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Background and purpose Activation of the immune system correlates with the severity and the prognosis of patients with heart failure (HF). Here, we aim to identify and characterize long non-coding RNAs (lncRNAs) as a potential mechanistic link between the activation of the immune system and the pathophysiology of HF. Methods and results Using next-generation sequencing we found a yet uncharacterized lncRNA to be significantly upregulated in peripheral blood mononuclear cells of ischemic cardiomyopathy patients compared to controls, which we named Heat4 – Heart-disease associated transcript 4 (N=4; 2.05-fold increase; p Conclusion The lncRNA Heat4 is elevated in the blood of patients with HF. Heat4 limits the extent of the inflammatory response of non-classical monocytes and leads to a faster regeneration after vascular injury. Heat4 is located in the cytoplasm of monocytes interacting with the pro-inflammatory proteins IP1/IP2 and repealing their extracellular release. Modulating Heat4 levels may represent a novel strategy for treatment of cardiovascular diseases with impaired vascular functions. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Projektfoerderung im Bereich der Herzmedizin, Leipzig

Background and purpose Cardiogenic shock (CS) remains the leading cause of death in acute myocardial infarction (AMI), with high mortality rates of 40–50%. The long non-coding RNA (lncRNA) Heat4 is associated with the inflammatory response of non-classical monocytes. Previous experimental work shows that this mechanism may be important in heart failure (HF) and during regeneration after vascular injury. Here, we investigate the association of Heat4 with survival in patients with chronic HF and assessed its regulation in AMI and CS. Methods and results Heat4 was elevated in the blood of HF patients compared to age-matched non-failing controls (+5.2-fold; HF: N=63; Controls: N=38; p Conclusion The lncRNA Heat4 is upregulated in the blood of patients with chronic heart failure, acute myocardial infarction and cardiogenic shock. In CS, Heat4 is dynamically regulated. These data set the stage to further assess Heat4 blood levels as a strategy for risk stratification and potential treatment target in HF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Projektfoerderung im Bereich der Herzmedizin, Leipzig

Ambulante Herzgruppen sind ein wichtiger Teil der kardiovaskularen Langzeitpravention. Der eigentlich notwendigen Ausweitung des Angebotes ambulanter Herzgruppen steht der zunehmende arztliche Fachkraftemangel entgegen, da bisher alle Herzgruppen von Arzten begleitet werden mussen. Studiendaten zeigen, dass wahrend der letzten Jahrzehnte das Risiko von schwerwiegenden kardiovaskularen Ereignissen wahrend Bewegungstherapie gesunken ist. Dies ist v. a. auf die Fortschritte der kardiovaskularen Medizin im Hinblick auf Revaskularisationsstrategien und medikamentose Therapie zuruckzufuhren. Es erscheint somit nicht mehr notwendig, jede Herzgruppe von einem Arzt begleiten zu lassen, sondern es sollte eine Risikostratifikation erfolgen. In der „Standardherzgruppe“ ist keine arztliche Anwesenheit erforderlich. Die Gruppe wird von einem nichtarztlichen Herzgruppenleiter angeleitet, der uber eine entsprechende Qualifikation verfugt. Zudem muss ein automatischer externer Defibrillator (AED) vor Ort sein und die Moglichkeit eines sofortigen Notrufes an den Rettungsdienst gegeben sein. In der „Herzgruppe mit erhohtem Betreuungsbedarf“ wird hingegen eine arztliche Anwesenheit benotigt. In diese Gruppe werden Patienten eingeteilt, bei denen Risikokriterien, wie z. B. Angina pectoris oder Dyspnoe bei Belastung, erfullt sind. Ausgenommen von dieser Risikostratifikation sind Patienten, die die Aufnahmekriterien einer „Herzinsuffizienzherzgruppe“ erfullen. Diese neu seit Anfang 2020 eingefuhrte Hochrisikoherzgruppe wird durch speziell ausgebildete Herzgruppenleiter und Arzte angeleitet. Es wird kalkuliert, dass nach der vorgeschlagenen Regelung bei etwa 50 % aller Herzgruppenpatienten keine arztliche Gruppenbegleitung mehr benotigt wird. Durch dieses Modell konnten zukunftig noch mehr Patienten von ambulanten Herzgruppen profitieren, ohne dass ein Verlust an Sicherheit oder Effektivitat zu befurchten ware.

As a result of the continuous development of modern cancer treatment, more cancer patients can be cured every year. However, since many patients experience cardiovascular problems before, during and after their cancer treatment, cardio-oncology is becoming increasingly important. Numerous therapies can cause cardiotoxicity, such as chemotherapy, immunotherapy, antibody therapy and radiotherapy. If these remain undetected, the patient may develop, e.g. heart failure or severe heart valve damage. The broad spectrum of cardiovascular comorbidities has become an immense challenge for cardiologists and oncologists. Cardio-oncology also deals with the effects that cancer has on the cardiovascular system. New research indicates that the tumor itself also has direct negative effects on the heart, mediated by messenger substances. Therefore, it is important to understand which cancer patients are at increased cardiovascular risk, thereby enabling the development of new therapeutic approaches in the long term to maintain mobility and improve patient prognosis.

Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

Aims Reduced muscle endurance (RME) in patients with HFpEF and HFrEF is associated with structural and metabolic changes in skeletal muscle. We investigated the role of kynurenine (Kyn) as a potential marker in detecting RME. Additionally, we described the likely distorted metabolic pathways in serum in patients with RME and both preserved (HFpEF) and reduced (HFrEF) ejection fraction. Methods Fifty-five participants were prospectively recruited (17 HFpEF, 18 HFrEF outpatients and 20 healthy controls, HC). All participants underwent echocardiography, CPET, isokinetic muscle function tests. Quantification of metabolites in serum was performed using liquid chromatography tandem mass spectrometry. Results In a linear regression, Kyn was an independent predictor for RME after adjusting for alanine, glutamate, ornithine, spermine and short-chain-ACs (B: −8.2 per 1μM increase, 95% CI: −13.01, −3.30, p=0.001). Kyn showed 83% sensitivity and 70% specificity (area under the curve 0.83) in detecting RME. Patients with RME and HFpEF showed reduced levels of long-chain-, medium-chain-, medium-/long-chain-ACs ratios and alanine (p Conclusions Kyn shows high potential as biomarker for detecting RME. RME was associated with impaired fatty acid oxidation rates in HFpEF patients and with reduced concentrations of AAs in those with HFrEF. Funding Acknowledgement Type of funding sources: None.

Background and purpose Activation of the immune system correlates with the severity and the prognosis of patients with heart failure (HF). This study aims to identify and characterize long non-coding RNAs (lncRNAs) as a potential mechanistic link between the pathophysiology of HF and the activation of the immune system. Methods and results Next-generation sequencing (NGS) studies identified a 2.05-fold increase of the lncRNA Heat4 in the blood of patients with HF compared to controls, which was validated in a larger cohort (HF: N=63; Controls: N=38; p Conclusion The long non-coding RNA Heat4 is elevated in the blood of HF patients. Mechanistically, Heat4 limits the extent of the inflammatory response of non-classical monocytes. Therefore, Heat4 may provide a regulatory link between inflammation and HF. Funding Acknowledgement Type of funding sources: None.

As a result of the continuous development of modern cancer treatment, more cancer patients can be cured every year. However, since many patients experience cardiovascular problems before, during and after their cancer treatment, cardio-oncology is becoming increasingly important. Numerous therapies can cause cardiotoxicity, such as chemotherapy, immunotherapy, antibody therapy and radiotherapy. If these remain undetected, the patient may develop, e.g. heart failure or severe heart valve damage. The broad spectrum of cardiovascular comorbidities has become an immense challenge for cardiologists and oncologists. Cardio-oncology also deals with the effects that cancer has on the cardiovascular system. New research indicates that the tumor itself also has direct negative effects on the heart, mediated by messenger substances. Therefore, it is important to understand which cancer patients are at increased cardiovascular risk, thereby enabling the development of new therapeutic approaches in the long term to maintain mobility and improve patient prognosis.Durch eine fortwährende Weiterentwicklung der modernen Krebstherapie können jedes Jahr mehr Patienten mit Tumorerkrankung geheilt werden. Da es bei vielen Patienten jedoch kardiovaskuläre Probleme vor, während und nach ihrer Tumorbehandlung gibt, wird die Kardioonkologie immer wichtiger. Es gibt viele Therapien, die eine Kardiotoxizität verursachen können, so etwa Chemo‑, Immun‑, Antikörper- und Strahlentherapien. Bleiben diese unerkannt, kann der Patient unter anderem eine Herzinsuffizienz oder eine schwerwiegende Schädigung der Herzklappen entwickeln. Für Kardiologen und Onkologen ist das breite Spektrum der kardiovaskulären Komorbiditäten eine immense Herausforderung geworden. Die Kardioonkologie befasst sich daneben auch mit den Effekten der Tumorerkrankung selbst auf das kardiovaskuläre System. Neue Forschungsergebnisse weisen darauf hin, dass es auch direkte negative Einflüsse des Tumors auf das Herz gibt, die durch Botenstoffe vermittelt werden. Es ist daher wichtig zu verstehen, welche Patienten mit Tumorerkrankung ein erhöhtes kardiovaskuläres Risiko haben. So können langfristig neue Therapieansätze entwickelt werden, um Mobilität zu erhalten und die Prognose der Patienten zu verbessern.

