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Abstract Sarcopenia is characterized by a decline in muscle strength, generalized loss of skeletal muscle mass, and impaired physical performance, which are common outcomes used to screen, diagnose, and determine severity of sarcopenia in older adults. These outcomes are associated with poor quality of life, increased risk of falls, hospitalization, and mortality in this population. The development of sarcopenia is underpinned by aging, but other factors can lead to sarcopenia, such as chronic diseases, physical inactivity, inadequate dietary energy intake, and reduced protein intake (nutrition‐related sarcopenia), leading to an imbalance between muscle protein synthesis and muscle protein breakdown. Protein digestion and absorption are also modified with age, as well as the reduced capacity of metabolizing protein, hindering older adults from achieving ideal protein consumption (i.e., 1–1.5 g/kg/day). Nutritional supplement strategies, like animal (i.e., whey protein) and plant‐based protein, leucine, and creatine have been shown to play a significant role in improving outcomes related to sarcopenia. However, the impact of other supplements (e.g., branched‐chain amino acids, isolated amino acids, and omega‐3) on sarcopenia and related outcomes remain unclear. This narrative review will discuss the evidence of the impact of these nutritional strategies on sarcopenia outcomes in older adults.

Abstract Background The prevalence of sarcopenia and its impact in older patients undergoing inpatient cardiac rehabilitation (iCR) after cardiac procedure has been insufficiently studied. The main aim of this study was to evaluate the prevalence of sarcopenia and quantify the functional capacity of older sarcopenic and non-sarcopenic patients participating in iCR. Methods Prospective, observational cohort study within the framework of the ongoing multicenter prehabilitation study “PRECOVERY”. A sample of 122 patients ≥75 years undergoing iCR after cardiac procedure were recruited in four German iCR facilities and followed up 3 months later by telephone. At iCR (baseline), the Strength, Assistance with walking, Rise from a chair, Climb stairs and Falls (SARC-F) questionnaire was used to identify sarcopenic patients. In addition, Katz-Index, Clinical Frailty Scale (CFS), handgrip strength (HGS), Short Physical Performance Battery (SPPB) and 6-minute walk distance (6MWD) measured functional capacity and frailty at baseline. Outcomes were prevalence of sarcopenia and the correlation of sarcopenia to functional capacity and frailty at baseline as well as the SARC-F score at follow-up. The Wilcoxon test was applied for pre-post-test analysis. Correlation between sarcopenia and 6MWD, SPPB score and HGS was tested with the eta coefficient with one-way ANOVA. Results Complete assessments were collected from 101 patients (79.9 ± 4.0 years; 63% male). At baseline, the mean SARC-F score was 2.7 ± 2.1; 35% with sarcopenia. Other baseline results were Katz-Index 5.7 ± 0.9, CFS 3.2 ± 1.4, HGS 24.9 ± 9.9 kg, SPPB score 7.5 ± 3.3 and 6MWD 288.8 ± 136.5 m. Compared to baseline, fewer patients were sarcopenic (23% versus 35%) at follow-up. In the subgroup of sarcopenic patients at baseline (n = 35), pre-post comparison resulted in a significant SARC-F improvement (p = 0.017). There was a significant correlation between sarcopenia measured by SARC-F and poor results in the assessments of functional capacity (p 0.546). Conclusions The prevalence of sarcopenia in older patients at iCR after cardiac procedure is high (35%) and remains high at follow-up (23%). Sarcopenia screening is important since the diagnosis of sarcopenia in these patients correlates significantly with poor functional capacity. The results indicate that these patients may benefit from prehabilitation aimed at improving perioperative outcomes, increasing functional capacity and mitigating adverse effects. Trial registration German Clinical Trials Register (DRKS; http://www.drks.de ; DRKS00032256). Retrospectively registered on 13 July 2023.

Abstract Maintaining cancer patients’ exercise capacity and therefore patients’ ability to live a self-determined life is of huge importance, but little is known about major determinants. We sought to identify determinants of exercise capacity in patients with a broad spectrum of cancer types, who were already receiving cancer treatment or about to commence such therapy. Exercise capacity was assessed in 253 consecutive patients mostly suffering from advanced cancer using the 6-min walk test (6-MWT). All patients underwent echocardiography, physical examination, resting electrocardiogram, hand grip strength (HGS) measurement, and laboratory assessments. Patients were divided into two groups according to the median distance in the 6-MWT (459 m). Patients with lower exercise capacity were older, had significantly lower HGS and haemoglobin and higher values of high sensitive (hs) Troponin T and NT-proBNP (all p 0.2). Using multivariable logistic regression, we found that the presence of anaemia (odds ratio (OR) 6.172, 95% confidence interval (CI) 1.401–27.201, p = 0.016) as well as an increase in hs Troponin T (OR 3.077, 95% CI 1.202–5.301, p = 0.019) remained independent predictors of impaired exercise capacity. Increasing HGS was associated with a reduced risk of a lower exercise capacity (OR 0.896, 95% CI 0.813–0.987, p = 0.026). Screening patients for elevated hs troponin levels as well as reduced HGS may help to identify patients at risk of lower exercise capacity during cancer treatment.

