Editors' highlight picks from 2023 in ESC heart failure.

Heart failure is a devastating syndrome affecting an increasingly high number of patients worldwide. Its aetiology and pathogenesis are complex with the involvement of factors ranging from the genetic material through valvular dysfunctions to numerous organs beyond the entire cardiovascular system. Based on continuous efforts of the heart failure scientific community we have witnessed major advances in many related disciplines during the last year. For example, epidemiological aspects-paving the road for improved risk prevention-have been thoroughly analysed for various geographical regions. Additionally, evidence-based approaches now allow the introduction of novel guideline recommended medical therapies (i.e. sodium-glucose transporter 2 inhibitors, and iron supplementation) while basic and translational research aim to explore additional molecular targets for future heart failure diagnostics and medications. All above aspects are addressed in this article, where a selection of articles published in the ESC Heart Failure journal in 2023 are highlighted. The editors are confident that the scientific contributions of ESC Heart Failure effectively served a highly relevant area of cardiovascular research last year.

The beneficial therapeutic effects of plant-derived natural products for the treatment of sarcopenia.

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.

Safety and Efficacy of Intravenous Ferric Derisomaltose Compared to Iron Sucrose for Iron Deficiency Anemia in Patients with Chronic Kidney Disease With and Without Heart Failure.

Ferric derisomaltose (FDI) is an intravenous (IV) high-dose iron formulation approved in the US for the treatment of iron deficiency anemia in adults who are intolerant of/have had an unsatisfactory response to oral iron, or who have non-dialysis-dependent chronic kidney disease (NDD-CKD). FERWON-NEPHRO was a randomized, open-label, multicenter clinical trial evaluating the safety and efficacy of a single infusion of FDI 1,000 mg versus up to 5 doses of iron sucrose (IS) 200 mg (recommended cumulative dose, 1,000 mg) over 8 weeks in patients with NDD-CKD and iron deficiency anemia. Of 1,525 patients included in the safety analysis, 244 (16%) had a history of heart failure (HF). Overall, the rate of serious or severe hypersensitivity reactions was low and did not differ between treatment groups. Cardiovascular adverse events (AEs) were reported for 9.4% of patients who had HF and 4.2% who did not. Time to first cardiovascular AE was longer following administration of FDI compared with IS (hazard ratio: 0.59 [95% CI: 0.37, 0.92]; p=0.0185), a difference that was similar in patients with or without HF (p=0.908 for interaction). Patients achieved a faster hematological response (assessed by changes in hemoglobin and ferritin concentrations, and increase in transferrin saturation) with FDI versus IS. In conclusion, in patients with NDD-CKD, a single infusion of FDI was safe, well tolerated, and was associated with fewer cardiovascular AEs and a faster hematological response, compared to multiple doses of IS. These effects were similar for patients with and without HF.

Iron deficiency in heart failure.

Iron deficiency is a major heart failure co-morbidity present in about 50% of patients with stable heart failure irrespective of the left ventricular function. Along with compromise of daily activities, it also increases patient morbidity and mortality, which is independent of anaemia. Several trials have established parenteral iron supplementation as an important complimentary therapy to improve patient well-being and physical performance. Intravenous iron preparations, in the first-line ferric carboxymaltose, demonstrated in previous clinical trials superior clinical effect in comparison with oral iron preparations, improving New York Heart Association functional class, 6 min walk test distance, peak oxygen consumption, and quality of life in patients with chronic heart failure. Beneficial effect of iron deficiency treatment on morbidity and mortality of heart failure patients is waiting for conformation in ongoing trials. Although the current guidelines for treatment of chronic and acute heart failure acknowledge importance of iron deficiency correction and recommend intravenous iron supplementation for its treatment, iron deficiency remains frequently undertreated and insufficiently diagnosed in setting of the chronic heart failure. This paper highlights the current state of the art in the pathophysiology of iron deficiency, associations with heart failure trajectory and outcome, and an overview of current guideline-suggested treatment options.

An overview of anamorelin as a treatment option for cancer-associated anorexia and cachexia.