Malignant diseases lead to a decline in physical performance in a large number of patients. This includes a reduction of the musculoskeletal system, restrictions in cardiovascular fitness and psychogenically influenced syndromes such as fatigue and asthenia. It is not yet clear to what extent physical training can counteract these limitations or undesirable side effects and how this training needs to be designed in the individual situation.The aim of this article is to find out whether physical training can be performed in cancer patients, how this training should be designed and which physical disorders can be influenced favorably.In this review, the currently available work on this topic was evaluated and classified with regard to its feasibility and effects in cancer patients.Physical training can be performed without complications in most patients even under treatment for the underlying malignant disease. It has a positive effect on physical performance, cardiovascular function, the perception of one's own cancer and overall well-being. Ideally, physical training for cancer patients should include a mixture of strength and endurance training. It should be carried out regularly and its intensity should be slowly increased. The type of physical activity should be adapted to the individual needs of the patient, take into account the particularities of the malignant disease and exclude any risk to the patient.In summary, a physical training program to accompany cancer therapy should be offered to virtually all patients with malignant disease.HINTERGRUND: Maligne Erkrankungen führen oft zu einem Rückgang der körperlichen Leistungsfähigkeit. Dies beinhaltet neben einer Beeinträchtigung des muskuloskeletalen Systems und Einschränkungen der kardiovaskulären Fitness auch psychogen beeinflusste Syndrome wie Fatigue oder Asthenie. Es ist bislang unklar, inwieweit körperliches Training diesen Einschränkungen entgegenwirken kann und wie dieses Training im individuellen Fall ausgestaltet werden sollte.Ziel dieser Arbeit ist es zu eruieren, ob körperliches Training bei Patienten mit Tumorerkrankung durchgeführt werden kann, wie dieses Training gestaltet werden sollte und welche Störungen oder unerwünschte Nebenwirkungen dabei günstig beeinflusst werden können.In dieser Übersichtsarbeit wurden die aktuell verfügbaren Arbeiten zum Thema evaluiert und bezüglich ihrer Durchführbarkeit und Auswirkungen bei Patienten mit Krebserkrankungen eingeordnet.Körperliches Training kann bei den meisten Patienten auch unter Therapie der malignen Grunderkrankung komplikationslos durchgeführt werden. Es wirkt sich positiv auf körperliche Leistungsfähigkeit, Herz-Kreislauf-Funktion, Wahrnehmung der eigenen Krebserkrankung und Gesamtbefinden aus. Idealerweise sollte körperliches Training beim Patienten mit Tumorerkrankung eine Mischung aus Kraft- und Ausdauertraining beinhalten. Es sollte regelmäßig durchgeführt und in seiner Intensität langsam gesteigert werden. Die Art der körperlichen Aktivität sollte an die individuellen Bedürfnisse des Patienten angepasst sein, Besonderheiten der Krebserkrankung berücksichtigen und eine Gefährdung des Patienten ausschließen.Zusammenfassend lässt sich sagen, dass nahezu jedem Patienten mit maligner Erkrankung ein therapiebegleitendes körperliches Training angeboten werden sollte.

Im klinischen Alltag wird einem Eisenmangel nicht immer ausreichend Beachtung geschenkt. Diagnostik und Therapie sind vielfach unzureichend. Dies ist vor allem bei Patienten mit chronischen Erkrankungen ein negativer Einflussfaktor in Bezug auf Lebensqualitat, korperliche Leistungsfahigkeit und Therapieansprechen. In dieser Ubersicht wird daher erortert, warum eine Diagnostik ausgerichtet an der individuellen Situation des Patienten notwendig ist. Zudem werden in diesem Zusammenhang wichtige Laborparameter vorgestellt. Ferner werden Argumente fur eine fruhzeitige und ausreichende Eisengabe bei verschiedenen chronischen Erkrankungen dargelegt. Die derzeit verfugbaren oralen und intravenosen Eisenpraparate werden hinsichtlich ihres therapeutischen Potenzials und ihrer Risiken naher beleuchtet.

Background Anaemia and iron deficiency (ID) are important factors for muscle function and exercise capacity in patients with chronic heart failure (HF). Their interaction in HF remains to be defined. Methods A total of 280 out-patients with stable chronic HF were enrolled with mean age of 67.0±10.7 years, 21%female, mean left ventricular ejection fraction (LVEF) was 38.9±13.4%, mean Body Mass Index (BMI) 29.3±5.5 kg/m2]. Anaemia was defined according to World Health Organization criteria [Haemoglobin (Hb) Results A total of 89 (32%) chronic HF patients had anaemia and 142 (51%) had iron deficiency at baseline. Patients with anaemia showed significant lower exercise capacity compared to patients without anaemia (peak VO2: 15.3±4.6 vs. 18.5±4.8 kg/min p0.05). Conclusion Both anaemia and ID are strongly associated with reduced exercise capacity in patients with HF. The effect of anaemia and iron deficiency together is stronger than that of anemia and ID alone. Reduced SPPB, 6MWT, and HGS are important risk factors for the development of anaemia or ID.

