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    ABSTRACT: Body wasting in the context of chronic illness is associated with reduced quality of life and impaired survival. Recent clinical trials have investigated different approaches to improve patients’ skeletal muscle mass and strength, exercise capacity, and survival in the context of cachexia and body wasting, many of them in patients with cancer. The aim of this article was to summarize clinical trials published over the past 2 years. Therapeutic approaches discussed include appetite stimulants, such as megestrol acetate, L-carnitine, or melatonin, anti-inflammatory drugs, such as thalidomide, pentoxyphylline, or a monoclonal antibody against interleukin-1α as well as ghrelin and the ghrelin agonist anamorelin; nutritional support, and anabolics, such as enobosarm and testosterone.
    Journal of the American Medical Directors Association. 11/2014;
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    ABSTRACT: Serum phosphorus abnormalities may pose a risk on the cardiovascular system. In heart failure (HF) phosphorus homeostatic mechanisms are altered and may be modified by modern HF therapy. The impact of therapy optimization on phosphorus abnormalities and related outcome remains unknown. In 722 patients with HF subjected to treatment up-titration we analyzed the prevalence of serum phosphorus abnormalities and their relation to HF severity on top of optimal treatment, and we assessed adjusted risk of phosphorus abnormalities at different stages of HF. We analyzed predictors of hypo- and hyperphosphatemia and relation to prognosis. Hypophosphatemia was associated with better response to therapy, was more prevalent in milder HF, and the association was independent of age, sex, BMI, etiology of HF, kidney function and the use of diuretics. Hypophosphatemic patients lost more phosphorus into urine. They had also less catabolic profile. Patients with hyperphosphatemia on top of optimal therapy responded worse to treatment. Hyperphosphatemia was more prevalent in advanced HF, but the effect was attenuated after adjustment for potential confounders. Clinical and biochemical profiles of hyperphosphatemics suggested domination of catabolism. Neither hypophosphatemia nor hyperphosphatemia modifies the outcome Serum phosphorus abnormalities are related to HF severity on top of optimal therapy. Hypophosphatemia occurring on HF up-titration therapy likely has a multifactorial pathophysiology comprising of urinary phosphorus wasting and refeeding effects. Hyperphosphatemia is linked to the catabolic profile but the effect of renal impairment can't be ruled out. The prognostic impact of serum phosphorus abnormalities remain to be established.
    International Journal of Cardiology 11/2014; 177(1):248–254. · 6.18 Impact Factor
  • Stephan von Haehling, Stefan D Anker
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    ABSTRACT: Cachexia is a serious but underrecognised consequence of many chronic diseases. Its prevalence ranges from 5-15 % in end-stage chronic heart failure to 50-80 % in advanced cancer. Cachexia is also part of the terminal course of many patients with chronic kidney disease, chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis. Mortality rates of patients with cachexia range from 10-15 % per year in COPD through 20-30 % per year in chronic heart failure and chronic kidney disease to 80 % in cancer. The condition is also associated with poor quality of life. In the industrialised world, the overall prevalence of cachexia (due to any disease and not necessarily associated with hospital admission) is growing and it currently affects around 1 % of the patient population, i.e. around 9 million people. It is also a significant health problem in other parts of the globe. Recently there have been advances in our understanding of the multifactorial nature of the condition, and particularly of the role of inflammatory mediators and the imbalance of anabolism and catabolism. Several promising approaches to treatment have failed to live up to the challenge of phase III clinical trials, but the ghrelin receptor agonist anamorelin seems to have fulfilled at least some early promise. Further advances are urgently needed.
    Journal of cachexia, sarcopenia and muscle. 11/2014;
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    ABSTRACT: Muscle wasting is a common complication accompanying stroke. Although it is known to impair poststroke recovery, the mechanisms of subacute catabolism after stroke have not been investigated in detail. The aim of this study is to investigate mechanisms of local and systemic catabolism and muscle wasting (sarcopenia) in a model of ischemic stroke systematically.
