The association between iron deficiency and outcomes: a secondary analysis of the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial.

In the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial, the use of intravenous iron did not reduce the need for blood transfusion or reduce patient complications or length of hospital stay. As part of the trial protocol, serum was collected at randomisation and on the day of surgery. These samples were analysed in a central laboratory for markers of iron deficiency. We performed a secondary analysis to explore the potential interactions between pre-operative markers of iron deficiency and intervention status on the trial outcome measures. Absolute iron deficiency was defined as ferritin <30 µg.l-1 ; functional iron deficiency as ferritin 30-100 µg.l-1 or transferrin saturation < 20%; and the remainder as non-iron deficient. Interactions were estimated using generalised linear models that included different subgroup indicators of baseline iron status. Co-primary endpoints were blood transfusion or death and number of blood transfusions, from randomisation to 30 days postoperatively. Secondary endpoints included peri-operative change in haemoglobin, postoperative complications and length of hospital stay. Most patients had iron deficiency (369/452 [82%]) at randomisation; one-third had absolute iron deficiency (144/452 [32%]) and half had functional iron deficiency (225/452 [50%]). The change in pre-operative haemoglobin with intravenous iron compared with placebo was greatest in patients with absolute iron deficiency, mean difference 8.9 g.l-1 , 95%CI 5.3-12.5; moderate in functional iron deficiency, mean difference 2.8 g.l-1 , 95%CI -0.1 to 5.7; and with little change seen in those patients who were non-iron deficient. Subgroup analyses did not suggest that intravenous iron compared with placebo reduced the likelihood of death or blood transfusion at 30 days differentially across subgroups according to baseline ferritin (p = 0.33 for interaction), transferrin saturation (p = 0.13) or in combination (p = 0.45), or for the number of blood transfusions (p = 0.06, 0.29, and 0.39, respectively). There was no beneficial effect of the use of intravenous iron compared with placebo, regardless of the metrics to diagnose iron deficiency, on postoperative complications or length of hospital stay.

International Exercise Recommendations in Older Adults (ICFSR): Expert Consensus Guidelines.

The human ageing process is universal, ubiquitous and inevitable. Every physiological function is being continuously diminished. There is a range between two distinct phenotypes of ageing, shaped by patterns of living - experiences and behaviours, and in particular by the presence or absence of physical activity (PA) and structured exercise (i.e., a sedentary lifestyle). Ageing and a sedentary lifestyle are associated with declines in muscle function and cardiorespiratory fitness, resulting in an impaired capacity to perform daily activities and maintain independent functioning. However, in the presence of adequate exercise/PA these changes in muscular and aerobic capacity with age are substantially attenuated. Additionally, both structured exercise and overall PA play important roles as preventive strategies for many chronic diseases, including cardiovascular disease, stroke, diabetes, osteoporosis, and obesity; improvement of mobility, mental health, and quality of life; and reduction in mortality, among other benefits. Notably, exercise intervention programmes improve the hallmarks of frailty (low body mass, strength, mobility, PA level, energy) and cognition, thus optimising functional capacity during ageing. In these pathological conditions exercise is used as a therapeutic agent and follows the precepts of identifying the cause of a disease and then using an agent in an evidence-based dose to eliminate or moderate the disease. Prescription of PA/structured exercise should therefore be based on the intended outcome (e.g., primary prevention, improvement in fitness or functional status or disease treatment), and individualised, adjusted and controlled like any other medical treatment. In addition, in line with other therapeutic agents, exercise shows a dose-response effect and can be individualised using different modalities, volumes and/or intensities as appropriate to the health state or medical condition. Importantly, exercise therapy is often directed at several physiological systems simultaneously, rather than targeted to a single outcome as is generally the case with pharmacological approaches to disease management. There are diseases for which exercise is an alternative to pharmacological treatment (such as depression), thus contributing to the goal of deprescribing of potentially inappropriate medications (PIMS). There are other conditions where no effective drug therapy is currently available (such as sarcopenia or dementia), where it may serve a primary role in prevention and treatment. Therefore, this consensus statement provides an evidence-based rationale for using exercise and PA for health promotion and disease prevention and treatment in older adults. Exercise prescription is discussed in terms of the specific modalities and doses that have been studied in randomised controlled trials for their effectiveness in attenuating physiological changes of ageing, disease prevention, and/or improvement of older adults with chronic disease and disability. Recommendations are proposed to bridge gaps in the current literature and to optimise the use of exercise/PA both as a preventative medicine and as a therapeutic agent.