INTRODUCTION: Cancer cachexia is a complex multifaceted syndrome involving functional impairment, changes in body composition, and nutritional disorders. The treatment of cancer cachexia can be based on these three domains of the syndrome. Phase II and III trials of anamorelin, a ghrelin mimetic agent, have been shown to increase body weight in patients with cancer cachexia, mainly by increasing muscle and fat mass. Anamorelin has been shown to improve anorexia scores. AREAS COVERED: This review aims to outline the effect of anamorelin on body composition and functional parameters as well as to discuss the clinical importance of these alterations in patients with cancer cachexia. EXPERT OPINION: To date, there is no treatment approved to enhance body composition and functional parameters in patients with cancer cachexia. Anamorelin, the most advanced therapy to treat cachexia, has not yielded convincing results in all aspects of the syndrome. In particular, no effect has been noted on physical function and long-term survival. Along with these essential improvements for future interventions with anamorelin, subsequent studies must address other etiologies of cancer, rather than non-small cell lung cancer, and add complementary therapies, such as exercise training and nutritional interventions, in an attempt to overcome cancer cachexia.

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.

Nutraceutical support in heart failure: a position paper of the International Lipid Expert Panel (ILEP).

Heart failure (HF) is a complex clinical syndrome that represents a major cause of morbidity and mortality in Western countries. Several nutraceuticals have shown interesting clinical results in HF prevention as well as in the treatment of the early stages of the disease, alone or in combination with pharmacological therapy. The aim of the present expert opinion position paper is to summarise the available clinical evidence on the role of phytochemicals in HF prevention and/or treatment that might be considered in those patients not treated optimally as well as in those with low therapy adherence. The level of evidence and the strength of recommendation of particular HF treatment options were weighed up and graded according to predefined scales. A systematic search strategy was developed to identify trials in PubMed (January 1970 to June 2019). The terms 'nutraceuticals', 'dietary supplements', 'herbal drug' and 'heart failure' or 'left verntricular dysfunction' were used in the literature search. The experts discussed and agreed on the recommendation levels. Available clinical trials reported that the intake of some nutraceuticals (hawthorn, coenzyme Q10, l-carnitine, d-ribose, carnosine, vitamin D, probiotics, n-3 PUFA and beet nitrates) might be associated with improvements in self-perceived quality of life and/or functional parameters such as left ventricular ejection fraction, stroke volume and cardiac output in HF patients, with minimal or no side effects. Those benefits tended to be greater in earlier HF stages. Available clinical evidence supports the usefulness of supplementation with some nutraceuticals to improve HF management in addition to evidence-based pharmacological therapy.

Micronutrient Depletion in Heart Failure: Common, Clinically Relevant and Treatable.

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 deficiency in heart failure.

: Due to aging of the patients with heart failure, comorbidities are an emerging problem and, among them, iron deficiency is an important therapeutic target, independently of concomitant hemoglobin level. Iron deficiency affects up to 50% of heart failure patients, and it has been largely established its association with poor quality of life, impaired exercise tolerance and higher mortality. Randomized controlled trials (RCTs) and meta-analyses have demonstrated that intravenous iron supplementation in heart failure patients with iron deficiency positively affects symptoms, quality of life, exercise tolerance (as measured by VO2 peak and 6MWT), with a global trend to reduction of hospitalization rates. Current European Society of Cardiology Guidelines for heart failure recommend a diagnostic work-up for iron deficiency in all heart failure patients and intravenous iron supplementation with ferric carboxymaltose for symptomatic patients with iron deficiency, defined by ferritin level less than 100 µg/l or by ferritin 100-300 µg/l with TSAT less than 20%. On-going studies will provide new evidence for a better treatment of this important comorbidity of heart failure patients.

The Role of Nutraceuticals in Statin Intolerant Patients.

Statins are the most common drugs administered for patients with cardiovascular disease. However, due to statin-associated muscle symptoms, adherence to statin therapy is challenging in clinical practice. Certain nutraceuticals, such as red yeast rice, bergamot, berberine, artichoke, soluble fiber, and plant sterols and stanols alone or in combination with each other, as well as with ezetimibe, might be considered as an alternative or add-on therapy to statins, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. These nutraceuticals could exert significant lipid-lowering activity and might present multiple non-lipid-lowering actions, including improvement of endothelial dysfunction and arterial stiffness, as well as anti-inflammatory and antioxidative properties. The aim of this expert opinion paper is to provide the first attempt at recommendation on the management of statin intolerance through the use of nutraceuticals with particular attention on those with effective low-density lipoprotein cholesterol reduction.