Muscle wasting is one of the main causes for exercise intolerance and ventilatory inefficiency in patients with heart failure and a strong predictor of frailty and reduced survival. The prevalence of sarcopenia is at least 20% in patients with heart failure. Patients with heart failure often have subclinical systemic inflammation, which may exert sustained effects on skeletal muscle. Besides exercise, nutrition should also be carefully evaluated as an appropriate diet with selected nutraceuticals may be able to stimulate muscle anabolism and inhibit muscle catabolism. This review summarizes the epidemiological and clinical trial evidence supporting the recommendations for the use of nutraceuticals with anti-inflammatory properties in heart failure and provides an overview of the state of the evidence for nutraceutical supplementation to prevent and/or mitigate heart failure muscle wasting.

Abstract Background Ageing is accompanied by a progressive loss of skeletal muscle mass and strength, potentially determining the insurgence of sarcopenia. Evidence suggests that motoneuron and neuromuscular junction (NMJ) degeneration contribute to sarcopenia pathogenesis. Seeking for strategies able to slow down sarcopenia insurgence and progression, we investigated whether a 2‐year mixed‐model training involving aerobic, strength and balance exercises would be effective for improving or preserving motoneuronal health and NMJ stability, together with muscle mass, strength and functionality in an old, sarcopenic population. Methods Forty‐five sarcopenic elderly (34 females; 11 males) with low dual‐energy X‐ray absorptiometry (DXA) lean mass and Short Physical Performance Battery (SPPB) score

Abstract Sarcopenia is an age‐related muscle disorder typically associated with a poor quality of life. Its definition has evolved over time, and several underlying causes of sarcopenia in the elderly have been proposed. However, the exact mechanisms involved in sarcopenia, as well as effective treatments for this condition, are not fully understood. The purpose of this article was to conduct a comprehensive review of previous evidence regarding the definition, diagnosis, risk factors, and efficacy of plant‐derived natural products for sarcopenia. The methodological approach for the current narrative review was performed using PubMed, Scopus, and Web of Science databases, as well as Google Scholar (up to March 2021) in order to satisfy our objectives. The substantial beneficial effects along with the safety of some plant‐derived natural products including curcumin, resveratrol, catechin, soy protein, and ginseng on sarcopenia are reported in this review. Based on clinical studies, nutraceuticals and functional foods may have beneficial effects on physical performance, including handgrip and knee‐extension strength, weight‐lifting capacity, time or distance travelled before feeling fatigued, mitochondrial function, muscle fatigue, mean muscle fibre area, and total number of myonuclei. In preclinical studies, supplementation with herbs and natural bioactive compounds resulted in beneficial effects including increased plantaris mass, skeletal muscle mass and strength production, increased expression of anabolic factors myogenin, Myf5 and MyoD, enhanced mitochondrial capacity, and inhibition of muscle atrophy and sarcopenia. We found that several risk factors such as nutritional status, physical inactivity, inflammation, oxidative stress, endocrine system dysfunction, insulin resistance, history of chronic disease, mental health, and genetic factors are linked or associated with sarcopenia. The substantial beneficial effects of some nutraceuticals and functional foods on sarcopenia, including curcumin, resveratrol, catechin, soy protein, and ginseng, without any significant side effects, are reported in this review. Plant‐derived natural products might have a beneficial effect on various components of sarcopenia. Nevertheless, due to limited human trials, the clinical benefits of plant‐derived natural products remain inconclusive. It is suggested that comprehensive longitudinal clinical studies to better understand risk factors over time, as well as identifying a treatment strategy for sarcopenia that is based on its pathophysiology, be undertaken in future investigations.

Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10–25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease.The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety.

Cachexia is associated with poor prognosis in heart failure. Here the authors show that mice and patients with cardiac cachexia display reduced skeletal muscle expression and circulating levels of Musclin. Musclin ablation in skeletal muscle worsens, while its muscle-specific overexpression ameliorates heart failure in mice.

Aim: Despite concerns about cardiovascular implications in coronavirus disease-2019 (COVID-19) patients, not all COVID-19 patients are visited by cardiologists and recommended to perform comprehensive cardiovascular assessments including measurement of biomarkers and echocardiography. We aimed to investigate the reasons for seeking cardiology care and to assess our cardiologists' diagnostic approaches to COVID-19 patients with potential cardiovascular involvement. Methods and Results: In this prospective, observational study, data of all consecutive COVID-19 patients admitted to six designated hospitals for COVID-19 in Iran in whom bedside cardiology consultation was requested were collected. A total of 148 patients including 105 (71%) males were included. The mean age was 57 ± 17 years. The most common reasons for cardiology consultation were dyspnea (56.7%), chest pain (12.8%), and suspected arrhythmias (10.8%). The most common comorbidities were hypertension (40.5%), diabetes mellitus (19.6%), and coronary heart disease (18.9%). A 12-lead electrocardiography (ECG) was obtained in all patients. Point-of-care ultrasonography or limited transthoracic echocardiography (TTE) was performed in 106 (71.6%) patients, and complete TTE was performed in 35 (23.4%) patients. Cardiac troponin was measured in 63 (42.6%) patients, and N-terminal pro B-type natriuretic peptide level was measured in 34 (23%) patients. Overall, 51 (34.5%) patients underwent invasive mechanical ventilation, inotropes were used in 29 (19.6%) patients, and 40 (27%) patients died. Conclusions: While preventing unnecessary investigations, the cardiologists should not overlook the lifesaving role of ubiquitous diagnostic modalities (such as ECG and TTE) in early detection and management of cardiac involvement in COVID-19.