Tumour biomarkers: association with heart failure outcomes.

BACKGROUND: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics. OBJECTIVES: To explore the association between tumour biomarkers and HF outcomes. METHODS: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumour biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1 and AFP. RESULTS: During a median follow-up of 21 months, 555 (27%) patients reached the primary end-point of all-cause mortality. CA125, CYFRA 21-1, CEA and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P < 0.001, P for trend < 0.001) and were, respectively, associated with a hazard ratio of 1.17 (95% CI 1.12-1.23; P < 0.0001), 1.45 (95% CI 1.30-1.61; P < 0.0001), 1.19 (95% CI 1.09-1.30; P = 0.006) and 1.10 (95% CI 1.05-1.16; P < 0.001) for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, haemoglobin and beta blocker). All tumour biomarkers (except AFP) had significant associations with secondary end-points (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a noninferior AUC compared with NT-proBNP (0.68) for all-cause mortality (P = 0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC = 0.71) improved the predictive value of the model for all-cause mortality (P = 0.0002 compared with NT-proBNP). CONCLUSIONS: Several established tumour biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumour biomarkers are also dysregulated in HF.

International Clinical Practice Guidelines for Sarcopenia (ICFSR): Screening, Diagnosis and Management.

OBJECTIVES: Sarcopenia, defined as an age-associated loss of skeletal muscle function and muscle mass, occurs in approximately 6 - 22 % of older adults. This paper presents evidence-based clinical practice guidelines for screening, diagnosis and management of sarcopenia from the task force of the International Conference on Sarcopenia and Frailty Research (ICSFR). METHODS: To develop the guidelines, we drew upon the best available evidence from two systematic reviews paired with consensus statements by international working groups on sarcopenia. Eight topics were selected for the recommendations: (i) defining sarcopenia; (ii) screening and diagnosis; (iii) physical activity prescription; (iv) protein supplementation; (v) vitamin D supplementation; (vi) anabolic hormone prescription; (vii) medications under development; and (viii) research. The ICSFR task force evaluated the evidence behind each topic including the quality of evidence, the benefit-harm balance of treatment, patient preferences/values, and cost-effectiveness. Recommendations were graded as either strong or conditional (weak) as per the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Consensus was achieved via one face-to-face workshop and a modified Delphi process. RECOMMENDATIONS: We make a conditional recommendation for the use of an internationally accepted measurement tool for the diagnosis of sarcopenia including the EWGSOP and FNIH definitions, and advocate for rapid screening using gait speed or the SARC-F. To treat sarcopenia, we strongly recommend the prescription of resistance-based physical activity, and conditionally recommend protein supplementation/a protein-rich diet. No recommendation is given for Vitamin D supplementation or for anabolic hormone prescription. There is a lack of robust evidence to assess the strength of other treatment options.

Novel endotypes in heart failure: effects on guideline-directed medical therapy.

Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

[Iron deficiency : Recognition and treatment]. / Eisenmangel : Erkennen und behandeln.

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.

Models of sarcopenia: Short review.

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?

Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.

INTRODUCTION: Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. METHODS AND RESULTS: BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05). CONCLUSION: Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%.

Ghrelin.

BACKGROUND: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

[Iron deficiency in chronic heart failure: from diagnosis to therapy]. / Eisenmangel bei chronischer Herzinsuffizienz: Von der Diagnose zur Therapie.

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.

Relation of impaired interorgan communication and parasympathetic activity in chronic heart failure and multiple-organ dysfunction syndrome.