Therapeutic considerations of sarcopenia in heart failure patients.

INTRODUCTION: Sarcopenia is a common feature, and affects 20-47% of patients with heart failure (HF). Sarcopenia is also an independent predictor of impaired functional capacity, even after adjusting for clinical relevant variables, which is associated with adverse outcome in patients with HF. Areas covered: Several different pathophysiological pathways are involved in sarcopenic processes including altered nutrient intake and absorption, hormonal factor, inflammatory processes, oxidative stress, cellular proteolysis, and unhealthy lifestyle. Nutritional therapy, physical activity and/or exercise training have been associated with improved muscle mass or physical performance in HF. Few studies reported beneficial effects for muscle mass and physical performance, in those who received angiotensin-converting enzyme (ACE) inhibitors, or/and beta-blocker. In addition, testosterone, selective androgen receptor modulators, ghrelin agonist and myostatin inhibitors are currently under study as possible future therapeutic options. Expert commentary: Regular and adequate level of physical activity and/or exercise training, and sufficient nutritional intake or special nutritional supplementation may represent the best strategy for prevention or delay of sarcopenia and worsening physical performance in patients with HF. Maximal tolerated dosages of standard therapies for HF such as ACE-inhibitors or beta-blockers are first-line strategy, however it is difficult to recommend other pharmacological agents as part of routine treatment of sarcopenia.

Muscle wasting in heart failure : The role of nutrition.

Muscle wasting and malnutrition are common complications in patients with advanced heart failure (HF); however, both remain underdiagnosed and undertreated although they both play relevant roles in the progression of HF. The risk of muscle wasting in patients with HF increases in those patients with malnutrition or at risk of malnutrition. Muscle wasting and malnutrition are thought to be positively influenced by adequate therapeutic interventions such as physical activity and nutritional support. Consequently, early detection of malnutrition in patients with HF is recommended. This review discusses muscle wasting and nutritional status, describing the effects of malnutrition on muscle wasting in patients with HF. We review specific issues related to muscle wasting and nutritional status in patients with HF; however, no established strategies currently exist to focus on patients suffering from muscle wasting with malnutrition.

Neuromuscular electrical stimulation for muscle wasting in heart failure patients.

Neuromuscular electrical stimulation (NMES) seems to be safe and beneficial in improvement in functional capacity, muscle strength, and quality of life when compared with conventional aerobic exercise, while the change in muscle fiber composition and muscle size was conflicting in patients with heart failure (HF). Moreover, NMES studies seem to have beneficial effects on pro-inflammatory cytokine, oxidative enzyme activity, and protein anabolic and catabolic metabolism that are the key molecular mechanism of muscle wasting in patients with HF. We review specific issues related to the effects of NMES on muscle wasting in patients with HF, whether NMES seems to be an alternative exercise modality preventing or improving in muscle wasting for HF patients who are unable or unwilling to engage in conventional exercise training; however no established strategies currently exist to focus on the patients with HF accompanied by muscle wasting.

Influence of essential amino acids on muscle mass and muscle strength in patients with cerebral stroke during early rehabilitation: protocol and rationale of a randomized clinical trial (AMINO-Stroke Study).

BACKGROUND: Patients with stroke are at a high risk for long-term handicap and disability. In the first weeks after stroke muscle wasting is observed frequently. Early post-stroke rehabilitation programs are directed to improve functional independence and physical performance. Supplementation with essential amino acids (EAAs) might prevent muscle wasting and improve rehabilitation outcome by augmenting muscle mass and muscle strength. We aim to examine this in a double blinded, randomized placebo-controlled clinical trial. METHODS: Patients with ischemic or haemorrhagic stroke will be enrolled at begin of the early post-stroke rehabilitation in a parallel group interventional trial. Oral supplementation of EAAs or placebo will be given for 12 weeks in a double blinded manner. Physical and functional performance will be assessed by exercise testing before supplementation of EAAs as well as at discharge from the in-patient rehabilitation, at 12 weeks and 1 year afterwards. DISCUSSION: This is the first randomized double-blinded placebo-controlled clinical study aiming to assess the effect of the EAAs supplementation on muscle strength, muscle function and physical performance in stroke patients during early post-stroke rehabilitation. Supplementation of EAAs could prevent muscle mass wasting and improve functional independence after stroke. TRIAL REGISTRATION: The study is registered at the German registry for clinical trials as well as at World Health Organization (WHO; number DRKS00005577).

