Improving exercise capacity and quality of life using non-invasive heart failure treatments: evidence from clinical trials.

Endpoints of large-scale trials in chronic heart failure have mostly been defined to evaluate treatments with regard to hospitalizations and mortality. However, patients with heart failure are also affected by very severe reductions in exercise capacity and quality of life. We aimed to evaluate the effects of heart failure treatments on these endpoints using available evidence from randomized trials. Interventions with evidence for improvements in exercise capacity include physical exercise, intravenous iron supplementation in patients with iron deficiency, and - with less certainty - testosterone in highly selected patients. Erythropoiesis-stimulating agents have been reported to improve exercise capacity in anaemic patients with heart failure. Sinus rhythm may have some advantage when compared with atrial fibrillation, particularly in patients undergoing pulmonary vein isolation. Studies assessing treatments for heart failure co-morbidities such as sleep-disordered breathing, diabetes mellitus, chronic kidney disease and depression have reported improvements of exercise capacity and quality of life; however, the available data are limited and not always consistent. The available evidence for positive effects of pharmacologic interventions using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists on exercise capacity and quality of life is limited. Studies with ivabradine and with sacubitril/valsartan suggest beneficial effects at improving quality of life; however, the evidence base is limited in particular for exercise capacity. The data for heart failure with preserved ejection fraction are even less positive, only sacubitril/valsartan and spironolactone have shown some effectiveness at improving quality of life. In conclusion, the evidence for state-of-the-art heart failure treatments with regard to exercise capacity and quality of life is limited and appears not robust enough to permit recommendations for heart failure. The treatment of co-morbidities may be important for these patient-related outcomes. Additional studies on functional capacity and quality of life in heart failure are required.

Early rehabilitation after stroke: relationship between the heart rate variability and functional outcome.

AIMS: Impaired autonomic nervous system regulation is frequently observed in patients with stroke. The aim of this prospective study was to evaluate the impact of cardiac autonomic tone on functional outcome after the early post-stroke rehabilitation. METHODS AND RESULTS: One hundred and three consecutive patients (67 ± 11 years, body mass index (BMI) 27.1 ± 5.4 kg/m2 , 64% men) with ischaemic (84% of patients) and haemorrhagic stroke were studied. Depressed heart rate variability (HRV), as a surrogate marker of increased sympathetic tone, was defined by the standard deviation of NN intervals < 100 ms and HRV triangular index ≤ 20 assessed from a 24 h Holter electrocardiogram at admission to rehabilitation (23 ± 16 days after stroke). Twenty-two per cent of patients had depressed HRV at baseline and were comparable with patients with normal HRV with regard to their functional [Barthel Index (BI), modified Rankin Scale (mRS), and Rivermead Motor Assessment (RMA)] and biochemical status. After a 4-week follow-up, 70% of patients with depressed HRV showed a cumulative functional disability, defined by mRS ≥ 4, BI ≤ 70, and RMA ≤ 5, in contrast to patients with normal HRV (35%, P = 0.003). Patients with depressed HRV showed a worse functional status by BI (-16%, P < 0.001), RMA (-12%, P < 0.05), and mRS (+16%, P < 0.01), compared with patients with normal HRV. Cumulative functional disability was associated with depressed HRV (odds ratio 4.25, 95% confidence interval 1.56-11.54, P < 0.005) after adjustment for age, sex, and body mass index (odds ratio 4.6, 95% confidence interval 1.42-14.97, P < 0.05). CONCLUSIONS: The presence of autonomic cardiovascular dysregulation in patients with subacute stroke was associated with adverse functional outcome after the early post-stroke rehabilitation.

Cachexia, muscle wasting, and frailty in cardiovascular disease.