BACKGROUND: We investigated the relationship of impaired autonomic function and severity of illness in chronic heart failure (CHF) and multiple-organ dysfunction syndrome (MODS) as an end stage of CHF. Furthermore, we assessed the link of parasympathetic modulation of the heart rate and inflammatory activation in CHF and MODS. METHODS: Sixty-five patients admitted for worsening of CHF were retrospectively enrolled in this study. In addition, 65 age- and sex-matched patients with pronounced MODS were assigned for comparison of autonomic function and C-reactive protein in patients with CHF or MODS, respectively. Heart rate variability (HRV) parameters of the time and frequency domain as markers of autonomic function were analyzed from 24-hour Holter electrocardiograms. RESULTS: The more pronounced the severity of illness as expressed by the Acute Physiology and Chronic Health Evaluation score, the more the HRV was impaired. This effect was particularly seen for overall variability (SD of RR intervals) and HRV parameters characterizing the parasympathetic modulations of the heart rate (high, very low frequency power). C-reactive protein levels as markers of inflammation were inversely related to high and very low frequencies. CONCLUSION: Our results allow for speculation that autonomic dysfunction in CHF indicates a beginning of uncoupled interorgan communication potentially leading to MODS as characterized by disruption of communication between the organs.

Plasma adiponectin in heart failure with and without cachexia: catabolic signal linking catabolism, symptomatic status, and prognosis.

BACKGROUND AND AIMS: 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. METHODS AND RESULTS: 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, p > 0.4), 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 p < 0.01). Furthermore, ADPN correlated with VO2 at anaerobic threshold (r = -0.34, p < 0.05). ADPN was highest in cachectic patients (cCHF, 16%) vs. non-cachectic (ncCHF) (18.7 ± 15.0 vs. 12.5 ± 9.9 mg/l; p < 0.05). ADPN indicated mortality risk independently of established prognosticators (HR: 1.04 95% CI: 1.02-1.07; p < 0.0001). 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. CONCLUSION: 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.

[Commentary on the 2010 ESC guidelines on device therapy in heart failure ]. / Kommentar zu den ESC-Leitlinien zur Device-Therapie bei Herzinsuffizienz 2010.

As part of the 2010 focused update of ESC guidelines on device therapy in heart failure, the guidelines on pacemakers in the treatment of heart failure were renewed. A new feature is that cardiac resynchronization therapy (CRT) is indicated for New York Heart Association (NYHA) class III and IV irrespective of the presence of left ventricular dilatation and specified for NYHA class IV (patient ambulatory, stable, life expectancy >6 months). Furthermore, NYHA class II (but not class I) has been added when there is left bundle branch block and QRS duration ≥150 ms. CRT is also indicated for patients in NYHA class III-IV with permanent atrial fibrillation and heart failure [left ventricular ejection fraction (LVEF) ≤ 35%] when QRS is ≥ 130 ms and ventricular rate has slowed either spontaneously or by AV node ablation. In patients with heart failure (NYHA class II-IV, LVEF ≤ 35%) who need a pacemaker for AV block, CRT is generally indicated to avoid progression of heart failure caused by right ventricular stimulation, also in cases of intrinsic QRS <120 ms. For patients with terminal heart failure who are not eligible for heart transplantation, treatment with a left ventricular assist device can be performed as destination therapy. The new guidelines expand the indication for device therapy in heart failure based on the newest study findings, particularly for patients in NYHA class II, and specify the old guidelines. There are still uncertainties that must be investigated in randomized trials regarding patients with permanent atrial fibrillation, the indication for CRT in heart block, and the question of CRT with pacemaker or defibrillator.

Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Elevated levels of asymmetric dimethylarginine in chronic heart failure: a pathophysiologic link between oxygen radical load and impaired vasodilator capacity and the therapeutic effect of allopurinol.

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.

ADQI 7: the clinical management of the Cardio-Renal syndromes: work group statements from the 7th ADQI consensus conference.

Many patients with heart failure have underlying renal dysfunction, and similarly, patients with kidney failure are prone to cardiac failure. This has led to the concept of cardio-renal syndromes, which can be an acute or chronic cardio-renal syndrome, when cardiac failure causes deterioration in renal function, or acute and/or chronic Reno-Cardiac syndrome, when renal dysfunction leads to cardiac failure. Patients who develop these syndromes have increased risk of hospital admission and mortality. Although there are clinical guidelines for managing both heart failure and chronic kidney disease, there are no agreed guidelines for managing patients with cardio-renal and/or Reno-Cardiac syndromes, as these patients have typically been excluded from clinical trials. We have therefore reviewed the currently available published literature to outline a consensus of current best clinical practice for these patients.