BackgroundThe risk of myocarditis after mRNA vaccination against COVID-19 has emerged recently. Current evidence suggests that young male patients are predominantly affected. In the majority of the cases, only mild symptoms were observed. However, little is known about cardiac magnetic resonance (CMR) imaging patterns in mRNA-related myocarditis and their differences when compared to classical viral myocarditis in the acute phase of inflammation.Methods and resultsIn total, 10 mRNA vaccination-associated patients with myocarditis were retrospectively enrolled in this study and compared to 10 patients suffering from viral myocarditis, who were matched for age, sex, comorbidities, and laboratory markers. All patients (n = 20) were hospitalized and underwent a standardized clinical examination, as well as an echocardiography and a CMR. Both, clinical and imaging findings and, in particular, functional and volumetric CMR assessments, as well as detailed tissue characterization using late gadolinium enhancement and T1 + T2-weighted sequences, were compared between both groups. The median age of the overall cohort was 26 years (group 1: 25.5; group 2: 27.5; p = 0.57). All patients described chest pain as the leading reason for their initial presentation. CMR volumetric and functional parameters did not differ significantly between both groups. In all cases, the lateral left ventricular wall showed late gadolinium enhancement without significant differences in terms of the localization or in-depth tissue characterization (late gadolinium enhancement [LGE] enlargement: group 1: 5.4%; group 2: 6.5%; p = 0.14; T2 global/maximum value: group 1: 38.9/52 ms; group 2: 37.8/54.5 ms; p = 0.79 and p = 0.80).ConclusionThis study yielded the first evidence that COVID-19 mRNA vaccine-associated myocarditis does not show specific CMR patterns during the very acute stage in the most affected patient group of young male patients. The observed imaging markers were closely related to regular viral myocarditis in our cohort. Additionally, we could not find any markers implying adverse outcomes in this relatively little number of patients; however, this has to be confirmed by future studies that will include larger sample sizes.

Abstract The impact of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) on diastolic function is less known. We describe a 46‐year‐old man with a history of mild hypertension who presented to the emergency department with fever, cough, and myalgia for 2 days. The patient was tested positive for SARS‐CoV‐2. He was admitted and started on a combination of antiviral and antimicrobial therapy. He developed respiratory distress 2 days later, and O2 saturation declined. Blood tests showed an increased N‐terminal pro‐B type natriuretic peptide (NT‐proBNP) level, and echocardiography showed normal left ventricular ejection fraction and E/e′ ratio of 16. Computed tomography scan showed interstitial pulmonary oedema and prominent peripheral pulmonary vascular markings. Given these findings, heart failure with preserved ejection fraction (HFpEF) was considered. Low‐dose diuretic was started, and fluid administration was restricted, resulting in a decrease in NT‐proBNP level, clinical and haemodynamic stabilization, and improved oxygenation. This case highlights the occurrence of HFpEF in coronavirus disease 2019.

Background: In light of overlapping symptoms, discrimination between non-ST-elevation (NSTE) acute coronary syndrome (ACS) and acute heart failure (HF) is challenging, particularly in patients with equivocal clinical presentation for suspected ACS. We sought to evaluate the diagnostic and prognostic properties of copeptin in this scenario. Methods: Data from 1088 patients from a single-center observational registry were used to test the ability of serial high sensitivity cardiac troponin T (hs-cTnT)—compared to copeptin, or a combination of copeptin with hs-cTnT—to discriminate acute HF from uncomplicated non-ST-elevation myocardial infarction (NSTEMI) and to evaluate all-cause mortality after 365 days. Patients with STEMI, those with unstable angina and either normal or undetectable hs-cTnT concentrations were excluded. The findings were validated in an independent external NSTE-ACS cohort. Results: A total of 219 patients were included in the analysis. The final diagnosis was acute HF in 56 and NSTE-ACS in 163, with NSTEMI in 78 and unstable angina having stable elevation of hs-cTnT >ULN in 85. The rate of all-cause death at 1 year was 9.6% and occurred significantly more often in acute HF than in NSTE-ACS (15 vs. 6%, p < 0.001). In the test cohort, the area under the receiver operator curve (AUC) for the discrimination of acute HF vs. NSTE-ACS without HF was 0.725 (95% confidence interval [CI] 0.625–0.798) for copeptin and significantly higher than for hs-cTnT at 0 h (AUC = 0.460, 0.370–0.550) or at 3 h (AUC = 0.441, 0.343–0.538). Copeptin and hs-cTnT used either as continuous values or at cutoffs optimized to yield 90% specificity for acute HF were associated with significantly higher age- and sex-adjusted risk for all-cause mortality at 365 days. The findings from the test cohort were consistently replicated in the independent external NSTE-ACS validation cohort. Conclusions: High concentrations of copeptin in patients with suspected NSTE-ACS and equivocal clinical presentation suggest the presence of acute HF compared to uncomplicated NSTE-ACS and are associated with higher rates of all-cause death at 365 days.