Background Sarcopenia has been recently identified as a co-morbidity in patients with heart failure. Whether sarcopenia affects prognosis in non-cachectic HF patients is unknown. Purpose To assess the determinants of sarcopenia and its prognostic value in elderly males with HF. Methods A total of 73 non-diabetic, non-cachectic, male patients with HF and reduced left ventricular ejection fraction ≤40% (age: 68±7 years, left ventricular ejection fraction 29±8%) were enrolled. Sarcopenia was evaluated in accordance with revised definition of European working group on sarcopenia in older people 2 from 2018. Probable sarcopenia (or presarcopenia) was defined as low muscle strength, evaluated by lowest tertile of grip strength. A sarcopenia diagnosis was confirmed by the presence of low muscle quantity in addition to the low muscle strength, expressed as lowest tertile of appendicular skeletal muscle mass (ASM) adjusted by height square. Muscle mass was measured by dual energy X-ray absorptiometry. Patients were divided into 3 groups according to the diagnosis of the presarcopenia/sarcopenia/nonsarcopenia and were compared in respect to survival. Results 14 (19%) and 13 (18%) patients were diagnosed with presarcopenia and sarcopenia, respectively. They were older compared to nonsarcopenia patients (72±6 and 73±6 vs. 65±7, p Survival sarcopenia in heart failure Conclusions The rate of presarcopenia and sarcopenia was high in non-cachectic, elderly men with HF, and these patients have impaired survival compared to the patients with normal skeletal muscle status. Acknowledgement/Funding Grant of the Ministery of Science of Republic of Serbia 175033

Background Cardiovascular (CV) blood biomarkers are considered prognostic markers of CV dysfunction during anti-cancer treatment. It is largely unknown, whether they are also prognostic markers for mortality. Purpose To investigate the prognostic impact of CV and inflammatory biomarker levels in cancer patients without significant CV disease at baseline on all-cause mortality. Methods We enrolled 138 unselected cancer patients without significant CV disease from November 2017 until December 2018 (age 63±14yrs, 45%male, body mass index (BMI) 25.5±7.7kg/m2) and 25 healthy controls (age 57±10yrs, 36% male, BMI 25.1±3.4kg/m2). The cancer group consisted of 85 lymphoma (62%), 25 breast cancer (18%), 10 colorectal cancer (7%), 11 non-small cell lung cancer (8%) and 7 other types of cancer (5%) patients. All cancer stages were represented (25% I/II, 76% III/IV). For biomarker analyses, blood samples were taken from an antecubital vein. Results N-terminal pro brain natriuretic peptide (NT-proBNP), high-sensitive Troponin T (hsTnT) and C-reactive protein (CRP) were significantly increased in cancer patients vs. healthy controls (90 ng/L [85–94] vs. 40 ng/L [35–45], p Conclusion In cancer patients without significant CV disease, plasma levels of the CV biomarkers NT-proBNP, hsTnT and the inflammatory biomarker CRP are elevated compared to healthy controls. All three blood biomarkers are independent prognostic markers of short-term mortality.

Biomarkers may help to rapidly differentiate heart failure from noncardiac causes of acute dyspnea. Natriuretic peptides are especially useful for this purpose and should be measured in all patients presenting with acute onset dyspnea. Due to their excellent negative predictive value, a normal serum concentration of natriuretic peptides makes acute heart failure unlikely. Assays exist for B‑type natriuretic peptide (BNP), N‑terminal pro-B-type natriuretic peptide (NT-proBNP) and midregional pro-atrial natriuretic peptide (MR-proANP) with established cut-offs in the acute setting. Importantly, in patients treated with an angiotensin receptor-neprilysin inhibitor (ARNI), NT-proBNP (or MR-proANP) should be used instead of BNP, since the latter is increased by ARNI treatment. Besides their established diagnostic value in heart failure patients, the measurement of natriuretic peptides provides prognostic information and may help in guiding therapy. Additionally, multiple other biomarkers reflect several pathophysiological processes involved in heart failure patients. Their diagnostic and prognostic impact in heart failure needs to be established.

Evaluation of secondary hyperparathyroidism (SHPT) and its prognostic impact on all-cause mortality in elderly males with heart failure (HF). Seventy three males (67 ± 7 years old) with systolic HF were included. Baseline PTH was measured. Patients were grouped according to PTH cut-off levels of 65 pg/ml (>65 pg/ml = SHPT vs. normal PTH). All-cause mortality was evaluated at 6-year follow-up. SHPT was diagnosed in 43 (59 %) patients. They were more severe compared to the patients with normal PTH regarding NYHA functional class (2.4 ± 0.5 vs. 2.1 ± 0.2, p = 0.001), quality of life score (34 ± 14 vs. 24 ± 12, p = 0.005), 6-min walking distance (378 ± 79 vs. 446 ± 73 m, p

Approximately 40-50% of the population over 80years of age suffers from sarcopenia making this condition a major geriatric clinical disorder and a key challenge to healthy aging. The hallmark symptom of sarcopenia is the loss of muscle mass and strength without the loss of overall body weight. Sarcopenic patients are likely to have worse clinical outcomes and higher mortality compared to healthy individuals. This review will focus on animal models designed to study sarcopenia including hind-limb unloading, de-nervation, and immobilization by using casts or wire strategies, as well as using aged rodents. Currently there are no registered treatments for sarcopenia. Most sarcopenic individuals show signs of physical frailty, which leads to increases the prevalence of balance disorders, falls, fractures and pain. Therefore, is it essential to develop and use relevant animal models to further the research on sarcopenia therapy?