The last several years have seen increasing interest in understanding cachexia, muscle wasting, and physical frailty across the broad spectrum of patients with cardiovascular illnesses. This interest originally started in the field of heart failure, but has recently been extended to other areas such as atrial fibrillation, coronary artery disease, peripheral artery disease as well as to patients after cardiac surgery or transcatheter aortic valve implantation. Tissue wasting and frailty are prevalent among many of the affected patients. The ageing process itself and concomitant cardiovascular illness decrease lean mass while fat mass is relatively preserved, making elderly patients particularly prone to develop wasting syndromes and frailty. The aim of this review is to provide an overview of the available knowledge of body wasting and physical frailty in patients with cardiovascular illness, particularly focussing on patients with heart failure in whom most of the available data have been gathered. In addition, mechanisms of wasting and possible therapeutic targets are discussed.

Muscle wasting as an independent predictor of survival in patients with chronic heart failure.

BACKGROUND: Skeletal muscle wasting is an extremely common feature in patients with heart failure, affecting approximately 20% of ambulatory patients with even higher values during acute decompensation. Its occurrence is associated with reduced exercise capacity, muscle strength, and quality of life. We sought to investigate if the presence of muscle wasting carries prognostic information. METHODS: Two hundred sixty-eight ambulatory patients with heart failure (age 67.1 ± 10.9 years, New York Heart Association class 2.3 ± 0.6, left ventricular ejection fraction 39 ± 13.3%, and 21% female) were prospectively enrolled as part of the Studies Investigating Co-morbidities Aggravating Heart Failure. Muscle wasting as assessed using dual-energy X-ray absorptiometry was present in 47 patients (17.5%). RESULTS: During a mean follow-up of 67.2 ± 28.02 months, 95 patients (35.4%) died from any cause. After adjusting for age, New York Heart Association class, left ventricular ejection fraction, creatinine, N-terminal pro-B-type natriuretic peptide, and iron deficiency, muscle wasting remained an independent predictor of death (hazard ratio 1.80, 95% confidence interval 1.01-3.19, P = 0.04). This effect was more pronounced in patients with heart failure with reduced than in heart failure with preserved ejection fraction. CONCLUSIONS: Muscle wasting is an independent predictor of death in ambulatory patients with heart failure. Clinical trials are needed to identify treatment approaches to this co-morbidity.

Muscle mass, muscle strength, and functional capacity in patients with heart failure of Chagas disease and other aetiologies.

AIMS: Patients with Chagas disease and heart failure (HF) have a poor prognosis similar to that of patients with ischaemic or dilated cardiomyopathy. However, the impact of body composition and muscle strength changes in these aetiologies is still unknown. We aimed to evaluate these parameters across aetiologies in two distinct cohort studies [TESTOsterone-Heart Failure trial (TESTO-HF; Brazil) and Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF; Germany)]. METHODS AND RESULTS: A total of 64 male patients with left ventricular ejection fraction ≤40% were matched for body mass index and New York Heart Association class, including 22 patients with Chagas disease (TESTO-HF; Brazil), and 20 patients with dilated cardiomyopathy and 22 patients with ischaemic heart disease (SICA-HF; Germany). Lean body mass (LBM), appendicular lean mass (ALM), and fat mass were assessed by dual energy X-ray absorptiometry. Sarcopenia was defined as ALM divided by height in metres squared <7.0 kg/m2 (ALM/height2 ) and handgrip strength cut-off for men according to the European Working Group on Sarcopenia in Older People. All patients performed maximal cardiopulmonary exercise testing. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Chagasic and ischaemic patients had lower total fat mass (16.3 ± 8.1 vs. 19.3 ± 8.0 vs. 27.6 ± 9.4 kg; P < 0.05) and reduced peak oxygen consumption (VO2 ) (1.17 ± 0.36 vs. 1.15 ± 0.36 vs. 1.50 ± 0.45 L/min; P < 0.05) than patients with dilated cardiomyopathy, respectively. Chagasic patients showed a trend towards decreased LBM when compared with ischaemic patients (48.3 ± 7.6 vs. 54.2 ± 6.3 kg; P = 0.09). Chagasic patients showed lower handgrip strength (27 ± 8 vs. 37 ± 11 vs. 36 ± 14 kg; P < 0.05) and FBF (1.84 ± 0.54 vs. 2.75 ± 0.76 vs. 3.42 ± 1.21 mL/min/100 mL; P < 0.01) than ischaemic and dilated cardiomyopathy patients, respectively. There was no statistical difference in the distribution of sarcopenia between groups (P = 0.87). In addition, FBF correlated positively with LBM (r = 0.31; P = 0.012), ALM (r = 0.25; P = 0.046), and handgrip strength (r = 0.36; P = 0.004). In a logistic regression model using peak VO2 as the dependent variable, haemoglobin (odds ratio, 1.506; 95% confidence interval, 1.043-2.177; P = 0.029) and ALM (odds ratio, 1.179; 95% confidence interval, 1.011-1.374; P = 0.035) were independent predictors for peak VO2 adjusted by age, left ventricular ejection fraction, New York Heart Association, creatinine, and FBF. CONCLUSIONS: Patients with Chagas disease and HF have decreased fat mass and exhibit reduced peripheral blood flow and impaired muscle strength compared with ischaemic HF patients. In addition, patients with Chagas disease and HF show a tendency to have greater reduction in total LBM, with ALM remaining an independent predictor of reduced functional capacity in these patients. The percentage of patients affected by sarcopenia was equal between groups.