(1) Background: Insulin resistance (IR) is a characteristic pathophysiologic feature in heart failure (HF). We tested the hypothesis that skeletal muscle metabolism is differently impaired in patients with reduced (HFrEF) vs. preserved (HFpEF) ejection fraction. (2) Methods: carbohydrate and lipid metabolism was studied in situ by intramuscular microdialysis in patients with HFrEF (59 ± 14y, NYHA I-III) and HFpEF (65 ± 10y, NYHA I-II) vs. healthy subjects of similar age during the oral glucose load (oGL); (3) Results: There were no difference in fasting serum and interstitial parameters between the groups. Blood and dialysate glucose increased significantly in HFpEF vs. HFrEF and controls upon oGT (both p < 0.0001), while insulin increased significantly in HFrEF vs. HFpEF and controls (p < 0.0005). Muscle tissue perfusion tended to be lower in HFrEF vs. HFpEF and controls after the oGL (p = 0.057). There were no differences in postprandial increases in dialysate lactate and pyruvate. Postprandial dialysate glycerol was higher in HFpEF vs. HFrEF and controls upon oGL (p = 0.0016); (4) Conclusion: A pattern of muscle glucose metabolism is distinctly different in patients with HFrEF vs. HFpEF. While postprandial IR was characterized by impaired tissue perfusion and higher compensatory insulin secretion in HFrEF, reduced muscle glucose uptake and a blunted antilipolytic effect of insulin were found in HFpEF.

Abstract Background The role of statins in patients with heart failure (HF) of different levels of left ventricular ejection fraction (LVEF) remains unclear especially in the light of the absence of prospective data from randomized controlled trials (RCTs) in non-ischemic HF, and taking into account potential statins’ prosarcopenic effects. We assessed the association of statin use with clinical outcomes in patients with HF. Methods We searched PubMed, EMBASE, Scopus, Google Scholar and Cochrane Central until August 2018 for RCTs and prospective cohorts comparing clinical outcomes with statin vs non-statin use in patients with HF at different LVEF levels. We followed the guidelines of the 2009 PRISMA statement for reporting and applied independent extraction by multiple observers. Meta-analyses of hazard ratios (HRs) of effects of statins on clinical outcomes used generic inverse variance method and random model effects. Clinical outcomes were all-cause mortality, cardiovascular (CV) mortality and CV hospitalization. Results Finally we included 17 studies (n = 88,100; 2 RCTs and 15 cohorts) comparing statin vs non-statin users (mean follow-up 36 months). Compared with non-statin use, statin use was associated with lower risk of all-cause mortality (HR 0.77, 95% confidence interval [CI], 0.72–0.83, P

Background Patients with breast cancer can be affected by cardiotoxic reactions through cancer therapies. Cardiac biomarkers, like NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) and high‐sensitivity cardiac troponin T, might have predictive value. Methods and Results Echocardiography, ECG, hemodynamic parameters, NT‐proBNP and high‐sensitivity cardiac troponin T were assessed in 853 patients with early‐stage breast cancer randomized in the German Breast Group GeparOcto‐GBG 84 phase III trial. Patients received neo‐adjuvant dose‐dense, dose‐intensified epirubicin, paclitaxel, and cyclophosphamide (iddEPC group, n=424) or paclitaxel, non‐pegylated doxorubicin, and in triple negative breast cancer, (paclitaxel, non‐pegylated doxorubicin, carboplatin group, n=429) treatment for 18 weeks. Patients positive for human epidermal growth receptor 2 (n=354, 41.5%) received monoclonal antibodies on top of allocated therapy; 119 (12.9%) of all patients showed a cardiotoxic reaction during therapy (15 [1.8%] using a more strict definition). Presence of cardiotoxic reactions was irrespective of treatment allocation (P=0.31). Small but significant increases in NT‐proBNP developed early in patients with a cardiotoxic reaction as compared with those without in whom NT‐proBNP rose only towards the end of therapy (P=0.04). High‐sensitivity cardiac troponin T rose early in both groups. Logistic regression showed that NT‐proBNP (odds ratio [OR], 1.03; 95% CI, 1.008–1.055; P=0.01) and hemoglobin (OR, 1.31; 95% CI, 1.05–1.63; P=0.02) measured at 6 weeks after treatment initiation were significantly associated with cardiotoxic reactions. Conclusions NT‐proBNP and hemoglobin are significantly associated with cardiotoxic reactions in patients with early‐stage breast cancer undergoing dose‐dense and dose‐intensified chemotherapy, but high‐sensitivity cardiac troponin T is not. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT02125344.

Aims: Metabolic and structural perturbations in skeletal muscle have been found in patients with heart failure (HF) both with preserved (HFpEF) and reduced (HFrEF) ejection fraction in association with reduced muscle endurance (RME). We aimed in the current study to create phenotypes for patients with RME and HFpEF compared to RME HFrEF according to their metabolomic profiles and to test the potential of Kynurenine (Kyn) as a marker for RME. Methods: Altogether, 18 HFrEF, 17 HFpEF, and 20 healthy controls (HC) were prospectively included in the current study. The following tests were performed on all participants: isokinetic muscle function tests, echocardiography, spiroergometry, and varied blood tests. Liquid chromatography tandem mass spectrometry was used to quantify metabolites in serum. Results: Except for aromatic and branched amino acids (AA), patients with HF showed reduced AAs compared to HC. Further perturbations were elevated concentrations of Kyn and acylcarnitines (ACs) in HFpEF and HFrEF patients (p < 0.05). While patients with HFpEF and RME presented with reduced concentrations of ACs (long- and medium-chains), those with HFrEF and RME had distorted AAs metabolism (p < 0.05). With an area under the curve (AUC) of 0.83, Kyn shows potential as a marker in HF and RME (specificity 70%, sensitivity 83%). In a multiple regression model consisting of short-chain-ACs, spermine, ornithine, glutamate, and Kyn, the latest was an independent predictor for RME (95% CI: −13.01, −3.30, B: −8.2 per 1 µM increase, p = 0.001). Conclusions: RME in patients with HFpEF vs. HFrEF proved to have different metabolomic profiles suggesting varied pathophysiology. Kyn might be a promising biomarker for patients with HF and RME.