Serum phosphorus level is related to degree of clinical response to up-titration of heart failure pharmacotherapy.

Serum phosphorus abnormalities may pose a risk on the cardiovascular system. In heart failure (HF) phosphorus homeostatic mechanisms are altered and may be modified by modern HF therapy. The impact of therapy optimization on phosphorus abnormalities and related outcome remains unknown. In 722 patients with HF subjected to treatment up-titration we analyzed the prevalence of serum phosphorus abnormalities and their relation to HF severity on top of optimal treatment, and we assessed adjusted risk of phosphorus abnormalities at different stages of HF. We analyzed predictors of hypo- and hyperphosphatemia and relation to prognosis. Hypophosphatemia was associated with better response to therapy, was more prevalent in milder HF, and the association was independent of age, sex, BMI, etiology of HF, kidney function and the use of diuretics. Hypophosphatemic patients lost more phosphorus into urine. They had also less catabolic profile. Patients with hyperphosphatemia on top of optimal therapy responded worse to treatment. Hyperphosphatemia was more prevalent in advanced HF, but the effect was attenuated after adjustment for potential confounders. Clinical and biochemical profiles of hyperphosphatemics suggested domination of catabolism. Neither hypophosphatemia nor hyperphosphatemia modifies the outcome Serum phosphorus abnormalities are related to HF severity on top of optimal therapy. Hypophosphatemia occurring on HF up-titration therapy likely has a multifactorial pathophysiology comprising of urinary phosphorus wasting and refeeding effects. Hyperphosphatemia is linked to the catabolic profile but the effect of renal impairment can't be ruled out. The prognostic impact of serum phosphorus abnormalities remain to be established.

Prevalence, incidence, and clinical impact of sarcopenia: facts, numbers, and epidemiology-update 2014.

Sarcopenia is now defined as a decline in walking speed or grip strength associated with low muscle mass. Sarcopenia leads to loss of mobility and function, falls, and mortality. Sarcopenia is a major cause of frailty, but either condition can occur without the other being present. Sarcopenia is present in about 5 to 10 % of persons over 65 years of age. It has multiple causes including disease, decreased caloric intake, poor blood flow to muscle, mitochondrial dysfunction, a decline in anabolic hormones, and an increase in proinflammatory cytokines. Basic therapy includes resistance exercise and protein and vitamin D supplementation. There is now a simple screening test available for sarcopenia-SARC-F. All persons 60 years and older should be screened for sarcopenia and treated when appropriate.

An overview of recent developments in the treatment of heart failure: update from the ESC Congress 2013.

The European Society of Cardiology held their annual congress in Amsterdam between the 31st of August and 4 September 2013 to discuss the latest developments in the field. The meeting included an update of the latest treatments currently under investigation for the treatment of heart failure. Updates were provided on the RELAX-AHF study that had, for the first time, demonstrated an improvement in post-discharge outcome in patients with acute heart failure treated with seralaxin. The meeting also gave the opportunity to highlight the latest goings on from the promising agent omecamtiv mecarbil as shown in the ATOMIC-AHF study. Indeed, its unique inotropic effect showed a potential to improve dyspnea without increasing myocardial oxygen consumption. Other presentations at the meeting included: a recent study evaluating ultrafiltration in the treatment of acute HF with renal impairment and the effects of the vasodilator cinaciguat. The unremarkable results from the recent ASTRONAUT study with aliskiren were also touched upon. It is important to note that while the data from seralaxin and omecamtiv mecarbil has been promising, the long term benefits of these therapies in heart failure still need to be evaluated. The authors also highlight the need for these promising agents to be further evaluated in women and other ethnic groups.

The role of micronutrients and macronutrients in patients hospitalized for heart failure.

The detrimental pathophysiology of heart failure (HF) leaves room for physiologic and metabolomic concepts that include supplementation of micronutrients and macronutrients in these patients. Hence myocardial energetics and nutrient metabolism may represent relevant treatment targets in HF. This review focuses on the role of nutritive compounds such as lipids, amino acids, antioxidants, and other trace elements in the setting of HF. Supplementation of ferric carboxymaltose improves iron status, functional capacity, and quality of life in HF patients. To close the current gap in evidence further interventional studies investigating the role of micro- and macronutrients are needed in this setting.