Acute effects of oral triglyceride load on dynamic changes in peripheral endothelial function in heart failure patients with reduced ejection fraction and healthy controls.

BACHGROUND: Postprandial hyperlipaemia impairs endothelial function, possibly via oxidative-stress-mediated mechanisms. The aim of this study was to evaluate the acute effects of an oral triglyceride load (OTGL) on peripheral endothelial function in heart failure patients with reduced ejection fraction (HFrEF) compared to healthy controls. DESIGN: Prospective cross-sectional. METHODS: We enrolled 47 patients with HFrEF and 20 healthy controls. Peripheral endothelial function was assessed with EndoPAT2000 technology using a reactive hyperaemia index (RHI) and pulse wave amplitude (PWA) at baseline (after 8-h overnight fasting) as well as 1, 2, 3 and 4-h post-OTGL consumption (250-ml cream drink). Pulse wave amplitude index (PWAI) was calculated as a ratio of PWA at each time point to the baseline PWA. RESULTS: RHI at baseline was lower in HFrEF patients compared to controls (1.7 ± 0.3 and 2.3 ± 0.6, respectively; P = 0.001). The OTGL accounted for a physiologic increase in PWA in healthy controls (p = 0.01), but this change was not observed in HFrEF patients. After 4 h, vasodilator response was significantly increased in healthy controls but not patients with HFrEF (2.3 ± 1.3 vs. 1.3 ± 0.8 respectively, P < 0.05). CONCLUSIONS: The main finding of this study was the impaired postprandial dynamic changes in peripheral endothelial function in patients with HFrEF compared to healthy controls. A high-fat load that caused acute hypertriglyceridaemia significantly increased resting blood flow and peak flow at reactive hyperaemia in healthy subjects. By contrast, patients with HFrEF exhibited impaired dynamic changes in peripheral endothelial function after oral triglyceride load.

Heart failure and sleep-disordered breathing: susceptibility to reduced muscle strength and preclinical congestion (SICA-HF cohort).