    10/2014;
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    ABSTRACT: Abstract Aims: The risk of neonates for severe infection/sepsis is reciprocally proportional to gestational age and birth weight. As monocytes and dendritic cells (DC) are recognised key antigen-presenting immune cells, we aimed to elucidate whether neonatal age is associated with reduced expression of human-leukocyte antigen-DR (HLA-DR) antigens on subsets of monocytes and DCs. Methods: Forty-three consecutive neonates (20 male, mean gestational age 236.0±26.8 days; mean 1-min Apgar score 7.5±2.0) were included in a monocentric prospective observational analysis. Patients were grouped according to gestational age (n=15 full-term, n=28 pre-term defined as <33 weeks). Ten healthy adult volunteers were assessed also. Flow-cytometric assessment of HLA-DR expression was performed in subsets of peripheral blood myeloid and plasmacytoid DCs (MDC and PDC) and monocytes (CD14brightCD16negative/CD14positiveCD16positive/CD14dimCD16positive). Clinical and routine laboratory data were followed up. Results: At birth, leukocyte counts were increased in full-term neonates. Monocyte counts were significantly increased in neonates when compared with adults (all P<0.05). A significant numerical increase of CD14brightCD16negative and CD14positiveCD16positive monocytes was noted in pre-term and full-term neonates (all P<0.05), while HLA-DR expression in these subsets was significantly diminished (most pronounced in pre-term infants, P<0.0001). MDC and PDC HLA-DR expression was reduced also (all P<0.05). Clinical indices (e.g., pH, days on antibiotics/mechanical ventilation, fever/sepsis) were not found to correlate with immunological indices. Conclusions: We observed a markedly diminished HLA-DR expression on monocyte and DC subsets in pre-term and full-term neonates, which may contribute to impaired antimicrobial defence mechanisms in the early days of life.
    Journal of perinatal medicine. 10/2014;
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    ABSTRACT: Background Patients with colorectal cancer (CRC) often present with dyspnea and fatigue. These are also frequent symptoms in patients with chronic heart failure (CHF). Objectives We hypothesized that similar patterns of cardiovascular perturbations are present in CRC and CHF. Methods We prospectively studied 50 patients with CRC, 51 patients with CHF, and 51 control subjects. The CRC group was divided into 2 subgroups: patients who underwent chemotherapy (n = 26) and chemotherapy-naive patients (n = 24). We assessed exercise capacity (spiroergometry), cardiac function (echocardiography), heart rate variability (Holter electrocardiography), body composition (dual-energy x-ray absorptiometry), and blood parameters. Results Compared with the control arm, the left ventricular ejection fraction (CRC group 59.4%; control group 62.5%) and exercise performance as assessed by peak oxygen consumption (peak VO2) (CRC group 21.8 ml/kg/min; control group 28.0 ml/kg/min) were significantly reduced in CRC patients (both p < 0.02). Markers of heart rate variability were markedly impaired in CRC patients compared with control subjects (all p < 0.008). Compared with the control group, the CRC group also showed reduced lean mass in the legs and higher levels of the endothelium-derived C-terminal-pro-endothelin-1 (both p < 0.02). Major determinants of cardiovascular function were impaired in chemotherapy-treated patients and in the chemotherapy-naive patients, particularly with regard to exercise capacity, left ventricular ejection fraction, lean mass, and heart rate variability (all p < 0.05 vs. control subjects). Conclusions Some aspects of cardiovascular function are impaired in patients with CRC. More importantly, our findings were evident independently of whether patients were undergoing chemotherapy.