Alterations to the body composition, i.e. the makeup of skeletal muscle, fat and bone density, are frequent in heart insufficiency. Their prevalence and clinical consequences are often underestimated. Cachexia is recognized as a complex multifactorial syndrome in chronic diseases that leads to weight loss. This point constitutes the essential differential criterion from sarcopenia. Cachexia is defined as a non-edematous weight loss of more than 5% within 12 months or less. Cachexia means weight loss, while sarcopenia means loss of muscle mass without weight loss because the functional muscle can be replaced by adipocytes. Sarcopenia is defined as a skeletal muscle mass index (SMMI) of at least 2 standard deviations below the mean value of a healthy young reference group between 20 and 30 years of the same sex and ethnic background. At the same time the walking speed is reduced to 1 m/s or the distance covered in a 6-min walk is400m. The determination of loss of muscle mass should be carried out by whole body scanning, ideally with dual-energy x‑ray absorptiometry. A reliable and simple method for measurement of performance capability is the short physical performance battery (SPPB) test. The treatment of sarcopenia and cardiac cachexia in patients with heart insufficiency is still a great challenge. Power and endurance training, nutritional supplementation and drug therapy are possible therapeutic approaches; however, the study situation is unsatisfactory.

Iron deficiency does not always receive sufficient attention in daily clinical practice. Diagnostic and treatment possibilities are underutilized. This leads to a negative impact on patients' quality of life, exercise capacity, and treatment response, especially in patients with chronic diseases. In this overview, important diagnostic parameters that should be assessed to detect iron deficiency are outlined. In addition, important laboratory parameters are provided. Furthermore, the necessity for early and sufficient iron supplementation for various chronic diseases is presented. In addition, the risks and benefits of currently available oral and intravenous options for iron treatment are outlined.

Anamie und Eisenmangel sind haufige Begleitphanomene bei Patienten mit chronischer Herzinsuffizienz. Sie konnen die bereits eingeschrankte korperliche Leistungsfahigkeit weiter reduzieren. Kurzlich vorgelegte Daten zeigen, dass bereits Eisenmangel allein, also auch ohne gleichzeitig bestehende Anamie, Auswirkungen auf Lebensqualitat, Leistungsfahigkeit und wohl auch auf die Mortalitat hat. Zu unterscheiden sind absoluter und funktioneller Eisenmangel, wobei dem ersten ein echter Eisenmangel, dem zweiten eine Mobilisierungsstorung aus den Eisenspeichern zugrunde liegt. Eine intravenose Eisensubsitution hat bei beiden Formen in der Studie FAIR-HF zu einer deutlichen Verbesserung der Lebensqualitat und der Leistungsfahigkeit beigetragen. Die Diagnose kann anhand einfacher Laborparameter, insbesondere dem Serumferritin und der Transferrinsattigung, gestellt werden. Eine Substitution ist nach der aktuell verfugbaren Datenlage in intravenoser Form sinnvoll, wobei die substitutierte Menge dem individuellen Bedarf angepasst werden muss.