AIMS: Increased sympathetic activation in patients with heart failure (HF) and sleep-disordered breathing (SDB) provokes cardiac decompensation and protein degradation and could lead to muscle wasting and muscle weakness. The aim of this study was to investigate the differences in body composition, muscle function, and the susceptibility of preclinical congestion among patients with HF and SDB compared with those without SDB. METHODS AND RESULTS: We studied 111 outpatients with stable HF who were enrolled into the Studies Investigating Co-morbidities Aggravating Heart Failure. Echocardiography, short physical performance battery (SPPB), cardiopulmonary exercise testing, dual-energy X-ray absorptiometry, bioelectrical impedance analysis (BIA), tests of muscle strength, and polygraphy were performed. SDB was defined as apnoea/hypopnoea index (AHI) >5 per hour of sleep. Central sleep apnoea (CSA) and obstructive sleep apnoea (OSA) were defined as AHI >50% of central or obstructive origin, respectively. A total of 74 patients (66.7%) had any form of SDB [CSA (24 patients, 32.4%), OSA (47 patients, 63.5%)]. Patients with SDB showed increased muscle weakness (chair stand), reduced muscle strength, and lower values of SPPB score (P < 0.05). Patients with SDB did not show overt clinical signs of cardiac decompensation compared with those without SDB (P > 0.05) but had increased amounts of water (total body water, intracellular, and extracellular) measured using BIA (P < 0.05). Increased amounts of total body water were associated with the severity of SDB and inversely with muscle strength and exercise capacity measured by anaerobic threshold (P < 0.05). Altogether, 17 patients had muscle wasting. Of these, 11 (65%) patients had SDB (statistically not significant). CONCLUSIONS: SDB is highly prevalent in patients with HF. Patients with SDB have lower muscle strength and tend to be more susceptible to preclinical congestion.

Selective androgen receptor modulators (SARMs) as pharmacological treatment for muscle wasting in ongoing clinical trials.

INTRODUCTION: Skeletal muscle wasting is a frequent clinical problem encountered in patients with chronic diseases. Increased levels of inflammatory markers play a role in the imbalance between muscle protein synthesis and degradation. Although testosterone has long been proposed as a treatment for patients with muscle wasting, undesirable side effects have raised concerns about prostatic hypertrophy in men as well as virilization in women. Selective androgen receptor modulators (SARMs) have demonstrated similar results like testosterone at improving lean body mass (LBM) with less side effects on androgen-dependent tissue. AREAS COVERED: This review outlines the ongoing clinical development in the field of SARMs and their effectiveness in improving body composition and physical function. The included articles were collected at pubmed.gov and analyzed integrally. EXPERT OPINION: There is an unmet clinical need for safe and effective anabolic compounds such as SARMs. Despite the effect on LBM shown by SARMs in phase II clinical trials, results on improved physical function and muscle strength are still lacking and long-term outcomes have to be assessed in these patients. Moreover, there is a need to determine the effect of resistance exercise training and protein intake associated with SARMs in the treatment of patients with muscle wasting.

Inflammatory biomarkers of frailty.

Frailty is a functional term that describes a decline in physiological functions that leads to dependency, vulnerability to stressors, high risk for adverse health outcomes, increased risk of falls, and increased morbidity and mortality. The central role of inflammation and the cross-talk between frailty and sarcopenia have led to a condition termed physical frailty, in which muscle atrophy is viewed as the biological substratum of physical frailty. Different paradigms of ageing, including "inflamm-ageing", "oxi-inflamm-ageing", and "inflamm-inactivity" reveal inflammation as a common driver of age-related frailty. The key role of inflammation in frailty conditions have led to numerous studies screening for potential inflammatory biomarkers of frailty. This review summarizes the present knowledge of inflammatory biomarkers that are considered promising tools to evaluate frailty. Inflammatory biomarkers for different pathophysiological pathways have been identified, and can be divided into markers of inflammation, oxidative stress, muscle protein turnover and physical inactivity. Described candidate inflammatory biomarkers could support diagnosis, prognosis, and therapeutic decisions in frail elderly. Furthermore, exercise training and nutritional counselling could be implemented in the standard care of the elderly in order to prevent, delay, or ameliorate frailty and to reduce the levels of blood inflammatory biomarkers. Such tools and decision-making outcomes would improve selection and treatment of the elderly and contribute to the ultimate goal - healthy ageing.

Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 12th Cachexia Conference.