Summary: Background: The Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial showed that, compared with usual care, a structured remote patient management (RPM) intervention done over 12-months reduced the percentage of days lost due to unplanned cardiovascular hospitalisations and all-cause death. The aim of the study was to evaluate whether this clinical benefit seen for the RPM group during the initial 12 month follow-up of the TIM-HF2 trial would be sustained 1 year after stopping the RPM intervention. Methods: TIM-HF2 was a prospective, randomised, multicentre trial done in 43 hospitals, 60 cardiology practices, and 87 general practitioners in Germany. Patients with heart failure, New York Heart Association functional class II or III, and who had been hospitalised for heart failure within 12 months before randomisation were randomly assigned to either the RPM intervention or usual care. At the final study visit (main trial), the RPM intervention was stopped and the 1 year extended follow-up period started, which lasted 1 year. The primary outcome was percentage of days lost due to unplanned cardiovascular hospitalisations and all-cause mortality. Analyses were done using the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01878630. Findings: Between Aug 13, 2013, and May 12, 2017, 1538 patients were enrolled (765 to the remote patient management group and 773 to the usual care group) in the main trial. 671 of 765 patients in the remote patient management group and 673 of 773 in the usual care group completed the main trial and started the extended follow-up period up to 1 year later. In the extended follow-up period, the percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause mortality did not differ significantly between groups weighted mean 5·95% [95% CI 4·59–7·31] in the RPM group vs 6·64% [95% CI 5·19–8·08] in the usual care group [rate ratio 0·79; 95% CI 0·78–1·21]). However, when data from the main trial and the extended follow-up period were combined, the percentage of days lost due to unplanned cardiovascular hospitalisation or all-cause death was significantly less in patients allocated to the RPM group (382 [50%] of 765; weighted mean 9·28%; 95% CI 7·76–10·81) than in the UC group (398 [51%] of 773; 11·78%; 95% CI 10·08–13·49; ratio of weighted average 0·79; 95% CI 0·62–1·00; p=0·0486). Interpretation: The positive effect of our RPM intervention on morbidity and mortality over the course of the main trial was no longer observed 1 year after stopping the RPM intervention. However, because the TIM-HF2 trial was not powered to show significance during the extended follow-up period, our results are exploratory and require further research. Funding: German Federal Ministry of Education and Research.

Regarding the management of suspected Non-ST-segment-elevation acute coronary syndrome (ACS), the main Biomarker-in-Cardiology (BIC)-8 randomized controlled trial study had reported non-inferiority for the incidence of major adverse cardiac events at 30 days in the Copeptin group (dual marker strategy of copeptin and hs-cTnT at presentation) compared to the standard process (serial hs-cTnT testing). However, in 349 (38.7%) of the 902 patients, high-sensitivity cardiac troponin was not available for the treating physicians. High sensitivity cardiac troponin T was re-measured from thawed blood samples collected at baseline. This cohort qualified for a re-analysis of the 30-day incidence rate of MACE (death, survived cardiac death, acute myocardial infarction, re-hospitalization for acute coronary syndrome, acute unplanned percutaneous coronary intervention, coronary bypass grafting, or documented life-threatening arrhythmias), or components of the primary endpoint including death or death/MI. After re-measurement of troponin and exclusion of 9 patients with insufficient blood sample volume, 893 patients qualified for re-analysis. A total of 57 cases were detected with high sensitivity cardiac troponin T ≥ 14 ng/L who had been classified as “troponin negative” based on a conventional cardiac troponin T or I < 99th percentile upper limit of normal. Major adverse cardiac events rates after exclusion were non-inferior in the Copeptin group compared to the standard group (4.34% (95% confidence intervals 2.60–6.78%) vs. 4.27% (2.55–6.66%)). Rates were 53% lower in the per-protocol analysis (HR 0.47, 95% CI: 0.18–1.15, p = 0.09). No deaths occurred within 30 days in the discharged low risk patients of the Copeptin group. Copeptin combined with high sensitivity cardiac troponin is useful for risk stratification and allows early discharge of low-to-intermediate risk patients with suspected acute coronary syndrome is as safe as a re-testing strategy at 3 h or later.