Rome was not built in a day. Likewise, if one considers the evolution of systemic anti-cancer treatment, it took decades to go from acceptance of any therapy at all to single agents achieving isolated tumour responses (without prolongation of survival) to the current use of combination regimens as adjuvant therapy to surgery. Such incremental progress has led to improved quality of life and eventually survival for patients with some types of cancer. Cachexia and skeletal muscle wasting in cancer are significant clinical problems of high medical need for a large proportion of cancer patients and associated with very poor quality of life and very high mortality.1,2 An effective treatment of a complex multifactorial syndrome such as cachexia will likely evolve from a series of steps of discovery and new interventions before a comprehensive multimodal strategy can be identified that improves patient’s quality and quantity of life.3 There are reasons to be optimistic about the possibility that in the future, cachexia may be treated effectively. A number of drugs have already been developed that target key underlying mechanisms, namely, reduced food intake and altered metabolism and regulation of muscle mass, with the latter being split into pro-anabolic and anti-catabolic approaches. However, there is also some reason to be concerned because of the wide variability in current trial design, including different inclusion criteria, endpoints, analysis plans and the definition of best concomitant supportive care. Taken to the extreme, such differences in general approach have resulted in divergent opinions on what to consider a meaningful clinical endpoint by the European Medicines Agency (EMA) versus the US Food and Drug Administration (FDA). A result has been that in the clinical development programmes of some drugs, different endpoint assessments for American versus European regulatory authorities within the same trials using the same source data have been adopted. An example is the case of the POWER 1 and 2 trials testing the selective androgen receptor modulator enobosarm in patients with cancer suffering from muscle wasting.4–6 There has been a considerable influence from regulatory authorities on trial design. In the last 10 years, some regulatory authorities have consistently suggested that the design of randomized controlled trials testing treatments for cachexia should be aimed at demonstrating appropriate risk versus benefit, where benefit is defined as concomitant improvement in skeletal muscle mass (or lean mass) and relevant/meaningful physical function or improved survival. Whilst this is an admirable goal, from recent phase III trial results, this appears to be possibly unachievable with single modality interventions. Equally, it is not defined to whom the change is supposed to be ‘meaningful’: patient, caregiver, doctor, nurse or healthcare provider? The recent phase III trials of enobosarm used a co-primary end-point of lean body mass and stair climb power.4–6 Based on the FDA agreed co-primary responder analysis the trials failed to reach significance, principally because of lack of benefit in terms of the functional end point. In the responder analysis demanded by the FDA, an increase in performance of at least 10% for stair-climb power test was required for a patient to be considered to have benefited clinically [paper submitted]. Preventing a decline in performance was not considered in these analyses. In the analysis suggested by the EMA (which generally aims to assess clinically meaningful change regardless of direction), the same data were analysed using continuous data, and one of the two POWER trials may be considered successful, as both tests for change in lean mass and for stair-climb power showed significant changes over time. The two trials also had to be different, because of different background chemotherapy demanded in the inclusion criteria (i.e. taxane and non-taxane based). It is not clear, whether these are two trials in two orphan-type cancer indications (with different results), or are instead two trials in one indication with inconsistent results. It all depends on your approach to drug development (and maybe also on the regulatory body you talk to), but certainly it is a confusing situation by any standard. Similarly, the phase III (ROMANA) trials of the ghrelin receptor agonist anamorelin have shown significant benefit in terms of lean and fat body mass, but not for hand grip strength.7 These findings are not completely unexpected since whilst in healthy young individuals there is a strong positive correlation between muscle mass and muscle strength/power per se and between changes thereof,8,9 in older, sick individuals, the magnitude of strength generated by a certain unit of mass tends to be lower. These findings suggest that preservation/augmentation of muscle mass does not necessarily always translate into clinical benefits in non-muscular aspects of the cachexia syndrome as other factors may remain unchanged from a unimodal approach (e.g. targeting muscle anabolism). If other aspects of the cachexia syndrome remain unchanged (like systemic inflammation and catabolism or physical inactivity and undernutrition), can unimodal approaches lead to an increase in physical activity and/or preservation of independence? It appears that a more comprehensive approach to the cachexia syndrome is warranted if the reference outcomes of improved physical activity/preservation of independence are to be pursued. Still, preservation of function (and not its improvement) may also be a laudable aim of treatment development in cachexia, and regulatory guidance should permit for that. However, unlike areas such as hypertension where a given change in blood pressure is accepted as a surrogate for clinical events, it has to be recognized that in cachexia, the ‘relevance’ or ‘meaningfulness’ of a change in surrogates such as hand grip strength, stair-climb power, leg extension strength or timed sit-up-and-go is not known. Perhaps direct measures of patients’ daily physical activity would be better? In the related field of COPD-associated body wasting, exercise rehabilitation is well established with extensive guideline recommendations that are evidence-based.10 These guidelines have been developed over time and are multimodal in focus and are explicitly aimed at improving physical functioning and physical activity levels, nutritional status and quality of life. For patients with heart failure, chronic kidney disease, stroke or ageing-related frailty, such multimodal approaches are frequently considered,11–13 but evidence is so far weak compared with what has been achieved in COPD. Novel therapeutic agents under development for cachexia mostly focus on specific aspects of the syndrome (e.g. muscle anabolism, inflammation or appetite stimulation).14 Surely, phase III registration trials should assess safety in general, but efficacy specifically in relation to the target of the drug based on its mechanism of action. It may not be right to discard an intervention as ineffective because it does not yet affect a functional outcome, if, in fact – when inserted into a multimodal intervention that reflects the multifaceted aspect of the cachexia syndrome – the drug shows extended benefits that touch on issues such as health-related quality of life, patient-reported symptoms and tolerance of anti-cancer therapy. In the context of a complex disease process and a desire for multimodal therapies, regulatory advice on co-therapy with nutrition and exercise is also needed. Suggestions as to how best to include in this context supportive care in clinical trials 15 may also be helpful. We understand that this may include additional clinical trials for food products and supportive care approaches and surely this is acceptable, if the rules of the ‘game’ are clear for the good of our patients. Regulators need to be engaged in encouraging the testing of these modalities and their systematic inclusion in trial designs. In heart failure, such activities have already been initiated and aim to shift the development and authorization of medicines from the molecule paradigm to their evaluation in the context of the whole healthcare regimen.16 If a trial of a new agent incorporates these elements and is successful, it cannot lie with the pharmaceutical company to ensure that such adjuncts are available in precisely the same format everywhere in the world. Rather, the approved drug label may need to recommend such adjuncts for optimal effect. Clearly, this is not an easy field for new developments, but the medical need is great and the commercial returns for those who make it may be big. Once drugs are approved, the longer process of incorporating new agents into best clinical practice can begin. It should be clear to pharmaceutical companies, academic trialists and regulators that they may need to be more realistic about what can be achieved in a single step. Maybe also the adaptive licensing approach proposed by EMA 13 can help in this process of developing regulatory pathways. A willingness to consider current data with an open mind and a ‘Notice on Regulatory Guidance’ on cachexia trial design for cancer and beyond that cuts across continents would be a major step forwards to maintain drug development momentum, if there is to be genuine progress at this exciting juncture in the development of cachexia therapy. We want to help make that a reality whichever way we can.