This article highlights preclinical and clinical studies in the field of wasting disorders that were presented at the 12th Cachexia Conference held in Berlin, Germany, in December 2019. Herein, we summarize the biological and clinical significance of different strategies including antibodies that target Fn14, Spsb 1, SAA1 treatment, ZIP14, a MuRF1 inhibitor, and new diagnostic tools like T-cell communication targets and cut-offs for the detection of skeletal muscle wasting. Of particular interest were the transplantation of mesenchymal stromal cells and muscle stem cell communication. Importantly, one presentation discussed the effect of metal ion transporter ZIP14 loss that reduces cancer-induced cachexia. The potential of anti-ZIP14 antibodies and zinc chelation as anti-cachexia therapy may require testing in patients with cancer cachexia. Large clinical studies were presented such as RePOWER (observational study of patients with primary mitochondrial myopathy), MMPOWER (treatment with elamipretide in patients with primary mitochondrial myopathy), and ACT-ONE as well as new mouse models like the KPP mouse. Promising treatments include rapamycin analogue treatment, anamorelin, elanapril, glucocorticoids, SAA1, antibodies that target Fn14, and a MuRF1 inhibitor. Clinical studies investigated novel approaches, including the role of exercise. It remains a fact, however, that effective treatments for cachexia and wasting disorders are urgently needed in order to improve patients' quality of life and their survival.

Cardiac cachexia.

Cachexia is a multifactorial disease characterized by a pathologic shift of metabolism towards a more catabolic state. It frequently occurs in patients with chronic diseases such as chronic heart failure and is especially common in the elderly. In patients at risk, cardiac cachexia is found in about 10% of heart failure patients. The negative impact of cardiac cachexia on mortality, morbidity, and quality of life demonstrates the urgent need to find new effective therapies against cardiac cachexia. Furthermore, exercise training and nutritional support can help patients with cardiac cachexia. Despite ongoing efforts to find new therapies for cachexia treatment, also new preventive strategies are needed.

Why is Iron Deficiency Recognised as an Important Comorbidity in Heart Failure?

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.

Cardiac cachexia: the mandate to increase clinician awareness.

PURPOSE OF REVIEW: Heart failure is a frequent problem in an ageing population, associated with high rates of morbidity and mortality. Today, it is important to not only treat heart failure itself but also the related comorbidities. Among them, cardiac cachexia is one of the major challenges. It is a complex multifactorial disease with a negative impact on quality of life and prognosis. Therefore, prevention, early recognition and treatment of cardiac cachexia is essential. RECENT FINDINGS: Cardiac cachexia frequently presents with skeletal as well as heart muscle depletion. Imaging-based diagnostic techniques can help to identify patients with cardiac cachexia and muscle wasting. Several blood biomarkers are available to detect metabolic changes in cardiac cachexia. SUMMARY: Several studies are currently ongoing to better comprehend the underlying pathophysiological mechanisms of cardiac cachexia and to find new treatments. It is essential to diagnose it as early as possible to initiate therapy.

Comparing erosion and organ accumulation rates of lead and alternative lead-free ammunition fed to captive domestic ducks.

Lead poisoning of birds of prey from ingestion of ammunition lead has been well documented. Alternative, lead-free ammunition is widely available, but the toxicokinetics of other metals in birds are poorly understood. We tested the erosion of lead, copper, zinc, iron and brass by feeding domestic Pekin ducks (Anas platyrhynchos forma domestica) defined numbers of small metal pellets. The accumulation of these metals was analysed in the breast muscle, brain, pancreas, liver and kidney. Four weeks after application, the ducks were euthanized and necropsied, internal organs tested for metal accumulation and gizzard pellets collected and weighed to record loss by erosion. Degree of erosion was highest in zinc pellets (81% mass loss), followed by iron (46%) and lead (45%) and was only marginal in copper and brass. Only lead showed highly elevated levels of accumulation in organs compared to controls.

Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 11th Cachexia Conference.