Introduction: Inflammatory cardiomyopathy (ICM) frequently leads to myocardial fibrosis, resulting in permanent deterioration of the left ventricular function and an unfavorable outcome. Soluble suppression of tumorigenicity 2 receptor (sST2) is a novel marker of inflammation and fibrosis in cardiovascular tissues. sST2 was found to be helpful in predicting adverse outcomes in heart failure patients with reduced ejection fraction. The aim of this study was to determine the association of sST2 plasma levels with cardiac magnetic resonance (CMR) and echocardiography imaging features of left ventricular impairment in ICM patients, as well as to evaluate the applicability of sST2 as a prognosticator of the clinical status in patients suffering from ICM. Methods: We used plasma samples of 89 patients presenting to the Heart Center Leipzig with clinically suspected myocardial inflammation. According to immunohistochemical findings in endomyocardial biopsies (EMB) conducted in the context of patients’ diagnostic work-up, inflammatory cardiomyopathy was diagnosed in 60 patients (ICM group), and dilated cardiomyopathy in 29 patients (DCM group). All patients underwent cardiac catheterization for exclusion of coronary artery disease and CMR imaging on 1.5 or 3 Tesla. sST2 plasma concentration was determined using ELISA. Results: Mean plasma concentration of sST2 in the whole patient cohort was 45.8 ± 26.4 ng/mL (IQR 27.5 ng/mL). In both study groups, patients within the highest quartile of sST2 plasma concentration had a significantly lower left ventricular ejection fraction (LV-EF) compared to patients within the lowest sST2 plasma concentration quartile (26 ± 11% vs. 40 ± 13%, p = 0.05 for ICM and 24 ± 13% vs. 51 ± 10%, p = 0.004 for DCM). sST2 predicted New York Heart Association (NYHA) class III/IV at 12 months follow-up more efficiently in ICM compared to DCM patients (AUC 0.85 vs. 0.61, p = 0.02) and was in these terms superior to NT-proBNP and cardiac troponin T. ICM patients with sST2 plasma concentration higher than 44 ng/mL at baseline had a significantly higher probability of being assigned to NYHA class III/IV at 12 months follow-up (hazard ratio 2.8, 95% confidence interval 1.01–7.6, log rank p = 0.05). Conclusion: Plasma sST2 levels in ICM patients reflect the degree of LV functional impairment at hospital admission and predict functional NYHA class at mid-term follow-up. Hence, ST2 may be helpful in the evaluation of disease severity and in the prediction of the clinical status in ICM patients.

Abstract Chloride is the principal anion of the extracellular fluid and vital for both serum electroneutrality and acid-base homeostasis. The aim of this review is to investigate the relevance of dyschloremia in the critically ill. An extensive literature research was conducted on www.pubmed.org. In addition, the references of included articles were searched for further possible investigation regarding chloride. Articles investigating the relevance of dyschloremia in the critically ill were included. All articles were screened in regard to dyschloremia in the critically ill. Chloride is essential for blood pressure control, decarboxylation/gas transport, renal function, and gastrointestinal homeostasis. “Dyschloremia,” i.e., serum chloride levels not within the limits of normal, may commonly be observed on ICUs and appear mainly induced by iatrogenic measures (i.e., infusion of chloride-rich fluids). Hypo- and hyperchloremia appear linked to increased mortality in defined ICU populations, but evidence is sparse. Data show that hyperchloremia may not only be linked to hyperchloremic metabolic acidosis, but also to increased hemodynamic instability and vasopressor need (e.g., in patients after major surgery). Nevertheless, it is currently unknown whether such effects would be directly or indirectly mediated. Moreover, recent evidence points to an increased incidence of acute kidney injury and need for renal replacement therapy in patients with advanced hyperchloremia. Current knowledge on chloride is largely limited by heterogeneous trial design and mostly abundant data on specific fluid replacement strategies. The aim of this review is to summarize key consequences of chloride in critical illness and to discuss implications for daily clinical practice and future research.

There is an increasing awareness of the prevalence of iron deficiency in patients with heart failure (HF), and its contributory role in the morbidity and mortality of HF. Iron is a trace element necessary for cells due to its capacity to transport oxygen and electrons. The prevalence of iron deficiency increases with the severity of HF. For a long time the influence of iron deficiency was underestimated, especially in terms of worsening of cardiovascular diseases and developing anaemia. In recent years, studies with intravenous iron agents in patients with iron deficiency and HF showed new insights into the improvement of iron therapy. Additionally, experimental studies supporting the understanding of iron metabolism and the resulting pathophysiological pathways of iron have been carried out. The aim of this mini review is to highlight why iron deficiency is recognised as an important comorbidity in HF.

Co-morbidities have been recognised as playing a crucial role in the progress of the older patient with HF in particular. The 2016 ESC/HFA HF guidelines stress the significance of co-morbidities more than any previous guidelines have. Iron deficiency is a comorbidity, that has received very little attention until the last decade, as evidence has accumulated both for the significance of this co-morbidity and the emergence of safe effective therapies that appear to offer significant benefits to the HF population who suffer this co-morbidity.

