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Background and Aims Evidence is lacking that correcting iron deficiency (ID) has clinically important benefits for patients with heart failure with preserved ejection fraction (HFpEF). Methods FAIR-HFpEF was a multicentre, randomized, double-blind trial designed to compare intravenous ferric carboxymaltose (FCM) with placebo (saline) in 200 patients with symptomatic HFpEF and ID (serum ferritin < 100 ng/mL or ferritin 100–299 ng/mL with transferrin saturation < 20%). The primary endpoint was change in 6-min walking test distance (6MWTD) from baseline to week 24. Secondary endpoints included changes in New York Heart Association class, patient global assessment, and health-related quality of life (QoL). Results The trial was stopped because of slow recruitment after 39 patients had been included (median age 80 years, 62% women). The change in 6MWTD from baseline to week 24 was greater for those assigned to FCM compared to placebo [least square mean difference 49 m, 95% confidence interval (CI) 5–93; P =.029]. Changes in secondary endpoints were not significantly different between groups. The total number of adverse events (76 vs. 114) and serious adverse events (5 vs. 19; rate ratio 0.27, 95% CI 0.07–0.96; P =.043) was lower with FCM than placebo. Conclusions In patients with HFpEF and markers of ID, intravenous FCM improved 6MWTD and was associated with fewer serious adverse events. However, the trial lacked sufficient power to identify or refute effects on symptoms or QoL. The potential benefits of intravenous iron in HFpEF with ID should be investigated further in a larger cohort. [ABSTRACT FROM AUTHOR]

In an ageing society, the importance of maintaining healthy life expectancy has been emphasized. As a result of age-related decline in functional reserve, frailty is a state of increased vulnerability and susceptibility to adverse health outcomes with a serious impact on healthy life expectancy. The decline in skeletal muscle mass and function, also known as sarcopenia, is key in the development of physical frailty. Both frailty and sarcopenia are highly prevalent in patients not only with advanced age but also in patients with illnesses that exacerbate their progression like heart failure (HF), cancer, or dementia, with the prevalence of frailty and sarcopenia in HF patients reaching up to 50–75% and 19.5–47.3%, respectively, resulting in 1.5–3 times higher 1-year mortality. The biological mechanisms of frailty and sarcopenia are multifactorial, complex, and not yet fully elucidated, ranging from DNA damage, proteostasis impairment, and epigenetic changes to mitochondrial dysfunction, cellular senescence, and environmental factors, many of which are further linked to cardiac disease. Currently, there is no gold standard for the treatment of frailty and sarcopenia, however, growing evidence supports that a combination of exercise training and nutritional supplement improves skeletal muscle function and frailty, with a variety of other therapies being devised based on the underlying pathophysiology. In this review, we address the involvement of frailty and sarcopenia in cardiac disease and describe the latest insights into their biological mechanisms as well as the potential for intervention through exercise, diet, and specific therapies. [ABSTRACT FROM AUTHOR]

Importance Sarcopenia, the age-related loss of muscle mass and strength/function, is an important clinical condition. However, no international consensus on the definition exists. Objective The Global Leadership Initiative in Sarcopenia (GLIS) aimed to address this by establishing the global conceptual definition of sarcopenia. Design The GLIS steering committee was formed in 2019–21 with representatives from all relevant scientific societies worldwide. During this time, the steering committee developed a set of statements on the topic and invited members from these societies to participate in a two-phase International Delphi Study. Between 2022 and 2023, participants ranked their agreement with a set of statements using an online survey tool (SurveyMonkey). Statements were categorised based on predefined thresholds: strong agreement (>80%), moderate agreement (70–80%) and low agreement (<70%). Statements with strong agreement were accepted, statements with low agreement were rejected and those with moderate agreement were reintroduced until consensus was reached. Results 107 participants (mean age: 54 ± 12 years [1 missing age], 64% men) from 29 countries across 7 continents/regions completed the Delphi survey. Twenty statements were found to have a strong agreement. These included; 6 statements on 'general aspects of sarcopenia' (strongest agreement: the prevalence of sarcopenia increases with age (98.3%)), 3 statements on 'components of sarcopenia' (muscle mass (89.4%), muscle strength (93.1%) and muscle-specific strength (80.8%) should all be a part of the conceptual definition of sarcopenia)) and 11 statements on 'outcomes of sarcopenia' (strongest agreement: sarcopenia increases the risk of impaired physical performance (97.9%)). A key finding of the Delphi survey was that muscle mass, muscle strength and muscle-specific strength were all accepted as 'components of sarcopenia', whereas impaired physical performance was accepted as an 'outcome' rather than a 'component' of sarcopenia. Conclusion and relevance The GLIS has created the first global conceptual definition of sarcopenia, which will now serve to develop an operational definition for clinical and research settings. [ABSTRACT FROM AUTHOR]