Цель. Оценить влияние урсодеоксихолевой кислоты (УДХК) на функцию эндотелия и маркеры воспаления у больных хронической сердечной недостаточностью (ХСН). Введение. Эндотелиальная дисфункция, которая обычно наблюдается у больных ХСН, вносит вклад в возникающее при этом состоянии ограничение способности выполнять физические нагрузки. Бактериальные липополисахариды могут способствовать высвобождению провоспалительных цитокинов и усугублять эндотелиальную дисфункцию. УДХК — желчная кислота, используемая при лечении заболеваний печени с холестазом, обладает противовоспалительным и цитопротекторными свойствами и может способствовать образованию смешанных мицелл вокруг липополисахарида. Эти свойства могут быть полезными для улучшения периферического кровотока у пациентов с ХСН. Материал и методы. Проведено проспективное одноцентровое двойное слепое рандомизированное плацебо-контролируемое перекрестное исследование УДХК у 17 пациентов мужского пола с клинически стабильной ХСН [II/III функционального класса по New York Heart Association (NYHA) с фракцией выброса левого желудочка

Muscle protein metabolism is the main determinant in the development of both sarcopenia and cachexia. A vast array of pathophysiological mechanisms is involved in the dysbalance between anabolic and catabolic factors. Unlike cachexia, sarcopenia is not usually associated with weight loss. However, one of the prominent features of sarcopenia is the development of functional impairment and its clinical consequences. Over the last several years, a large number of studies has been published that buttress the value of essential amino acids as a nutritional supplement in sarcopenia and in chronic illnesses that are frequently associated with the development of cachexia. Such illnesses include diabetes mellitus, chronic heart and chronic renal failure, chronic obstructive pulmonary disease and malignant diseases. This article reviews the pathophysiological background of muscle protein metabolism as well as sarcopenia and cachexia as clinical entities. Moreover, this article provides an overview of studies that used essential amino acids as a nutritional supplement in the aforementioned illnesses.

Cachexia develops in the course of many chronic diseases such as malign tumours, chronic heart failure, chronic kidney failure, rheumatoid arthritis, or AIDS. In most cases, the development of cachexia worsens morbidity and mortality of the underlying disease. Unfortunately, the term „cachexia” is still not routinely used by clinicians, although the clinical impact of cachexia is difficult to overestimate. The reasons include the difficult question of a uniform definition of cachexia, but also the absence of specific therapies. The aim of this article is to provide an overview of the pathophysiology and potential therapeutic approaches to cachexia in chronic heart failure. We particularly discuss the role of inflammation and the regulation of appetite.

Inflammatory cytokines are thought to contribute to the development and progression of chronic heart failure (CHF). It has been shown that especially tumor necrosis factor-alpha (TNF) is activated in patients with CHF and exerts detrimental effects on the myocardium. Recent studies have demonstrated that circulating levels of TNF, soluble TNF receptors 1 and 2 and interleukin-6 are strong prognostic markers. The results of two randomized studies directly antagonizing TNF in CHF patients were rather disappointing. Nevertheless, TNF antagonism remains a therapeutic option and should be focussed on patients with systemic immune activation, particularly at times of exacerbation.

Cachexia is seen in a number of chronic diseases, and it is always associated with a poor prognosis. Irrespective of etiology, the development of cachexia appears to share a common pathophysiological pathway. This includes induction of proteasome-dependent myofibril-degradation, which is thought to be secondary to stimulation by enhanced levels of pro-inflammatory cytokines. Elevation of tumor necrosis factor-alpha (TNFalpha) and other plasma cytokines has been demonstrated in many conditions associated with cachexia. Despite improved pathophysiological understanding, a specific treatment for cachexia has not yet been established. Whilst direct TNFalpha antagonism has therapeutic appeal, this review will focus on manipulation of downstream pathways and the potential benefits. For example, nuclear factor-kappaB (NF-kappaB) is one of the most important signal transducers of TNFalpha, and drugs targeting this signalling cascade might be useful in the treatment of cachexia. Although the use of some of these substances, for example glucocorticoids, remains controversial, others may prove beneficial in the treatment of this syndrome. The role of other approaches such as proteasome-inhibitors remains to be elucidated. Alternatively, interleukin-10 and other immunosuppressive cytokines may also be able to counterbalance certain features of cachexia.