    Journal of the American College of Cardiology 09/2014; 64(13):1310–1319. · 14.09 Impact Factor
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    ABSTRACT: Background Blood flow in the intestinal arteries is reduced in patients with stable heart failure (HF) and relates to gastrointestinal (GI) symptoms and cardiac cachexia. Objectives The aims of this study were to measure arterial intestinal blood flow and assess its role in juxtamucosal bacterial growth, GI symptoms, and cachexia in patients with HF. Methods A total of 65 patients and 25 controls were investigated. Twelve patients were cachectic. Intestinal blood flow and bowel wall thickness were measured using ultrasound. GI symptoms were documented. Bacteria in stool and juxtamucosal bacteria on biopsies taken during sigmoidoscopy were studied in a subgroup by fluorescence in situ hybridization. Serum lipopolysaccharide antibodies were measured. Results Patients showed 30% to 43% reduced mean systolic blood flow in the superior and inferior mesenteric arteries and celiac trunk (CT) compared with controls (p < 0.007 for all). Cachectic patients had the lowest blood flow (p < 0.002). Lower blood flow in the superior mesenteric artery and CT was correlated with HF severity (p < 0.04 for all). Patients had more feelings of repletion, flatulence, intestinal murmurs, and burping (p < 0.04). Burping and nausea or vomiting were most severe in patients with cachexia (p < 0.05). Patients with lower CT blood flow had more abdominal discomfort and immunoglobulin A–antilipopolysaccharide (r = 0.76, p < 0.02). Antilipopolysaccharide response was correlated with increased growth of juxtamucosal but not stool bacteria. Patients with intestinal murmurs had greater bowel wall thickness of the sigmoid and descending colon, suggestive of edema contributing to GI symptoms (p < 0.05). In multivariate regression analysis, lower blood flow in the superior mesenteric artery, CT (p < 0.04), and inferior mesenteric artery (p = 0.056) was correlated with the presence of cardiac cachexia. Conclusions Intestinal blood flow is reduced in patients with HF. This may contribute to juxtamucosal bacterial growth and GI symptoms in patients with advanced HF complicated by cachexia.
    Journal of the American College of Cardiology 09/2014; 64(11):1092–1102. · 14.09 Impact Factor
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    Stefan D Anker, Stephan von Haehling
    Journal of cachexia, sarcopenia and muscle. 09/2014;
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    ABSTRACT: Background Male ageing is characterized by diminished circulating androgens with several adverse psychosomatic consequences and can be aggravated by concomitant chronic diseases. According to the European Male Aging Study (EMAS) Group, late-onset hypogonadism (LOH) refers to testosterone deficiency accompanied by sexual complaints.AimWe investigated the prevalence of LOH in men with systolic heart failure (HF), and its clinical determinants and prognostic consequences.Methods Among 201 men with systolic HF (age: 60 ± 11 years), serum total testosterone (TT) was assessed using an immunoassay, and estimated free testosterone (eFT) was calculated using Vermeulen's formula. LOH was diagnosed when TT < 3.2 ng/mL and eFT < 64 pg/mL were accompanied by three sexual symptoms (decrease in the number of morning erections, reduced potency, and low libido) of at least moderate severity assessed using the Aging Males' Symptoms Scale.ResultsDecreased frequency of morning erections, reduced potency, and low libido were experienced by 56%, 62%, and 55% of men with HF, respectively; whereas 67%, 61%, and 44% of subjects complained of at least one, two, and three symptoms, respectively. Hypogonadal TT and eFT were observed in 34% and 47% of patients, respectively; and in 33% subjects, both TT and eFT were reduced. Finally, 30 men with HF (15%) were diagnosed with LOH as compared with 2% in a European male population (EMAS). In a multivariable model, older age and higher serum uric acid were independently associated with greater LOH prevalence (both P < 0.05). Among men aged ≤60 years (but not in those aged >60 years), LOH increased 5-year all-cause mortality in the univariable model; however, when adjusted for HF severity, the association lost its statistical significance.Conclusions Men with systolic HF commonly report sexual complaints. LOH—the combination of sexual dysfunction and testosterone deficiency—occurs more frequently than in a general male population. LOH does not affect long-term mortality, when adjusted for HF severity.
    ESC Heart Failure. 09/2014; 1(1).
  • Stefan D. Anker, Stephan Haehling, Zoltán Papp
    ESC Heart Failure. 09/2014; 1(1).