This article highlights the updates from preclinical and clinical studies into the field of wasting disorders that were presented at the 11th Cachexia Conference held in Maastricht, the Netherlands, in December 2018. Herein, we summarize the biological and clinical significance of different markers and new diagnostic tools and cut-offs for the detection of skeletal muscle wasting, including micro-RNAs, siRNAs, epigenetic targets, the ubiquitin-proteasome system, mammalian target of rapamycin signalling, news in body composition analysis including the D3-creatine dilution method, and electrocardiography that was modified to enable segmental impedance spectroscopy. Of particular interest were the beneficial effects of BIO101 on muscle cell differentiation, hypertrophy of myofibers associated with mammalian target of rapamycin pathways activation, and the effect of metal ion transporter ZIP14 loss that reduces cancer-induced cachexia. The potential of anti-ZIP14 antibodies and zinc chelation as anti-cachexia therapy should be tested in patients with cancer cachexia. Big randomized studies were presented such as RePOWER (observational study of patients with primary mitochondrial myopathy), STRAMBO (influence of physical performance assessed as score and clinical testing), MMPOWER (treatment of elamipretide in subjects with primary mitochondrial myopathy), FORCE (examined differences in relative dose intensity and moderate and severe chemotherapy-associated toxicities between a strength training intervention and a control group), and SPRINTT (effectiveness of exercise training in healthy aging). Effective treatments were urothelin A, rapamycin analogue treatment, epigenetic factor BRD 4 and epigenetic protein BET, and the gut pathobiont Klebsiella oxytoca. Clinical studies that investigated novel approaches, including urolithin A, the role of gut microbiota, metal ion transporter ZIP14, lysophosphatidylcholine and lysophosphatidylethanolamine, and BIO101, were described. It remains a fact, however, that effective treatments of cachexia and wasting disorders are urgently needed in order to improve patients' quality of life and their survival.

Body weight changes and incidence of cachexia after stroke.

BACKGROUND: Body weight loss is a frequent complication after stroke, and its adverse effect on clinical outcome has been shown in several clinical trials. The purpose of this prospective longitudinal single-centre observational study was to investigate dynamical changes of body composition and body weight after ischemic stroke and an association with functional outcome. METHODS: Sixty-seven consecutive patients (age 69 ± 11 years, body mass index 27.0 ± 4.1 kg/m2 , 42% female patient, mean ± SD) with acute ischemic stroke with mild to moderate neurological deficit (National Institute of Health Stroke Scale median 4, ranged 0-12) were analysed in the acute phase (4 ± 2 days) and at 12 months (389 ± 26 days) follow-up. Body composition was examined by dual energy X-ray absorptiometry. Cachexia was defined according to the consensus definition by body weight loss ≥5% within 1 year and additional clinical signs. Lean tissue wasting was considered if a ratio of upper and lower limbs lean mass sum to squared height (kg/m2 ) was ≤5.45 kg/m2 for female patient and ≤7.25 kg/m2 for male patient. RESULTS: According to the body weight changes after 12 months, 42 (63%) patients had weight gain or stable weight, 11 (16%) patients had moderate weight loss, and 14 (21%) patients became cachectic. A relative decline of 19% of fat tissue and 6.5% of lean tissue was observed in cachectic patients, while no changes of lean tissue were observed in non-cachectic patients after 12 months. The modified Rankin Scale was 48% higher (2.1 ± 1.6, P < 0.05), Barthel Index was 22% lower (71 ± 39, P < 0.01), and handgrip strength was 34% lower (21.9 ± 13.0, P < 0.05) in cachectic compared to non-cachectic patients after 12 months. The low physical performance if defined by Barthel Index <60 points was linked to the lean tissue wasting (OR 44.8, P < 0.01), presence of cachexia (OR 20.8, P < 0.01), and low body mass index <25 kg/m2 (OR 11.5, P < 0.05). After adjustment for cofounders, lean tissue wasting remained independently associated with the low physical performance at 12 months follow-up (OR 137.9, P < 0.05). CONCLUSIONS: In this cohort study, every fifth patient with ischemic stroke fulfilled the criteria of cachexia within 12 months after index event. The incidence of cachexia was 21%. Cachectic patients showed the lowest functional and physical capacity.

Iron deficiency in patients with heart failure with preserved ejection fraction and its association with reduced exercise capacity, muscle strength and quality of life.