Iron deficiency (ID) is common in patients with cardiovascular disease. Up to 60% of patients with coronary artery disease, and an even higher proportion of those with heart failure (HF) or pulmonary hypertension have ID; the evidence for cerebrovascular disease, aortic stenosis and atrial fibrillation is less robust. The prevalence of ID increases with the severity of cardiac and renal dysfunction and is probably more common amongst women. Insufficient dietary iron, reduced iron absorption due to increases in hepcidin secondary to the low-grade inflammation associated with atherosclerosis and congestion or reduced gastric acidity, and increased blood loss due to anti-thrombotic therapy or gastro-intestinal or renal disease may all cause ID. For older people in the general population and patients with HF with reduced ejection fraction (HFrEF), both anaemia and ID are associated with a poor prognosis; each may confer independent risk. There is growing evidence that ID is an important therapeutic target for patients with HFrEF, even if they do not have anaemia. Whether this is also true for other HF phenotypes or patients with cardiovascular disease in general is currently unknown. Randomized trials showed that intravenous ferric carboxymaltose improved symptoms, health-related quality of life and exercise capacity and reduced hospitalizations for worsening HF in patients with HFrEF and mildly reduced ejection fraction (<50%). Since ID is easy to treat and is effective for patients with HFrEF, such patients should be investigated for possible ID. This recommendation may extend to other populations in the light of evidence from future trials. [ABSTRACT FROM AUTHOR]

It has become a bit of cliché to say that obesity is one of the chief risk factors for the development of heart failure (HF).[1] Even though this is certainly true, the situation appears to change significantly in patients with manifest HF for whom an "obesity paradox" has been suggested. In addition, the authors mention that the beneficial effect of ARNI treatment does not differ between groups divided by either BMI or WHtR, which is also inconsistent with one potential theory that could explain the obesity paradox, i.e. obese patients are more likely to benefit from the treatment. [Extracted from the article]

The article presents the discussion on abnormal atrial structure and function termed as atrial myopathy or atrial disease being common in patients with heart failure (HF). Topics include atrial dilatation, fibrosis, and functional impairment being common if not universal accompaniments of both HF and AF; and containing collagen synthesis and degradation, autonomic innervation, activated platelets, and coagulation factors, and inflammatory pathways.

Background Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for the treatment of adults with hyperkalaemia. This post hoc analysis of an open-label, single-arm trial (NCT02163499) compared SZC efficacy and safety >12 months among outpatients with hyperkalaemia and Stages 4 and 5 chronic kidney disease (CKD) versus those with Stages 1–3 CKD. Methods Adults with serum K+ ≥5.1 mmol/L (measured by point-of-care i-STAT device) received SZC 10 g three times daily for 24–72 h until normokalaemia (i-STAT K+ 3.5–5.0 mmol/L) was achieved [correction phase (CP)], followed by once daily SZC 5 g for ≤12 months [maintenance phase (MP)]. Here, patients were stratified by baseline estimated glomerular filtration rate (eGFR <30 or ≥30 mL/min/1.73 m2). Study endpoints included percent achieving normokalaemia during CP and MP, mean serum K+ and bicarbonate during MP, and adverse events (AEs). Results Of 751 patients enrolled, 289 (39%), 453 (60%) and 9 (1%) had baseline eGFR values of <30, ≥30 mL/min/1.73 m2 or missing, respectively. During the CP, 82% of patients achieved normokalaemia in both eGFR subgroups within 24 h, and 100 and 95% with baseline eGFR <30 and ≥30 mL/min/1.73 m2, respectively, within 72 h. Corresponding proportions with normokalaemia during the MP were 82 and 90% at Day 365, respectively. Mean serum K+ reduction from baseline during the CP was sustained throughout the MP and serum bicarbonate increased. AEs during the MP were more common in the eGFR <30 ≥30 mL/min/1.73 m2 subgroup. Conclusions SZC corrects hyperkalaemia and maintains normokalaemia among outpatients regardless of the CKD stage. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the net clinical and prognostic effects of intravenous (i.v.) iron therapy in patients with systolic heart failure (HF) and iron deficiency (ID). We performed an aggregate data meta-analysis (random effects model) of randomized controlled trials that evaluated the effects of i.v. iron therapy in iron-deficient patients with systolic HF. We searched electronic databases up to September 2014. We identified five trials which fulfilled the inclusion criteria (509 patients received i.v. iron therapy in comparison with 342 controls). Intravenous iron therapy has been shown to reduce the risk of the combined endpoint of all-cause death or cardiovascular hospitalization [odds ratio (OR) 0.44, 95% confidence interval (CI) 0.30-0.64, P < 0.0001], and the combined endpoint of cardiovascular death or hospitalization for worsening HF (OR 0.39, 95% CI 0.24-0.63, P = 0.0001). Intravenous iron therapy resulted in a reduction in NYHA class (data are reported as a mean net effect with 95% CIs for all continuous variables) (-0.54 class, 95% CI -0.87 to -0.21, P = 0.001); an increase in 6-min walking test distance (+31 m, 95% CI 18-43, P < 0.0001); and an improvement in quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ) score +5.5 points, 95% CI 2.8-8.3, P < 0.0001; European Quality of Life-5 Dimensions (EQ-5D) score +4.1 points, 95% CI 0.8-7.3, P = 0.01; Minnesota Living With Heart Failure Questionnaire (MLHFQ) score -19 points, 95% CI:-23 to -16, P < 0.0001; and Patient Global Assessment (PGA) +0.70 points, 95% CI 0.31-1.09, P = 0004]. The evidence indicates that i.v. iron therapy in iron-deficient patients with systolic HF improves outcomes, exercise capacity, and quality of life, and alleviates HF symptoms. [ABSTRACT FROM AUTHOR]