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    Sandra Palus, Stephan von Haehling, Jochen Springer
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    ABSTRACT: The syndrome of cachexia, i.e., involuntary weight loss in patients with underlying diseases, sarcopenia, i.e., loss of muscle mass due to aging, and general muscle atrophy from disuse and/or prolonged bed rest have received more attention over the last decades. All lead to a higher morbidity and mortality in patients, and therefore, they represent a major socio-economic burden for the society today. This mini-review looks at recent developments in basic research that are relevant to the loss of skeletal muscle. It aims to cover the most significant publication of last 3 years on the causes and effects of muscle wasting, new targets for therapy development, and potential biomarkers for assessing skeletal muscle mass. The targets include the following: (1) E-3 ligases TRIM32, SOCS1, and SOCS3 by involving the elongin BC ubiquitin-ligase, Cbl-b, culling 7, Fbxo40, MG53 (TRIM72), and the mitochondrial Mul1; (2) the kinase MST1; and (3) the G-protein Gαi2. D(3)-creatine has the potential to be used as a novel biomarker that allows to monitor actual change in skeletal muscle mass over time. In conclusion, significant development efforts are being made by academic groups as well as numerous pharmaceutical companies to identify new target and biomarker muscles, as muscle wasting represents a great medical need, but no therapies have been approved in the last decades.
    International Journal of Cardiology 08/2014; · 6.18 Impact Factor
  • Journal of Cardiac Failure 08/2014; 20(8):S3. · 3.32 Impact Factor
  • Stephan von Haehling
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    ABSTRACT: To the Editor: Kress and Hall (April 24 issue)(1) describe neuromuscular problems commonly observed in the intensive care unit (ICU) during critical illness. Critical illness polyneuropathy is a generalized axonal neuropathy with predominance in the lower extremities.(2) Entrapment neuropathy is also quite common in the ICU. Loss of subcutaneous fat during a long stay in the ICU makes peripheral nerves susceptible to compression injury, particularly at the fibular head (leading to diminished power of the anterior tibialias) and at the ulnar groove (leading to diminished power in the intrinsic hand muscles). The problem can be avoided simply by awareness and . . .
    New England Journal of Medicine 07/2014; 371(3):287-8. · 54.42 Impact Factor
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    ABSTRACT: Matrix metalloproteinase 9 (MMP-9) is crucial for physiological tissue repair and pathophysiological myocardial remodeling. The regulation of its functioning has been shown to be mediated by formation of complexes with tissue inhibitor of metalloproteinases 1 (TIMP-1) and neutrophil gelatinase associated lipocalin (NGAL). We investigated the mRNA and protein expression of MMP-9, TIMP-1 and NGAL, the formation of complexes, their gelatinolytic activity and cellular localization in left ventricle (LV) from 10 female pigs with induced systolic heart failure (HF), 5 control pigs, and a woman with severe HF. The MMP-9, TIMP-1 and NGAL mRNA in LV did not differ between diseased and healthy pigs. In all pigs MMP-9, TIMP-1 and NGAL proteins were present in LV as high molecular weight (HMW) complexes (115, 130, 170 and 220 kDa), and no monomers were found. A 80 and 115 kDa gelatinolytically active bands were present in all LV homogenates. A 130-kDa active band was seen only in LV from pigs with severe HF. Similar results were found in the explanted heart of a female patient with severe HF. The incubation of the homogenates of porcine LV at 37°C resulted in appearance of 88 kDa active band, which was accompanied by a decreased intensity of HMW bands. The incubation of the homogenates of porcine LV (depleted of active MMP-9) with trypsin generated 80 and 115 kDa active bands. Immunohistochemistry revealed the presence of MMP-9 in the cytoplasm of porcine cardiomyocytes, but not in cardiofibroblasts. Our data suggest that MMP-9 originates from cardiomyocytes, forms the gelatinolytically inactive complexes with TIMP-1 and NGAL, present in normal and failing myocardium, likely serving as a reservoir of active MMP-9. Further studies are needed to elucidate the role of these HMW complexes in the extracellular matrix remodeling during the progression of HF, which presence should be considered when developing efficient strategies inhibiting myocardial matrix metalloproteinases.
    Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 06/2014; 65(3):365-75. · 2.48 Impact Factor
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    John E Morley, Stephan von Haehling, Stefan D Anker
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    ABSTRACT: The two most common muscle wasting diseases in adults are sarcopenia and cachexia. Despite differences in their pathophysiology, it is believed that both conditions are likely to respond to drugs that increase muscle mass and muscle strength. The current gold standard in this regard is exercise training. This article provides an overview of candidate drugs to treat muscle wasting disease that are available or in development. Drugs highlighted here include ghrelin agonists, selective androgen receptor molecules, megestrol acetate, activin receptor antagonists, espindolol, and fast skeletal muscle troponin inhibitors.
    Journal of cachexia, sarcopenia and muscle. 05/2014;
  • S von Haehling, S D Anker
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    ABSTRACT: Anaemia and iron deficiency are frequent co-morbidities in patients with chronic heart failure. Both are bound to worsen an already reduced exercise capacity in these patients. Recent data have demonstrated that iron deficiency alone, i. e. without concomitant anaemia, reduces quality of life, exercise capacity and likely also surivival. Two clinical entities should be differentiated in this context: absolute and functional iron deficiency, the first being an absolute deficiency of iron, the second representing a disturbed mobilisation capacity. The FAIR-HF study has shown that intravenous iron administration can improve quality of life and exercise capacity in affected patients. A correct diagnosis can easily be arrived at using parameters such as serum ferritin and transferrin saturation. Replenishing iron stores is most useful using the intravenous route, and administered doses need to be adjusted to individual needs.
    DMW - Deutsche Medizinische Wochenschrift 04/2014; 139(16):841-4. · 0.65 Impact Factor
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    ABSTRACT: Muscle wasting and cachexia are the ultimate consequence of aging and a variety of acute and chronic illnesses. Significant efforts are made by many stakeholders to develop effective therapies. An important aspect of successful therapeutic development research is a common nomenclature for effective communication between researchers and clinicians, to the public, and also with regulatory bodies. Despite several efforts to develop consensus definitions for cachexia and sarcopenia, including such new terms for muscle wasting as myopenia, a common conceptual approach and acceptable vocabulary and classification system are yet to be established. Notwithstanding the potential need to translate such disease definitions and terminologies into different languages, we advocate the use of the term "muscle wasting" as the unifying entity that represents the single most common disease process across a large spectrum of cachexia and in sarcopenia-associated disorders. In this paper, we outline a first proposal for the disease nomenclature and classification of "Muscle Wasting Diseases." This concept can be applied in acute and chronic disease settings. It is pertinent for wasting diseases, cachexia, and sarcopenia of any severity and due to any underlying illness. The concept of muscle wasting disease underscores the most common denominator of the underlying wasting processes, i.e., muscle wasting, without ignoring the advanced disease states that are also accompanied by fat tissue wasting. The term muscle wasting disease is easily understood by both the scientific community and the lay public. This may promote its general use and efforts to heighten education and awareness in the field.
    Journal of cachexia, sarcopenia and muscle. 03/2014;
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    ABSTRACT: This article highlights preclinical and clinical studies in the field of wasting disorders that were presented at the 7th Cachexia Conference held in Kobe, Japan, in December 2013. This year, the main topics were the development of new methods and new biomarkers in the field of cachexia and wasting disorders with particular focus on inflammatory pathways, growth differentiation factor-15, myostatin, the ubiquitin proteasome-dependent pathway, valosin and the regulation of ubiquitin-specific protease 19 that is involved in the differentiation of myogenin and myosin heavy chain. This article presents highlights from the development of drugs that have shown potential in the treatment of wasting disorders, particularly the ghrelin receptor agonist anamorelin, the myostatin antagonist REGN1033, the selective androgen receptor modulators enobosarm and TEI-E0001, and the anabolic catabolic transforming agent espindolol. In addition, novel data on the prevalence and detection methods of muscle wasting/sarcopenia are presented, including the D3-creatine dilution method and several new biomarkers.
    Journal of cachexia, sarcopenia and muscle. 03/2014;

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