BACKGROUND: The prevalence of iron deficiency (ID) in outpatients with heart failure with preserved ejection fraction (HFpEF) and its relation to exercise capacity and quality of life (QoL) is unknown. METHODS: 190 symptomatic outpatients with HFpEF (LVEF 58 ± 7%; age 71 ± 9 years; NYHA 2.4 ± 0.5; BMI 31 ± 6 kg/m2) were enrolled as part of SICA-HF in Germany, England and Slovenia. ID was defined as ferritin < 100 or 100-299 µg/L with transferrin saturation (TSAT) < 20%. Anemia was defined as Hb < 13 g/dL in men, < 12 g/dL in women. Low ferritin-ID was defined as ferritin < 100 µg/L. Patients were divided into 3 groups according to E/e' at echocardiography: E/e' ≤ 8; E/e' 9-14; E/e' ≥ 15. All patients underwent echocardiography, cardiopulmonary exercise test (CPX), 6-min walk test (6-MWT), and QoL assessment using the EQ5D questionnaire. RESULTS: Overall, 111 patients (58.4%) showed ID with 89 having low ferritin-ID (46.84%). 78 (41.1%) patients had isolated ID without anemia and 54 patients showed anemia (28.4%). ID was more prevalent in patients with more severe diastolic dysfunction: E/e' ≤ 8: 44.8% vs. E/e': 9-14: 53.2% vs. E/e' ≥ 15: 86.5% (p = 0.0004). Patients with ID performed worse during the 6MWT (420 ± 137 vs. 344 ± 124 m; p = 0.008) and had worse exercise time in CPX (645 ± 168 vs. 538 ± 178 s, p = 0.03). Patients with low ferritin-ID had lower QoL compared to those without ID (p = 0.03). CONCLUSION: ID is a frequent co-morbidity in HFpEF and is associated with reduced exercise capacity and QoL. Its prevalence increases with increasing severity of diastolic dysfunction.

Identification and regulation of the long non-coding RNA Heat2 in heart failure.

AIMS: Circulating immune cells have a significant impact on progression and outcome of heart failure. Long non-coding RNAs (lncRNAs) comprise novel epigenetic regulators which control cardiovascular diseases and inflammatory disorders. We aimed to identify lncRNAs regulated in circulating immune cells of the blood of heart failure patients. METHODS AND RESULTS: Next-generation sequencing revealed 110 potentially non-coding RNA transcripts differentially expressed in peripheral blood mononuclear cells of heart failure patients with reduced ejection fraction. The up-regulated lncRNA Heat2 was further functionally characterized. Heat2 expression was detected in whole blood, PBMNCs, eosinophil and basophil granulocytes. Heat2 regulates cell division, invasion, transmigration and immune cell adhesion on endothelial cells. CONCLUSION: Heat2 is an immune cell enriched lncRNA that is elevated in the blood of heart failure patients and controls cellular functions.

Iron Deficiency in Heart Failure: An Overview.

Iron deficiency is an extremely common comorbidity in patients with heart failure, affecting up to 50% of all ambulatory patients. It is associated with reduced exercise capacity and physical well-being and reduced quality of life. Cutoff values have been identified for diagnosing iron deficiency in heart failure with reduced ejection fraction as serum ferritin, <100 µg/l, or ferritin, 100 to 300 µg/l, with transferrin saturation of <20%. Oral iron products have been shown to have little efficacy in heart failure, where the preference is intravenous iron products. Most clinical studies have been performed using ferric carboxymaltose with good efficacy in terms of improvements in 6-min walk test distance, peak oxygen consumption, quality of life, and improvements in New York Heart Association functional class. Data from meta-analyses also suggest beneficial effects for hospitalization rates for heart failure and reduction in cardiovascular mortality rates. A prospective trial to investigate effects on morbidity and mortality is currently ongoing. This paper highlights current knowledge of the pathophysiology of iron deficiency in heart failure, its prevalence and clinical impact, and its possible treatment options.