The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) controls tryptophan metabolism and is induced by pro-inflammatory stimuli. We investigated whether immunostimulatory treatment with granulocyte–macrophage colony-stimulating factor (GM-CSF) influences IDO activity and tryptophan metabolism in sepsis. Thirty-six patients with severe sepsis/septic shock and sepsis-associated immunosuppression (assessed using monocytic human leukocyte antigen-DR (mHLA-DR) expression) were assessed in a controlled trial of GM-CSF or placebo treatment for 8 days. Using tandem mass spectrometry, levels of tryptophan, kynurenine, kynurenic acid, quinolinic acid, 5-hydroxytryptophan, serotonin, and estimated IDO activity were determined in a blinded fashion over a 9-day interval. At baseline, tryptophan and metabolite levels did not differ between the study groups. Although tryptophan levels were unchanged in both groups over the treatment interval (all p>0.8), IDO activity was markedly reduced after GM-CSF treatment (35.4 ± 21.0 vs 21.6 ±9.9 (baseline vs day 9), p = 0.02). IDO activity differed significantly between the 2 groups after therapy ( p = 0.03). Metabolites downstream of IDO (kynurenine, quinolinic acid, kynurenic acid) were all induced in sepsis and declined in the GM-CSF group, but not in controls. Serotonin pathway metabolites remained unchanged in both groups (all p>0.15). Moreover, IDO activity correlated with procalcitonin ( p< 0.0001, r = 0.56) and mHLA-DR levels ( p = 0.005, r = −0.28) in the overall samples group. Thus, GM-CSF therapy is associated with decreased IDO activity and reduced kynurenine pathway catabolites in sepsis. This may be due to an improved antibacterial defence. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors are revolutionizing cancer treatment, but lead to the occurrence of immune related adverse events including ICI-associated myocarditis (ICIM). To date, transcriptional alterations of this rare phenomenon with a high mortality rate are not characterized. 19 ICIM patients at the University Hospitals Heidelberg and Kiel showed diverse clinical presentations. Comparative transcriptomics was able to distinguish ICIM patients from patients with dilated cardiomyopathy or virus-induced myocarditis in the upregulation of 3784 genes. The RNA-based analyses and immunohistology revealed a potential role of an inflammasome-regulating protein, GBP5, as a potential pathomechanism in cardiomyocytes. These alterations may help to diagnose ICIM and potentially enable to identify patients at risk in an early stage. Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing use leads to an increase of immune-related adverse events (irAEs). Among them, ICI-associated myocarditis (ICIM) is a rare irAE with a high mortality rate. We aimed to characterize the transcriptional changes of ICIM myocardial biopsies and their possible implications. Patients suspected for ICIM were assessed in the cardio-oncology units of University Hospitals Heidelberg and Kiel. Via RNA sequencing of myocardial biopsies, we compared transcriptional changes of ICIM (n = 9) with samples from dilated cardiomyopathy (DCM, n = 11), virus-induced myocarditis (VIM, n = 5), and with samples of patients receiving ICIs without any evidence of myocarditis (n = 4). Patients with ICIM (n = 19) showed an inconsistent clinical presentation, e.g., asymptomatic elevation of cardiac biomarkers (hs-cTnT, NT-proBNP, CK), a drop in left ventricular ejection fraction, or late gadolinium enhancement in cMRI. We found 3784 upregulated genes in ICIM (FDR < 0.05). In the overrepresented pathway 'response to interferon-gamma', we found guanylate binding protein 5 and 6 (compared with VIM: GBP5 (log2 fc 3.21), GBP6 (log2 fc 5.37)) to be significantly increased in ICIM on RNA- and protein-level. We conclude that interferon-gamma and inflammasome-regulating proteins, such as GBP5, may be of unrecognized significance in the pathophysiology of ICIM. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article on iron deficiency and risk of early readmission following a hospitalization for acute heart failure.