The obesity paradox in chronic heart failure (HF) has a number of facets that require discussion. These involve beliefs, various statistical results, and clinical messages. We believe that the paradox is here to stay—the data are just too overwhelming for us to believe otherwise. The main question, however, is what should be the message for patients and their physicians? Clinical Pharmacology & Therapeutics (2011) 90 1, 188–190. doi:10.1038/clpt.2011.72

Interleukin (IL)-10 is an important immunoregulatory cytokine that mediates its effects via a transmembrane receptor complex consisting of two different chains, IL-10R1 and IL-10R2. While IL-10R2 is ubiquitously expressed and does not bind IL-10 primarily, the expression of IL-10R1 determines cellular responsiveness. However, the current knowledge about the expression and regulation of IL-10R1 is still limited. Here we analyzed the expression of IL-10R1 on monocytic cells and demonstrated that human blood monocytes carried about 720 IL-10-binding sites on their surface. Compared with lymphocytes and various tissue cells and tissues, blood monocytes expressed the highest IL-10R1 levels. The in vitro differentiation of these cells into macrophages provoked a further increase of IL-10R1 surface expression. In contrast, their differentiation into myeloid dendritic cells (mDCs) resulted in reduced surface IL-10R1 levels. The different IL-10R1 levels expressed by monocyte-derived antigen-presenting cell populations were reflected in their different responsiveness toward IL-10. Importantly, also in vivo developed immature macrophages and mDCs showed different IL-10 sensitivity. These data suggest that, compared with monocytes and macrophages, mDCs partially escape from IL-10's inhibitory mechanisms by downregulating IL-10R1.

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 survival. 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.

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.

Adiponectin (ADPN) as an adipose tissue hormone contributes to regulation of energy metabolism and body composition and is associated with cardiovascular risk profile parameters. Cardiac cachexia may develop as a result of severe catabolic derangement in chronic heart failure (CHF). We aimed to determinate an abnormal ADPN regulation as a link between catabolic signalling, symptomatic deterioration and poor prognosis.We measured plasma ADPN in 111 CHF patients (age 65 ± 11, 90% male, left ventricular ejection fraction (LVEF) 36 ± 11%, peak oxygen consumption (peakVO2) 18.1 ± 5.7 l/kg*min, body mass index (BMI) 27 ± 4 kg/m(2), all mean ± standard deviation) and 36 healthy controls of similar age and BMI. Body composition was assessed by dual energy X-ray absorptiometry, insulin sensitivity was evaluated by homoeostasis model assessment, exercise capacity by spiroergometry. Plasma ADPN did not differ between CHF vs. controls (13.5 ± 11.0 vs. 10.5 ± 5.3 mg/l, p0.4), but increased stepwise with NYHA functional class (I/II/III: 5.7 ± 1.4/10.7 ± 8.3/19.2 ± 14.0 mg/l, ANOVA p0.01). Furthermore, ADPN correlated with VO2 at anaerobic threshold (r = -0.34, p0.05). ADPN was highest in cachectic patients (cCHF, 16%) vs. non-cachectic (ncCHF) (18.7 ± 15.0 vs. 12.5 ± 9.9 mg/l; p0.05). ADPN indicated mortality risk independently of established prognosticators (HR: 1.04 95% CI: 1.02-1.07; p0.0001). ADPN above the mean (13.5 mg/l) was associated with a 3.4 times higher mortality risk in CHF vs. patients with ADPN levels below the mean.Circulating ADPN is abnormally regulated in CHF. ADPN may be involved in impaired metabolic signalling linking disease progression, tissue wasting, and poor outcome in CHF.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide-dependent vasodilation. In 113 patients with chronic heart failure (CHF) and 26 controls, ADMA level was studied in relation to peripheral blood flow and vasodilator capacity. Further, the effects of allopurinol on concentrations of reactive oxygen species (ROS) and ADMA and peripheral vasodilator capacity were tested in a double-blind design. ADMA level was found to be elevated in CHF patients as compared with controls and increased in parallel with New York Heart Association (NYHA) class and exercise capacity (all P < 0.0001). The level of ADMA predicted resting blood flow (P < 0.05) and postischemic vasodilator capacity (P < 0.001). Sixty eight patients died during the follow-up period. The level of ADMA predicted survival after multivariable adjustment (P = 0.04). Allopurinol reduced uric acid (UA) concentration (P < 0.001) and decreased ROS concentration (allantoin, P < 0.01). Allopurinol lowered ADMA concentration (P = 0.02); postischemic vasodilation as well as endothelium-dependent vasodilation (both P < 0.05) improved. ADMA may be a pathophysiologic factor that is modulated by ROS accumulation and contributes to impaired vascular regulation in CHF.

Chronic heart failure (CHF) represents a major public health burden in developed countries. The introduction of new treatments has helped to improve its prognosis in recent years. However, it is still not possible to directly target the immunological aspects of the disease. In fact, chronic immune activation with the up-regulation of pro-inflammatory substances in the plasma remains an important feature of the disease, independently of its aetiology. Autoimmune mechanisms play a significant role in a subgroup of patients with dilated cardiomyopathy. The interplay between the two systems has not been established so far. This review briefly summarizes immune and autoimmune mechanisms in CHF.