Abstract Background: Resting sympathetic hyperactivity and impaired parasympathetic reactivation after exercise have been described in patients with heart failure (HF). However, the association of these autonomic changes in patients with HF and sarcopenia is unknown. Objective: The aim of this study was to evaluate the impact of autonomic modulation on sarcopenia in male patients with HF. Methods: We enrolled 116 male patients with HF and left ventricular ejection fraction < 40%. All patients underwent a maximal cardiopulmonary exercise testing. Maximal heart rate was recorded and delta heart rate recovery (∆HRR) was assessed at 1st and 2nd minutes after exercise. Muscle sympathetic nerve activity (MSNA) was recorded by microneurography. Dual-energy X-ray absorptiometry was used to measure body composition and sarcopenia was defined by the sum of appendicular lean muscle mass (ALM) divided by height in meters squared and handgrip strength. Results: Sarcopenia was identified in 33 patients (28%). Patients with sarcopenia had higher MSNA than those without (47 [41-52] vs. 40 [34-48] bursts/min, p = 0.028). Sarcopenic patients showed lower ∆HRR at 1st (15 [10-21] vs. 22 [16-30] beats/min, p < 0.001) and 2nd min (25 [19-39] vs. 35 [24-48] beats/min, p = 0.017) than non-sarcopenic. There was a positive correlation between ALM and ∆HRR at 1st (r = 0.26, p = 0.008) and 2nd min (r = 0.25, p = 0.012). We observed a negative correlation between ALM and MSNA (r = -0.29, p = 0.003). Conclusion: Sympatho-vagal imbalance seems to be associated with sarcopenia in male patients with HF. These results highlight the importance of a therapeutic approach in patients with muscle wasting and increased peripheral sympathetic outflow.

An amendment to this paper has been published and can be accessed via the original article.

Cancer cachexia is a complex multifactorial syndrome marked by a continuous depletion of skeletal muscle mass associated, in some cases, with a reduction in fat mass. It is irreversible by nutritional support alone and affects up to 74% of patients with cancer—dependent on the underlying type of cancer—and is associated with physical function impairment, reduced response to cancer-related therapy, and higher mortality. Organs, like muscle, adipose tissue, and liver, play an important role in the progression of cancer cachexia by exacerbating the pro- and anti-inflammatory response initially activated by the tumor and the immune system of the host. Moreover, this metabolic dysfunction is produced by alterations in glucose, lipids, and protein metabolism that, when maintained chronically, may lead to the loss of skeletal muscle and adipose tissue. Although a couple of drugs have yielded positive results in increasing lean body mass with limited impact on physical function, a single therapy has not lead to effective treatment of this condition. Therefore, a multimodal intervention, including pharmacological agents, nutritional support, and physical exercise, may be a reasonable approach for future studies to better understand and prevent the wasting of body compartments in patients with cancer cachexia.

BackgroundSleep‐disordered breathing (SDB) after acute ischemic stroke is frequent and may be linked to stroke‐induced autonomic imbalance. In the present study, the interaction between SDB and peripheral endothelial dysfunction (ED) was investigated in patients with acute ischemic stroke and at 1‐year follow‐up. Methods and ResultsSDB was assessed by transthoracic impedance records in 101 patients with acute ischemic stroke (mean age, 69 years; 61% men; median National Institutes of Health Stroke Scale, 4) while being on the stroke unit. SDB was defined by apnea‐hypopnea index ≥5 episodes per hour. Peripheral endothelial function was assessed using peripheral arterial tonometry (EndoPAT‐2000). ED was defined by reactive hyperemia index ≤1.8. Forty‐one stroke patients underwent 1‐year follow‐up (390±24 days) after stroke. SDB was observed in 57% patients with acute ischemic stroke. Compared with patients without SDB, ED was more prevalent in patients with SDB (32% versus 64%; P

Heart failure (HF) is a chronic condition with many imbalances, including nutritional issues. Next to sarcopenia and cachexia which are clinically evident, micronutrient deficiency is also present in HF. It is involved in HF pathophysiology and has prognostic implications. In general, most widely known micronutrients are depleted in HF, which is associated with symptoms and adverse outcomes. Nutritional intake is important but is not the only factor reducing the micronutrient availability for bodily processes, because absorption, distribution, and patient comorbidity may play a major role. In this context, interventional studies with parenteral micronutrient supplementation provide evidence that normalization of micronutrients is associated with improvement in physical performance and quality of life. Outcome studies are underway and should be reported in the following years.

Iron is an element necessary for cells due to its capacity of transporting oxygen and electrons. One of the important co-morbidities in heart failure is iron deficiency. Iron has relevant biological functions, for example, the formation of haemoglobin, myoglobin and numerous enzymatic groups. The prevalence of iron deficiency increases with the severity of heart failure. For a long time, the influence of iron deficiency was underestimated especially in terms of worsening of cardiovascular diseases and of developing anaemia. In recent years, studies with intravenous iron agents in patients with iron deficiency and cardiovascular diseases indicated new insights in the improvement of therapy. Experimental studies support the understanding of iron metabolism. Many physicians remain doubtful of the use of intravenous iron due to reports of side effects. The aim of this review is to describe iron metabolism in humans, to highlight the influence of iron deficiency on the course and symptoms of heart failure, discuss diagnostic tools of iron deficiency and provide guidance on the use of intravenous iron.

Sleep-disordered breathing (SDB) is a common comorbidity in a number of cardiovascular diseases, and mounting clinical evidence demonstrates that it has important implications in the long-term outcomes of patients with cardiovascular disease (CVD). While recognition among clinicians of the role of SDB in CVD is increasing, it too often remains neglected in the routine care of patients with CVD, and therefore remains widely undiagnosed and untreated. In this article, we provide an overview of SDB and its relationship to CVD, with the goal of helping cardiovascular clinicians better recognize and treat this important comorbidity in their patients. We will describe the two major types of SDB and discuss the pathophysiologic, diagnostic, and therapeutic considerations of SDB in patients with CVD.

Cachexia is a weight-loss process caused by an underlying chronic disease such as cancer, chronic heart failure, chronic obstructive pulmonary disease, or rheumatoid arthritis. It leads to changes in body structure and function that may influence the pharmacokinetics of drugs. Changes in gut function and decreased subcutaneous tissue may influence the absorption of orally and transdermally applied drugs. Altered body composition and plasma protein concentration may affect drug distribution. Changes in the expression and function of metabolic enzymes could influence the metabolism of drugs, and their renal excretion could be affected by possible reduction in kidney function. Because no general guidelines exist for drug dose adjustments in cachectic patients, we conducted a systematic search to identify articles that investigated the pharmacokinetics of drugs in cachectic patients.

Physical disability is a common result and a major complication after stroke. The skeletal muscle is the main effector organ accountable for this disability. Yet, metabolic, structural and functional impairment of muscle tissue are not recognized as potential targets to improve post-stroke rehabilitation and remobilisation. We aimed to investigate metabolic and structural characteristics of the lean tissue as predictors of muscle function in patients after acute stroke. We studied 40 patients (age 68±12y, BMI 27±4, mean±SD) at the beginning of post-stroke hospitalized rehabilitation. All patients had paretic or plegic deficits of the limb due to acute stroke. Maximum isometric handgrip strength was measured in the stronger / non-paretic arm by a dynamometer. Lean tissue characteristics were assessed by whole body impedance analyses (BIA). Resistance (tissue hydratation, R/H) and reactance (cell integrity, Xc/H) were assessed and phase angle (phase-α) vector analyses were performed to evaluate lean tissue quality. Patients were grouped into tertials for muscle strength (hand grip in tertial 1/2/3: 17.07±4.10 N / 28.33±2.84 N / 41.21±7.97 N). Tertials were similar for BMI and age. Lean tissue quality measures increased stepwise with muscle strength tertials (phase-α in tertial 1/2/3: 4.28±0.84 / 4.80±1.06 / 5.51±0.91; ANOVA p=0.0064). Univariable regression analysis showed a significant association between muscle strength and tissue structure characteristics (R/H: r=0.48, p=0.0016; phase-α: r=0.55, p=0.0002). After multivariable adjustment for age and BMI, R/H and phase-α remained significant predictors of muscle strength (R/H: joint r=0.65, p=0.0009; phase-α: joint r=0.65, p=0.0009). In conclusion, poor lean tissue quality is a major determining factor to predict muscle strength in patients after stroke. Body impedance is an easy applicable tool to evaluate tissues metabolic and structural characteristics during post-stroke rehabilitation. BIA assessments may be helpful to support the rehabilitation process of patients after stroke by stressing the aspects of tissue quality.

ObjectivesWe hypothesised that assessment of plasma C-terminal pro-endothelin-1 (CT-proET-1), a stable endothelin-1 precursor fragment, is of prognostic value in patients with chronic heart failure (CHF), beyond other prognosticators, including N-terminal pro-B-type natriuretic peptide (NT-proBNP).MethodsWe examined 491 patients with systolic CHF (age: 63±11 years, 91% men, New York Heart Association [NYHA] class [I/II/III/IV]: 9%/45%/38%/8%, 69% ischemic etiology). Plasma CT-proET-1 was detected using a chemiluminescence immunoassay.ResultsIncreasing CT-proET-1 was a predictor of increased cardiovascular mortality at 12-months of follow-up (standardized hazard ratio 1.42, 95% confidence interval [CI] 1.04-1.95, p = 0.03) after adjusting for NT-proBNP, left ventricular ejection fraction (LVEF), age, creatinine, NYHA class. In receiver operating characteristic curve analysis, areas under curve for 12-month follow-up were similar for CT-proET-1 and NT-proBNP (p = 0.40). Both NT-proBNP and CT-proET-1 added prognostic value to a base model that included LVEF, age, creatinine, and NYHA class. Adding CT-proET-1 to the base model had stronger prognostic power (pConclusionsPlasma CT-proET-1 constitutes a novel predictor of increased 12-month cardiovascular mortality in patients with CHF. High CT-proET-1 together with high NT-proBNP enable to identify patients with CHF and particularly unfavourable outcomes.

BACKGROUND:Overproduction of pro-inflammatory cytokines is a well established factor in the progression of chronic heart failure (CHF). Changes in cellular immunity have not been widely studied, and the impact of standard medication is uncertain. Here we investigate whether a leukocyte redistribution occurs in CHF and whether this effect is influenced by beta-blocker therapy. METHODOLOGY:We prospectively studied 75 patients with systolic CHF (age: 68+/-11 years, left ventricular ejection fraction 32+/-11%, New York Heart Association class 2.5+/-0.7) and 20 age-matched healthy control subjects (age: 63+/-10 years). We measured the response of cells to endotoxin exposure in vitro, analysed subsets of lymphocytes using flow cytometry, and assessed plasma levels of the pro-inflammatory markers interleukin 1, 6, tumor necrosis factor-alpha, and soluble tumor necrosis factor receptors 1 and 2. PRINCIPAL FINDINGS:While no differences in the number of leukocytes were noted between patients with CHF and healthy controls, we detected relative lymphopenia in patients with CHF (p